CN1376065A - Compositions having improved stability - Google Patents

Compositions having improved stability Download PDF

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Publication number
CN1376065A
CN1376065A CN00813496A CN00813496A CN1376065A CN 1376065 A CN1376065 A CN 1376065A CN 00813496 A CN00813496 A CN 00813496A CN 00813496 A CN00813496 A CN 00813496A CN 1376065 A CN1376065 A CN 1376065A
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Prior art keywords
compositions
agent
solvent
liquid
composition
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CN00813496A
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CN1211085C (en
Inventor
J·E·哈诺卡
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Procter and Gamble Ltd
Procter and Gamble Co
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Procter and Gamble Ltd
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Priority claimed from US09/467,333 external-priority patent/US20020082307A1/en
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    • 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
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    • 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
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Abstract

The present invention pertains to improved stability of compositions that deliver pharmaceutical active ingredients. These compositions have exceptional stability when used in various product forms including liquid elixirs placed into the mouth and eventually swallowed, or can be delivered via 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.

Description

The compositions of improved stability
Invention field
The present invention relates to send the improvement of the stability of drug delivery composition of active components.Send into the liquid elixir use that the oral cavity is finally swallowed when comprising with various product forms, or can discharge edible capsule by lozenge, liquid metering doser, aerosol apparatus and the liquid of filling liquid send when passing, these compositionss are stable in the extreme.These compositionss especially can be used for treating the disease relevant with respiratory tract disease.
Background of invention
Send the approach of passing medicinal active ingredient to comprise to send and pass active component by intranasal, pulmonary, cheek, Sublingual, transdermal, vagina and rectum and ophthalmic administration.Yet prevailing is the compositions of swallowing.When these compositionss were swallowed, they entered intestines and stomach and are absorbed in the whole body blood circulation.The article of being swallowed by the people (comprising food, beverage and medicine) enter stomach and flow into intestinal from stomach.Many chemical compounds relevant with food, beverage or medicine penetrate the mucosa of intestines and stomach, and enter from the blood of the effusive mesenteric vein of intestinal.Enter liver from the effusive blood flow of mesenteric vein.Metabolic enzyme in the intestinal mucosa regulating liver-QI can chemically change the character that enters the material of health whole body blood circulation from intestinal by liver.
Respiratory tract disease comprises far-ranging disease, comprises viral infection and to the anaphylaxis of the anaphylactogen that sucks.The disease that viral infection in people's upper respiratory tract causes is commonly referred to flu or influenza.This disease is very general in the crowd and can causes and significantly do not accommodate misery.The suction of anaphylactogen also can be played identical with viral infection or negative effect greatly to the crowd.
Also be regarded as prophylaxis of viral infections or method effectively and easily hypersensitive.When by viral infection, the natural immunology defense of health and the time range that infects antagonism be 3 days to 2 weeks.At this moment, the medicine of conventional use to treat the symptom of these respiratory tract diseases promptly uncomfortable.These symptoms comprise nasal obstruction and watery nasal discharge, nose laryngalgia and inflammation, cough, pantalgia, fever and headache.In these symptoms, it is the most serious problem and discomfort that out of contior cough that shows effect is considered as by many people.Normal breathing has been disturbed in cough, thereby has increased headache and throat pain, and other people's insomnia that makes the patient and live together with the patient.
The compositions that is used for the treatment of above-mentioned disease is generally following pharmacology and divides a kind of of apoplexy due to endogenous wind: antihistaminic, Decongestant, cough medicine, expectorant, mucolytic, analgesic, antipyretic and anti-inflammatory agent.These compositionss are prepared to many product forms, the liquid sugar sirup of the usefulness of the most generally swallowing and elixir, oral cavity dropping liquid and lozenge and inhalant and topical cream and emulsion (can discharge volatilizer is inhaled into by entering respiratory tract behind the nasal cavity).Usually these compositionss of swallowing rapidly, or they are dissolved in the oral cavity lentamente.They contain activating agent such as guaifenesin (assisting health to remove excessive respiratory mucus or sputum), diphenhydramine (reduce at body and reply viral infection and the histamine counter productive that produces comprises cough and other symptom) and dextromethorphan (work in the part at human brain and control coughre flex) usually.Dextromethorphan is to alleviate the most frequently used active component of cough in the world in these active component.
People's such as Pankania (Boots Company) U.S. Patent No. 4,839,176 (on June 13rd, 1989) discloses the purposes that contains bisulfites in the tablet of CMC in manufacturing and has avoided degraded.People's such as Keel (Monsanto) U.S. Patent No. 4,474,985 (on JIUYUE 25th, 1993) discloses the method for the colourless shelf-life that increases thick N-amino-phenol.This method comprises thick N-acetyl-amino phenol is dissolved in the solvent that contains Reducing agent (as metabisulfite).People's such as Haslam U.S. Patent No. 4,478,882 (on November 23rd, 1984) and U.S. Patent No. 4,474,752 (on November 2nd, 1984) (all transfer Merck﹠amp; Co.) disclose to contain and entered the compositions that makes the polymer of liquid gelled behind the body cavity.Disclosed is that a series of microbiological antiseptics comprise sodium sulfite and sodium thiosulfate.Do not prove the special chemically stable benefit that product form provided as yet with regard to this area known to the present patent application people by contained solution or liquid base.
Summary of the invention
So far also unconsummated is when special reagent is added compositions, can influence just rising with the blended reactive compound of conventional solvent.Surprising is that in containing the fluid composition of medicinal active ingredient, some blended intercalating agent and Reducing agent can improve the stability of active component in these compositionss.
Compositions of the present invention provides excellent sending of Orally taken product form to pass.When being incorporated into various oral product forms (lozenge, liquid metering doser, aerosol apparatus and the edible capsule of liquid slow-release that comprise elixir, filling liquid), these compositionss yet have the fabulous shelf-life.These compositionss especially can be used for treating the symptom relevant with respiratory tract disease.
Careful and after having studied medicinal, the treatment and side effect profile of reactive compound diligently, realized to play the positive effect that improves therapeutic effect and do not increased side effect or toxic compositions.These chemical compounds can improve the stability that is used to send the product form of passing these compositionss.The realization of this benefit is by add the reagent that can improve this active component stability in preparation in containing formulations of active ingredients.These reagent can reduce effectively and even eliminate the unstability that the Ways of Oxidative because of active component causes, thereby prolonged the storage period of compositions.
So an object of the present invention is to provide the compositions of improvement, be used for the treatment of the symptom relevant with respiratory tract disease, reduce the outbreak of cough especially as far as possible.In a particularly preferred embodiment, compositions is to be in anhydrous, hydrophilic liquid form in the very stable environment, pass active component and comprise cough medicine, antihistaminic (comprising the non-sedating antihistaminic), Decongestant, expectorant, mucolytic, analgesics, antipyretic and anti-inflammatory agent to send fast, and the local anesthetic that is used for the treatment of symptoms of respiratory disease.Available various product form and/or packing are sent to pass and are selected to take these compositionss.Compositions of the present invention provides ideal activity, simultaneously minimum is reduced in the potential side effect of reactive compound.Provide rapidly saturating mucosa to send to pass that to state method for compositions also be one object of the present invention.
Definition and term
Below be the definition of term in the description of the present invention:
1. saturating mucosa send to be passed
Finger reaches the application of medicine to oral cavity (comprising cheek (buccal), lip, gums, maxillary and tongue) mucosa medicine and penetrates the purpose that the skin on these sites enters blood flow.
2. therapeutic dose
Refer to when with the appropriate format administration of human, reach the amount of substance of required effect and adverse side effect minimum in vivo.
3. active constituents of medicine/active component:
Refer to when giving, health be produced the chemical molecular of required effect with appropriate amount and form.
4. active metabolite
The chemical compound of the active constituents of medicine that finger forms when active component generation metabolism.
