EP1216044A1 - Compositions a stabilite amelioree - Google Patents

Compositions a stabilite amelioree

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Publication number
EP1216044A1
EP1216044A1 EP00970493A EP00970493A EP1216044A1 EP 1216044 A1 EP1216044 A1 EP 1216044A1 EP 00970493 A EP00970493 A EP 00970493A EP 00970493 A EP00970493 A EP 00970493A EP 1216044 A1 EP1216044 A1 EP 1216044A1
Authority
EP
European Patent Office
Prior art keywords
composition
active
solvent
liquid
composition according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP00970493A
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German (de)
English (en)
Inventor
Jayant Eknath Khanolkar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Procter and Gamble Co
Original Assignee
Procter and Gamble Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/467,333 external-priority patent/US20020082307A1/en
Application filed by Procter and Gamble Co filed Critical Procter and Gamble Co
Publication of EP1216044A1 publication Critical patent/EP1216044A1/fr
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/12—Mucolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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 liquid-filled lozenges, metered liquid dosing devices, atomizers and liquid- releasing, edible capsules. Such compositions are particularly useful for treating symptoms associated with respiratory illnesses.
  • compositions that are swallowed are absorbed into the general blood circulation. Items swallowed by humans, including food, drink, and medicines, enter the stomach and from there flow into the intestine. Many of the chemicals associated with the food, drink, or medicine pass through the mucosal membranes in the gastrointestinal tract and into the blood in the mesenteric veins draining from the intestine. The blood flow from the mesenteric veins passes into the liver. Metabolizing enzymes in the mucosal membranes of the intestine and in the liver can chemically alter the nature of substances passing from the intestine, through the liver, and into the common blood circulation of the body.
  • Respiratory illnesses covers a broad range of ailments, including viral infections and allergic reaction to inhaled allergens.
  • Viral infections in the upper respiratory tract of humans leads to illness usually referred to as colds, or influenza.
  • Such an illness is quite common in the general population and can be the cause of significant discomfort and suffering.
  • Allergen inhalation also negatively impacts a fair number in the population at the same or even at a greater degree than those having a viral infection.
  • compositions used to treat the above mentioned symptoms generally fall into one of the following pharmacological classifications: antihistamines; decongestants; antitussives; expectorants; mucolytics; analgesics, antipyretic and anti-inflammatory agents.
  • the compositions are manufactured in a number of product forms, the most common being liquid syrups and elixirs for swallowing, mouth drops and lozenges as well as inhalants and topical creams or lotions that release volatile agents that are inhaled through the nose into respiratory tract.
  • the compositions are typically swallowed immediately, or slowly dissolved in the mouth.
  • dextromethorphan that acts within the part of the human brain controlling the coughing reflex.
  • actives such as guaifenesin, that aids the body in the removal of excess respiratory mucus or phlegm, diphenhydramine, that lessens the negative effects including coughing and other symptoms due to histamine produced in the body in response to the viral infection, and dextromethorphan, that acts within the part of the human brain controlling the coughing reflex.
  • dextromethorphan is the most commonly used active in the world for relief of cough.
  • compositions comprising polymers that provide gelling of the liquid when entering the body cavity.
  • a group of microbiological preservatives including sodium bisulfite and sodium thiosulfate.
  • the art known to the applicants does not demonstrate a specific chemical stabilization benefit by the inclusion of solution or liquid-based product forms..
  • 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 including elixirs, liquid-filled lozenges, metered liquid dosing devices, atomizers and liquid-releasing, edible capsules. Such compositions are particularly useful for treating symptoms associated with respiratory illnesses.
  • compositions can be made to positively improve the therapeutic effect without increased side effects or toxicity.
  • These compounds have improved stability in the product form selected to deliver such compositions. This benefit is achieved by adding to the active containing formulation agents that promote stability of the active in the formulation. These agents are effective in reducing and even eliminating instability due to the active's oxidation degradation pathway, thereby extending the shelf life of the compositions.
  • One object, therefore, of the present invention is to provide improved compositions for treating the symptoms associated with respiratory ailments, particularly minimizing fits of coughing.
