WO1995001792A1 - Composes anti-h2-antihistaminiques - Google Patents

Composes anti-h2-antihistaminiques Download PDF

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Publication number
WO1995001792A1
WO1995001792A1 PCT/US1994/007528 US9407528W WO9501792A1 WO 1995001792 A1 WO1995001792 A1 WO 1995001792A1 US 9407528 W US9407528 W US 9407528W WO 9501792 A1 WO9501792 A1 WO 9501792A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
antiflatulent
antihistamine
hydrate
stereoisomers
Prior art date
Application number
PCT/US1994/007528
Other languages
English (en)
Inventor
Robert T. Sims
William Slivka
Original Assignee
Merck & Co., Inc.
Mcneil-Ppc, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co., Inc., Mcneil-Ppc, Inc. filed Critical Merck & Co., Inc.
Priority to AU72550/94A priority Critical patent/AU7255094A/en
Publication of WO1995001792A1 publication Critical patent/WO1995001792A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795

Definitions

  • H 2 antagonists are commonly prescribed to treat and prevent ulcers in the walls of the stomach, duodenum or esophagus. H2 antagonists are also used to treat non-ulcerative conditions. Damage to the mucus lining surrounding these tissues enables destructive action of stomach acids which erodes the underlying tissue. Commonly known H2 antagonists for the treatment of ulcers include cimetidine, ranitidine, nizatidine, roxatidine and famotidine.
  • Antihistamines useful for the treatment of cold, flu or allergy symptoms are generally catergorized into conventional and non- sedating antihistamines.
  • the conventional antihistamines exhibit an anticholinergic effect which may be advantageous to the cold, flu or allergy sufferer.
  • the conventional antihistamines may also have an advantage for the subject who wishes to induce drowsiness while concurrently relieving the targeted symptoms.
  • the non- conventional antihistamines have benefits to those patients in need of treatment but who need to stay awake or alert. See Martindale's The Extra Pharmacopoeia, 443 (1989) and references cited therein. Antihistamines may also be useful in the treatment of nausea.
  • Antihistamines are further classified into Hi receptor antagonists and H2 receptor antagonists and additionally are classified into five groups based upon their chemical structure. These groups include the ethanolamines (e.g. diphenhydramine) which have both sedative effects and muscarinic effects; ethylenediamines (e.g. mepyramine) which apparently have less central activity but may produce skin sensitization and gastric disturbances; alkylamines (e.g. chlorpheniramine) which are potent Hi antagonists which have relatively little sedative effect and produce central nervous system stimulation; piperazines (e.g. meclizine) which have anti-emetic effects; and phenothiazines (e.g.
  • promethazine which have pronounced antimuscarinic effects, anti-emetic effects and cause sedation and photosensitivity reactions.
  • Antihistamines have been utilized in a number of multiingredient formulations wherein diphenhydramine salts have been employed. Their primary use has been in combination cold, flu or allergy medications which also have analgesic properties. See Martindale's The Extra Pharmacopoeia, p. 453 (1989). Combinations of Hi antagonists (including diphenhydr ⁇ amine) and H2 antagonists and other active ingredients including NSAIDs or proton pump inhibitors have been disclosed. See U.S. Pat. Nos. 5,037,815 and 4,757,060; EPO 0 320 551 Al and EPO 0 426 479 Al.
  • an advantage is that the overall symptoms of gastrointestinal distress can be effectively treated with a combination of the most powerful H2 antagonist available (famotidine) with an antihistamine wherein the combination simultaneously treats, relieves and prevents symptoms associated with excess gastric acid secretion or evolution in the stomach and esophagus respectively while also promoting flu, cold, allergy and/or nausea relief with a pharmaceutically effective amount of an antihistamine selected from the conventional or non-conventional antihistamines.
  • This composition specifically excludes NSAIDs or proton pump inhibitors.
  • the present invention therefore provides an effective dual treatment of gastrointestinal disorders using the combination of famotidine with an antihistamine such as diphenhydr ⁇ amine hydrochloride, and optionally and antiflatulent.
  • the claimed combination is particularly useful for treating gastrointestinal distress, including nausea, accompanied by cold, flu or allergy symptoms.
  • the claimed combination is advantageously used at night since famotidine provides long lasting systemic relief while the diphenhydramine salt provides anti-cold, flu, allergy and nausea relief and has a sedative effect.
  • Other H2 antagonists that can be used with this invention include ranitidine, cimetidine, nizatidine and roxatidine.
