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WO2000000193A1 - Methodes et preparations pharmaceutiques permettant de prevenir et de traiter le mal des transports - Google Patents

Methodes et preparations pharmaceutiques permettant de prevenir et de traiter le mal des transports Download PDF

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Publication number
WO2000000193A1
WO2000000193A1 PCT/US1999/014657 US9914657W WO0000193A1 WO 2000000193 A1 WO2000000193 A1 WO 2000000193A1 US 9914657 W US9914657 W US 9914657W WO 0000193 A1 WO0000193 A1 WO 0000193A1
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WO
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Prior art keywords
clemastine
pharmaceutically acceptable
pharmaceutical formulation
formulation according
acceptable salt
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Ceased
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PCT/US1999/014657
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English (en)
Inventor
Vincent D. Romeo
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Marina Biotech Inc
Original Assignee
MDRNA Inc
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Filing date
Publication date
Application filed by MDRNA Inc filed Critical MDRNA Inc
Priority to AU48417/99A priority Critical patent/AU4841799A/en
Publication of WO2000000193A1 publication Critical patent/WO2000000193A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

  • the present invention relates to methods and pharmaceutical formulations for preventing and treating motion sickness, and more particularly to methods and pharmaceutical formulations for preventing and treating motion sickness with antihistamines.
  • Motion sickness is a common malady suffered by many individuals in the general population.
  • the primary cause of this disorder is excessive stimulation of the inner ear from repetitive angular and linear acceleration and deceleration due to environmental conditions.
  • Common environmental conditions that subject an individual to repetitive acceleration and deceleration thereby inducing motion sickness are travel by car, travel by sea, and travel by airplane.
  • Common symptoms of motion sickness include nausea and vomiting.
  • an individual can experience hyperventilation, excessive salivation, pallor, profuse cold sweats and somnolence.
  • An individual can also experience dizziness, headache, general discomfort and fatigue.
  • an individual with motion sickness is rendered incapacitated for some length of time.
  • the present invention is a method of preventing motion sickness in an individual susceptible of developing motion sickness by administering to the individual an effective amount of clemastine, or its pharmaceutically acceptable salt.
  • the clemastine is administered prior to the individual's exposure to environmental conditions that can induce motion sickness in the individual.
  • the clemastine is preferably in the form of the pharmaceutically acceptable salt, clemastine fumarate.
  • a preferred route of administering clemastine to the individual is transmucosal delivery, with delivery being accomplished through any acceptable delivery system, for example, gels, patches, aerosol sprays, ointments, etc.
  • clemastine is delivered through intranasal administration for short term treatment, and through a transmucosal patch for long term treatment.
  • a method of treating motion sickness is also provided. This is accomplished by administering an effective amount of clemastine, or its pharmaceutically acceptable salt, to an individual exhibiting symptoms of motion sickness.
  • the clemastine is administered to the individual during or after exposure to environmental conditions that induced the motion sickness in the individual.
  • the clemastine is preferably provided as clemastine fumarate. Intranasal administration is a preferred route of administration.
  • the present invention provides a pharmaceutical formulation for preventing motion sickness in a mammal comprising clemastine or pharmaceutically acceptable salt thereof.
  • Such methods and pharmaceutical formulations include administering to an individual an effective amount of the antihistamine, clemastine.
  • Clemastine is a well-known antihistamine, which is primarily used in over-the- counter allergy medications .
  • Clemastine is [R-(R* ,R* )] -2- [2- [ 1 -(4-chloropheny 1)- 1 - phenylethoxy]ethyl]ethyl]-l-methylpyrrolidine and exhibits the following general structure:
  • clemastine free base can be used with the present invention, it is preferable to use a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt is clemastine fumarate which is available from Sandoz Pharmaceuticals Inc., USA.
  • Clemastine fumarate is (+)-(2R)-2-[2-[(R)-p-chloro- ⁇ - methyl- ⁇ -phenylbenzyl)oxyl-ethyl]-l-methylpyrrolidine fumarate and exhibits the following general structure:
  • clemastine include those salt- forming acids and bases which do not substantially increase the toxicity of the compound.
  • suitable salts include salts of alkali metals such as magnesium, potassium and ammonium.
  • Salts of mineral acids include hydrochloric, hydriodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, as well as salts of organic acids such as tartaric, acetic, citric, malic, benzoic, succinic, arylsulfonic, e.g. p-toluenesulfonic acids, and the like.