  • One particularly preferred composition is in the form of an anhydrous, hydrophilic liquids in a very stable environment for rapid delivery of actives including antitussives; antihistamines (including non-sedating antihistamines); decongestants; expectorants; mucolytics; analgesic, antipyretic and anti-inflammatory agents and local anesthetics for treating the symptoms of respiratory illnesses.
  • the compositions can be dosed using a variety of product forms and, or package delivery options.
  • the compositions of the present invention provide desired activity while minimizing potential side effects of the active compounds. It is also an objective of the subject invention to provide methods for achieving rapid transmucosal delivery of the aforementioned compositions. Definitions and Terms
  • pharmaceutical active/active refers to the chemical molecule which exerts the desired effect on the body, when administered in the proper amount and form.
  • molecules of the active are free and unencumbered from diffusion by association in crystalline or amorphous solid forms, or poly molecular association.
  • percent solubility value refers to the equilibrium solubility limit or maximum solubility of a molecule in a solvent at usual room temperature, expressed as the weight percent of the molecule in the composition.
  • compositions of the present invention comprise pharmaceutical actives also referred to herein as "actives" for treating illnesses, particularly symptoms associated with respiratory ailments such as colds, influenza as well as allergy.
  • actives include those frequently used for treating the most problematic symptoms including a stuffy and runny nose, soreness and inflammation in the nose and throat, fits of coughing, general aches in the body, fever, and headache; see US Patent 5,196,436, Smith, issued May 23, 1993; incorporated herein by reference.
  • actives when actives are combined with certain materials in formulations for delivery of the active, utilizing particular materials to enhance long term stability of the formulation is an important benefit. In a stable formulation the actives are efficiently delivered to produce a positive impact.
  • the composition comprises a pharmaceutical active and a stabilizing material along with other commonly known ingredients to make a composition for delivery of said actives.
  • the composition comprises a solvent that is a hydrophilic, water-miscible, anhydrous solvent wherein the pharmaceutical active in its un-ionized form has a percent solubility value in the solvent at ambient temperature that is equal to or greater than 0.075% and the pharmaceutical active is in its free, un-ionized form as a monomolecular dispersion in the solvent.
  • the preferable pharmaceutical actives of the present invention have molecular weight of less than 500 grams per mole, is capable of being ionized when in an aqueous solvent and has an octanol-water partition coefficient when in the un-ionized form of at least 100.
  • the octanol-water partition coefficient is disclosed in A. Martin, P. Bustamante, and A.H.C. Chun, Physical Pharmacy. Fourth Edition, Lea and Febiger publishers, Philadelphia, 1993, page 237; herein incorporated by reference.
  • the actives that comprise compositions of the present invention include actives that fall into at least one of the following pharmacological classifications: antitussives; antihistamines; non-sedating antihistamines; decongestants; expectorants; mucolytics, analgesic, antipyretic anti- inflammatory agents, local anesthetics and mixtures thereof.
  • pharmacological classifications include J. G. Hardman, The Pharmacologic Basis of Therapeutics, Ninth Edition, McGraw-Hill, New York, 1995.
  • actives that fall in these pharmacological classifications are those that are suited for absorption through mucosal tissues. These actives can be used alone or in combination with other actives not necessarily absorbed in this manner and may be formulated within existing formulation techniques.
  • the concentration of actives in the solvent portion of the composition is preferably less than or equal to 125% of the percent solubility value, more preferably less than or equal to the percent solubility value of the pharmaceutical active.
  • the active is preferably in solution as monomolecular dispersion.
  • the absorbed actives useful in the present invention are present in the solvent system at a level from about 0.075% to about 25.0%, preferably from about 0.28% to 10.0% by weight of the composition. It is preferred that said active is in it free, un-ionized form as a monomolecular dispersion in said solvent system. In the cases where either the salt forms or ionized forms of the drug active exist, it is preferred to use the uncharged free (non salt) form of the drug in the present invention.
  • Antitussives are actives of particularly use for arresting uncontrollable fits coughing.
  • Antitussives useful in the present invention include, but, are not restricted to the group consisting of codeine, dextrometho ⁇ han, dextro ⁇ han, diphenhydramine, hydrocodone, noscapine, oxycodone, pentoxyverine, mo ⁇ hine, pholcodeine and mixtures thereof.