  • compositions for use in the prevention, treatment and relief of mild to moderate stomach and esophagus disorders in patients in need of treatment thereof including the prevention, treatment and relief of heartburn while concomitantly treating symptoms associated with colds, flu, allergies and nausea.
  • the composition comprises:
  • This invention is also directed to a method of preventing, relieving and treating indigestion, sour stomach, nausea, flatulence, heartburn, overindulgence, gastroesophageal reflux (“GER”)and other gastrointestinal disorders and flu, cold and allergy symptoms in patients in need of treatment thereof, comprising administering to such organism:
  • mammals or mammalian organism or patients are used interchangeably herein, and include but are not limited to mammals such as humans, dogs, cats, horses and cows.
  • the preferred patient in need of treatment thereof is a human.
  • treatment encompasses the complete range of therapeutically positive effects associated with pharmaceutical medication including reduction of, alleviation of and relief from the symptoms or illness which affect the organism.
  • Famotidine may be purchased in bulk quantities as it is currently available on the market, and formulated via typical formulation processes with antihistamines wherein the combination is suitable for tablet, capsule, effervescent, chewable tablet or liquid formulations of the claimed combination including known and effective delivery systems. Famotidine as a prescription drug product is sold in the United States under the trademark PEPCID®. The antihistamines claimed in combination with famotidine are available from numerous manufacturers. Simethicone is a well known anti-flatulent and is sold by a number of manufacturers. The quantities utililized to treat flatulence vary depending upon the severity of the condition. The Physicians Desk Reference, 46th Ed. (1992) on pages 1155-56 describes the various quantities and dosage regimes for typical simethicone formulations.
  • Alpha-D-galactosidase is a known enzyme which degrades indigestible sugars found in beans or bean products. These anti-flatulents may be added as optional ingredients to the H2 antagonist/antihistamine combination. The active ingredients in the claimed combination are therefore readily available. See also European Patent Application 0,076,530 published on April 13, 1983.
  • the absence of the inactive stereoisomer of the antihistamine in the present composition avoids undesirable side effects that may accompany ingestion and metabolism of the non-biologically active stereoisomer. These include any toxic interactions and in addition metabolic energy is saved when only one stereoisomer of the antihistamine is used in the claimed combination.
  • the use of the potent H2 antagonist such as famotidine combined with an antihistamine or an active stereoisomer of an antihistamine provides significant dosage form advantages since less of the H2 antagonist and the antihistamine is needed to formulate a suitable dosage form and provides for a more practical size tablet or capsule.
  • compositions of the present invention are useful in the prevention, treatment and relief of various mild to moderate gastrointestinal disorders including indigestion, sour stomach, overindulgence, heartburn, gastroesophageal reflux, nausea, and flatulence if an optional anti-flatulent is added.
  • the compositions are also useful in the treatment of symptoms such as runny nose, sneezing, sniffles and itchy or watery eyes that often accompany colds, flus or allergies.
  • an antihistamine selected from either the conventional or non-conventional class, or further selected from an Hi receptor antagonist or an H2 receptor antagonist and in particular from members of the five known chemical classes, including but not limited to the biologically active and pharmaceutically effective stereoisomers thereof in substantially pure form, combined with an H2 antagonist selected from famotidine, a compound of the formula:
  • composition is also advantageously used to provide anti- flatulent relief.
  • the claimed combination is used to prevent, treat and relieve the symptoms associated with gastric acid secretion while simultaneously preventing, relieving and treating the symptoms of gastro-esophageal reflux and colds, flu and allergy, and optionally, flatulence. Therefore, the animal, patient, or organism in need of treatment thereof benefits from the claimed pharmaceutical composition.
  • H2 antagonists are well known in the treatment of ulcers and other gastrointestinal disorders and may be used, according to the present invention, in combination with an antihistamine and optionally with the addition of simethicone or ADG.
  • H2 antagonists used for ulcer therapy fall into four major structural classes: imidazole derivatives; substituted furans; aminoalkylphenoxy derivatives and guanidinothiazole compounds.