5. unimolecule disperses
The molecule that refers to active component is free, the obstruction that is not subjected to crystal or noncrystal solid-state form or polymolecular to associate and spread.
6. percent dissolution degree value
Refer to the equilbrium solubility limit or the maxima solubility of molecule in solvent under the room temperature, represent with the percentage by weight of molecule in compositions.
7. anhydrous solvent
Refer to that water content is less than 5% solvent.
Detailed Description Of The Invention
Medicinal active ingredient
Compositions of the present invention contains medicinal active ingredient (this paper is also referred to as " active component ") treats disease, especially relevant with respiratory tract disease symptom such as flu, influenza and allergy.These active component comprise be generally used for treating most of debatable symptom (comprise the nasal obstruction and watery nasal discharge, nose larynx pain and inflammation, the outbreak of cough, pantalgia, fever and headache) active component; Referring to the U.S. Patent No. 5,196,436 (on March 23rd, 1993) of Smith, this paper includes it as a reference in.In the present invention, when sending some material mixing of passing active component in active component and the compositions, it is useful especially using the material that improves the preparation long-term stability.In stable formulation, active component can send effectively passs the generation positive effect.
Compositions contains medicinal active ingredient and stabilizing agent and the conventional known composition that compositions is sent pass described active component.In a preferred embodiment, compositions contains solvent, this solvent be hydrophilic, can with the blended anhydrous solvent of water, wherein be equal to or greater than 0.075% with the percent dissolution degree value of medicinal active ingredient in this solvent of nonionic form, and medicinal active ingredient is unimolecule with its free nonionic form and disperses in solvent in room temperature.
The molecular weight of preferred medicinal active ingredient of the present invention can ionization in aqueous solvent less than every mole of 500 gram, and when existing with the nonionic form, octanol-water partition coefficient is at least 100.At A.Martin, " the physics medicine " of P.Bustamante and A.H.C.Chun, the 4th edition, Lea and Febigerpublishers, Philadelphia discloses the partition coefficient of capryl alcohol-water in 1993, the 237 pages, and this paper includes it as a reference in.
The active component that constitutes the present composition is included in following pharmacology and divides apoplexy due to endogenous wind at least a composition: cough medicine, antihistaminic, non-sedating antihistaminic, Decongestant, expectorant, mucolytic, analgesics, antipyretic and anti-inflammatory medicine, local anesthetic and their mixture.The list of references of describing the purposes of these active component comprise J.G.Hardman's " therapeutic pharmacological basis ", the 9th edition, McGraw-Hill, NewYork, 1995.Be that those are applicable to the active component that absorbs by mucosal tissue in these pharmacologys divide the active component of apoplexy due to endogenous wind.Can unite use separately or with other active component (needn't absorb by this way), and these active component can be prepared with existent method.
When use was used for the active component of mucosa absorption, the concentration of active component more preferably was the percent dissolution degree value that is less than or equal to medicinal active ingredient preferably for being less than or equal to 125% dissolubility percentage ratio in the compositions solvent part.For the benefit that makes the present composition reaches maximum, preferably active component disperses with unimolecule in solution.The active component that is used for absorption of the present invention is about 0.075% to 25.0% of composition weight in the level that exists of solvent system, preferably is 0.28% to 10.0%.Preferably, described active component form with its free nonionicization in described solvent system exists.When active constituents of medicine can salt form or Ionized form when existing, should use the medicine of uncharged free (non-salt) form in the present invention.
Cough medicine is the active component that is used in particular for preventing uncontrollable coughing fit.Be used for cough medicine of the present invention and comprise (but being not restricted to): codeine, dextromethorphan, dextrorphan (dextrophan), diphenhydramine, hydrocodone, narcotine, oxycodone, pentoxyverine, morphine, adaphol and their mixing.In these cough medicines, dextromethorphan is preferred.Known dextromethorphan has the medical active of cough medicine, and referring to the U.S. Patent No. 5,196,436 of Smith, this paper includes it as a reference in.As described herein, " dextromethorphan " refers to racemethorphan, 3-methoxyl group-17-methylmorphine (racemization-cis-1,3,4,9,10,10a-six hydrogen-6-methoxyl group-11-methyl-2H-10, luxuriant and rich with fragrance and its pharmaceutically acceptable salt of 4a-imino group ethenylidene.The compositions that the present invention contains dextromethorphan contains 0.1% to 9.3% dextromethorphan of having an appointment, and preferably is about 0.26% to 6.2%, more preferably is 1.16% to 4.6%.Other cough/coldrex active component that in containing the compositions of dextromethorphan, can also comprise other safe and effective amount.
Be used for antihistaminic of the present invention and comprise (but being not restricted to): he is fixed for acrivastine, Ah Za, brompheniramine, chlorphenamine, clemastine, plug pyridine in heptan, dexbrompheniramine, dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, meclizine, thephorin, phenyltoloxamine, promethazine, pyrrole draw quick, tripelennamine, triprolidine and their mixing.Can be used for non-sedative antihistamine of the present invention medicated bag and draw together (but being not restricted to): astemizole, cetirizine, ebastine, fexofenadine (fexofenadine), loratadine and their mixing.Can be used for Decongestant of the present invention and comprise (but being not restricted to): benzo hydramine, isoephedrine, ephedrine, phenylephrine, hydroxyl first imidazoles and their mixing.Be used for expectorant of the present invention and comprise (but being not restricted to): ammonium chloride, guaifenesin, hippo liquid extract, potassium iodide and their mixing.Can be used for mucolytic of the present invention and comprise (but being not restricted to): acetylcysteine, ambroxol, bromhexine and their mixing.Can be used for analgesic of the present invention, antipyretic and anti-inflammatory agent and comprise (but being not restricted to): acetaminophen, aspirin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketorolac, nabumetone, naproxen, piroxicam, caffeine and their mixing.Be used for local anesthetic of the present invention and comprise (but being not restricted to): lidocaine, benzocaine, phenol, dyclonine, benzonatate and their mixing.
Solvent
Keep the non-ionic form of medicinal active ingredient with selected solvent.The solvent of the present composition partly accounts for 60% to 99.975%, preferably is 70% to 99%, more preferably is 85% to 98% composition weight.
In ambient temperature or room temperature, solvent of the present invention is normally liquid.It can be water miscible or water is blendable.Be selected to preferred solvents of the present invention: propylene glycol, ethanol, Polyethylene Glycol are PEG, propylene glycol carbonate, diethylene glycol monomethyl ether, poloxamer, sweet furfural (glycofurol), glycerol, polyvinyl pyrrolidone (PVP), Transcutol TM2-(2-ethoxy ethoxy) ethanol, Lauroglycol 90 TM(fatty acid ester and propylene glycol), Labrasol TM(glyceride and macrogol ester), Capryol 90 TM(Capryol 90) and their mixing all can be from Gattefosse SA.Company of 69804 Saint Priest Cedex, and France buys.Propylene glycol and ethanol are particularly preferred.For some product of the present invention, particularly preferably be the mixture of these solvents.For example, if product form is elixir, liquid capsule or the lozenge that contains liquid, then solvent is the mixture of propylene glycol, ethanol and PEG.If product form is a spray, solvent is the mixture of propylene glycol, ethanol, PEG and common propylene glycol carbonic ester.The level of forming each solvent of these mixture depends on the required aesthetic effect that reaches of formulator.The anhydrous form of above-mentioned solvent most preferably.
Intercalating agent
Found to add intercalating agent and can useful especially chemically stable effect have been arranged the active component that constitutes the present composition.Contain active component phase phase time in addition in the compositions when intercalating agent is present in, this amazing phenomenon just takes place.For example, when active component be dissolved in the nonpolar environment of compositions or mutually in the time, selected intercalating agent can be at polar phase, in water.Therefore, although be separate mutually in, the chemical stability of active component still obtains positive influences.And when active component and intercalating agent are dissolved in same solvent altogether, then can not observe the same stable benefit.So the intercalating agent that is used for compositions depends on selected active component and dissolubility thereof.