  • Particular examples of preferred pharmaceutically acceptable salts of clemastine include clemastine fumarate, clemastine sulfate, clemastine tartrate, clemastine lactate, clemastine hydrochloride and combinations thereof.
  • the present invention includes a pharmaceutical formulation for preventing motion sickness in a mammal comprising clemastine or pharmaceutically acceptable salt thereof.
  • pharmaceutical formulation is intended to include a pharmaceutically acceptable carrier which incorporates the active agent, i.e., clemastine or pharmaceutically acceptable salt thereof.
  • pharmaceutical carrier includes pharmaceutical formulations designed for oral, lingual, sublingual, buccal and intrabuccal administration which can be made, with an inert diluent or with an edible carrier.
  • Clemastine formulations may be enclosed in gelatin capsules or compressed into tablets.
  • the pharmaceutical formulations of the present invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • Tablets, pills, capsules, troches and the like may also contain binders, recipients, disintegrating agent, lubricants, sweetening agents, and flavoring agents.
  • binders include microcrystalline cellulose, gum tragacanth or gelatin.
  • excipients include starch or lactose.
  • disintegrating agents include alginic acid, corn starch and the like.
  • lubricants include magnesium stearate or potassium stearate.
  • An example of a glidant is colloidal silicon dioxide.
  • sweetening agents include sucrose, saccharin and the like.
  • flavoring agents include peppermint, methyl salicylate, orange flavoring and the like.
  • clemastine salt such as for example, clemastine fumarate
  • the amount of pharmaceutically acceptable clemastine salt used can vary depending on the amount needed to prevent motion sickness in the mammal.
  • the amount of clemastine salt used is from about 0.01% to below about 40%, more preferably, from about 1% to below about 35%, and most preferably, from about 1% to below about 30% by weight of the total weight of the formulation (w/w).
  • the practitioner is guided by skill and knowledge in the field, and the present invention includes without limitation amounts of clemastine that are needed to achieve the described effect.
  • the clemastine is administered to the individual by any acceptable delivery route (e.g., transmucosal or enteral).
  • suitable delivery routes include, but are not limited to, oral, parenteral, intranasal, vaginal, rectal, lingual, sublingual, buccal, intrabuccal, ocular, pulmonary, transmucosal and transdermal intranasal delivery.
  • Intranasal administration is a preferred route of delivery due to the rapid onset of therapeutically effective blood plasma levels.
  • Clemastine formulations of the present invention can easily be administered parenterally such as for example, by intravenous, intramuscular, intrathecal or subcutaneous injection.
  • Parenteral administration can be accomplished by incorporating the clemastine formulations of the present invention into a solution or suspension.
  • solutions or suspensions may also include sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents.
  • Parenteral formulations may also include antibacterial agents such as for example, benzyl alcohol or methyl parabens, antioxidants such as for example, ascorbic acid or sodium bisulfite and chelating agents such as EDTA.
  • Buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose may also be added.
  • the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic. Rectal administration includes administering the pharmaceutical formulations into the rectum or large intestine. This can be accomplished using suppositories or enemas. Suppository formulations can easily be made by methods known in the art.
  • suppository formulations can be prepared by heating glycerin to about 120° C, dissolving clemastine in the glycerin, mixing the heated glycerin after which purified water may be added, and pouring the hot mixture into a suppository mold.
  • the present invention includes nasally administering to the mammal a therapeutically effective amount of clemastine or pharmaceutically acceptable salt thereof.
  • nasally administering or nasal administration includes administering clemastine or pharmaceutically acceptable salt thereof to the mucous membranes of the nasal passage or nasal cavity of the mammal.
  • the present invention provides a pharmaceutical formulation comprising a therapeutically effective amount of clemastine or pharmaceutically acceptable salt thereof in combination with a nasal delivery system.
  • a nasal delivery system include nasal sprays, nasal drops, suspensions, gels, ointments, creams, powders, nasal tampons or nasal sponges containing clemastine or pharmaceutically acceptable salt thereof.
  • Nasal powder formulations can be made by mixing clemastine or pharmaceutically acceptable salt thereof with an excipient, both possessing the desired particle size. Other methods to make a suitable powder formulation can be selected. First, a solution of clemastine or pharmaceutically acceptable salt thereof is made, followed by precipitation, filtration and pulverization. It is also possible to remove the solvent by freeze drying, followed by pulverization of the powder in the desired particle size by using conventional techniques, known in the pharmaceutical arts. Powders can be administered using a nasal insufflator or any other suitable device. Powders may also be administered in such a manner that they are placed in a capsule. The capsule is set in an inhalation or insufflation device. A needle is penetrated through the capsule to make pores at the top and the bottom of the capsule and air is sent to blow out the powder particles. Powder formulation can also be administered in a jet-spray of an inert gas or suspended in liquid organic fluids.