  • Famotidine (N'-(aminosulfonyl)-3-[[[2-[(diamino- methylene)amino]-4-thiazolyl]methyl]thio] propanimidamide), a member of the last-noted class above, is a competitive inhibitor of histamine H2-receptors and its primary pharmacological activity is the inhibition of gastric acid secretion. Famotidine suppresses both the acid concentration and the volume of gastric acid secretion. Famotidine is well tolerated and has minimal side effects and thus advantageously may be used in the present invention in combination with an antihistamine. Famotidine is also the most potent and selective H2 antagonist.
  • Antihistamines are used to diminish or alleviate the actions of histamine in mammalian organisms by competitive or reversible blockade of histamine receptor sites on mammalian tissues. Antihist ⁇ amines are also useful for the treatment of nausea. Hi receptors when activated cause vasodilation, increased capillary permeability, flare and itch reactions of the skin and contraction of smooth muscle in the bronchi and gastrointestinal tract while H2 receptors when activated promote gastric acid secretion and vasodilation.
  • Hi antagonists are useful to treat allergic reactions while antiliistamines are generally effective in relieving symptoms of seasonal rhinitus, perinnial allergic rhinitus and various other disorders as listed and described in Martindale's The Extra Pharmacopoeia, (1989) on page 444.
  • diphenhydramine hydrochloride also known as 2-benzhydryloxy-N,N-dimethylethylamine hydrochloride, is used as the antihistamine in the present invention in combination with famotidine.
  • Antihistamines may also be used to alleviate nausea.
  • the antihistamines employed herein are selected from the conventional or non-sedating types and may further be chosen from the five distinct chemical classes.
  • the conventional antihistamines competitively antagonize those pharmacological effects of histamine which are mediated through activation of histamine H2 receptor sites on effector cells.
  • the conventional antihistamines also exhibit an anticholinergic (drying) effect.
  • the conventional antihistamine is selected from, for example, chlo heniramine, brompheniramine, dexchlo ⁇ heniramine, dexbrompheniramine, tripelennamine, cyproheptadine, carbinoxamine, bromodiphenhydramine, diphenhydramine or a pharmaceutically acceptable salt, hydrate, or polymorph thereof.
  • the non-sedating antihistamine is selected from, for example, acirvastine, AHR-11325, astemizole, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine or terfenadine or a pharmaceutically acceptable salt, hydrate, or polymorph thereof.
  • a therapeutically active stereoisomer of an antihistamine such as diphenhydramine HCL, substantially free of its other inactive or less active stereoisomers may be employed in the instant invention.
  • a therapeutically active stereoisomer substantially free of its other inactive or less active stereoisomers means that the ratio of active stereoisomer to inactive or less active stereoisomer(s) is at least 90:10.
  • HPLC high performance liquid chromatography
  • suitable chromatographic or separation means may be used to purify or isolate the active stereoisomer (enantiomer or diastereomer) from its readily available racemic mixture.
  • famotidine or its pharmaceutically effective salts, hydrates, stereoisomers or polymorphs thereof with an antihistamine and an optional anti-flatulent provides a combination which simultaneously and selectively provides prevention, treatment and relief of discomfort and injury to the stomach, esophagus, or duodenum from excess production of gastric acid while concurrently treating cold, allergy and flu symptoms and optionally flatulence.
  • famotidine in combination with an antihistamine may not interact with alcohol so that it may be administered prior to or during ingestion of meals or beverages which contain alcohol and, therefore, a patient in need of rapid treatment of gastrointestinal distress may take the drug combination at an appropriate time which may be during a meal in which alcohol was consumed.
  • the combination of an antihistamine with famotidine provides relief of gastroesophageal reflux while also providing long acting relief from and treatment of gastrointestinal disorders associated with gastric acid secretion.
  • famotidine which is a highly potent H2 antagonist with an antihistamine and optionally with an antiflatulent, reduces the size and weight of all pharmaceutical delivery forms or combination formulations and therefore improves patient compliance or tolerance.
  • the tablet or capsule form of this combination is more readily swallowable by patients in need of treatment thereof.
  • Famotidine or a pharmaceutically effective salt, hydrate, stereoisomer or polymorph thereof, is advantageously used in the present invention in combination with an antihistamine, for example one selected from the ethanolamine class such as diphenhydramine hydrochloride, and optionally with an antiflatulant.
  • the amount of antihistamine added per dosage may be from 1-200 mgs depending upon the specific drug.
  • the amount of famotidine used in the present invention in humans may range from 2.5 mg/dosage to 80mg/dosage .
