Source: http://www.google.com/patents/US5116847?ie=ISO-8859-1
Timestamp: 2015-05-05 04:11:43
Document Index: 696742462

Matched Legal Cases: ['art 3', 'art 4', 'art 2', 'art 1', 'art 4', 'art 4', 'art 1', 'art 2', 'art 1', 'art 2', 'art 3', 'art 3']

Patent US5116847 - Use of loperamide and related compounds for treatment of respiratory disease ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsThe subject invention involves compositions and methods of using loperamide and related compounds for treatment of symptoms associated with respiratory diseases....http://www.google.com/patents/US5116847?utm_source=gb-gplus-sharePatent US5116847 - Use of loperamide and related compounds for treatment of respiratory disease symptomsAdvanced Patent SearchPublication numberUS5116847 APublication typeGrantApplication numberUS 07/645,855Publication dateMay 26, 1992Filing dateJan 25, 1991Priority dateJan 25, 1991Fee statusLapsedAlso published asWO1992012715A2, WO1992012715A3Publication number07645855, 645855, US 5116847 A, US 5116847A, US-A-5116847, US5116847 A, US5116847AInventorsSheri A. Gilbert, Haruko Mizoguchi, Robert P. Charest, Timothy P. O'Neill, Ronald L. SmithOriginal AssigneeThe Procter & Gamble CompanyExport CitationBiBTeX, EndNote, RefManPatent Citations (3), Non-Patent Citations (97), Referenced by (27), Classifications (11), Legal Events (6) External Links: USPTO, USPTO Assignment, EspacenetUse of loperamide and related compounds for treatment of respiratory disease symptoms
US 5116847 AAbstract
The subject invention involves compositions and methods of using loperamide and related compounds for treatment of symptoms associated with respiratory diseases.
1. A method of treatment of symptoms associated with respiratory diseases, of humans and lower animals, comprising administration to the human or lower animal safe and effective amount of a compound having the structure: ##STR3## wherein each --R is independently hydrogen or lower alkyl, or the two --Rs are connected to form a cyclic lower alkyl; each --A is independently phenyl or halophenyl; --B--is --CH2 CH2 --or --CH2 CH(CH3)--; --R' is hydrogen or methyl; and --A' is phenyl or substituted phenyl;or N-oxide thereof, or a pharmaceutically-acceptable salt thereof. 2. The method of claim 1 wherein each --R is C1 -C4 alkyl, and --R' is hydrogen.
3. The method of claim 2 wherein --A' is 4-halophenyl.
4. The method of claim 1 wherein the compound is loperamide or N-oxide thereof, or a salt thereof.
5. The method of claim 4 wherein the compound is loperamide hydrochloride.
6. The method of claim 1 wherein a composition comprising the compound is administered to a human, and the quantity of compound administered is from about 1 μg to about 4 mg per dose.
7. The method of claim 4 wherein a composition comprising the compound is administered to a human, and the quantity of compound administered is from about 1 μg to about 4 mg per dose.
8. The method of claim 7 wherein the composition is administered topically, and the quantity of the compound administered is from about 20 μg to about 2 mg per dose.
9. The method of claim 7 wherein the composition is administered topically, intranasally, and the quantity of the compound administered is from about 40 μg to about 1 mg per dose.
10. A composition, for use in the nasal passages and sinuses for treatment of symptoms associated with respiratory diseases, in the form of an aqueous solution comprising:(a) a safe and effective amount of a compound having the structure: ##STR4## wherein each --R is independently hydrogen or lower alkyl, or the two --Rs are connected to form a cyclic lower alkyl; each --A is independently phenyl or halophenyl; --B--is --CH2 CH2 --or --CH2 CH(CH3)--; --R' is hydrogen or methyl; and --A' is phenyl or substituted phenyl; or N-oxide thereof, or a pharmaceutically-acceptable salt thereof, and (b) a safe and effective amount of a preservative selected from the group consisting of benzalkonium chloride, thimerosal, and phenylmercuric acetate. 11. The composition of claim 10 wherein the compound is loperamide or a salt thereof, the compound being at a concentration of from about 0.002% to about 1% in the composition.
12. A composition, for treatment of symptoms associated with respiratory diseases, inthe form of an aqueous soluton comprising:(a) a safe and effective amount of loperamide or a salt thereof; and (b) a safe and effective amount of another drug active selected from the group consisting of antihistamines, decongestants, expectorants, bronchodilators, and antitussives. 13. The composition of claim 12 wherein the other drug active is selected from the group consisting of antitussives and bronchodilators.
14. The composition of claim 12 wherein the other drug active is selected from the group consisting of antihistamines and decongestants.
15. A composition, for treatment of symptoms associated with respiratory diseases, in the form of an aqueous solution comprising:(a) a safe and effective amount of loperamide or a salt thereof; and (b) a safe and effective amount of a steroidal or non-steroidal anti-inflammatory drug agent. 16. A composition, for treatment of symptoms asociated with respiratory diseases, in the form of an aqueous solution comprising:(a) a safe and effective amount of loperamide or a salt thereof; and (b) a safe and effective amount of an anticholinergic drug agent. 17. A combination comprising:(a) a container comprising a means for topical application selected from the group consisting of dropper means, spray means and inhalation mist means, the container containing: (b) a composition, for treatment of symptoms associated with respiratory diseases, in the form of an aqueous solution comprising a safe and effective amount of a compound having the structure: ##STR5## wherein each --R is independently hydrogen or lower alkyl, or the two --Rs are conencted to form a cyclic lower alkyl; each --A is independently phenyl or halophenyl; --B--is --CH2 CH2 --or --CH2 CH(CH3)--; --R' is hydrogen or methyl; and --A' is phenyl or substituted phenyl;or N-oxide thereof, or a pharmaceutically-acceptable salt thereof. 18. The combination of claim 17 wherein the container comprises a dropper means, and the compound is loperamide or a salt thereof, the compound being at a concentration of from about 0.002% to about 1% in the composition.
19. The combination of claim 17 wherein the container comprises a spray means, and the compound is loperamide or a salt thereof, the compound being at a concentration of from about 0.002% to about 1% in the composition.
20. The combiantion of claim 17 wherein the container comprises an inhalation mist or powder means, and the compound is loperamide or a salt thereof, he compound being at a concentration of from about 0.002% to about 1% in the composition.
The subject invention relates to the use of loperamide and related compounds for the treatment of symptoms such as nasal congestion, runny nose, sneezing, itchy nose, itchy eyes, watery eyes, cough, bronchoconstriction and post-nasal drip. Such symptoms are associated with respiratory diseases such as colds, flu, allergic and vasomotor rhinitis, asthma and bronchitis.
Loperamide is an opiate agonist used for the treatment of diarrhea; see "5396. Loperamide", The Merck Index, Tenth Edition, M. Windholz, ed., p. 797; and Physicians' Desk Reference for Nonprescription Drugs, 11th Ed. (1990), E. R. Barnhart, pub., pp. 593-594. Loperamide is one of a class of compounds disclosed in U.S. Pat. No. 3,714,159 issued to Janssen, Niemegeers, Stokbroekx & Vandenberk on Jan. 30, 1973. Lomeramide N-oxide is disclosed in "Drug Compendium", Comprehensive Medicinal Chemistry, Vol. 6 (1990), C. Hansch, P. G. Sammes, J. B. Taylor & C. J. Drayton, eds., Pergamon Press, N.Y., p. 629, and in Niemegeers, C. J. E., F. Awouters, F. M. Lenaerts, K. S. K. Artois & J. Vermeire, "Antidiarrheal Specificity and Safety of the N-Oxide of Loperamide (R 58 425) in Rats", Drug Development Research, Vol. 8 (1986), pp. 279-286. The above references are hereby incorporated herein by reference.