  • dextrometho ⁇ han is preferred.
  • Dextrometho ⁇ han is known to have pharmacological activity as an antitussive agent and is described in US Patent 5,196,436, Smith; inco ⁇ orated herein by reference.
  • dextrometho ⁇ han means racemetho ⁇ han, 3-methoxy-17- methylmo ⁇ hinan (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 comprising dextrometho ⁇ han preferably comprise from about 0.1% to about 9.3%, more preferably from about 0.26% to about 6.2% and most preferably from about 1.16% to about 4.6% dextrometho ⁇ han.
  • Other safe and effective amounts of other cough/cold drug actives may be included in such dextrometho ⁇ han-containing compositions.
  • Antihistamines useful in the present invention include, but, are not restricted to the group consisting of acrivastine, azatadine, brompheniramine, chlo ⁇ heniramine, clemastine, cyproheptadine, dexbrompheniramine, dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, meclizine, pheninamine, phenyltoloxamine, promethazine, pyrilamine, tripelennamine, triprolidine and mixtures thereof.
  • Non-sedating antihistamines useful in the present invention include, but, are not restricted to the group consisting of astemizole, cetirizine, ebastine, fexofenadine, loratidine, terfenadine, and mixtures thereof.
  • Decongestants useful in the present invention include, but, are not restricted to the group consisting of phenylpropanolamine, pseudoephedrine, ephedrine, phenylephrine, oxymetazoline, and mixtures thereof
  • Expectorants useful in the present invention include, but, are not restricted to the group consisting of ammonium chloride, guafenesin, ipecac fluid extract, potassium iodide and mixtures thereof.
  • Mucolytics useful in the present invention include, but, are not restricted to the group consisting of acetylcycsteine, ambroxol, bromhexine and mixtures thereof.
  • Analgesic, antipyretic and anti- inflammatory agents useful in the present invention include, but, are not restricted to the group consisting of acetaminophen, aspirin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, nabumetone, naproxen, piroxicam, caffeine and mixtures thereof.
  • Local anesthetics useful in the present invention include, but, are not restricted to the group consisting of lidocaine, benzocaine, phenol, dyclonine, benzonotate and mixtures thereof.
  • Solvents The un-ionized form of the pharmaceutical active is maintained using a selected group of solvents.
  • the solvent portion of compositions of the present invention comprises from about 60% to about 99.975%, preferably from 70% to about 99% and most preferably from about 85% to about 98% by weight of the composition.
  • the solvent of the present invention is normally liquid at ambient or room temperatures. It is water-soluble or water-miscible. 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, polyvinylpyrrolidone (PVP), TranscutolTM (2-(2 ethoxyethathoxy) ethanol), Lauroglycol 90TM (fatty acid esters and propylene glycol), LabrasolTM (glyceryl and polyethylene glycol esters), Capryol 90TM (propylene glycol monocaprylate and mixtures thereof all available from Gattefosse SA.
  • 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, polox
  • Propylene glycol and ethanol is particularly preferred.
  • the solvent is a combination of propylene glycol, ethanol, and PEG.
  • the solvents is a combination of propylene glycol, ethanol, PEG and usually propylene carbonate.
  • the level of each solvent that makes up these mixtures is partially dependent on aesthetic benefits sought by the formulator. Most preferable are anhydrous forms of the above solvents.
  • Chelating Agents have been found to have a beneficial chemical stabilizing effect on the actives comprising the present invention. This phenomena su ⁇ risingly takes place where the chelating agent is present in a phase of the composition other than the phase of the composition containing the active.
  • the chelating agent selected could be a polar phase, such as water. Therefore, despite being in separate phases, the chemical stability of the active is still positively impacted. The same stability benefit is not observed when the active and the chelating agent are co-soluble in the solvent. Therefore, the chelating agents useful in the composition depend on the active 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. Not to be bound by theory, it is reasonable to postulate that metal cations play major role in the formation of oxidizing species.