Be used for the intercalating agent that intercalating agent of the present invention comprises those chelating transition metal ionss such as ferrum, copper, zinc and other metal.Be not wishing to be bound by theory, can in the formation of oxidizing substance, play a major role by the reasonable assumption metal cation.The reaction of generation free radical relates to the transfer by the electronics of the redox cycle between two different valence state.The common catalysis automatic oxidation reaction of the heavy metal of trace.In fact, be low to moderate the speed of carrying out that the 0.05ppm metal ion just is enough to the initiated oxidation reaction and increases this chain reaction.Referring to W.Lund, pharmacopeia, the 12nd edition, 287﹠amp; 290 pages, The Pharmaceutical Press, 1994, this paper includes it as a reference in.
Shown that intercalating agent can reduce the easiness of the electron transfer reaction between these valence states.This specific character of intercalating agent has been prevented the autoxidation reaction.This just can explain why intercalating agent can be protected medicinal active ingredient effectively.Oxidation rate during known alkaline pH and degree are big during than acid ph value.This part is because bivalent cation has the trend of more catalytic oxidations in alkaline medium.Referring to Townsend M.W. and Byron P.R. " formulation additives is to the effect of cryodesiccated ribonuclease A degraded ", PharmacuticalResearch the 7th volume, No.10,1086-1091 page or leaf (1990).Some side chains contain nitrogen other medicinal compound also demonstrate and can be stablized by EDTA, referring to A.G.﹠amp; Summan A.M..When having vitamin C, EDTA has demonstrated the acetylamino group that can stablize effectively in medicine and the food colored compound and has prevented that they are subjected to light degradation, referring to " Journal of Clinical Pharmacology and Therapeutics " the 17th volume, 107-109 page or leaf (1992).
Being used for intercalating agent of the present invention is that 5 to 12 scope is stable at non-water and aqueous medium, pH, and effectively.Preferred intercalating agent is selected from: the disodium salt of ethylenediaminetetraacetic acid (EDTA) and calcium salt, EDTA four sodium, sodium hexameta phosphate (SHMP), citric acid, phosphoric acid, two (hydroxyethyl) glycine, oxine and their mixing.
The level that is used for intercalating agent of the present invention depends on the amount of introducing the metal ion of preparation by the approach of the pollution of composition.In the present invention, the level of used intercalating agent is about 0.005% to 1.000%, preferably is about 0.150% to 0.050%, more preferably is about the weight of 0.300% to 0.010% compositions.
Reducing agent
Also observe when having Reducing agent in the intercalating agent in the invention described above, Reducing agent can obviously increase the shelf-life.Even when the level of intercalating agent in the preparation is very low when being low to moderate 0.001% situation also like this.The prolongation of shelf-life just Reducing agent as the improvement of antioxidant long-term effect.Be not wishing to be bound by theory, it is believed that reduction reaction when having intercalating agent (oxidation of Reducing agent) carries out with different processes.When having intercalating agent, initial action depends on the generation of superoxide radical group, and when not having intercalating agent, O 2 0Free-radical oxidation material in addition will participate in initial action.Therefore intercalating agent serves a dual purpose in the aerobic oxidation of Reducing agent.It with can catalysis the trace metal complexation of spontaneous oxidation, thereby change the mechanism that causes.It also can pass through to remove the disrupting agent of the oxidative free radical of reaction of propagation chain as chain.Thereby obviously increased the chemically stable effect of Reducing agent to active component of the present invention.This phenomenon betide astoundingly when active component and Reducing agent be when being in not in the homophase.For example, when active component be dissolved in the nonpolar environment of compositions or mutually in the time, selected Reducing agent should be dissolved in polar phase such as the water.So, although be separate mutually in, the chemical stability of active component is subjected to positive influences.When active component and Reducing agent are dissolved in solvent altogether, then do not observe this identical Stabilization.Depend on selected active component and dissolubility thereof so be used for the Reducing agent of the present composition.
Reducing agent is to have than medicine or be used for protecting to the low material of antioxidative adjuvant oxidation-reduction potential.So when having oxidant, Reducing agent is than medicine or the easier oxidation of adjuvant.Referring to W.Lund, pharmacopeia, the 12nd edition, the 290th page, The Pharmaceutical Press, 1994, this paper includes it as a reference in.Reducing agent of the present invention has the electrode potential value.This is by defining and measure with standard electric chemistry reference battery by this spy (Nernst) equation.Therefore the value that will obtain is called E 0Standard electrode EMF (with volt (V) for measuring).Relatively the standard electrode EMF of different material can be used for assessing the effectiveness of different Reducing agents, referring to Wells, and the medicine preformulation, Ellis Horwood Limited Publishing, 1988, the 168-172 pages or leaves, this paper includes it as a reference in.The electrode potential value E that is used for Reducing agent of the present invention 0Approximately greater than-0.119V, preferably be about-0.119V is to+0.250V.Preferred Reducing agent is selected from metabisulfite and bisulfites, comprises their sodium salt and potassium salt; Dithiothreitol, DTT; Thiourea; Sodium thiosulfate; TGA; Tertiary butylated hydroquinone (terbutyhydroquinone) (TBHQ); Acetylcysteine; Hydroquinone and their mixture.
The level that is used for Reducing agent of the present invention is about 0.005% to 1.000%, preferably is about 0.050% to 0.500%, more preferably is about the weight of 0.010% to 0.200% compositions.
Work with the oxidation-compound donator of sacrificing own rather than active component by conduct, Reducing agent protects medicinal active ingredient of the present invention to avoid degraded.Intercalating agent also can by with the preparation composition in the chelating of the metal ion (comprising essence, freshener and sweeting agent and the potential metal ion that moves out from packaging material) that exists, also can play practical protective effect.When these metal ions do not exist, have only seldom or do not produce oxygen base or the peroxy free radical that produces by metallic catalyst.This is with the stable pharmaceutical active component.
Though use the addition effect of Reducing agent and chelate can not be amazing together, it be surprising using the resulting benefit of these specific reductants.In addition, when using the intercalating agent that surpasses all metal ions aequum level in the chelating system (not continuing to produce metal ion), viewed benefit also is surprising.Be not wishing to be bound by theory, it is believed that the intercalating agent such as the EDTA that there are excessive levels, the degraded of Reducing agent such as sodium metabisulfite is shockingly suppressed.Continue to keep the existence of Reducing agent in the present composition, can preserve the medicinal active ingredient in the higher levels of compositions.
Optional member
Water can be used for compositions of the present invention.In the present invention, the top level of water is about 10% of composition weight, preferably is about 1% to 10% of composition weight, more preferably is about 5% to 10% of composition weight, is about 5% to 8% of composition weight best.
Usually the composition that uses with flu and treatment of influenza medicine can use with disclosed active constituents of medicine herein.Such composition is at United States Patent (USP) 5,196, has in 436 openly, and the document is incorporated herein by reference.In addition, can use following ingredients in the present invention.
Buffer agent and buffer mixture (comprise as oligomict ealkaline buffer, pKa is 8 to 10), comprise alkali salt, carbonate and their mixture of triethanolamine, tromethane, amino acid salts (comprising glycine, glycylglycine, glutamine or other amino acid whose alkali salt), phosphoric acid.Buffer agent provides and makes the variation (in 8-10 scope) of compositions opposing saliva to the pH that dilution caused of compositions.
Buffer agent and buffer mixture (comprise as oligomict ealkaline buffer, pKa is 8 to 10), comprise alkali salt, carbonate and their mixing of triethanolamine, trometamol, amino acid salts (comprising glycine, glycylglycine, glutamine or other amino acid whose alkali salt), phosphoric acid.Buffer agent provides the variation (in the 8-10 scope) that makes the pH that compositions in the compositions opposing saliva caused its dilution.