Loperamide is similar to other opiate agonists in having binding affinities at mu and delta opiate receptors. See, e.g., Mackerer, C. R., G. A. Clay & E. Z. Dajani, "Loperamide Binding to Opiate Receptor Sites of the Brain and Myenteric Plexus", Journal of Pharmacology and Experimental Therapeutics, Vol. 199, No. 1 (1976), pp. 131-140; Stahl, K. D., W. Van Bever, P. Janssen & E. J. Simon, "Receptor Affinity and Pharmacological Potency of a Series of Narcotic Analgesic, Anti-Diarrheal and Neuroleptic Drugs", Eurpoean Journal of Pharmacology, Vol. 46 (1977), pp. 199-205; Wuster, M. & A. Herz, "Opiate Agonist Action of Antidiarrheal Agents In Vitro and In Vivo--Findings in Support for Selective Action", Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 301 (1978), pp. 187-194; and Giagnoni, G., L. Casiraghi, R. Senini, L. Revel, D. Parolaro, M. Sala & E. Gori, "Loperamide: Evidence of Interaction with μ and δ Opioid Receptors", Life Sciences, Vol. 33, Suppl. 1 (1983), pp. 315-318. It is generally accepted that mu and/or delta opioid agonists bind to opioid receptors on the presynaptic terminals of peripheral parasympathetic nerves or sensory nerves and inhibit the release of neurotransmitters from these nerve terminals in a number of model systems. See, e.g., Mudge, A. W., S. E. Leeman & G. D. Fischbach, "Enkephaline Inhibits Release of Substance P from Sensory Neurons in Culture and Decreases Action Potential Duration" , Proceedings of the National Academy of Science, USA, Vol. 76, No. 1 (Jan. 1979), pp. 526-530; Frossard, N. & P. J. Barnes, "μ-Opioid Receptors Modulate Non-cholinergic Constrictor Nerves in Guinea-Pig Airways", European Journal of Pharmacology, Vol. 141 (1987), pp. 519-522; Burleigh, D. E., "Opioid and Non-opioid Actions of Loperamide on Cholinergic Nerve Function in Human Isolated Colon", European Journal of Pharmacology, Vol. 152 (1988), pp. 39-46; Belvisi, M. G., D. F. Rogers & P. J. Barnes, "Neurogenic Plasma Extravasation: Inhibition by Morphine in Guinea Pig Airways In Vivo", Journal of Applied PhysiologyVol. 66 (1989), pp. 268-272; and Matran, R., C.-R. Martling & J. Lundberg, "Inhibition of Cholinergic and Non-adrenergic, Non-cholinergic Bronchoconstriction in the Guinea Pig Mediated by Neuropeptide Y and α2 -adrenoceptors and Opiate Receptors", European Journal of Pharmacology, Vol. 163 (1989), pp. 15-23. This inhibition is prevented or reversed by the mu and delta selective opioid antagonist naloxone.
References which disclose the biological and chemical activity of loperamide include the following: Balkovetz, D. F., Y. Miyamoto, C. Tiruppathi, V. B. Mahesh, F. H. Leibach & V. Ganapathy, "Inhibition of Brush-border Membrane Na+-H+ Exchanger by Loperamide", Journal of Pharmacology and Experimental Therapeutics, Vol. 243, No. 1 (Oct. 1987), pp. 150-154; Beubler, E. & P. Badhri, "Comparison of the Antisecretory Effects of Loperamide and Loperamide Oxide in the Jejunum and the Colon of Rats In-vivo", J. Pharm. Pharmacol., Vol. 42 (1990), pp. 689-692; Chang, E. B., D. R. Brown, N. S. Wang & M. Field, "Secretagogue-induced Changes in Membrane Calcium Permeability in Chicken and Chincilla Ileal Mucosa. Selective Inhibition by Loperamide", J. Clin. Invest., Vol. 78, No. 1 (Jul., 1986), pp. 281-287; Haag, K., R. Lubcke, H. Knauf, E. Berger & W. Gerok, "Determination of Rheogenic Ion Transport in Rat Proximal Colon In Vivo", Pflugers Arch., Vol. 405, Suppl. 1 (1985), pp. S67-S70; Hantz, E., A. Cao, R. S. Phadke & E. Taillandier, "The Effect of Loperamide on the Thermal Behavior of Dimyristoylphosphatidylcholine Large Unilamellar Vesicles", Chem. Phys. Lipids (Ireland), Vol. 51, No. 2 (Oct. 1989), pp. 75-82; Hardcastle, J., P. T. Hardcastle & J. Cookson, "Inhibitory Actions of Loperamide on Absorptive Processes in Rat Small Intestine", Gut, Vol. 27, No. 6 (Jun. 1986), pp. 686-694; Hardcastle, J., P. T. Hardcastle & J. Goldhill, "The Effect of Loperamide Oxide on Prostaglandin-Stimulated Fluid Transport in Rat Small Intestine", J. Pharm. Pharmacol., Vol. 42, No. 5 (May, 1990), pp. 364-366; Hardcastle, J., P. T. Hardcastle, N. W. Read & J. S. Redfern, "The Action of Loperamide in Inhibiting Prostaglandin-induced Intestinal Secretion in the Rat", British Journal of Pharmacology, Vol. 74, No. 3 (Nov. 1981), pp. 563-569; Hughes, S., N. B. Higgs & L. A. Turnberg, "Antidiarrhoeal Activity of Loperamide: Studies of its Influence on Ion Transport Across Rabbit Ileal Mucosa In Vitro", Gut, Vol. 23, No. 11 (Nov. 1982), pp. 974-979; Kachur, J. F., D. W. Morgan & T. S. Gaginella, "Effect of Dextromethorphan on Guinea Pig Ileal Contractility In Vitro: Comparison with Levomethorphan, Loperamide and Codeine", Journal of Pharmacology and Experimental Therapeutics, Vol. 239, No. 3 (Dec. 1986), pp. 661-667; Knauf, H. & K. Haag, "Modelling of Colonic Cl- and K+ Transport Under Resting and Secreting Conditions", Pflugers Arch., Vol. 407, Supplement 2 (1986), pp. S85-S89; Marcais-Collado, H., G. Uchida, J. Costentin, J. C. Schwartz & J. M. Lecompte, "Naloxone-reversible Antidiarrheal Effects of Enkephalinase Inhibitors", European Journal of Pharmacology, Vol. 144, No. 2 (Dec. 1, 1987), pp. 125-132; Marsboom, R., V. Herin, A. Verstraeten, R. Vandesteene & J. Fransen, "Loperamide, a Novel Type of Antidiarrheal Agent. Part 3: In Vitro Studies on the Peristaltic Reflex and Other Experiments on Isolated Tissues", Arzneimittelforschung, Vol. 24, No. 10 (Oct. 1974), pp. 1641-1645; Marsboom, R., V. Herin, A. Verstraeten, R. Vandesteene & J. Fransen, "Loperamide, a Novel Type of Antidiarrheal Agent. Part 4: Studies on Subacute and Chronic Toxicity and the Effect on Reproductive Processes in Rats, Dogs and Rabbits", Arzneimittelforschung, Vol. 24, No. 10 (Oct. 1974), pp. 1645-1649; Megens, A. A., L. L. Canters, F. H. Awouters & C. J. Niemegeers, "Is In Vivo Dissociation Between the Antipropulsive and Antidiarrheal Properties of Opioids in Rats Related to Gut Selectivity? ", Arch. Int. Pharmacodyn. Ther., Vol. 298 (Mar.