  • the free radical producing reactions involve the transfer of electrons by redox cycling between two different valence stages. Trace amount of heavy metal ions often catalyze auto-oxidation reaction. In fact as little as 0.05 ppm metal ions may be sufficient to initiate the oxidation and enhance the rate of propagation of the chain reaction. See W. Lund, The Pharmaceutical CODEX. 12 th Edition, p.287 & 290 The Pharmaceutical Press, 1994, inco ⁇ orated herein by reference
  • Chelating agents have been shown to reduce the facileness of the electron transfer reactions between these valance stages. This characteristic of chelating agents dampens auto- oxidation reactions. This could explain why chelating agents are effective in protecting pharmaceutical actives.
  • the rate and extent of oxidation is known to be greater at alkaline pH than acidic pH values. This may be due in part to what appears to be a greater tendency of the divalent cations to catalyze oxidation reactions in alkaline medium. See 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, pp.1086- 1091 (1990).
  • the chelating agents useful in present invention are stable and effective in non-aqueous and aqueous medium and in pH range between 5 to 12.
  • Preferred chelating agents are selected from the group consisting of disodium and calcium salts of Ethyl ene diamine tetraacetic acid (EDTA), tetrasodium EDTA, sodium hexametaphosphate (SHMP), citric acid, phosphoric acid, Di(hydroxyethyl)glycine,8-hydroxyquinoline and mixtures thereof.
  • the level of chelating agents useful in the present invention depends on the load of metal ions likely to be introduced into the formulation by way of contamination of the ingredients.
  • the chelating agents are used at levels from about 0.005% to 1.000%, preferably from about 0.150% to about 0.050%, and most preferably from about 0. 300% to about 0.010% by weight of the composition.
  • Chelating agents therefore, are capable of playing a dual role in the aerobic oxidation of reducing agents. It complexes trace metals which could catalyze spontaneous oxidation and thus change the mechanism of initiation. It can also act as chain breaker by scavenging the oxidizing radicals which propagate the reaction chain. Therefore, the reducing agent's chemical stabilizing effect on the actives comprising the present invention is dramatically increased. This phenomena su ⁇ risingly takes place where the active is in different phase than the reducing agent. For example, where the active is soluble in a non-polar environment or phase of the composition, the reducing agent selected should be soluble in a polar phase, such as water. Therefore, despite being in separate phases, the chemical stability of the active is still positively impacted. The same stability benefit is not observed when the WO 01/22967 PCT/TJSOO/26402
  • the active and the reducing agent are co-soluble in the solvent. Therefore, the reducing agents useful in the composition depend on the active selected and its solubility.
  • Reducing agents are substances that have a lower redox potential than the drug or adjuvant that they are intended to protect against oxidation. Thus reducing agents are more readily oxidized than the drug or adjuvant and are effective in the presence of oxidizing agents. See W. Lund The Pharmaceutical DODEX. 12 th Edition, p.290, The Pharmaceutical Press, 1994, inco ⁇ orated herein by reference. Reducing agents of the present have a electrode potential value. This is defined by the Nernst equation and measured using practically standard electrochemical reference cells. The resulting values are therefore called the Standard Electrode Potential, of E° as measured in volts of (V).
  • the reducing useful in the present invention have an Electrode Potential value E° greater than about -0.119V, preferably from about -0.119V to +0.250V.
  • Preferred reducing agents are selected from the group consisting of the salts of meta bisulfite and bisulfite, including their sodium and potassium salts, dithiothreitol, thiourea, sodium thiosulphate, thioglycolic acid, terbuty hydroquinone (TBHQ), acetyl cysteine, hydroquinone and mixtures thereof.
  • the level of reducing agents useful in the present invention is from about 0.005% to 1.000%, preferably from about 0.050% to about 0.500%, and most preferably from about 0.010% to 0.200% by weight of the composition.
  • the reducing agent protects the pharmaceutical active in the invention from degrading by acting as a donor-oxidizing compound that sacrifices itself to oxidation rather than the active itself.
  • Chelators also afford some practical protection by chelating the metal ions present in formulation ingredients including flavorings, coolants and sweetners as well as the potential migration of metal ions from 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 stabilizing the pharmaceutical actives.
  • Water may be used in compositions of the present invention.