  • Clemastine or pharmaceutically acceptable salt thereof can also be brought into a viscous base, using systems, conventionally used, for example natural gums, methylcellulose and derivatives, acrylic polymers (carbopol) and vinyl polymers (polyvinylpyrrolidone).
  • Pharmaceutical formulations of the present invention may include, many other excipients, known from the pharmaceutical arts, such as preservatives, surfactants, solubilizing agents, adhesives, antioxidants, buffers, viscosity and absorption enhancing agents and agents to adjust the pH and osmolarity.
  • clemastine or pharmaceutically acceptable salt thereof is combined with a suitable delivery system for absorption across the nasal mucosa of a mammal.
  • the nasal delivery system includes a pharmaceutically acceptable buffer, a solubilizing agent, a thickening agent, a humectant, absorption enhancer and combinations thereof.
  • Such nasal delivery system can take various forms including for example, aqueous solutions and non-aqueous solutions.
  • Aqueous solutions include for example, aqueous gels, aqueous suspensions, aqueous liposomes, aqueous emulsions, aqueous microemulsions.
  • Non aqueous solutions include, for example, non-aqueous gels, non-aqueous suspensions, non-aqueous liposomes, non-aqueous emulsions and non-aqueous microemulsions.
  • the various forms of the nasal delivery system set forth above can include a buffer to maintain the pH of clemastine or pharmaceutically acceptable salt thereof, a pharmaceutically acceptable thickening agent, solubilizing agents, humectant, absorption enhancer and combinations thereof.
  • suitable forms of buffering agents can be selected so that when the formulation is delivered into the nasal cavity of a mammal, selected pH ranges are achieved therein upon contact with, e.g., the nasal mucosa.
  • the pH is between about 3.0 to below about 9.0. Most preferably, the pH is about 6.0.
  • Buffers that are suitable for use in the present invention include, for example, acetate, citrate, prolamine, carbonate and phosphate buffers and combinations thereof.
  • Some particularly preferred buffers include sodium citrate dihydrate, monopotassium phosphate, disodium phosphate and citric acid.
  • the pharmaceutical formulations of the present invention may include a pH adjusting agent.
  • pH adjusting agents include trolamine, sulfuric acid, sodium hydroxide, diluted hydrochloric acid and the like.
  • compositions of the present invention may include solubilizing agents or solubility enhancers which increase the solubility of clemastine in pharmaceutically acceptable solvents.
  • Pharmaceutical compositions containing clemastine solubilizing agents are disclosed in U.S. Patent No. 5,770,618 to Behl et al., the entire disclosure is hereby incorporated by reference.
  • Solubilizing agents include organic acids or salts of organic acids that are mixed with clemastine. Such organic salts dramatically increase the solubility of clemastine in a pharmaceutically acceptable solvent.
  • clemastine and its salts are slightly soluble in pharmaceutically acceptable aqueous solvents. This has, in turn, prevented the formulation of liquid pharmaceutical compositions containing an adequate concentration of clemastine.
  • a solubilizing effective amount of an organic acid or its salt is utilized to increase the solubility of clemastine in the solvent.
  • a "solubilizing effective amount” is any amount of an organic acid or its salt utilized to increase the solubility of clemastine over the solubility exhibited by a control composition, at a comparable pH, that does not contain the organic acid or its salt.
  • the solubilizing effective amount of the organic acid or its salt is an amount that provides the formulation with a solubilizing agent concentration of at least about 0.1% to about 50.0% of the organic acid or its salt.
  • the actual concentration of the organic acid or its salt utilized will vary with the amount of clemastine to be solubilized and with the selection of the organic acid or its salt as the solubilizing agent. It will also depend upon the solubility of the solubilizing agent itself.
  • any pharmaceutically acceptable organic acid or its salt can be utilized as the solubilizing agent in the present invention.
  • a preferred class of such solubilizing agents is carboxylic acids or their salts.