-Apr., 1989), pp. 220-229; Megens, A. A., L. L. Canters, F. H. Awouters & C. J. Niemegeers, "Normalization of Small Intestinal Propulsion with Loperamide-like Antidiarrheals in Rats", European Journal of Pharmacology, Vol. 178, No. 3 (Mar. 27, 1990), pp. 357-364; Mellstrand, T., "Loperamide--An Opiate Receptor Agonist with Gastrointestinal Motility Effects", Scand. J. Gastroenterol. Suppl., Vol. 130 (1987), pp. 65-66; Miller, R. J., D. R. Brown, E. B. Change & D. D. Friel, "The Pharmacological Modification of Secretory Responses", Ciba Found. Symp., Vol. 112 (1985), pp. 155-174; Nakayama, S., T. Yamasato & M. Mitzutani, "Effects of Loperamide on the Motility of the Isolated Intestine in Guinea Pigs, Rats and Dogs", Niooon Heikatsukin Gakkai Zasshi, Vol. 13, No. 2 (Jun., 1977), pp. 69-74; Niemegeers, C. J., F. M. Lenaerts & P. A. Janssen, "Loperamide, a Novel Type of Antidiarrheal Agent. Part 2: In Vivo Parenteral Pharmacology and Acute Toxicity in Mice. Comparison with Morphine, Codeine and Diphenoxylate", Arzneimittelforschung, Vol. 24, No. 10 (Oct. 1974), pp. 1636-1641; Niemegeers, C. J., F. M. Lenaerts & P. A. Janssen, "Loperamide, a Novel Type of Antidiarrheal Agent. Part 1: In Vivo Oral Pharmacology and Acute Toxicity. Comparison with Morphine, Codeine, Diphenoxylate and Difenoxine", Arzneimittelforschung, Vol. 24, No. 10 (Oct. 1974), pp. 1633-636; Sandhu, B. K., P. J. Milla & J. T. Harries, "Mechanisms of Action of Loperamide", Scand. J. Gastroenterol, Suppl., Vol. 84 (1983), pp. 85-92; Stahl, K. D., W. van Bever, P. Janssen & E. J. Simon, "Receptor Affinity and Pharmacological Potency of a Series of Narcotic Analgesic, Anti-diarrheal and Neuroleptic Drugs", European Journal of Pharmacology, Vol. 46, No. 3 (Dec. 1, 1977), pp. 199-205; Stoll, R., H. Stern, H. Ruppin & W. Domschke, "Effect of Two Potent Calmodulin Antagonists on Calcium Transport of Brush Border and Basolateral Vesicles for Human Duodenum", Ailment. Pharmacol. Ther., Vol. 1, No. 5 (1987), pp. 415-424; Stoll, R., H. Ruppin & W. Domschke, "Calmodulin-mediated Effects of Loperamide on Chloride Transport by Brush Border Membrane Vesicles from Human Ileum", Gastroenterology, Vol. 95, No. 1 (Jul. 1988), pp. 69-76; Turnberg, L. A., "Antisecretory Activity of Opiates In Vitro and In Vivo in Man", Scand. J. Gastroenterol. Suppl., Vol. 84 (1983), pp. 79-83; Turnheim, K., "Antidiarrheal Agents: Tools and Therapeutic Agents", Z. Gastroenterol. (West Germany), Vol. 27, No. 2 (Feb. 1989), pp. 112-119; Verhaeren, E. H., M. J. Dreessen & J. A. Lemli, "Influence of 1,8-Dihydroxyanthraquinone and Loperamide on the Paracellular Permeability Across Colonic Mucosa", J. Pharm. Pharmacol., Vol. 33, No. 8 (Aug. 1981), pp. 526-528; Wehner, F., "Membrane Effects of Loperamide in Absorbing and Secreting Guinea-Pig Gallbladder Epithelium", Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 335, Supplement (1987), p. R45; Wehner, F., J. M. Winterhager & K. U. Peterson, "Selective Blockage of Cell Membrane K Conductance by an Antisecretory Agent in Guinea-Pig Gallbladder Epithelium", Pfugers Arch. (West Germany), Vol 414, No. 3 (Jul. 1989), pp. 331-339.
Tamaski, J., N. Sakai, K. Isono & T. Takizawa, "Inhibition by Loperamide of Chloride Transport Across Canine Cultured Tracheal Epithelium", European Journal of Pharmacology, Vol. 190 (1990), pp. 255-258, speculates that the inhalation of loperamide could be of value in the treatment of patients with excessive airway surface fluid.
Evidence suggests that sensory C-fiber activation is important in the induction of symptoms associated with rhinitis; see, e.g., Saria, A., "Neuroimmune Interactions in the Airways: lmplications for Asthma, Allergy and Other Inflammatory Airway Diseases", Brain, Behavior, and ImmunityVol 2 (1988), pp. 318-321; Wolf, G. "New Aspects in the Pathogenesis and Therapy of Hyperreactive Rhinopathy", Laryng. Rhinol. Otol., Vol 67 (1988), pp. 438-445; and Stjarne, P., L. Lundblad, J. M. Lundberg & A. Anggard, "Capsaicin and Nicotine-Sensitive Afferent Neurons and Nasal Secretion in Healthy Human Volunteers and in Patients with Vasomotor Rhinitis", British Journal of Pharmacology,. Vol. 96 (1989), pp. 693-710. In respiratory tissue, C-fiber activation causes the local release of inflammatory neuropeptides and also initiates a parasympathetic reflex. Both of these actions produce physiologic changes that can result in the symptoms of rhinorrhea and congestion; see, e.g., Stjarne, et al. and Geppetti, P., B. M. Fusco, S. Marabini, C. A. Maggi, M. Fanciullacci & F. Sicuteri, "Secretion, Pain and Sneezing Induced by the Application of Capsaicin in the Nasal Mucosa in Man", British Journal of Pharmacology, Vol. 93 (1988), pp. 509-514.
It has been reported that the opioid antagonist nalmefene is useful for the treatment of rhinitis; see, e.g., U.S. Pat. No. 4,880,813 issued to Frost on Nov. 14, 1989, and PCT Patent Application Publication No. WO 87/02586 of Key Pharmaceuticals, Inc., inventor: Tuttle, published May 7, 1987.
It is an object of the subject invention to provide novel methods for the treatment of rhinitis.
It is further object of the subject invention to provide novel methods for the topical, intranasal treatment of rhinitis.
The subject invention involves the use of compounds, or N-oxide thereof, or pharmaceutically-acceptable salts thereof, having the structure; ##STR1## wherein each --R independently selected from hydrogen and lower alkyl, or the two --Rs are conencted to form a cyclic lower alkyl; each --A is independently selected from phenyl and halophenyl; --B--is selected from --CH2 CH2 --and --CH2 CH(CH3)--; --R' is hydrogen or methyl; and --A' is phenyl or substituted phenyl;
for treatment of symptoms associated with respiratory diseases.
As used herein, "lower alkyl" means alkyl which is preferably unsubstituted C1 -C6 straight or branched alkyl, preferably saturated, more preferably C1 -C4, more preferably still ethyl, and especially methyl.
As used herein, "lower alkoxy" means --O--lower alkyl.
As used herein, "cyclic lower alkyl" means cyclic alkyl which is preferably unsubstituted C3 -C8, preferably unsaturated, more preferably C5 -C6.
As used herein, "substituted phenyl" means phenyl which is preferably mono-, di- or trisubstituted, more preferably mono-substituted, especially in the 4-position. Preferred phenyl substituents include lower alkyl, lower alkoxy, halo and trifluoromethyl. As used herein, "halophenyl" means substituted phenyl which is substituted with fluoro, chloro, bromo, and/or iodo. Preferred halo substituents are fluoro and chloro.
The subject invention involves a new use of compounds, or N-oxide thereof, or pharmaceutically-acceptable salts thereof, having the structure: ##STR2##
In Structure (1), each --R is independently selected from hydrogen and lower alkyl, or the two --Rs are connected to form a cyclic lower alkyl.
In Structure (1), each --A is independently selected from phenyl or halophenyl; preferred are 4-F-phenyl and especially phenyl.
In Structure (1), --B--is --CH2 CH2 --or --CH2 CH(CH3)--, preferably --CH2 CH2 --.
In Structure (1), --R' is hydrogen or methyl, preferably hydrogen.
In Structure (1), --A' is phenyl or substituted phenyl; especially preferred is 4-Cl-phenyl.
Preferred salts of the compounds of Structure (1) include hydrochloride, hydrobromide, acetate, citrate, lactate, tartrate, succinate and maleate.
A preferred compound of Structure (1) is loperamide, 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperdinebutanamide, or the N-oxide thereof, and especially the hydrochloride salt of loperamide or its N-oxide.