  • the maximum level of water is about 10%, preferably from about 1% to about 10% more preferably from 5% to about 10% and most preferably from about 5% to about 8% by weight of the composition.
  • ingredients normally associated with cold and influenza treatment medicines can be used with the pharmaceutical actives disclosed herein. Such ingredients are disclosed in US Patent 5,196,436, inco ⁇ orated herein by reference. Additionally, the following ingredients may be used in the present invention:
  • Buffers and mixtures of buffering agents include triethanolamine, tromethamine, salts of amino acids, including alkaline salts of glycine, glycylglycine, glutamine or other amino acids, alkaline salts of phosphate, carbonate and mixtures thereof.
  • the buffers provide compositional resistance to pH changes upon dilution of the composition with saliva within the range of 8 to 10.
  • Buffers and mixtures of buffering agents include triethanolamine, tromethamine, salts of amino acids, including alkaline salts of glycine, glycylglycine, glutamine or other amino acids, alkaline salts of phosphate, carbonate and mixtures thereof.
  • the buffers provide compositional resistance to pH changes upon dilution of the composition with saliva within the range of 8 tolO.
  • Sweeteners including aspartame, saccharin and its salts, SucraloseTM (sold by the McNeil Specialty Products Co., New Brunswick, NJ); ProsweetTM (sold by the Virginia Dare Extract Co., New York, NY); MagnasweetTM (sold by MAFCO Worldwide Co ⁇ ., Licorice Division, Camden, NJ); ammonium glycyrrhizinate, its salts, TalinTM (Thaumatin) and its diluted products, such as Talin GA90, (sold by the Talin Food Company, Birkenhead, England); and Acesulfame K, and mixtures thereof.
  • the products made with sweeteners are orally consumed it is preferable that products such as lozenges utilize sweeteners that are sugar free, or non-cariogenic. This means that the sweetener will not be metabolized by cariogenic bacteria in the oral cavity and hence they cannot generate an acidic environment. If this is not possible, then the products may be formulated to contain an alkaline buffer with a pKa of greater than 7, preferably 8 for preconditioning the oral cavity.
  • Flavorants include anise, oil of peppermint, oil of clove, eucalyptus, lemon, lime, honey lemon, red fruit, mint, grapefruit, orange, cherry cola and mixtures thereof.
  • Sensory agents Also useful herein are sensory agents selected from the group consisting of coolants, salivating agents, warming agents. Preferably these agents are present in the compositions at a level of from about 0.001%) to about 10 %, preferably from about 0.1% to about 1%, by weight of the composition.
  • Suitable cooling agents and warming agents include carboxamides, menthols, thymol, camphor, capsicum, phenol, eucalyptus oil, benzyl alcohol, salicyl alcohol, ethanol, clove bud oil, and hexylresorcinol, ketals, diols, and mixtures thereof.
  • Preferred warming agents include thymol, camphor, capsicum, phenol, benzyl alcohol, salicyl alcohol, ethanol, clove bud oil, and hexylresorcinol, nicotinate esters such as benzyl nicotinate, ketals, diols, and mixtures thereof.
  • Preferred coolants are the paramenthan carboxyamide agents such as N-ethyl-p-menthan-
  • Preferred coolants are the paramenthan carboxyamide agents such as N-ethyl-p-menthan-3- carboxamide.
  • Another preferred paramenthan carboxyamide agent is N,2,3-trimethyl-2- isopropylbutanamide, known as "WS-23", and mixtures of WS-3 and WS-23.
  • Additional preferred coolants are selected from the group consisting of menthol, 3-1- menthoxypropane-l,2-diol, known as TK-10 supplied by Takasago Perfumery Co., Ltd., Tokyo,
  • menthone glycerol acetal known as MGA, manufactured by Haarmann and Reimer
  • menthyl lactate known as Frescolat® manufactured by Haarmann and Reimer, and mixtures thereof.
  • Additonal cooling agents include cyclic sulphones and sulphoxides and others, all of which are described in U.S. Patent 4,032,661, issued June 28, 1977, to Rowsell et al., which is herein inco ⁇ orated by reference.
  • menthol and “menthyl” as used herein include dextro- and levoratotory isomers of these compounds and racemic mixtures thereof.