  • 5 to 40 mgs/dosage is administered in combination with 10 to 50 mgs/dosage of diphenhydramine hydrochloride.
  • a tablet containing 5 mgs of famotidine may be administered 4 times daily with an effective amount of diphenhydramine and suitable inert ingredients also contained within the tablet.
  • the amount of simethicone per dosage may vary depending upon the degree of antiflatulent strength desired, and may range, e.g., from 20 to 80 mgs. Maxium strength antiflatulents administered in tablet form four times per day may contain 125 mgs of simethicone per tablet.
  • Maxium strength antiflatulents administered in tablet form four times per day may contain 125 mgs of simethicone per tablet.
  • antacid/anti- gas formulations contain, for example, 20-40 mgs/chewable tablet or teaspoonful of liquid suspension of simethicone and 200 mgs of aluminum hydroxide and 200 mgs of magnesium hydroxide. Two to four tablets between meals or at bedtime or 2-4 teaspoonfuls between meals and at bedtime containing the above quantities are administered daily.
  • ADG is an enzyme known to assist in the hydrolysis of indigestible sugars which are often found in beans or bean products.
  • the quantity of ADG utilized in the present invention depends upon the concentration of active enzyme and upon the quantity of beans or other source of indigestible sugars ingested.
  • the amount of ADG that may be employed ranges from about 675 to 31,000 GalU ("alpha galactosidase units"), and preferably from about 675 to 2250 GalU. See WO90/14101 or PCT/US90/02643,
  • each of the active ingredients may vary depending upon the severity of the condition and the particular biochemistry and need of the patient or other organism in need of treatment thereof.
  • the quantities of the active ingredient may also vary depending upon whether the active ingredients are administered in tablet or liquid form or via some other suitable delivery method.
  • a physician or clinician or veterinarian of ordinary skill in the art may readily determine suitable dosages of any prescription medication containing the claimed invention.
  • the combination claimed in the instant invention is advantageously administered orally. However, in patients with hypersecretory conditions, intractable ulcers, or in patients who are unable to take oral medication, the claimed combination may be administered intravenously in a suitable dosage within the limits described for oral treatment if the optional simethicone is not included.
  • the present composition may be administered in the form of tablets, caplets, gelcaps, capsules, elixirs, syrups, effervescents, lozenges, fast-dissolving wafers or suspensions.
  • the active ingredients may be admixed with a pharmaceutically acceptable diluent such as lactose, sucrose, cellulose, dicalcium phosphate, calcium sulfate, mannitol, and, in a liquid composition, ethyl alcohol.
  • the active components may also be formulated in sustained release or effervescent formulations. These formulations depending upon whether they are sustained release or effervescent may be employed in oral, dermal, rectal or vaginal administrations.
  • the sustained release formulations also include layered formulations which provide for distinct release ratio and thus may be more effective in allowing for short and long term relief.
  • simethicone or alpha-D-galactosidase may be added to each of the above formulations or examples to provide anti-flatulent relief.
  • the quantity of simethicone administered to a patient in need of treatment thereof may vary according to patient need, but may be, for example, the typical known dosage range to treat flatulence (20-40 mgs per tablet or per 5 ml liquid dosage form) or may be increased as necessary.
  • the amount of ADG that may be employed in the above formulations ranges from about 675 to about 2250 GalU, or may be increased as necessary.
  • the inactive ingredients in the tablet form may further include dextrates, mannitol, magnesium stearate, Yellow 10, collodial silicon dioxide and Blue 1 or Red 27 while the liquid form(s) may further include inactives such as butylparaben, carboxy- methylcellulose sodium, flavors, hydroxypropyl methylcellulose, microcrystalline cellulose, propylparaben, and purified water.
  • inactives such as butylparaben, carboxy- methylcellulose sodium, flavors, hydroxypropyl methylcellulose, microcrystalline cellulose, propylparaben, and purified water.
  • the previous examples are to be construed as non-limiting and additional dosages and dosage forms or routes of administration may be varied depending upon the individual patient being treated for either the primary (excess acid leading to gastrointestinal or esophageal disturbance or damage) or secondary (infections) symptoms of gastrointestinal disorders.
  • known pharmaceutically acceptable excipients or agents may be added as inactive ingredients to the claimed active combination in a variety of forms including