  • Carboxylic acid salts that can be utilized in accordance with the present invention include, but are not limited to, acetate, gluconate, ascorbate, citrate, fumarate, lactate, tartrate, malate, maleate, succinate and combinations thereof. Of these carboxylic acid salts, acetate, tartrate and gluconate are preferred. Most preferred solubilizing agents include maleic acid and fumaric acid.
  • the desired organic acid salt may not be available in a United States Pharmacopeia (USP) grade.
  • USP United States Pharmacopeia
  • Solvents to be utilized in accordance with the present invention include any solvent system, as long as it is pharmaceutically acceptable.
  • the solvent preferably is a polar solvent, since it is believed that the polar nature of the solvent will facilitate the ionic interactions between the organic acid or its salt and the clemastine.
  • the polar solvent is water.
  • Combinations of solvents can also be utilized in accordance with the present invention.
  • Combinations of solvents can include combinations of polar solvents, combinations of non-polar solvents, and combinations of polar and non-polar solvents.
  • Suitable solvents include water, saline, alcohol, glycerin, propylene glycol and the like.
  • the amount of solvent is sufficient to dissolve clemastine or pharmaceutically acceptable salt thereof.
  • the organic acid or its salt and clemastine are admixed in the solvent.
  • the mixing of the components can be accomplished by any suitable means.
  • Conventional means of dissolving the pharmaceutical components can be utilized.
  • the components can be stirred, sonicated, shaken or vortexed.
  • the amount of time necessary to facilitate a complete dissolution of clemastine in the solvent will vary with the amount of clemastine utilized, the selected organic acid or its salt and the selected solvent. Typically, a time period of 24 hours is generally adequate. Longer times may be needed to achieve saturation solubilities. These parameters can be easily determined by one skilled in the art.
  • the viscosity of the formulations of the present invention can be maintained at a desired level using a pharmaceutically acceptable thickening agent.
  • Thickening agents that can be used in accordance with the present invention include for example, methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof. Such agents will also be used in the particulate formulations of the present invention.
  • the concentration of the thickening agent will depend upon the agent selected and the viscosity desired.
  • a most preferred thickening agent is polyvinyl alcohol. Such agent may be present in the formulation at a concentration of from about 0.1% to about 20% by weight of the total weight of the formulation.
  • the formulations of the present invention may also include a tolerance enhancer to reduce or prevent drying of the mucus membrane and to prevent irritation thereof.
  • Suitable tolerance enhancers that can be used in the present invention include humectants, such as for example, sorbitol, mineral oil, vegetable oil, glycerol, glycerin, glycine, soothing agents, membrane conditioners, sweeteners and combinations thereof.
  • the concentration of the tolerance enhancer(s) in the present formulations will also vary with the agent selected.
  • the tolerance enhancer can be present in the delivery system in a concentration ranging from about 0.01% to about 20% by weight of the pharmaceutical formulation.
  • a therapeutically acceptable absorption enhancer or surfactant is added to the nasal delivery system.
  • Preferred surfactants include polyoxyethylene derivatives and fatty acid partial esters of sorbitol anhydrides, oleic acid and combinations thereof.
  • Suitable surfactants include sodium lauryl sulfate, sodium salicylate, oleic acid, lecithin, dehydrated alcohol, Tween, Span, polyoxyl 40 stearate, polyoxy ethylene 50 stearate, edetate disodium, propylene glycol, glycerol monooleate, fusieates, bile salts, octoxynol and combinations thereof.
  • Tween includes all Tweens such as Tween 20, Tween 40, Tween 60, Tween 80 and the like.
  • Span include all Spans, such as Span 20, Span 40, Span 80 and the like.
  • Suitable absorption enhancers or surfactants include non-ionic, anionic, cationic surfactants and combinations thereof. These absorption enhancers can be present in the delivery system in a concentration ranging from about 0.01% to about 50% by weight of the total formulation.
  • preferred concentrations of sodium salicylate, sodium lauryl sulfate and edetate disodium can be from about 0.01% to about 5 % by weight of the total formulation.
  • Preferred concentrations of polyoxyl 40 stearate, lecithin, dehydrated alcohol can be from about 0.1% to about 10 % by weight of the total formulation.
  • Preferred concentrations of oleic acid can be from about 0.01% to about 5% by weight of the total formulation.
  • Preferred concentrations of propylene glycol and Tween 20 can be from about 0.1% to about 25% by weight of the total formulation.
  • the absorption enhancers or surfactants of the present invention increase plasma levels of free clemastine above that observed without the absorption enhancer.