  • TK-10 is described in detail in U.S. Patent 4,459,425, issued July 10, 1984 to Amano et al. and inco ⁇ orated herein by reference.
  • Salivating agents of the present invention include Jambu® manufactured by Takasago Perfumery Co., Ltd., Tokyo, Japan. METHOD OF USE
  • the delivery of drugs into the bloodstream by placing a dosage form into the mouth can be classified into two major subclasses dependent upon the desired action.
  • the drug is delivered into the blood abso ⁇ tion after swallowing (i.e. from the stomach, small intestine or colon) and in the other case where abso ⁇ tion, or a significant percentage of the absorbance occurs through the membranes of the oral cavity either immediately or via over extended time periods due to retention of the drug by mucoadhesive materials.
  • This route is generally referred to as "Buccal” or "oral mucosal" abso ⁇ tion' versus the former which is classically called the peroral route.
  • the form of the invention is a liquid elixir solution. It is intended to be applied to any of the mucosal membranes within the mouth. This can be achieved using a medicine dropper that is calibrated to indicate the proper amount to be administered, and squirting the elixir onto the tongue prior to swallowing.
  • the elixir can be atomized into mouth and throat and then swallowed. It can be encapsulated into some sort of shell which makes it portable and convenient to transport and administer without having to measure the quantity of liquid elixir. Examples of encapsulation shell includes hard candies as are used for lozenges, gelatin, or starch-based shells.
  • the elixir may be packaged into a small, disposable vial which can readily be opened and squirted or poured into the mouth, the entire vial containing exactly one therapeutic dose.
  • Typical dosage forms of the composition of the present invention contain no more than about 3 ml., preferable from about 0.2 ml. to about 3ml.
  • One preferred form is to encapsulate the liquid into a shell of hard candy or gelatin.
  • the shell containing substances to pretreat the mucosa and thereby enhance the abso ⁇ tion of the active from the liquid center.
  • the pretreatment occurs by sucking or chewing the shell material, and the advantage is gained by separating in time the treatment of the mucosa, which occurs first, followed by the presentation of the active to be absorbed.
  • substances for pretreatment of the mucosal membranes are membrane penetration enhancers that are commonly known in the art, examples including menthol, peppermint oil, surfactants such as polysorbate 80 or poloxamer.
  • Another example of a mucosal membrane pretreatment are buffers as listed above, which would precondition salivary micro environment pH in the range of 8 to 11.
  • Allow the composition to reside in the mixing vessel, open to the atmosphere for about 10 minutes. Filter the composition through a US # 100 mesh sieve (product density 1.07 g/ml.). Fill into amber glass bottles, and cap with an integrated cap / calibrated medicine dropper assembly.
  • Green Shade CSL-15689 obtained from the Warner Jenkins Co., St. Louis, MO, USA.
  • To this vessel add the additional propylene glycol and liquid sweeteners (Pro-sweet Liquid K).
  • Example IV Three individual actuations are sprayed into the mouth. Dextrometho ⁇ han is rapidly absorbed into the blood, and during spraying some portion of the sprayed liquid contacts the throat area, providing the additional benefit such as numbing of the irritated cough receptors there.
  • Example IV Three individual actuations are sprayed into the mouth. Dextrometho ⁇ han is rapidly absorbed into the blood, and during spraying some portion of the sprayed liquid contacts the throat area, providing the additional benefit such as numbing of the irritated cough receptors there.
  • Dextrometho ⁇ han is rapidly absorbed into the blood, and during spraying some portion of the sprayed liquid contacts the throat area, providing the additional benefit such as numbing of the irritated cough receptors there.
  • a person places a liquid filled lozenge into the mouth and sucks on the lozenge until the liquid fill is released. Some cough relief is obtained through the action of sucking on the shell of the lozenge. When the liquid center is released, dextrometho ⁇ han is rapidly absorbed into the blood.
  • Ethanol Add a portion of Ethanol to the active (Dextrometho ⁇ han Base) and solid sweetening agents (aucralose, monoammonium glycyrrizinate) and continuously mixed at low heat (30°C).