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  • Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

L'invention concerne des préparations pharmaceutiques destinées à la prévention, au traitement et au soulagement des troubles gastriques et ÷sophagiens légers à modérés tels que les indigestions, les aîgreurs d'estomac et les brûlures épigastriques tout en traitant les symptômes associés du rhume, de la grippe et des allergies, par administration de composés associant (i) une quantité d'anti-H2 suffisante pour soulager les troubles gastro-intestinaux ou ÷sophagiens, l'anti-H2 étant sélectionné dans la famille des composés dont la formulation est (I) ainsi que leurs dérivés sous forme de sels, d'hydrates, de stéréoisomères ou de polymorphes de qualité pharmaceutique et; (ii) de l'antihistaminique en quantité suffisante constitué à partir de l'un au moins des agents antihistaminiques ou de l'un de leurs stéréoisomères thérapeutiquement actifs (mais notablement exempts de leurs autres stéréisomères inactifs ou moins actifs) ainsi que leurs dérivés sous forme de sels, d'hydrates, ou de polymorphes de qualité pharmaceutique, et le cas échéant; (iii) un agent anti-flatulences en quantité suffisante, associant du siméthicone, de l'alpha-D-galactosidase et une base silicone; à l'exclusion des inhibiteurs de la pompe à protons ou des NSAID (anti-inflammatoires non stéroïdiens).
PCT/US1994/007528 1993-07-06 1994-07-05 Composes anti-h2-antihistaminiques WO1995001792A1 (fr)

Priority Applications (1)

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AU72550/94A AU7255094A (en) 1993-07-06 1994-07-05 H2 antagonist-antihistamine combinations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US8794093A 1993-07-06 1993-07-06
US087,940 1993-07-06

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WO1995001792A1 true WO1995001792A1 (fr) 1995-01-19

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU728423B2 (en) * 1996-10-04 2001-01-11 Mcneil-Ppc, Inc. Methods and compositions for preventing and treating heartburn
US6335347B1 (en) * 1997-10-10 2002-01-01 Schering Corporation Ethyl 4-(8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidene carboxylate polymorph
WO2004082669A2 (fr) * 2003-03-18 2004-09-30 Lifescape Biosciences Incorporated Compositions et procédés de traitement de coliques
US8058296B2 (en) 2008-11-25 2011-11-15 Richard Tokunaga Treatment and prevention of deleterious effects associated with alcohol consumption
CN103920131A (zh) * 2014-05-06 2014-07-16 张旭 一种治疗胃寒的药物及其制备方法
JP2016513692A (ja) * 2013-03-14 2016-05-16 メアゲーデ アールエックス リミテッド ライアビリティ カンパニー 下痢を治療するための製品及び方法
CN113271924A (zh) * 2018-11-29 2021-08-17 B.布劳恩梅尔松根股份公司 特别用于治疗粘膜和/或伤口的水性组合物
US11419868B2 (en) 2016-12-23 2022-08-23 White Sands Pharma Llc Low dose product and method for treating diarrhea