The subject invention involves the use of a safe and effective amount of the above compounds for treatment of symptoms associated with respiratory diseases, such as colds, flu, allergic and vasomotor rhinitis, asthma and bronchitis, of humans and lower animals, especially humans. Such symptoms can include, for example, one or more of nasal congestion, runny nose, sneezing, itchy nose, itchy eyes, watery eyes, cough, broncoconstriction and post-nasal drip. The subject invention particularly involves the treatment with the above compounds of upper respiratory nasal symptoms, such as nasal congestion, runny nose, sneezing, and post-nasal drip. The subject invention also particularly involves the treatment with the above compounds of lower respiratory symptoms, such as bronchoconstriction and cough. Relief of the above symptoms can be achieved by the methods of the subject invention with minimal or no side effects often associated with therapies for such symptoms, such as drowsiness, central nervous system excitation, or rebound congestion. A preferred mode of administering the above compounds in the methods of the subject invention is topical, intranasal administration, e.g., with nose drops, nasal spray or nasal mist inhalation. Another preferred mode of administering the above compounds in the methods of the subject invention is topical, bronchial administration by inhalation of vapor and/or mist or powder. Such modes of topical administration minimize or prevent any gastrointestinal effects of the compounds.
The methods and compositions of the subject invention involve a safe and effective amount of the above compounds. The phrase "safe and effective amount", as used herein for the above compounds or other substances, means an amount of the substance high enough to provide a significant positive modification of the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgement. A safe and effective amount of the substance will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy and like factors.
Each administration of a dose of a composition comprising a compound according to the methods of the subject invention preferably administers a dose within the range of from about 1 μg to about 4 mg of a compound, more preferably from about 20 μg to about 2 mg, more preferably still from about 40 μg to about 1 mg. The frequency of administration of a composition comprising a compound according to the subject invention is preferably from once to about 6 times daily, more preferably from about 2 times to about 4 times daily.
Another aspect of the subject invention is pharmaceutical compositions for topical administration of the above compounds to the eyes, nasal passages and sinuses, or bronchial passages and lungs. Preferred compositions for topical administration to eyes include eye drops. Preferred compositions for topical administration to the nasal passages and sinuses include nasal drops, nasal sprays, and vapors and/or mists for nasal inhalation. Preferred compositions for topical administration to the bronchial passages and lungs include vapors and/or mists or powders for inhalation.
The above topical compositions of the subject invention preferably comprise an above compound at a concentration of from about 0.002% to about 1%, more preferably from about 0.02% to about 0.2%, more preferably still from about 0.05% to about 0.1%. Preferred topical compositions of the subject invention are powder mixtures or aqueous-based solutions or suspensions; especially preferred are aqueous solutions.
Other ingredients which may be incorporated in such compositions include safe and effective amounts of preservatives, e.g., benzalkonium chloride, thimerosal, phenylmercuric acetate; and acidulants, e.g., acetic acid, citric acid, lactic acid, tartaric acid. Such compositions preferably include safe and effective amounts of isotonicity agents, e.g., salts such as sodium chloride; more preferred are non-electrolyte isotonicity agents, e.g., sorbitol, mannitol, lower molecular weight polyethylene glycol.
A particularly preferred ingredient of the compositions of the subject invention is a safe and effective amount of a solubilizing agent. Loperamide and its salts are sparingly soluble in water. A suitable solubilizing agent increases the solubility of loperamide and/or its salts in the aqueous compositions. Such solubilizing agents can also provide isotonicity for the aqueous compositions. Preferred solubilizing agents are modified cyclodextrins, preferably hydroxy-C1 -C6 alkyl derivatives, especially hydroxypropyl derivatives. A particularly preferred solubilizing agent is 2-hydroxypropyl-β-cyclodextrin. Solubilizing agents are preferably present in the compositions of the subject invention at a concentration of from about 0.1% to about 10%, more preferably from about 0.5% to about 5%.
The compositions of the subject invention also may comprise safe and effective amounts of one or more other active drug agents useful for treating the respiratory diseases of interest. Such other active drug agents and typical amounts dosed are disclosed in Physician's Desk Reference, 44th Edition (1990), E. R. Barnhardt, publisher, and Physician's Desk Reference for Nonprescription Drugs, 11th Edition (1990), E. R. Barnhardt, publisher, both of which are incorporated herein by reference.
The topical nasal compositions of the subject invention may include one or more of the following such other active drug agents: antihistamines, e.g., chlorpheniramine maleate, pyrilamine maleate, diphenhydramine hydrochloride, promethazine hydrochloride, doxylamine succinate, terfenadine, astemizole; decongestants, e.g., pseudoephedrine hydrochloride, phenyl propanolamine hydrochloride, phenylephrine hydrochloride, oxymetazoline hydrochloride, xylometazoline hydrochloride; steroidal anti-inflammatories, e.g., beclomethasone dipropionate, flunisolide; mast cell stabilizers, e.g., cromolyn sodium, nedocromil; anticholinergics, e.g., ipratropium bromide.
The topical bronchial compositions of the subject invention may include one or more of the following such other active drug agents: antitussives, e.g., dextromethorphan base or hydrobromide; bronchodilators, e.g., theophylline, metaproterenol, albuterol; steroidal anti-inflammatories, e.g., beclomethasone; mast cell stabilizers, e.g., cromolyn sodium.
Oral compositions of the subject invention may. include one or more of the following such other active drug agents: antihistamines, e.g., chlorpheniramine maleate, pyrilamine maleate, diphenhydramine hydrochloride, promethazine hydrochloride, doxylamine succinate, terfenadine, astemizole; decongestants, e.g., pseudoephedrine hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride; antitussives, e.g., dextromethorphan base or hydrobromide; nonsteroidal anti-inflammatories, e.g., aspirin, acetominophen, ibuprofen, naproxen; expectorants, e.g., guaifenesin; bronchodilators, e.g., theophylline, metaproterenol, albuterol; antibiotics.
Another aspect of the subject invention is a combination of a composition comprising an above compound in a container comprising a means for tophcal application of the composition to the eyes, nasal passages and sinuses, or bronchial passages and lungs. Preferred containers useful in such combinations include those comprising dropper means, spray means, or inhalation mist or powder means.
Containers comprising dropper means are useful for applying, as a liquid, either eye drops or nose drops topically to the eye or nasal passages, respectively. Such containers are well-known and commonly have such dropper means attached permanently or removably to the body of the container so that drops can be administered by inverting the container and/or by squeezing the container (the container being flexible). Another well-known dropper means is attached to a closure for the container and comprises a tube with a small hole in one end, the other end being open and attached to a flexible (e.g., rubber) bulb.
Containers comprising spray means are useful for applying a spray of liquid droplets topically directly to nasal passages. Well-known examples of such containers are flexible plastic containers having a spray nozzle fixedly attached thereto, the spray nozzle being designed for insertion into the nasal opening. When the container is squeezed, solution in the container is forced through the nozzle and emerges as a spray of droplets. Other well-known containers with spray means, e.g. pump sprays or aerosol sprays, can also be used in a similar manner.
Containers comprising inhalation mist means are useful for applying a fine mist or powder topically to nasal passages and/or bronchial passages and lungs. Such inhalers provide a fine mist or powder which can be inhaled either through the nose or the mouth, depending on the design of the inhaler. Inhalers designed for providing a mist or powder to be inhaled through the nose are useful for topical administration of compositions to nasal passages and/or bronchial passages and lungs. Inhalers designed for providing a mist or powder to be inhaled through the mouth are useful for topical administration of compositions to bronchial passages and lungs. Various containers having inhalation mist or powder means as a part of or fixedly attached to the containers are well-known, e.g., squeeze containers, pump containers, and aerosols.
The following non-limiting examples exemplify compositions and methods useful in the subject invention.
______________________________________Intranasal Composition                AmountIngredient           (weight/volume %)______________________________________Loperamide hydrochloride, U.S.P.                0.050Benzalkonium chloride                0.020Thimerosal           0.002d-Sorbitol           5.700Glycine              0.380Purified water       q.s.______________________________________
One-fifth ml of the composition of Example 1 is applied as drops from a dropper into each nostril of a patient with nasal congestion. The congestion is substantially diminished.
______________________________________Intranasal Composition                AmountIngredient           (weight/volume %)______________________________________Loperamide hydrochloride, U.S.P.                0.100Benzalkonium chloride                0.020d-Sorbitol           5.000Glycine              0.350Acetic acid (0.35  --M)                0.075Purified water       q.s.______________________________________
One-tenth ml of the composition of Example 2 is sprayed through a nozzle into each nostril of a patient with a runny nose. Nasal secretion is substantially reduced.