  • free clemastine plasma concentrations are increased by from about 5% to about 700%. Accordingly, a lower amount of drug can be used to achieve the same therapeutic levels that treat or prevent motion sickness.
  • ingredients may also be incorporated into the nasal delivery system provided they do not interfere with the action of clemastine or pharmaceutically acceptable salt thereof or significantly decrease the absorption of it across the nasal mucosa.
  • Such ingredients can include, for example, pharmaceutically acceptable excipients and preservatives.
  • the excipients that can be used in accordance with the present invention include, for example, bio-adhesives and/or swelling/thickening agents and combinations thereof. To extend shelf life, preservatives can be added to the present formulations.
  • Suitable preservatives that can be used with the present formulations include, for example, benzyl alcohol, parabens, thimerosal, chlorobutanol, benzalkonium and combinations thereof, with benzalkonium chloride being preferred.
  • the preservative will be present in the formulations in a concentration of from about 0.001% up to about 5% by weight of the total formulation. The exact concentration of the preservative, however, will vary depending upon the intended use and can be easily ascertained by one skilled in the art.
  • antioxidants include sodium metabisulfite, potassium metabisulfite, ascorbyl palmitate and the like.
  • the antioxidant and/or chelating agent will be present in the formulations in a concentration of from about 0.01% up to about 5% by weight of the total formulation.
  • the amount of clemastine required to provide an effective amount to the individual is dependent on a variety of factors. These factors include, but are not limited to, the delivery route, the age and weight of the individual, whether the clemastine is administered for prevention or treatment and the dosing regimen.
  • An effective amount of clemastine for the preventing motion sickness is an amount that significantly inhibits the onset of symptoms.
  • a significant inhibition of symptoms means that the individual's symptoms are inhibited by at least 60%, with at least 80% being preferred, and with at least 95% being more preferred.
  • An effective amount of clemastine for the prevention of motion sickness can range from about 1 mg to about 75 mg per dose.
  • clemastine is administered to an individual susceptible of developing motion sickness prior to being exposed to environmental conditions that can induce motion sickness.
  • the clemastine is administered to the individual within two hours prior of being exposed to environmental conditions.
  • the clemastine is administered to the individual within one hour prior of being exposed to environmental conditions, with 30 minutes being more preferable.
  • An individual susceptible of developing motion sickness is any individual (i.e., mammal) that has experienced motion sickness in the past or has a reasonable expectation of developing motion sickness.
  • An example of an individual having a reasonable expectation of developing motion sickness is a person receiving chemotherapy. The individual may never have had motion sickness, but after receiving chemotherapy may have a heightened susceptibility to developing motion sickness and, thus require preventive treatment.
  • mammals include humans, as well as pet animals such as dogs and cats, laboratory animals, such as rats and mice, and farm animals, such as horses and cows.
  • an effective amount of clemastine is administered to an individual exhibiting symptoms of motion sickness during or after exposure to environmental conditions that can induce motion sickness.
  • An effective amount of clemastine for this purpose is an amount that significantly reduces the symptoms being experienced by an individual.
  • a significant reduction of symptoms means that the individual's symptoms are reduced by at least 60%, with at least 80% being preferred, and with at least 95% being more preferred.
  • An effective amount of clemastine for the treatment of motion sickness may be the same or greater than the amounts given for prevention.
  • the treatment of motion sickness unlike prevention, also requires the rapid onset of therapeutically effective plasma levels of clemastine.
  • clemastine is administered via a transmucosal route since transmucosal delivery generally provides a more rapid onset of bioavailability as compared with oral delivery.
  • transmucosal route is intranasal delivery.
  • the pharmaceutical formulations for intranasal administration preferably include an amount of clemastine effective to deliver about 0.1 mL of the formulation into each nostril of the subject per dose.
  • clemastine fumarate in which 1.34 mg of clemastine fumarate is the equivalent of 1.0 mg clemastine, the pharmaceutical formulations should contain a clemastine concentration of at least about 6.7 mg/mL. Such concentrations can be adjusted by one skilled in the art to provide effective dosage amounts per number of daily dosages.
  • Example 1 A pharmaceutical formulation particularly useful for nasally administering clemastine to a mammal was prepared in the following manner. Approximately 0.6 g of Monopotassium Phosphate, USP, was dissolved in 90 mL of Purified Water, USP. Approximately 0.8 g of Disodium Phosphate, USP, was thereafter added and stirred to dissolution. After which approximately 3.0 g of Glycine, USP, (i.e., the solubilizing agent) was added and stirred to dissolution. This was followed by the addition of 0.01 g of Edetate Disodium Dihydrate, USP. Approximately 0.04 g of a 50% Benzalkonium Chloride Solution, NF, was added to the solution and stirred to dissolution.