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EP0320551A1 (fr) * 1986-03-04 1989-06-21 Bristol-Myers Company Compositions NSAID protégées contre les lésions gastro-intestinales avec un mélange de certains bloqueurs de récepteurs H1 et H2
WO1992000102A1 (fr) * 1990-06-22 1992-01-09 Beecham Group Plc Nouveau traitement

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Title
DIGESTIVE DISEASES AND SCIENCES, Volume 26, Number 4, issued April 1981, C.H. CHO et al., "Gastrointestinal Ulceration in the Guinea Pig in Response to Dimaprit, Histamine and H1- and H2-Blocking Agents", pages 306-311. *
DRUGS, Volume 38, Number 4, issued 1989, ADVENIER et al., "Rational Use of Antihistamines in Allergic Dermatological Conditions", pages 634-644. *
MOLECULAR PHARMACOLOGY, Volume 42, issued August 1992, R. SEIFERT et al., "Histamine Increases Cytosolic Ca2+ in HL-60 Promyelocytes Predominantly via H2 Receptors with an Unique Agonist/Antagonist Profile and Induces Functional Differentiation", pages 235-241. *
RESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY, Volume 79, Number 2, issued February 1993, S. KANETA et al., "Effects of H2-Antihistamines in Murine Models of Immediate Hypersensitivity and Chronic Inflammation", pages 167-184. *
S. BUDAVERI et al., "The Merck Index", Published 1989, by MERCK & CO., INC., (RAHWAY, N.J.), pages 617. *
VRACH DELO, Number 8, issued August 1990, G.V. LEONT'EVA et al., "Morphometric Analysis of Tissue Homeostasis In Peptic Ulcer Patients During Treatment with Antihistamine Preparations", pages 39-41. *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU728423B2 (en) * 1996-10-04 2001-01-11 Mcneil-Ppc, Inc. Methods and compositions for preventing and treating heartburn
US6335347B1 (en) * 1997-10-10 2002-01-01 Schering Corporation Ethyl 4-(8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidene carboxylate polymorph
WO2004082669A2 (fr) * 2003-03-18 2004-09-30 Lifescape Biosciences Incorporated Compositions et procédés de traitement de coliques
WO2004082669A3 (fr) * 2003-03-18 2005-03-17 Advanced Nutritional Sciences Compositions et procédés de traitement de coliques
US8058296B2 (en) 2008-11-25 2011-11-15 Richard Tokunaga Treatment and prevention of deleterious effects associated with alcohol consumption
EP2968205B1 (fr) * 2013-03-14 2017-10-11 Maregade RX LLC Produit et procédé pour le traitement de diarrhée
JP2016513692A (ja) * 2013-03-14 2016-05-16 メアゲーデ アールエックス リミテッド ライアビリティ カンパニー 下痢を治療するための製品及び方法
US9717726B2 (en) 2013-03-14 2017-08-01 Maregade Rx, LLC Product and method for treating diarrhea
US10034875B2 (en) 2013-03-14 2018-07-31 Maregrade RX, LLC Product and method for treating diarrhea
AU2017251701B2 (en) * 2013-03-14 2019-03-14 Maregade Rx, LLC Product and method for treating diarrhea
JP2019089796A (ja) * 2013-03-14 2019-06-13 メアゲーデ アールエックス リミテッド ライアビリティ カンパニー 下痢を治療するための製品及び方法
EP3581205A3 (fr) * 2013-03-14 2020-03-25 Maregade RX, LLC Produit et procédé de traitement de la diarrhée
JP2021046400A (ja) * 2013-03-14 2021-03-25 メアゲーデ アールエックス リミテッド ライアビリティ カンパニー 下痢を治療するための製品及び方法
US11058681B2 (en) 2013-03-14 2021-07-13 Maregade RX Product and method for treating diarrhea
CN103920131A (zh) * 2014-05-06 2014-07-16 张旭 一种治疗胃寒的药物及其制备方法
US11419868B2 (en) 2016-12-23 2022-08-23 White Sands Pharma Llc Low dose product and method for treating diarrhea
CN113271924A (zh) * 2018-11-29 2021-08-17 B.布劳恩梅尔松根股份公司 特别用于治疗粘膜和/或伤口的水性组合物

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