______________________________________Intranasal Composition                AmountIngredient           (weight/volume %)______________________________________Loperamide hydrochloride, U.S.P.                0.200Benzalkonium chloride                0.0202-Hydroxypropyl-&#946;-cyclodextrin                5.000Purified water       q.s.______________________________________
One-tenth ml of the composition of Example 3 is sprayed through a nozzle into each nostril of a patient with post-nasal drip. The post-nasal drip substantially ceases.
Patent CitationsCited PatentFiling datePublication dateApplicantTitleUS3714159 *Mar 30, 1971Jan 30, 1973Janssen Pharmaceutica Nv2,2-diaryl-4-(4'-aryl-4'-hydroxy-piper-idino)-butyramidesUS4880813 *Jul 22, 1988Nov 14, 1989Baker Cummins Pharmaceuticals, Inc.Method of treatment for allergic rhinitisWO1987002586A2 *Oct 27, 1986May 7, 1987Key PharmaMethod and composition for blocking antigen-induced allergic responses* Cited by examinerNon-Patent CitationsReference1"5450. Loperamide", The Merck Index, 11th Edition, S. Budavari, ed., p. 876.2"Drug Compendium", Comprehensive Medicinal Chemistry, vol. 6 (1990), C. Hansch, P. E. Sammes, J. B. Taylor & C. J. Drayton, eds., Pergamon Press, N.Y., pp. 628-629.3 *5450. Loperamide , The Merck Index, 11th Edition, S. Budavari, ed., p. 876.4Balkovetz, D. F., Y. Miyamoto, C. Tiruppathi, V. B. Mahesh, F. H. Leibach & V. Ganapathy, "Inhibition of Brush-border Membrane Na+ -H+ Exchanger by Loperamide", Journal of Pharmacology and Experimental Therapeutics, vol. 243, No. 1 (Oct. 1987), pp. 150-154.5 *Balkovetz, D. F., Y. Miyamoto, C. Tiruppathi, V. B. Mahesh, F. H. Leibach & V. Ganapathy, Inhibition of Brush border Membrane Na H Exchanger by Loperamide , Journal of Pharmacology and Experimental Therapeutics, vol. 243, No. 1 (Oct. 1987), pp. 150 154.6Belvisi, M. G., D. F. Rogers & P. J. Barnes, "Neurogenic Plasma Extravasation: Inhibition by Morphine in Guinea Pig Airways In Vivo", Journal of Applied Physiology, vol. 66 (1989), pp. 268-272.7 *Belvisi, M. G., D. F. Rogers & P. J. Barnes, Neurogenic Plasma Extravasation: Inhibition by Morphine in Guinea Pig Airways In Vivo , Journal of Applied Physiology, vol. 66 (1989), pp. 268 272.8Beubler, E. & P. Badhri, "Comparison of the Antisecretory Effects of Loperamide and Loperamide Oxide in the Jejunum and the Colon of Rats In-vivo", Journal of Pharmaceutics and Pharmacology, vol. 42 (1990), pp. 689-692.9 *Beubler, E. & P. Badhri, Comparison of the Antisecretory Effects of Loperamide and Loperamide Oxide in the Jejunum and the Colon of Rats In vivo , Journal of Pharmaceutics and Pharmacology, vol. 42 (1990), pp. 689 692.10Burleigh, D. E., "Opioid and Non-opioid Actions of Loperamide on Cholinergic Nerve Function in Human Isolated Colon", European Journal of Pharmacology, vol. 152 (1988), pp. 39-46.11 *Burleigh, D. E., Opioid and Non opioid Actions of Loperamide on Cholinergic Nerve Function in Human Isolated Colon , European Journal of Pharmacology, vol. 152 (1988), pp. 39 46.12Chang, E. B., D. R. Brown, N. S. Wang & M. Field, "Secretagogue-induced Changes in Membrane Calcium Permeability in Chicken and Chincilla Ileal Mucosa. Selective Inhibition by Loperamide", Journal of Clinical Investigation, vol. 78, No. 1 (Jul., 1986), pp. 281-287.13 *Chang, E. B., D. R. Brown, N. S. Wang & M. Field, Secretagogue induced Changes in Membrane Calcium Permeability in Chicken and Chincilla Ileal Mucosa. Selective Inhibition by Loperamide , Journal of Clinical Investigation, vol. 78, No. 1 (Jul., 1986), pp. 281 287.14 *Chemical Abstracts 82:106345z.15 *Drug Compendium , Comprehensive Medicinal Chemistry, vol. 6 (1990), C. Hansch, P. E. Sammes, J. B. Taylor & C. J. Drayton, eds., Pergamon Press, N.Y., pp. 628 629.16Frossard, N. & P. J. Barnes, "μ-Opioid Receptors Modulate Non-cholinergic Constrictor Nerves in Guinea-Pig Airways", European Journal of Pharmacology, vol. 141 (1987), pp. 519-522.17 *Frossard, N. & P. J. Barnes, Opioid Receptors Modulate Non cholinergic Constrictor Nerves in Guinea Pig Airways , European Journal of Pharmacology, vol. 141 (1987), pp. 519 522.18Geppetti, P., B. M. Fusco, S. Marabini, C. A. Maggi, M. Fanciullaci & F. Sicuteri, "Secretion, Pain and Sneezing Induced by the Application of Capsaicin in the Nasal Mucosa in Man", British Journal of Pharmacology, vol. 93 (1988), pp. 509-514.19 *Geppetti, P., B. M. Fusco, S. Marabini, C. A. Maggi, M. Fanciullaci & F. Sicuteri, Secretion, Pain and Sneezing Induced by the Application of Capsaicin in the Nasal Mucosa in Man , British Journal of Pharmacology, vol. 93 (1988), pp. 509 514.20Giagnoni, G., L. Casiraghi, R. Senini, L. Revel, D. Parolaro, M. Sala & E. Gori, "Loperamide: Evidence of Interaction with μ and delta Opioid Receptors", Life Sciences, vol. 33, Suppl. 1 (1983), pp. 315-318.21 *Giagnoni, G., L. Casiraghi, R. Senini, L. Revel, D. Parolaro, M. Sala & E. Gori, Loperamide: Evidence of Interaction with and delta Opioid Receptors , Life Sciences, vol. 33, Suppl. 1 (1983), pp. 315 318.22Haag, K., R. Lubcke, H. Knauf, E. Berger & W. Gerok, "Determination of Rheogenic Ion Transport in Rat Proximal Colon In Vivo", Pflugers Arch., vol. 405, Suppl. 1 (1985), pp. S67-S70.23 *Haag, K., R. Lubcke, H. Knauf, E. Berger & W. Gerok, Determination of Rheogenic Ion Transport in Rat Proximal Colon In Vivo , Pflugers Arch., vol. 405, Suppl. 1 (1985), pp. S67 S70.24Hantz, E., A. Cao, R. S. Phadke & E. Taillandier, "The Effect of Loperamide on the Thermal Behavior of Dimyristoylphosphatidylcholine Large Unilamellar Vesicles", Chemistry and Physics of Lipids (Ireland), vol. 51, No. 2 (Oct. 1989), pp. 78-82.25 *Hantz, E., A. Cao, R. S. Phadke & E. Taillandier, The Effect of Loperamide on the Thermal Behavior of Dimyristoylphosphatidylcholine Large Unilamellar Vesicles , Chemistry and Physics of Lipids (Ireland), vol. 51, No. 2 (Oct. 1989), pp. 78 82.26Hardcastle, J., P. T. Hardcastle & J. Cookson, "Inhibitory Actions of Loperamide on Absorptive Processes in Rat Small Intestine", Gut, vol. 27, No. 6 (Jun. 1986), pp. 686-694.27 *Hardcastle, J., P. T. Hardcastle & J. Cookson, Inhibitory Actions of Loperamide on Absorptive Processes in Rat Small Intestine , Gut, vol. 27, No. 6 (Jun. 1986), pp. 686 694.28Hardcastle, J., P. T. Hardcastle & J. Goldhill, "The Effect of Loperamide Oxide on Prostaglandin-Stimulated Fluid Transport in Rat Small Intestine", Journal of Pharmaceutics and Pharmacology, vol. 