Sweeting agent comprises aspartame, glucide and salt thereof, Sucralose TM(by McNeil SpecialtyProdducts Co., New Brunswick, NJ sale), Prosweet TM(by the Virginia Dare ExtractCo., New York, NY sale), Magnasweet TM(by MAFCO Woldwide Corp., LicoriceDivision, Camden, NJ sale), ammonium glycyrrhizinate and salt thereof, Talin TM(Thaumatin) and the product of its dilution such as Talin GA90 (by Talin Food Company, Birkenhead, England sells) and acesulfame K and their mixture.Because these products with sweeting agent preparation are oral, thereby preferably these products such as lozenge use sugar-free or not cariogenic sweeting agent.Sweeting agent can be by the living dental caries bacterial metabolism in the oral cavity in other words, thereby can not produce sour environment.If impossible, then product be mixed with and contain the ealkaline buffer of pKa, with the preset oral cavity greater than 7 (preferably being 8).
Essence comprises Fructus Foeniculi, Oleum menthae, Oleum Caryophylli, eucalyptus globulus, Fructus Citri Limoniae, Citrus aurantium Linn., Mel, Fructus Citri sinensis (honey lemon), red fruit, Herba Menthae, grapefruit, Fructus Citri tangerinae, the cherry certain kind of berries (cherry cola) and their mixing.
Sensory agent.Also can be used for sensory agent of the present invention is selected from: freshener, salivator, warm dose.Preferably, the level that these reagent exist in the compositions is about 0.001% to 10%, preferably is about 0.1% to 1% composition weight.
The freshener that is fit to and warm dose comprise benzamide type, menthol, thymol, Camphora, Fructus Capsici, phenol, Eucalyptus oil, benzyl alcohol, saligenin, ethanol, Flos Caryophylli pistil oil and hexyl resorcin, ketal, two pure and mild their mixture.Preferred warm dose comprises thymol, Camphora, Fructus Capsici, phenol, benzyl alcohol, saligenin, ethanol, Flos Caryophylli pistil oil and hexyl resorcin, nicotinate such as benzyl nicotinate, ketal, two pure and mild their mixture.
Preferred freshener is as N-ethyl-right- alkane-3-Methanamide (WS-3 to  alkane Methanamide (carboxamide), provide by Sterling Organics), as people's such as Watson U.S. Patent No. 4,136, described in 163 (on January 23rd, 1979), this paper includes it as a reference in.Preferred freshener is to  alkane Methanamide such as N-ethyl-right- alkane-3-Methanamide.Other is the N that is known as " WS-23 " to  alkane Methanamide preferably, 2, and 3-trimethyl-2-isopropyl butyramide, and the mixture of WS-3 and WS-23.
Other preferred freshener is selected from menthol, is called the 3-1- oxygen base propane-1 of TK-10, the 2-glycol is (by Takasago Perfumery Co., Ltd, Tokyo, Japan provides), be called the  ketone glycerine acetal (making) of MGA by Haarmann and Reimer, the lactic acid  ester of the called after Frescolat  that makes by Haarmann and Reimer and their mixture.
Other freshener comprises cyclic sulfones and sulfoxide etc., all can be referring to people's such as Rowsell U.S. Patent No. 4,032,661 (on June 28th, 1977), and this paper includes it as a reference in.
Term used herein " menthol " and "  yl " comprise dextrorotation and the laevoisomer and their racemic mixture of these mixture.
To the description of the TK-10 U.S. Patent No. 4,459,525 (on July 10th, 1984) referring to people such as Amano, this paper includes it as a reference in.
Salivator of the present invention comprises Takasago Perfumery Co., Ltd, Tokyo, the Jambu  that Japan makes.
Using method
By dosage form being placed mouth send the required action of method foundation of passing, can be divided into two kinds of main subgroups into blood flow with medicine.One, medicine send after swallowing to be passed into blood absorption (promptly from stomach, small intestinal or colon), and another kind is that main the absorption is film by the oral cavity, after no matter taking medicine immediately or make segment length's time of the delay of medicine by the mucoadhesive material.This path can be called " cheek " or " oral mucosa " usually and absorb, and the previous case then can be described as oral path.Up to the present, the administration in oral path is the most frequently used in the medicine that all were studied, it is in detail explained referring to Mayerson, M., " drug absorption principle " the 2nd chapter, " modern pharmacy ", the 2nd edition, G.S.Banker and C.T.Rhodes edits, Marcel DekkerInc., New York, 1990.
Sending in the method for passing of active component, what usually accept is that oral mucosa send that thereby pass must zone, targeting Sublingual realization rapid effect for curing in the oral cavity in, " administration of through port transmucosal " referring to D.Harris and J.R.Robinson, Journal of Pharmaceutical Science 81:1,1992.These drug desigies are become to place on the bottom, oral cavity in Sublingual, and keep segment length's time.But inventor of the present invention finds, any position of the oral mucosa in the present composition being placed on mouth, or even on tongue or under swallowing, can realize that the utmost point absorbs rapidly, and bioavailability improves greatly.
Form of the present invention is a liquid elixir solution.Can use it on intraoral any mucosa.This can be with the scale medicine dropper of indicating the appropriate amount that will give, and before swallowing elixir is penetrated on tongue.Can swallow then with this elixir at mouth and larynx internal spraying.Can be these elixirs are encapsulated with some shells, it can be carried and be easy to transport the amount that need not to measure liquid elixir with administration.The example of capsule shells comprises the hard sugar that is used for lozenge, gelatin or based on the shell of starch.Elixir can be packed in the little disposable bottle, this bottle is easy to open and elixir can be sprayed or pour in the mouth, and whole bottle accurately contains a dosage.The exemplary dosage form of the present composition contains in the 3ml, preferably is about 0.2ml to 3ml.
One preferred dosage form is with liquid capsuleization with hard sugar or gelatin shell.Shell contains the material of energy pretreatment mucosa, thereby improves the absorption after liquid enters.Suck or chew shell matter and just pretreatment can take place, also can obtain this benefit by being separated (first pretreatment, and then the active component of absorption existence) processing time of mucosa.The examples of substances that is used for the pretreatment mucosa is the common known membrane permeation reinforcing agent in this area, and its example comprises menthol, Oleum menthae, surfactant such as polysorbate80 or poloxamer.Pretreated other example of mucosa is above-mentioned buffer agent, the pH of saliva microenvironment can be controlled in 8 to 11 the scope.
Embodiment
Example I
Liquid elixir
Project Material % compositions (w/w)
?1 Propylene glycol 80.664
?2 Ethanol 9.000
?3 Pure water 5.000
?4 Disodiumedetate (EDTA disodium) 0.050
?5 Saccharin sodium 0.650
?6 Herba Menthae essence 2.000
?7 Acesulfame K 1 0.450
?8 Takasago10 2 0.100
?9 Menthone glycerine acetal (methone glycerine acetal) 0.300
?10 Ethyl methane Methanamide 0.070
?11 Monoammonium glycyrrhizinate 0.150
?12 The dextromethorphan base material 1.466
?13 Sodium metabisulfite 0.10
Totally 100.000
1 can be from Nutrinova Inc.Company of Somerset, NJ-08873, and USA buys acesulfame
2 can be from Takasago Company of Rockleigh, NJ-07657, and USA buys TK10
Part ethanol is added in active component (dextromethorphan base material) and the solid-state sweeting agent (Sucralose, glycyrrhizic acid monoammonium), and they are stirred at low temperature (30 ℃).In this container, add propylene glycol and liquid sweetener (Pro-sweeting agent liquid K).Intercalating agent (EDTA disodium), Reducing agent (sodium metabisulfite) and water are mixed, mix up to evenly.Mixture is added in the container, and mixed about 2 hours.In remaining ethanol, add premixed essence and coloring agent, it is added in the container that the solution of closely finishing is housed.Mixing is up to forming uniform solution.Allow compositions stay in the mixer, be open in the air about 10 minutes.Filter compositions (product density=1.07g/ml) with US#100 sieve.Inject the amber glass bottle, drip the device assembly with incorporate bottle cap/amount medicine and carry out capping.