  • active Dextrometho ⁇ han Base
  • solid sweetening agents aucralose, monoammonium glycyrrizinate
  • propylene glycol fatty acid esters and propylene glycol and liquid sweeteners (Pro-sweet Liquid K).
  • fatty acid esters and propylene glycol and liquid sweeteners (Pro-sweet Liquid K).
  • liquid sweetener Pro-sweet Liquid K
  • buffer Triethanolamine
  • Dissolve Dextrometho ⁇ han Base in portion of alcohol to make a premix In separate container add disodium EDTA and sodium metabisulfite to water and mix until uniform Add this mixture to the Dextrometho ⁇ han Base premix.
  • Dissolve Dextrometho ⁇ han Base in portion of alcohol to make a premix In separate container dissolve EDTA and sodium metabisulphite in water. Mix until uniform and cool to room temperature. Add this mixture to the Dextrometho ⁇ han Base. Mix until all materials are in solution. Add the remaining portion of alcohol, EDTA and the aesthetics package to the vessel containing the nearly completed solution. Allow the composition to reside in the mixing vessel, open to the atmosphere for about 10 minutes. Mix until homogeneous and filter through a US #100 mesh sieve. Fill in a amber glass bottles, and cap with an integrated cap/ calibrated medicine dropper assembly. About 1.5 grams of the elixir is dropped onto the tongue and then swallowed.
  • Dissolve Dextrometho ⁇ han Base in portion of alcohol to make a premix. In separate container mix water, sodium metabisulfite and disodium calcium EDTA. until clear. Cool it to room temperature. Add the mixture to the Dextrometho ⁇ han. Mix until uniform and cool to room temperature. Mix until all materials are in solution. Add the remaining portion of alcohol and the aesthetics package to the vessel containing the nearly completed solution. Allow the composition to reside in the mixing vessel, open to the atmosphere for about 10 minutes. Mix until homogeneous and filter through a US #100 mesh sieve. Fill chewable soft gelatin capsules using the above formulation. Said gelatin capsules are available from the trade by companies such as R. P. Scherer, of St. Petersberg, Florida. About 1.84 grams of the elixir is delivered to the mouth by mastication of the capsule(s) and then swallowed.
  • Pluronic F127 (BASF Specialty Chemicals, Mount Olive, N.J.) Preparation: Add propylene glycol and poloxamer to a clean vessel (main mix). While stirring, heat the mixture as appropriate to sufficiently melt the poloxamer. Once a uniform solution is obtained remove from heat source and continue mixing. In a separate vessel (alcohol pre-mix) add alcohol, guaifenesin, dextrometho ⁇ han base and monoammonium glyzeriziinate and mix until uniform. In another vessel (water pre-mix), add water, EDTA, sodium saccharin, acesulfame and sodium metabisulfite. Mix until all materials are dissolved.
  • Dissolve Dextrometho ⁇ han Base in portion of alcohol to make a premix In separate container add disodium EDTA and sodium metabisulfite to water and mix until uniform Add this mixture to the Dextrometho ⁇ han Base premix.

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Abstract

La présente invention concerne la stabilité améliorée de compositions qui libèrent des principes actifs pharmaceutiques. Ces compositions sont dotées d'une stabilité exceptionnelle lorsqu'elles sont utilisées dans des formes de produits variés, y comprises sous forme d'élixirs liquides placés dans la bouche et éventuellement avalés. Elles peuvent être aussi délivrées sous formes de pastilles remplies de liquide, de dispositifs doseurs de liquide, de pulvérisateurs et de capsules mangeables à libération de liquide. Ces compositions sont particulièrement utiles pour traiter des symptômes associés aux maladies respiratoires.
EP00970493A 1999-09-29 2000-09-26 Compositions a stabilite amelioree Ceased EP1216044A1 (fr)

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US15654099P 1999-09-29 1999-09-29
US156540P 1999-09-29
US09/467,333 US20020082307A1 (en) 1999-01-11 1999-12-20 Compositions having improved stability
US467333 1999-12-20
US17928900P 2000-01-31 2000-01-31
US179289P 2000-01-31
PCT/US2000/026402 WO2001022967A1 (fr) 1999-09-29 2000-09-26 Compositions a stabilite amelioree

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