42, No. 5 (May, 1990), pp. 364-366.29 *Hardcastle, J., P. T. Hardcastle & J. Goldhill, The Effect of Loperamide Oxide on Prostaglandin Stimulated Fluid Transport in Rat Small Intestine , Journal of Pharmaceutics and Pharmacology, vol. 42, No. 5 (May, 1990), pp. 364 366.30Hardcastle, J., P. T. Hardcastle, N. W. Read & J. S. Redfern, "The Action of Loperamide in Inhibiting Prostaglandin-induced Intestinal Secretion in the Rat", British Journal of Pharmacology, vol. 74, No. 3 (Nov. 1981), pp. 563-569.31 *Hardcastle, J., P. T. Hardcastle, N. W. Read & J. S. Redfern, The Action of Loperamide in Inhibiting Prostaglandin induced Intestinal Secretion in the Rat , British Journal of Pharmacology, vol. 74, No. 3 (Nov. 1981), pp. 563 569.32Hughes, S., N. B. Higgs & L. A. Turnberg, "Antidiarrheal Activity of Loperamide: Studies of its Influence on Ion Transport Across Rabbit Ileal Mucosa In Vitro", Gut, vol. 23, No. 11 (Nov. 1982), pp. 974-979.33 *Hughes, S., N. B. Higgs & L. A. Turnberg, Antidiarrheal Activity of Loperamide: Studies of its Influence on Ion Transport Across Rabbit Ileal Mucosa In Vitro , Gut, vol. 23, No. 11 (Nov. 1982), pp. 974 979.34Kachur, J. F., D. W. Morgan & T. S. Gaginella, "Effect of Dextromethorphan on Guinea Pig Ileal Contractility In Vitro: Comparison with Levomethorphan, Loperamide and Codeine", Journal of Pharmacology and Experimental Therapeutics, vol. 239, No. 3 (Dec. 1986), pp. 661-667.35 *Kachur, J. F., D. W. Morgan & T. S. Gaginella, Effect of Dextromethorphan on Guinea Pig Ileal Contractility In Vitro: Comparison with Levomethorphan, Loperamide and Codeine , Journal of Pharmacology and Experimental Therapeutics, vol. 239, No. 3 (Dec. 1986), pp. 661 667.36Knauf, H. & K. Haag, "Modelling of Colonic Cl- and K+ Transport Under Resting and Secreting Conditions", Pflugers Arch., vol. 407, Supplement 2 (1986), pp. S85-S89.37 *Knauf, H. & K. Haag, Modelling of Colonic Cl and K Transport Under Resting and Secreting Conditions , Pflugers Arch., vol. 407, Supplement 2 (1986), pp. S85 S89.38Mackerer, C. R., G. A. Clay & E. Z. Dajani, "Loperamide Binding to Opiate Receptor Sites of Brain and Myenteric Plexus", Journal of Pharmacology and Experimental Therapeutics, vol. 199, No. 1 (1976), pp. 131-140.39 *Mackerer, C. R., G. A. Clay & E. Z. Dajani, Loperamide Binding to Opiate Receptor Sites of Brain and Myenteric Plexus , Journal of Pharmacology and Experimental Therapeutics, vol. 199, No. 1 (1976), pp. 131 140.40 *Marcais Collado, H., G. Uchida, J. Costentin, J. C. Schwartz & J. M. Lecompte, Naloxone reversible Antidiarrheal Effects of Enkephalinase Inhibitors , European Journal of Pharmacology, vol. 144, No. 2 (Dec. 1, 1987), pp. 125 132.41Marcais-Collado, H., G. Uchida, J. Costentin, J. C. Schwartz & J. M. Lecompte, "Naloxone-reversible Antidiarrheal Effects of Enkephalinase Inhibitors", European Journal of Pharmacology, vol. 144, No. 2 (Dec. 1, 1987), pp. 125-132.42Marsboom, R., V. Herin, A. Verstraeten, R. Vandesteene & J. Fransen, "Loperamide, a Novel Type of Antidiarrheal Agent. Part 4: Studies on Subacute and Chronic Toxicity and the Effect on Reproductive Processes in Rats, Dogs and Rabbits", Arzneimittelforschung, vol. 24, No. 10 (Oct. 1974), pp. 1645-1649.43 *Marsboom, R., V. Herin, A. Verstraeten, R. Vandesteene & J. Fransen, Loperamide, a Novel Type of Antidiarrheal Agent. Part 4: Studies on Subacute and Chronic Toxicity and the Effect on Reproductive Processes in Rats, Dogs and Rabbits , Arzneimittelforschung, vol. 24, No. 10 (Oct. 1974), pp. 1645 1649.44 *Matran, R., C. R. Martling & J. M. Lundberg, Inhibition of Cholinergic and Non adrenergic, Non cholinergic Bronchoconstriction in the Guinea Pig Mediated by Neuropeptide Y and 2 adrenoceptors and Opiate Receptors , European Journal of Pharmacology, vol. 163 (1989), pp. 15 23.45Matran, R., C.-R. Martling & J. M. Lundberg, "Inhibition of Cholinergic and Non-adrenergic, Non-cholinergic Bronchoconstriction in the Guinea Pig Mediated by Neuropeptide Y and α2 -adrenoceptors and Opiate Receptors", European Journal of Pharmacology, vol. 163 (1989), pp. 15-23.46Megans, A. A., L. L. Canters, F. H. Awouters & C. J. Niemegeers, "Is In Vivo Dissociation Between the Antipropulsive and Antidiarrheal Properties of Opioids in Rats Related to Gut Selectivity?", Arch. Int. Pharmacodyn., vol. 298 (Mar.-Apr., 1989), pp. 220-229.47 *Megans, A. A., L. L. Canters, F. H. Awouters & C. J. Niemegeers, Is In Vivo Dissociation Between the Antipropulsive and Antidiarrheal Properties of Opioids in Rats Related to Gut Selectivity , Arch. Int. Pharmacodyn., vol. 298 (Mar. Apr., 1989), pp. 220 229.48Megens, A. A., L. L. Canters, F. H. Awouters & C. J. Neimegeers, "Normalization of Small Intestinal Propulsion with Loperamide-like Antidiarrheals in Rats", European Journal of Pharmacology, vol. 17, (1990), pp. 357-364.49 *Megens, A. A., L. L. Canters, F. H. Awouters & C. J. Neimegeers, Normalization of Small Intestinal Propulsion with Loperamide like Antidiarrheals in Rats , European Journal of Pharmacology, vol. 17, (1990), pp. 357 364.50Mellstrand, T., "Loperamide--An Opiate Receptor Agonist with Gastrointestinal Motility Effects", Scand. J. Gastroenterol. Suppl., vol. 130 (1987), pp. 65-66.51 *Mellstrand, T., Loperamide An Opiate Receptor Agonist with Gastrointestinal Motility Effects , Scand. J. Gastroenterol. Suppl., vol. 130 (1987), pp. 65 66.52Miller, R. J., D. R. Brown, E. B. Chang & D. D. Friel, "The Pharmacological Modification of Secretory Responses", Ciba Found. Symp., vol. 112 (1985), pp. 155-174.53 *Miller, R. J., D. R. Brown, E. B. Chang & D. D. Friel, The Pharmacological Modification of Secretory Responses , Ciba Found. Symp., vol. 112 (1985), pp. 155 174.54Mudge, A. W., S. E. Leeman & G. D. Fischbach, "Enkephalin Inhibits Release of Substance P from Sensory Neurons in Culture and Decreases Action Potential Duration", Proceedings of the National Academy of Science, USA, vol. 76, No. 1 (Jan. 1979), pp. 526-530.55 *Mudge, A. W., S. E. Leeman & G. D. Fischbach, Enkephalin Inhibits Release of Substance P from Sensory Neurons in Culture and Decreases Action Potential Duration , Proceedings of the National Academy of Science, USA, vol. 76, No. 1 (Jan. 1979), pp. 526 530.56Nakayama, S., T. Yamasato & M. Mitzutani, "Effects of Loperamide on the Motility of the Isolated Intestine in Guinea Pigs, Rats and Dogs", Jap. J. Smooth Muscle Res., vol. 13, No. 2 (Jun., 1977), pp. 69-74.57 *Nakayama, S., T. Yamasato & M. Mitzutani, Effects of Loperamide on the Motility of the Isolated Intestine in Guinea Pigs, Rats and Dogs , Jap. J. Smooth Muscle Res., vol. 13, No. 2 (Jun., 1977), pp. 69 74.58Niemegeers, C. J. E., F. Awouters, F. M. Lenaerts, K. S. K. Artois & J. Vermeire, "Antidiarrheal Specificity and Safety of the N-Oxide of Loperamide (R 58 425) in Rats", Drug Development Research, vol. 8 (1986), pp. 279-286.59 *Niemegeers, C. J. E., F. Awouters, F. M. Lenaerts, K. S. K. Artois & J. Vermeire, Antidiarrheal Specificity and Safety of the N Oxide of Loperamide (R 58 425) in Rats , Drug Development Research, vol. 8 (1986), pp. 279 286.60Niemegeers, C. J., F. M. Lenaerts & P. A. Janssen, "Loperamide, a Novel Type of Antidiarrheal Agent. Part 1: In Vivo Oral Pharmacology and Acute Toxicity. Comparison with Morphine, Codeine, Diphenoxylate and Difenoxine", Arzneimittelforschung, vol. 24, No. 10 (Oct. 1974), pp. 1633-1636.61Niemegeers, C. J., F. M. Lenaerts & P. A. Janssen, "Loperamide, a Novel Type of Antidiarrheal Agent. Part 2: In Vivo Parenteral Pharmacology and Acute Toxicity in Mice. Comparison with Morphine, Codeine, and Diphenoxylate", Arzneimittelforschung, vol. 24, No. 10 (Oct. 1974), pp. 1636-1641.62 *Niemegeers, C. J., F. M. Lenaerts & P. A. Janssen, Loperamide, a Novel Type of Antidiarrheal Agent. Part 1: In Vivo Oral Pharmacology and Acute Toxicity. Comparison with Morphine, Codeine, Diphenoxylate and Difenoxine , Arzneimittelforschung, vol. 24, No. 10 (Oct. 1974), pp. 1633 1636.63 *Niemegeers, C. J., F. M. Lenaerts & P. A. Janssen, Loperamide, a Novel Type of Antidiarrheal Agent. Part 2: In Vivo Parenteral Pharmacology and Acute Toxicity in Mice. Comparison with Morphine, Codeine, and Diphenoxylate , Arzneimittelforschung, vol. 24, No. 10 (Oct. 1974), pp. 1636 1641.64 *Physicians Desk Reference for Nonprescription Drugs, 12th Ed. (1990), E. R. Barnhardt, pub., p. 599.65Physicians' Desk Reference for Nonprescription Drugs, 12th Ed. (1990), E. R. Barnhardt, pub., p. 599.66Sandhu, B. K., P. J. Milla & J. T. Harries, "Mechanisms of Action of Loperamide", Scand. J. Gastroenterol. Suppl., vol. 84 (1983), pp. 85-92.67 *Sandhu, B. K., P. J. Milla & J. T. Harries, Mechanisms of Action of Loperamide , Scand. J. Gastroenterol. Suppl., vol. 84 (1983), pp. 85 92.68Saria, A., "Neuroimmune Interactions in the Airways: Implications for Asthma, Allergy and Other Inflammatory Airway Diseases", Brain, Behavior, and Immunity, vol. 2 (1988), pp. 318-321.69 *Saria, A., Neuroimmune Interactions in the Airways: Implications for Asthma, Allergy and Other Inflammatory Airway Diseases , Brain, Behavior, and Immunity, vol. 2 (1988), pp. 318 321.70Stahl, K. D., W. Van Bever, P. Janssen & E. J. Simon, "Receptor Affinity and Pharmacological Potency of a Series of Narcotic Analgesic, Anti-Diarrheal and Neuroleptic Drugs", European Journal of Pharmacology, vol. 46 (1977), pp. 199-205.71Stahl, K. D., W. van Bever, P. Janssen & E. J. Simon, "Receptor Affinity and Pharmacological Potency of a Series of Narcotic Analgesic, Anti-diarrheal and Neuroleptic Drugs", European Journal of Pharmacology, vol. 46, No. 3 (Dec. 1, 1977), pp. 199-205.72 *Stahl, K. D., W. Van Bever, P. Janssen & E. J. Simon, Receptor Affinity and Pharmacological Potency of a Series of Narcotic Analgesic, Anti Diarrheal and Neuroleptic Drugs , European Journal of Pharmacology, vol. 46 (1977), pp. 199 205.73 *Stahl, K. D., W. van Bever, P. Janssen & E. J. Simon, Receptor Affinity and Pharmacological Potency of a Series of Narcotic Analgesic, Anti diarrheal and Neuroleptic Drugs , European Journal of Pharmacology, vol. 46, No. 3 (Dec. 1, 1977), pp. 199 205.74Stjarne, P., L. Lundblad, J. M. Lundberg & A. Anggard, "Capsaicin and Nicotine-Sensitive Afferent Neurons and Nasal Secretion in Healthy Human Volunteers and in Patients with Vasomotor Rhinitis", British Journal of Pharmacology, vol. 96 (1989), pp. 693-701.75 *Stjarne, P., L. Lundblad, J. M. Lundberg & A. Anggard, Capsaicin and Nicotine Sensitive Afferent Neurons and Nasal Secretion in Healthy Human Volunteers and in Patients with Vasomotor Rhinitis , British Journal of Pharmacology, vol. 96 (1989), pp. 693 701.76Stoll, R., H. Ruppin & W. Domschke, "Calmodulin-mediated Effects of Loperamide on Chloride Transport by Brush Border Membrane Vesicles from Human Ileum", Gastroenterology, vol. 95, No. 1 (Jul. 1988), pp. 69-76.77 *Stoll, R., H. Ruppin & W. Domschke, Calmodulin mediated Effects of Loperamide on Chloride Transport by Brush Border Membrane Vesicles from Human Ileum , Gastroenterology, vol. 95, No. 1 (Jul. 1988), pp. 69 76.78Stoll, R., H. Stern, H. Ruppin & W. Domschke, "Effect of Two Potent Calmodiun Antagonists on Calcium Transport of Brush Border and Basolateral Vesicles for Human Duodenum", Aliment. Pharmacol. Ther., vol. 1, No. 5 (1987), pp. 415-424, (Abstract only).79 *Stoll, R., H. Stern, H. Ruppin & W. Domschke, Effect of Two Potent Calmodiun Antagonists on Calcium Transport of Brush Border and Basolateral Vesicles for Human Duodenum , Aliment. Pharmacol. Ther., vol. 1, No. 5 (1987), pp. 415 424, (Abstract only).80Tamaoki, J., N. Sakai, K. Isono & T. Takizawa, "Inhibition by Loperamide of Chloride Transport Across Canine Cultured Tracheal Epithelium", European Journal of Pharmacology, vol. 190 (1990), pp. 255-258.81 *Tamaoki, J., N. Sakai, K. Isono & T. Takizawa, Inhibition by Loperamide of Chloride Transport Across Canine Cultured Tracheal Epithelium , European Journal of Pharmacology, vol. 190 (1990), pp. 255 258.82Turnberg, L. A., "Antisecretory Activity of Opiates In Vitro and In Vivo in Man", Scand. J. Gastroenterol. Suppl., vol. 84 (1983), pp. 79-83.83 *Turnberg, L. A., Antisecretory Activity of Opiates In Vitro and In Vivo in Man , Scand. J. Gastroenterol. Suppl., vol. 84 (1983), pp. 79 83.84Turnheim, K., "Antidiarrheal Agents: Tools and Therapeutics", Z. Gastroenterol. (West Germany), vol. 27, No. 2 (Feb. 1989), pp. 112-119.85 *Turnheim, K., Antidiarrheal Agents: Tools and Therapeutics , Z. Gastroenterol. (West Germany), vol. 27, No. 2 (Feb. 1989), pp. 112 119.86VanNueten, J. M., P. A. J. Janssen & J. Fontaine, "Loperamide, a Novel Type of Antidiarrheal Agent. Part 3: In Vitro Studies on the Peristaltic Reflex and Other Experiments on Isolated Tissues", Arznneimittelforschung, vol. 24, No. 10 (Oct. 1974), pp. 1641-1645.87 *VanNueten, J. M., P. A. J. Janssen & J. Fontaine, Loperamide, a Novel Type