About 1.5 gram elixirs are dripped on the tongue, swallow down then.Dextromethorphan is absorbed in the blood rapidly.
Example II
Liquid elixir
Project Material % compositions (w/w)
?1 The dextromethorphan base material 2.055
?2 Ethanol 10.000
?3 Propylene glycol 63.075
?4 Disodiumedetate (EDTA) 0.1％
?5 Triethanolamine 3.740
?6 Sucralose 0.150
?7 Pro-sweeting agent liquid K 0.700
?8 Monoammonium glycyrrhizinate 0.050
?9 Essence 0.015
?10 Coloring agent 0.005
?11 Guaifenesin 20.00
?12 Sodium metabisulfite 0.200
Totally 100.000
Part ethanol is added in active component (dextromethorphan base material) and the solid-state sweeting agent (Sucralose, glycyrrhizic acid monoammonium), and they are stirred at low temperature (30 ℃).In this container, add propylene glycol, liquid sweetener (Pro-sweeting agent liquid K) and buffer agent (triethanolamine, liquid).Add EDTA disodium, sodium metabisulfite and water together, mix limpid until solution.Mixture is added in the container, enters guaifenesin and mixed about 2 hours.In remaining ethanol, add premixed essence and coloring agent, it is added in the container that the solution of closely finishing is housed.Mixing is up to forming uniform solution.Allow compositions stay in the mixer, be open in the air about 10 minutes.Mixing is up to forming uniform solution, and filters compositions (product density=1.07g/ml) with the US#100 sieve.Inject the amber glass bottle, drip the device assembly with incorporate bottle cap/amount medicine and carry out capping.
About 1.0ml elixir is dripped on the tongue, swallow down then.Dextromethorphan is absorbed in the blood rapidly.
EXAMPLE III
Liquid spray
Project Material % compositions (w/w)
?1 The dextromethorphan base material 3.425
?2 Sodium hexameta phosphate (SHMP) 0.050
?3 Propylene glycol 95.355
?5 Sucralose 0.300
?6 Pro-sweeting agent liquid K 0.700
?7 Monoammonium glycyrrhizinate 0.050
?8 Essence 0.015
?9 Coloring agent 1 0.005
?10 Sodium thiosulfate 0.100
Totally 100.000
1. from Warner Jenkins Co., St.Louis, the marennin CSL-15689 that MO, USA buy
The part propylene glycol is added in active component (dextromethorphan base material) and the solid-state sweeting agent (Sucralose, glycyrrhizic acid monoammonium), and they are stirred at low temperature (30 ℃).In this container, add propylene glycol and liquid sweetener (Pro-sweeting agent liquid K) again.Sodium hexameta phosphate (SHMP) and sodium thiosulfate are dissolved in the water, and are mixed to limpid.This mixture is added in the container, mixes all being dissolved in the solution about 2 hours up to all raw materials.In remaining ethanol, add premixed essence and coloring agent, it is added in the container that the solution of closely finishing is housed.Mixing is up to forming uniform solution.Allow compositions stay in the mixer, be open in the air about 10 minutes.Mixing is up to forming uniform solution, and filters compositions (product density=1.07g/ml) with the US#100 sieve.Inject manually opened atomizing pump and bottle.An example is that Calmar-AlberGmbH makes, and is furnished with the Mistette Mrak II of 16mm high viscosity head (send and pass the 0.2ml/ driving).
On tongue, carry out 3 sprayings separately.Dextromethorphan is absorbed in the blood rapidly, and the liquid of a part of ejection in spray process contacts with throat is regional, from and provide other benefit as making the cough receptor numbness of irriate.
EXAMPLE IV
Liquid spray
Project Material % compositions (w/w)
?1 The dextromethorphan base material 3.425
?2 Ethanol (100%) 5.350
?3 Propylene glycol 41.315
?4 Propylene glycol carbonate 40.000
?5 Triethanolamine 3.740
?6 Disodiumedetate (two sodium edtas) 0.050
?7 Sucralose 0.300
?8 Pro-sweeting agent liquid K 0.700
?9 Monoammonium glycyrrhizinate 0.050
?10 Essence 0.015
?11 Pure water 5.000
?12 Sodium metabisulfite 0.050
?13 Coloring agent 0.005
Totally 100.000
Part ethanol is added in active component (dextromethorphan base material) and the solid-state sweeting agent (Sucralose, glycyrrhizic acid monoammonium), and they are stirred at low temperature (30 ℃).In this container, add propylene glycol carbonate and propylene glycol, liquid sweetener (Pro-sweeting agent liquid K) Reducing agent and buffer agent (triethanolamine, liquid) again.Mixing all is dissolved in the solution up to all raw materials, about 2 hours.Allow compositions stay in the mixer, be open in the air about 10 minutes.In remaining ethanol, add premixed essence and coloring agent, it is added in the container that the solution of closely finishing is housed.Mixing is up to forming uniform solution, and filters compositions (product density=1.07g/ml) with the US#100 sieve.Inject manually opened atomizing pump and bottle.An example is that Calmar-Alber GmbH makes, and is furnished with the Mistette Mrak II of 16mm high viscosity head (send and pass the 0.2ml/ driving).
On tongue, carry out 3 sprayings separately.Dextromethorphan is absorbed in the blood rapidly, and the liquid of a part of ejection in spray process contacts with throat is regional, from and provide other benefit as making the cough receptor numbness of irriate.
EXAMPLE V
Liquid heart lozenge
Project Material % compositions (w/w)
?1 The dextromethorphan base material 2.055
??2 Ethanol (100%) ??2.000
??3 Pure water ??5.000
??4 Propylene glycol ??89.775
??5 Disodiumedetate ??0.050
??6 ??Sucralose ??0.300
??7 Pro-sweeting agent liquid K ??0.700
??8 Monoammonium glycyrrhizinate ??0.050
??9 Essence ??0.015
??10 Coloring agent ??0.005
??11 Sodium metabisulfite ??0.050
Totally 100.000
Part ethanol is added in active component (dextromethorphan base material) and the solid-state sweeting agent (Sucralose, glycyrrhizic acid monoammonium), and they are stirred at low temperature (30 ℃).In this container, add propylene glycol and liquid sweetener (Pro-sweeting agent liquid K).Mixing all is dissolved in the solution up to all raw materials, about 2 hours.Mixing is up to forming uniform solution.In remaining ethanol, add premixed essence and coloring agent, in the container of closely finishing solution is housed, add ethanol, EDTA disodium, sodium metabisulfite and water.Allow compositions stay in the mixer, be open in the air about 10 minutes.Mixing is up to forming uniform solution, and filters compositions (product density=1.07g/ml) with the US#100 sieve.As each lozenge of loading of extruding preparation, each lozenge contains 1.0ml liquid with conventional method.
Allow a tester that the lozenge of a filling liquid is placed mouth, suck this lozenge up to discharging liquid filler material.Can certain slowing down be arranged to cough by the shell of sucking lozenge.When discharging the liquid heart, dextromethorphan is absorbed in the blood rapidly.