  • a 50% Benzalkonium Chloride Solution, NF was added to the solution and stirred to dissolution.
  • the resulting formulation exhibited a pH of 6.4 ⁇ 0.5, and an organic salt concentration of 0.01 M.
  • the formulation contained a therapeutically effective
  • Example 2 A pharmaceutical formulation of clemastine fumarate was prepared in accordance with Example 1, utilizing fumaric acid as the solubilizing agent. The resulting formulation exhibited a pH of 6.4 ⁇ 0.5, and an organic acid salt concentration of 0.11 M. The formulation contained a therapeutically effective 6.7 mg/mL of clemastine fumarate. The summary of the components utilized to prepare the formulation is shown in Table 2.
  • Example 3 A pharmaceutical formulation of clemastine fumarate was prepared in accordance with Example 1 , utilizing maleic acid as the solubilizing agent. The resulting formulation exhibited a pH of 6.4 ⁇ .03 and an organic acid salt concentration of 0.11 M. The formulation contained a therapeutically effective 6.7 mg/mL of clemastine fumarate. A summary of the components utilized to prepare the formulation is shown in Table 3.
  • Example 4 A pharmaceutical formulation of clemastine fumarate was prepared in accordance with Example 1, utilizing maleic acid as the solubilizing agent. The resulting formulation exhibited a pH of 6.0 at ⁇ 0.5, and an organic acid salt concentration of 0.11 M. The formulation contained a therapeutically effective 6.7 mg/mL of clemastine fumarate. A summary of the components utilized to prepare the formulation is shown in Table 4.
  • a pharmaceutical formulation of clemastine fumarate was prepared in accordance with Example 1, utilizing citric acid as the solubilizing agent.
  • the resulting formulation had a pH of 6.4 ⁇ 0.3 and an organic salt concentration of approximately 0.1 M.
  • a summary of the components utilized to prepare the pharmaceutical formulation is shown in Table 5.

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Abstract

La présente invention concerne des méthodes et des préparations pharmaceutiques permettant de prévenir et de traiter le mal des transports. Ces méthodes consistent à administrer à un mammifère une dose efficace de clémastine ou d'un sel pharmaceutiquement acceptable de cette substance avant exposition à des conditions ambiantes pouvant déclencher le mal des transports. Selon un autre mode de réalisation, la présente invention concerne des méthodes et des préparations pharmaceutiques convenant pour le traitement du mal des transports et qui consistent dans l'administration à un mammifère qui présente les symptômes du mal des transports une dose efficace de clémastine ou d'un sel pharmaceutiquement acceptable de cette substance pendant ou après exposition à des conditions ambiantes pouvant déclencher ledit mal.
PCT/US1999/014657 1998-06-29 1999-06-29 Methodes et preparations pharmaceutiques permettant de prevenir et de traiter le mal des transports Ceased WO2000000193A1 (fr)

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US60/091,114 1998-06-29

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US9138228B2 (en) 2004-08-11 2015-09-22 Emory University Vascular conduit device and system for implanting
US9320875B2 (en) 2011-02-01 2016-04-26 Emory University Systems for implanting and using a conduit within a tissue wall
US9498437B2 (en) * 2003-06-27 2016-11-22 Mylan Specialty L.P. Inhalable formulations for treating pulmonary hypertension and methods of using same
US9532773B2 (en) 2011-01-28 2017-01-03 Apica Cardiovascular Limited Systems for sealing a tissue wall puncture
US10028741B2 (en) 2013-01-25 2018-07-24 Apica Cardiovascular Limited Systems and methods for percutaneous access, stabilization and closure of organs
US10485909B2 (en) 2014-10-31 2019-11-26 Thoratec Corporation Apical connectors and instruments for use in a heart wall
US10518012B2 (en) 2013-03-15 2019-12-31 Apk Advanced Medical Technologies, Inc. Devices, systems, and methods for implanting and using a connector in a tissue wall
WO2021211808A1 (fr) * 2020-04-16 2021-10-21 Atossa Therapeutics, Inc. Compositions et méthodes pour réduire l'infectivité d'un virus

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