of Antidiarrheal Agent. Part 3: In Vitro Studies on the Peristaltic Reflex and Other Experiments on Isolated Tissues , Arznneimittelforschung, vol. 24, No. 10 (Oct. 1974), pp. 1641 1645.88Verhaeren, E. H., M. J. Dreessen & J. A. Lemli, "Influence of 1,8-Dihydroxyanthraquinone and Loperamide on the Paracellular Permeability Across Colonic Mucosa", Journal of Pharmaceutics and Pharmacology, vol. 33, No. 8 (Aug. 1981), pp. 526-528.89 *Verhaeren, E. H., M. J. Dreessen & J. A. Lemli, Influence of 1,8 Dihydroxyanthraquinone and Loperamide on the Paracellular Permeability Across Colonic Mucosa , Journal of Pharmaceutics and Pharmacology, vol. 33, No. 8 (Aug. 1981), pp. 526 528.90Wehner, F., "Membrane Effects of Loperamide in Absorbing and Secreting Guinea-Pig Gallbladder Epithelium", Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 335, Supplement (1987), p. R45.91Wehner, F., J. M. Winterhager & K. U. Petersen, "Selective Blockage of Cell Membrane K Conductance by an Antisecretory Agent in Guinea-Pig Gallbladder Epithelium", Pflugers Arch. (West Germany), vol. 414, No. 3 (Jul. 1989), pp. 331-339.92 *Wehner, F., J. M. Winterhager & K. U. Petersen, Selective Blockage of Cell Membrane K Conductance by an Antisecretory Agent in Guinea Pig Gallbladder Epithelium , Pflugers Arch. (West Germany), vol. 414, No. 3 (Jul. 1989), pp. 331 339.93 *Wehner, F., Membrane Effects of Loperamide in Absorbing and Secreting Guinea Pig Gallbladder Epithelium , Naunyn Schmiedeberg s Archives of Pharmacology, vol. 335, Supplement (1987), p. R45.94Wolf, G., "New Aspects in the Pathogenesis and Treatment of Hyperreactive Rhinopathy", Laryng, Rhinol. Otol., vol. 67 (1988), pp. 438-445.95 *Wolf, G., New Aspects in the Pathogenesis and Treatment of Hyperreactive Rhinopathy , Laryng, Rhinol. Otol., vol. 67 (1988), pp. 438 445.96Wuster, M. & A. Herz, "Opiate Agonist Action of Antidiarrheal Agents In Vitro and In Vivo--Findings in Support for Selective Action", Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 301 (1978), pp. 187-194.97 *Wuster, M. & A. Herz, Opiate Agonist Action of Antidiarrheal Agents In Vitro and In Vivo Findings in Support for Selective Action , Naunyn Schmiedeberg s Archives of Pharmacology, vol. 301 (1978), pp. 187 194.* Cited by examinerReferenced byCiting PatentFiling datePublication dateApplicantTitleUS5599577 *May 31, 1995Feb 4, 1997Mcneil-Ppc, Inc.Simethicone containing pharmaceutical compositionsUS5849761 *Sep 12, 1995Dec 15, 1998Regents Of The University Of CaliforniaPeripherally active anti-hyperalgesic opiatesUS5849762 *Jul 14, 1997Dec 15, 1998Adolor CorporationPeripherally acting anti-pruritic opiatesUS5874450 *Sep 29, 1997Feb 23, 1999Nastech Pharmaceutical Company, Inc.Intranasal formulations for promoting sleep and method of using the sameUS5897858 *Nov 4, 1997Apr 27, 1999Schering-Plough Healthcare Products, Inc.Nasal spray compositions exhibiting increased retention in the nasal cavityUS5962477 *Jun 15, 1998Oct 5, 1999Adolor CorporationScreening methods for cytokine inhibitorsUS5994372 *Sep 12, 1996Nov 30, 1999Regents Of The University Of CaliforniaPeripherally active anti-hyperalgesic opiatesUS6086914 *Mar 12, 1999Jul 11, 2000Weinstein; Robert E.Nonsedating formulations for allergic rhinitis which possess antihistaminic and anticholinergic activityUS6166039 *Nov 24, 1998Dec 26, 2000Regents Of The Univ. Of CaliforniaPeripherally active anti-hyperalgesic opiatesUS6190691 *Jun 15, 1998Feb 20, 2001Adolor CorporationMethods for treating inflammatory conditionsUS6316483 *Nov 5, 1999Nov 13, 2001Schering CorporationOxymetazoline HCI and/or chlorpheniramine maleate nasal spray compositionsUS6355657Dec 30, 1999Mar 12, 2002Atrix Laboratories, Inc.System for percutaneous delivery of opioid analgesicsUS6451806 *Nov 29, 2000Sep 17, 2002Adolor CorporationMethods and compositions involving opioids and antagonists thereofUS6573282Aug 16, 1999Jun 3, 2003Adolor CorporationPeripherally active anti-hyperalgesic opiatesUS6576650Oct 23, 2000Jun 10, 2003Regents Of The University Of CaliforniaPeripherally active anti-hyperalgesic opiatesUS6608073Oct 1, 1999Aug 19, 2003New Millennium Pharmaceutical Research, Inc.Intranasal codeine for the rapid suppression of cough and rapid relief of painUS6824762 *Aug 28, 2001Nov 30, 2004Schering-Plough Healthcare Products Inc.Nasal spray compositionsUS8481559Oct 14, 2010Jul 9, 2013The Research Foundation Of State University Of New YorkMorphine and morphine precursorsUS8815890Aug 31, 2007Aug 26, 2014Robert E. WeinsteinRhinitis treatment regimensUS8865696Jun 21, 2013Oct 21, 2014The Research Foundation For The State University Of New YorkMorphine and morphine precursorsDE4218291A1 *Jun 3, 1992Dec 9, 1993Mattern Et Partner PharmazeutiDosierspray f�r pernasale ApplikationEP0852494A2 *Sep 12, 1996Jul 15, 1998Adolor CorporationPeripherally active anti-hyperalgesic opiatesEP0937460A2 *Apr 11, 1995Aug 25, 1999Adolor CorporationUse of an antidiarrheal for the manufacture of a medicament for the treatment of inflammatory conditionsEP1011647A1 *Jun 19, 1998Jun 28, 2000Adolor CorporationSpray formulations of antihyperalgesic opiates and method of treating topical hyperalgesic conditions and pruritus therewithWO1999003472A1 *Jun 19, 1998Jan 28, 1999Adolor CorpPeripherally acting anti-pruritic opiatesWO2000021515A2 *Oct 14, 1999Apr 20, 2000New Millennium PharmaceuticalIntranasal codeine for the rapid suppression of cough and rapid relief of painWO2009049242A1 *Oct 10, 2008Apr 16, 2009Harvard CollegeAutophagy inducing compounds and uses thereof in treating autophagy associated diseases* Cited by examinerClassifications U.S. Classification514/327, 514/849, 514/853International ClassificationA61K31/445, A61K9/00Cooperative ClassificationY10S514/853, Y10S514/849, A61K9/0043, A61K31/445European ClassificationA61K9/00M14, A61K31/445Legal EventsDateCodeEventDescriptionSep 26, 2000FPExpired due to failure to pay maintenance feeEffective date: 20000526May 28, 2000LAPSLapse for failure to pay maintenance feesDec 21, 1999REMIMaintenance fee reminder mailedSep 26, 1995FPAYFee paymentYear of fee payment: 4Jan 11, 1994CCCertificate of correctionFeb 19, 1991ASAssignmentOwner name: PROCTER & GAMBLE COMPANY, THEFree format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:GILBERT, SHERI A.;MIZOGUCHI, HARUKO;CHAREST, ROBERT P.;AND OTHERS;REEL/FRAME:005602/0540Effective date: 19910125RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services