Example VI
Liquid heart lozenge
Project Material % compositions (w/w)
?1 The dextromethorphan base material 2.055
?2 Ethanol (100%) 2.000
?3 Pure water 5.000
?4 Propylene glycol 79.725
?5 Disodiumedetate (EDTA) 0.050
?6 Sucralose 0.300
?7 Pro-sweeting agent liquid K 0.700
?8 Monoammonium glycyrrhizinate 0.050
?9 Essence 0.015
?10 Coloring agent 0.005
?11 Fatty acid ester and propylene glycol 1 10.00
?12 Sodium metabisulfite 0.100
Totally 100.000
1. from Gattefosse SA.Company of 69804 Saint Priest Cedex, France buys Lauroglycol 90
Part ethanol is added in active component (dextromethorphan base material) and the solid-state sweeting agent (Sucralose, glycyrrhizic acid monoammonium), and they are stirred at low temperature (30 ℃).In this container, add propylene glycol, fatty acid ester and propylene glycol, liquid sweetener (Pro-sweeting agent liquid K).The pre-preparation mixture of preparation EDTA disodium, sodium metabisulfite, and be added in this container.Mixing all is dissolved in the solution up to all raw materials, about 2 hours.In remaining ethanol, add premixed essence and coloring agent, it is added in the container that the solution of closely finishing is housed.Allow compositions stay in the mixer, be open in the air about 10 minutes.Mixing is up to forming uniform solution, and filters compositions (product density=1.07g/ml) with the US#100 sieve.As overstocking each lozenge of loading of preparation, each lozenge contains 1.0ml liquid with conventional method.
Allow a tester that the lozenge of a filling liquid is placed mouth, suck this lozenge up to discharging liquid filler material.Can certain slowing down be arranged to cough by the shell of sucking lozenge.When discharging the liquid heart, dextromethorphan is absorbed in the blood rapidly, and in 10 minutes relieving cough.
Example VII A
Liquid elixir
Project Material % compositions (w/w)
?1 The dextromethorphan base material 2.055
?2 Guaifenesin 20.00
??3 Ethanol (100%) ??10.000
??4 Propylene glycol ??53.135
??5 Triethanolamine ??3.740
??6 ??Sucralose ??0.150
??7 Pro-sweeting agent liquid K ??0.700
??8 Monoammonium glycyrrhizinate ??0.050
??9 Essence ??0.005
??10 Coloring agent ??0.005
??11 Disodiumedetate (EDTA disodium) ??0.050
??12 2-(2-ethoxy ethoxy) ethanol 1 ??10.00
??13 Sodium metabisulfite ??0.100
Totally 100.000
1 can be from Gattefosse SA.Company of 69804 Saint Priest Codex, and France buys Transcutol P.
Part ethanol is added in active component (dextromethorphan base material) and the solid-state sweeting agent (Sucralose, glycyrrhizic acid monoammonium), and they are stirred at low temperature (30 ℃).The mixture and the buffer agent (triethanolamine, liquid) that in this container, add propylene glycol, 2-(2-ethoxy ethoxy) ethanol, guaifenesin and liquid sweetener (Pro-sweeting agent liquid K).Mixing all is dissolved in the solution up to all raw materials, about 2 hours.Prepare essence and coloring agent premix, and it is added in the container that the solution of closely finishing is housed at residual water and ethanol and EDTA disodium and sodium metabisulfite.Mixing is up to forming uniform solution, and filters compositions (product density=1.07g/ml) with the US#100 sieve.Inject the amber glass bottle, drip the device assembly with incorporate bottle cap/amount medicine and carry out capping.
About 1.0ml gram elixir is dripped on the tongue, swallow down then.
Example VII A I
Liquid elixir
Project Material % compositions (w/w)
?1 The chlorphenamine base material 0.263
?2 The isoephedrine base material 4.593
??3 Ethanol (100%) ??10.000
??4 Propylene glycol ??83.974
??5 ??Sucralose ??0.150
??6 Pro-sweeting agent liquid K ??0.700
??7 Monoammonium glycyrrhizinate ??0.050
??8 Essence ??0.015
??9 Coloring agent ??0.005
??10 Two (ethoxy) glycine ??0.050
??11 The EDTA disodium ??0.10
??12 Sodium metabisulfite ??0.10
Totally 100.000
Part ethanol is added in active component (chlorphenamine base material and isoephedrine base material) and the solid-state sweeting agent (Sucralose, glycyrrhizic acid monoammonium), and they are stirred at low temperature (30 ℃).The mixture that in this container, adds propylene glycol, liquid sweetener (Pro-sweeting agent liquid K), two (ethoxy) glycine and buffer agent (triethanolamine, liquid).Mixing all is dissolved in the solution until all raw materials, about 2 hours.Mixture is added in the container, and mixed about 2 hours.Propylene glycol solution, EDTA disodium, sodium metabisulfite and the residual alcoholic acid premix of preparation essence and coloring agent, and it is added to is equipped with in the container of closely finishing solution.Mixing is up to forming uniform solution, and filters compositions (product density=1.07g/ml) with the US#100 sieve.Inject the amber glass bottle, drip the device assembly with incorporate bottle cap/amount medicine and carry out capping.
About 1.0ml gram elixir is dripped on the tongue, swallow down then.Chlorphenamine and isoephedrine are absorbed in the blood rapidly.
Example I X
Liquid elixir
Project Material % compositions (w/w)
?1 Acetaminophen (Acetoaminophen) 27.169
?2 The dextromethorphan base material 1.195
?3 The isoephedrine base material 2.671
?4 Ethanol (100%) 10.000
??5 Propylene glycol ??51.885
??6 Polyvinyl pyrrolidone 1 ??2.170
??7 Triethanolamine ??3.740
??8 ??Sucralose ??0.150
??9 Pro-sweeting agent liquid K ??0.700
??10 Monoammonium glycyrrhizinate ??0.050
??11 Essence ??0.015
??12 Coloring agent ??0.005
??13 Sodium metabisulfite ??0.050
??14 The EDTA disodium ??0.200
Totally 100.000
1. can buy PVP-K17PF from BASF Corp.
Dextromethorphan base material and isoephedrine base material be dissolved in the part ethanol obtain premix.In another container, propylene glycol is heated to about 70 ℃.In case all material dissolutions also form clear liquid, add acetaminophen, and continue to be heated to 110-120 ℃ and lasting the stirring.In case heater is just clarified in the solution clarification.Be cooled to room temperature.This mixture is added in dextromethorphan and the isoephedrine.Add liquid sweetener (Pro-sweeting agent liquid K) and buffer agent (triethanolamine) again.
Mixing all is dissolved in the solution until all raw materials.Preparation essence and the premix of coloring agent in residual ethanol, and EDTA disodium and sodium metabisulfite be added to be equipped with in the container of closely finishing solution.Allow this compositions remain in the mixer, and be open in the air about 10 minutes.Mixing is up to forming uniform solution, and filters compositions with the US#100 sieve.Inject the amber glass bottle, drip the device assembly with incorporate bottle cap/amount medicine and carry out capping.About 1.84 gram elixirs are dripped on the tongue, swallow down then.
Embodiment X
Liquid elixir
Project Material % compositions (w/w)
?1 Ethanol (100%) 88.334
?2 Water 10.00
?3 The dextromethorphan base material 1.466
?4 Ethylenediaminetetraacetic acid (EDTA) 0.10
?5 Sodium metabisulfite 0.10
Totally 100.000
The dextromethorphan base material is dissolved in the part ethanol obtains premix.In another container, add in the entry EDTA disodium and sodium metabisulfite and mix homogeneously.This mixture is added in the premix of dextromethorphan base material.
Mixing all is dissolved in the solution until all raw materials.Add remaining ethanol.Allow this compositions remain in the mixer, and be open in the air about 10 minutes.Mixing is up to forming uniform solution, and filters compositions with the US#100 sieve.Inject the amber glass bottle, drip the device assembly with incorporate bottle cap/amount medicine and carry out capping.About 1.84 gram elixirs are dripped on the tongue, swallow down then.
Embodiment XI
Liquid elixir
Project Material % compositions (w/w)
?1 Ethanol (100%) 84.434
?2 Water 10.00
?3 The dextromethorphan base material 1.466
?4 Ethylenediaminetetraacetic acid (EDTA) 0.05
?5 Sensation implant (aesthetics package) 1 4.000
?6 Sodium metabisulfite 0.05
Totally 100.000
1. referring to the foregoing description
The dextromethorphan base material is dissolved in the part ethanol obtains premix.In another container, EDTA and sodium metabisulfite are dissolved in the water.Mix homogeneously also is cooled to room temperature.This mixture is added in the dextromethorphan base material.
Mixing all is dissolved in the solution until all raw materials.In containing the container of closely finishing solution, add remaining ethanol, EDTA and sensation implant.Allow this compositions remain in the mixer, and be open in the air about 10 minutes.Mixing is up to forming uniform solution, and filters compositions with the US#100 sieve.Inject the amber glass bottle, drip the device assembly with incorporate bottle cap/amount medicine and carry out capping.About 1.5 gram elixirs are dripped on the tongue, swallow down then.
Embodiment XII
Flexible glue is chewed capsule
Project Material % compositions (w/w)
?1 Propylene glycol 25.572
?2 Glycerol 10.000
?3 The dextromethorphan base material 1.100
?4 The acetaminophen base material 32.500
?5 The isoephedrine base material 2.458
?6 Polyvinyl pyrrolidone 4.170
?7 The sensation implant 1 4.000
?8 Water 10.000
?9 Ethylenediaminetetraacetic acid (EDTA) calcium disodium 0.050
?10 Glyceryl and macrogol ester 2 10.00
?11 Sodium metabisulfite 0.15
Totally 100.000
1. referring to the foregoing description
2. can be from Gattefosse SA.Company of 69804 Saint Priest Credex, France buys Labrasol.
The dextromethorphan base material is dissolved in the part ethanol obtains premix.In another container, hot water and EDTA calcium disodium are heated to 70 ℃.Add acetaminophen, and continue to be heated to 110-120 ℃ and finish stirring.In case heater is just removed in the liquid clarification.Be cooled to room temperature.This mixture is added in the mixture of dextromethorphan and isoephedrine, up to mix homogeneously and be cooled to room temperature.Mixing all is dissolved in the solution until all raw materials.In containing the container of closely finishing solution, add remaining ethanol, polyvinyl pyrrolidone, sodium metabisulfite, glyceryl and macrogol ester and sensation implant.Allow this compositions remain in the mixer, and be open in the air about 10 minutes.Mixing is up to forming uniform solution, and filters compositions with the US#100 sieve.Above-mentioned preparation is injected masticable soft gelatin capsule.Described capsule can be buied from many companies, as R.P.Scherer.of St.Petersberg, Florida.By chewing capsule about 1.84 gram elixirs are sent into mouth, swallow down then.
Embodiment XIII
Flexible glue is chewed capsule
Project Material % compositions (w/w)
?1 Propylene glycol 74.750
?2 Glycerol 10.000
?3 The dextromethorphan base material 1.100
?4 The sensation implant 1 4.000
?5 Water 10.000
?6 Ethylenediaminetetraacetic acid (EDTA) calcium disodium 0.050
?7 Sodium metabisulfite 0.10
Totally 100.000
1. referring to the foregoing description
The dextromethorphan base material is dissolved in the part ethanol obtains premix.Mixing water, sodium metabisulfite and EDTA calcium disodium are limpid until solution in another container.It is cooled to room temperature.Adding is to dextromethorphan.Mix homogeneously also is cooled to room temperature.Mixing all is dissolved in the solution until all raw materials.In containing the container of closely finishing solution, add remaining ethanol and sensation implant.Allow this compositions remain in the mixer, and be open in the air about 10 minutes.Mixing is up to forming uniform solution, and filters compositions with the US#100 sieve.Above-mentioned preparation is injected masticable soft gelatin capsule.Described capsule can be buied from many companies, as R.P.Scherer.of St.Petersberg, Florida.By chewing capsule about 1.84 gram elixirs are sent into mouth, swallow down then.
Embodiment XIV
Liquid elixir
Project Material % compositions (w/w)
?1 The dextromethorphan base material 0.714
?2 Propylene glycol 20.2
?3 Ethanol (95%) 24.3
?4 Polyethylene Glycol 1 24.3
?5 The EDTA disodium 0.100
?6 Essence 0.340
?7 Coloring agent 0.034
?8 Phenol 2.14
?9 Saccharin sodium 0.150
?10 Pure water 28.922
?11 Sodium metabisulfite 0.50
Totally 100.000
1 can buy Carbowax 400 from Union Carbide
While stirring dextromethorphan and phenol are added in the propylene glycol.Propylene glycol is stirred on the limit, and the limit adds ethanol, essence and saccharin sodium.Add 10% mono phosphoric acid ester sodium pure water solution while stirring.Add coloring agent while stirring.Dissolve sodium metabisulfite in remaining water, the limit edged is stirred to final volume.
Embodiment XV
Liquid elixir
Project Material % compositions (w/w)
?1 The dextromethorphan base material 0.286
?2 Propylene glycol 20.45
?3 Ethanol (95%) 16.3
?4 Polyethylene Glycol 1 22.6
?5 Mono phosphoric acid ester sodium 0.240
?6 Essence 0.004
?7 Coloring agent 0.034
?8 Saccharin sodium 0.200
?9 The EDTA disodium 0.1
?10 Pure water 39.586
?11 Sodium metabisulfite 0.20
Totally 100.000
1 can buy Carbowax 400 from Union Carbide
While stirring dextromethorphan and phenol are added in the propylene glycol.Add propylene glycol, ethanol, essence and saccharin sodium while stirring.Add 10% mono phosphoric acid ester sodium pure water solution while stirring.Add coloring agent while stirring.Dissolve sodium metabisulfite in remaining water, the limit edged is stirred to final volume.
Embodiment XVI
Liquid for oral use
Project Material % compositions (w/w)
?1 The dextromethorphan base material 1.47
?2 Poloxamer 1 33.56
?3 Ethanol 10.51
?4 Saccharin sodium 0.3
?5 Glycyrrhizic acid monoammonium 0.05
?6 Essence 1.40
?7 Water 13.42
?8 Sodium metabisulfite 0.1
?9 The EDTA disodium 0.1
?10 Propylene glycol 39.09
Totally 100.000
1 can be from BASF Specialty Chemicals, and Mount Olive, N.J. buy poloxamer (pluronic F127).
Preparation:
Propylene glycol and poloxamer are added to (main mixture) in the clean container.During stirring, suitably heating is melted poloxamer fully.In case obtain uniform solution, promptly remove thermal source and continue and stir.In another container, add ethanol (ethanol premix), dextromethorphan base material and glycyrrhizic acid monoammonium, and mix homogeneously.In another container (water premix), add entry, EDTA, saccharin sodium, acesulfame and sodium metabisulfite.Mixing is all dissolved up to all raw materials.
To contain alcoholic acid premix is added in the main mixture that contains poloxamer.Mix homogeneously.During stirring, the premix that will contain water is added in the main mixture container, and continue to stir up to evenly.Subsequently, add required perfume ingredient and mix homogeneously.With suitable device about 1.5gm liquid is sent in the mouth.
Embodiment XVII:
The liquid of treatment cough
Project Material % compositions (w/w)
?1 The dextromethorphan base material 1.465
?2 Guaifenesin 20.00
?3 Sodium metabisulfite 0.10
?4 The EDTA disodium 0.10
?5 Saccharin sodium 0.40
?6 Glycyrrhizic acid list sodium 0.15
?7 Acesulfame 0.50
?8 Ethanol 10.5l
?9 Water 24.61
?10 Propylene glycol 10.95
?11 Poloxamer 1 29.08
?12 Essence 1.40
Totally 100.000
1 can be from BASF Specialty Chemicals, and Mount Olive, N.J. buy poloxamer (pluronic F127).
Preparation:
Propylene glycol and poloxamer are added to (main mixture) in the clean container.During stirring, suitably heating is melted poloxamer fully.In case obtain uniform solution, promptly remove thermal source and continue and stir.In another container, add ethanol (ethanol premix), guaifenesin, dextromethorphan base material and glycyrrhizic acid monoammonium, and mix homogeneously.In another container (water premix), add entry, EDTA, saccharin sodium, acesulfame and sodium metabisulfite.Mixing is all dissolved up to all raw materials.
To contain alcoholic acid premix is added in the main mixture that contains poloxamer.Mix homogeneously.During stirring, the premix that will contain water is added in the main mixture container, and continue to stir up to evenly.Subsequently, add required perfume ingredient and mix homogeneously.With suitable device about 1gm liquid is sent in the mouth.
Embodiment XVIII:
Liquid for oral use
Project Material % compositions (w/w)
?1 The dextromethorphan base material 2.20
?2 Sodium metabisulfite 0.10
?3 The EDTA disodium 0.10
?4 Saccharin sodium 0.40
?5 Glycyrrhizic acid list sodium 0.15
?6 Acesulfame 0.50
?7 Essence 1.40
?8 The isoephedrine hydrochlorate 6.00
?9 Poloxamer 1 34.5
?10 Propylene glycol 30.72
?11 Ethanol 10.51
?12 Water 13.42
Totally 100.000
1 can be from BASF Specialty Chemicals, and Mount Olive, N.J. buy poloxamer (pluronic F127).
Preparation:
Propylene glycol and poloxamer are added to (main mixture) in the clean container.During stirring, suitably heating is melted poloxamer fully.In case obtain uniform solution, promptly remove thermal source and continue and stir.In another container, add ethanol (ethanol premix), dextromethorphan base material and glycyrrhizic acid monoammonium, and mix homogeneously.In another container (premix of water), add entry, isoephedrine hydrochlorate, EDTA, saccharin sodium, acesulfame and sodium metabisulfite.Mixing is all dissolved up to all raw materials.
To contain alcoholic acid premix is added in the main mixture that contains poloxamer.Mix homogeneously.During stirring, the premix that will contain water is added in the main mixture container, and continue to stir up to evenly.Subsequently, add required perfume ingredient and mix homogeneously.With suitable device about 1gm liquid is sent in the mouth.
Embodiment XIX:
Liquid elixir
Project Material % compositions (w/w)
?1 Ethanol (100%) 88.334
?2 Water 10.00
?3 The dextromethorphan base material 1.466
?4 Ethylenediaminetetraacetic acid (EDTA) 0.10
?5 Sodium metabisulfite 0.10
Totally 100.000
The dextromethorphan base material is being dissolved in ethanol, obtaining premix.In another container, add in the entry EDTA disodium and sodium metabisulfite and mix homogeneously.In this mixture, add the dextromethorphan base premix.
Mixing all is dissolved in the water up to all raw materials.Be added in the required alcoholic solution.Allow compositions stay in the mixer, be open in the air about 10 minutes.Mixing is filtered with the US#100 sieve up to evenly.Inject the amber glass bottle, drip the device assembly with incorporate bottle cap/amount medicine and carry out capping.About 1.00 gram elixirs are dripped on the tongue, swallow down then or with the suitably administration of various dose volumes.

Claims (17)

1. the fluid composition of an improved stability, be preferably Orally administered composition, it is characterized in that, described compositions comprise active constituents of medicine, the dissolving described active component solvent and intercalating agent, described intercalating agent be present in the compositions mutually different with containing described composition of active components mutually in.
2. the fluid composition of an improved stability is preferably Orally administered composition, it is characterized in that, described compositions comprises solvent, intercalating agent and the Reducing agent of active constituents of medicine, the described active component of dissolving, the electrode potential value E of described Reducing agent 0Greater than pact-0.119V, preferably be about-0.119V is to+0.250V.
3. the fluid composition of an improved stability, be preferably Orally administered composition, it is characterized in that, described compositions comprises solvent, intercalating agent and the Reducing agent of active constituents of medicine, the described active component of dissolving, described intercalating agent be present in the compositions mutually different with containing described composition of active components mutually in, the electrode potential value E of described Reducing agent 0Greater than pact-0.119V, preferably be about-0.119V is to+0.250V.
4. as claim 1,2,3 arbitrary described compositionss, it is characterized in that described intercalating agent and Reducing agent are in the scope of pH5-10 and all be active in aqueous and non-aqueous solvent compositions.
5. as the arbitrary described compositions of claim 1-4, it is characterized in that, described intercalating agent is selected from: ethylenediaminetetraacetic acid (EDTA) disodium salt and calcium salt, EDTA four sodium, sodium hexameta phosphate (SHMP), citric acid, phosphoric acid, two (ethoxy) glycine, oxine and their mixture are preferably the calcium salt or the sodium salt of ethylenediaminetetraacetic acid (EDTA).
6. as the arbitrary described compositions of claim 1-5, it is characterized in that, the level of described intercalating agent is 0.005% to 1.000% of a composition weight, preferably is 0.050% to 0.150% of composition weight, more preferably is 0.300% to 0.010% of composition weight.
7. compositions as claimed in claim 2 is characterized in that, described Reducing agent is selected from: metabisulfite and bisulfites comprise their sodium salt and potassium salt; Dithiothreitol, DTT; Thiourea; Sodium thiosulfate; TGA; Tertiary butylated hydroquinone (TBHQ); Acetylcysteine; Hydroquinone and their mixture preferably are sodium metabisulfite and inclined to one side Potassium acid sulfite.
8. compositions as claimed in claim 7 is characterized in that, described Reducing agent is 0.005% to 1.000% of a composition weight, preferably is 0.050% to 0.500% of composition weight, more preferably is 0.010% to 0.200% of composition weight.
9. as the arbitrary described compositions of claim 1-8, it is characterized in that, described compositions contain hydrophilic, can be blended with water, medicinal active ingredient in the anhydrous solvent, wherein become the medicinal active ingredient of unionized form to be equal to or greater than 0.075%, and described medicinal active ingredient is scattered in described solvent and the described water as the unimolecule dispersion with its free unionized form in the percent dissolution degree value of room temperature in solvent.
10. as the arbitrary described compositions of claim 1-9, it is characterized in that the molecular weight of described medicinal active ingredient is less than every mole 500 gram, and can ionization in aqueous solvent, when being the unionized form, the partition coefficient of its capryl alcohol-water is at least 100.
11. as the arbitrary described compositions of claim 1-10, it is characterized in that described medicinal active ingredient is selected from: cough medicine, hydryllin, non-sedating hydryllin, Decongestant, expectorant, analgesics, mucolytic, antipyretic, antiinflammatory, local anesthetic and their mixture.
12. as the arbitrary described compositions of claim 1-11, it is characterized in that, be less than or equal to the percent dissolution degree value of 125% described active component in the concentration of the medicinal active ingredient described in the described solvent.
13., it is characterized in that as the arbitrary described compositions of claim 1-12, be 0.075% to 25.0% of composition weight in the level of the medicinal active ingredient described in the described solvent, preferably be 0.28% to 10.0%.
14., it is characterized in that described group of solvents preferably is about 70% to 99% composition weight into about 60% to 99.975% composition weight as the arbitrary described compositions of claim 1-13, more preferably be 85% to 98% composition weight.
15. as the arbitrary described compositions of claim 1-14, it is characterized in that, described solvent be hydrophilic, can be blended and anhydrous with water, be selected from: propylene glycol, ethanol, Polyethylene Glycol are EPG, propylene glycol carbonate, diethylene glycol monoethyl ether, poloxamer, sweet furfural, glycerol, polyvinyl pyrrolidone (PVP), 2-(2-ethoxy ethoxy) ethanol, fatty acid ester and propylene glycol, glyceryl and macrogol ester, Capryol 90 and their mixture.
16. one kind prepares claim 1,2,3 arbitrary described method for compositions, it is characterized in that, is not more than the described compositions of 3.0ml by orally give accumulated dose volume, treats respiratory tract disease with the compositions of described method.
17. method as claimed in claim 16 is characterized in that, described compositions is placed on any mucosa in oral cavity.
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HUP0202797A3 (en) 2004-05-28
AU7986500A (en) 2001-04-30
CA2385990A1 (en) 2001-04-05
HUP0202797A2 (en) 2003-01-28

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