US2918408A - Anti-spasmodic compositions specific for treating spasm of the colon - Google Patents

Anti-spasmodic compositions specific for treating spasm of the colon Download PDF

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US2918408A
US2918408A US651167A US65116757A US2918408A US 2918408 A US2918408 A US 2918408A US 651167 A US651167 A US 651167A US 65116757 A US65116757 A US 65116757A US 2918408 A US2918408 A US 2918408A
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methyl
spasmodic
colon
piperidyl benzilate
spasm
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US651167A
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John H Biel
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LAKESIDE LAB Inc
LAKESIDE LABORATORIES Inc
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LAKESIDE LAB Inc
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    • 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

Definitions

  • This invention relates to an ester of cyclic amino-alcohols and particularly to the benzilic acid ester of N- methyl-3-hydroxypiperidine, non-toxic methonium derivatives thereof, and pharmaceutical compositions of the same.
  • N-alkyl-4-piperidinol Some esters of N-alkyl-4-piperidinol have been found to be active anti-spasmodics or spasmolytics, but such esters have never been put into use. It is well known that changes in the positions of certain substituents on the piperidine ring may produce profound differences in the physiological activity and effects of such compounds, which differences are not predictable. Thus, N-methyl- 4-phenyl-4-propionoxypiperidine is a potent analgesic whereas the corresponding N-methyl-2-phenyl-2-propionoxy-piperidine has only slight anagesic properties and beta4-methyl-piperidine-ethyl benzoate has considerable anesthetic action while the 2 and 3-methyl derivatives have no such action. Hence, it will be seen that shifting a group from the 4-position of the piperidine ring may cause complete loss of activity.
  • an object of the present invention to provide a compound for pharmaceutical purposes and having the effect of reducing either involuntary muscle or nervous spasm.
  • Another object of the invention is to provide a compound having an anti-spasmodic effect in humans, which compound is long-lasting in action and which will have only a few undesirable side reactions of minor importance.
  • a further object of the invention is to provide a series of substituted acetic acid esters of N-methyl-3-piperidinol having longer activity and side reactions both less in numher and of lower intensity than other compounds now in use for reducing spasm of human muscle or nerves.
  • N-methyl-3-piperidyl benzilate of the formula in the form of non-toxic methonium salts is effective as an anti-spasmodic in both musculotropic and 'n'eurotropic spasms and has long duration of action with fewer undesirable side effects than various other anti-spasmodic; now used.
  • N-methyl-3-piperidyl benzilate methonium compounds have a unique, highly selective antispasmodic action in the lower part of the gastro-intestinal tract, i.e., the colon.
  • N-methyl-3-piperidyl benzilate methyl bromide is the first spasmolytic product which has ever been approved by the Food and Drug Administration as an agent which is selective for colonic disorders.
  • N-methyl-3-piperidyl benzilate methyl bromide salt has been established by thorough clinical investigations to be selective in the colon. Thus, it has been found to restore normal tone and motility in ulcerative colitis, irritable colon, mucous colitis, spastic colitis, diverticulitis, diverticuloses, and diarrhea following gastrointestinal surgery, and rectospasm while relieving pain, cramp, bloating and spasm avoiding urinary retention, dry mouth and visual difiiculties.
  • N-methyl-3-piperidyl benzilate may be prepared by preparing a mixture N-methyl of 3-chloro-piperidine and benzilic acid in isopropanol and refluxing the mixture. After filtering and concentrating the reaction mixture in vacuo it is added to water, acidified and the unreacted acid removed with ether. After neutralizing the aqueous layer, the product is extracted with ether and the solution dried. After removing the ether the free base is obtained by vacuum distillation.
  • the methonium salts of N-methyl-3piperidyl benzilate are readily formed by contacting the free base with a methylating agent in the presence of a suitable solvent such as an hydrous ether.
  • a suitable solvent such as an hydrous ether.
  • the desired salt forms quickly and generally precipitates from solution.
  • the methyl iodide, methyl bromide, methyl chloride and methyl sulfate salts may be formed.
  • the methonium salts which may be formed have the formula distillation in vacuo, the residue treated with dilute aqueous hydrochloric acid and the aqueous acid mixture exitracted repeatedly with ether.
  • the aqueous phase was separated, made 'strongly alkaline with 20% aqueous sodium hydroxide and extracted with ether.
  • the ether extracts" were dried with potassium carbonate and distilled; the product was collected at 175176 C. (0.03 mm.), yield 11.5 g. (59%).
  • Example 1 The ester base of Example 1 was dissolved in. 75 cc. of isopropyl alcohol and 3.4 g. (0.037 mole) methyl bromide added. The reaction mixture was allowed to stand at 30 C. for two days and the product isolated by filtration, yield, 13 g. (87%), MP. 228-229 C. dec.
  • the anti-spasmodic activity of methonium salts of N- methyI-B-piperidyl benzilate is about equal to atropine but is free of the side effects normally inherent with atropine therapy.
  • the therapeutic dose of methonium salts of N-methyl-3-piperidyl benzilate is generally in the range of to 50 mgm. per dose and may be administered at intervals throughout the day as needed although four doses a day are usually found to be highly satisfactory. The optimum dosage from all viewpoints appears to be 25 mgm. four times a day. Such dosages are of course administered orally, and preferably in tablet, capsule, or
  • Standard carriers like starch and sugar may be used as well as the ordinary lubricants, binders, and
  • disintegrating agents as are required to form tablets.
  • a pharmaceutical composition in unit dosage form adapted for human anti-spasmodic treatment without causing significant dryness of the mouth and dilation of the eye pupil comprising a member of the group consisting of N-methyl-3-piperidyl benzilate and compounds of the formula 1 ad p for-human pas diaucatmentwi hout sai s- 4 ing significant dryness of the mouth and dilation of the eye pupil comprising N-methyl-3-piperidyl benzilate methyl bromide and a pharmaceutical carrier.
  • a pharmaceutical composition in unit dosage form 5 adapted for human anti-spasmodic treatment without caus ing significant dryness of the mouth and dilation of the eye pupil comprising N-methyl-3-piperidyl benzilate methyl chloride and a pharmaceutical carrier.
  • An anti-spasmmodic pharmaceutical composition in unit dosage form adapted for human anti-spasmodic treatment without causing significant dryness of the mouth and dilation of the eye pupil comprising N-methyl-3- piperidyl benzilate methyl iodide and a pharmaceutical carrier.
  • An anti-spasmodic pharmaceutical composition in unit dosage form adapted for human anti-spasmodic treatment without causing significant dryness of the mouth and dilation of the eye pupil comprising N-methyl-3- piperidyl benzilate methyl sulfate and a pharmaceutical carrier.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Description

United States Patent ANTI-SPASMODIC COMPOSITIONS SPECIFIC FOR TREATING SPASM OF THE COLON John H. Biel, Milwaukee, Wis., assignor to Lakeside Laboratories, Inc., a corporation of Wisconsin No Drawing. Application April 8, 1957 Serial No. 651,167
15 Claims. (Cl. 167-65) This invention relates to an ester of cyclic amino-alcohols and particularly to the benzilic acid ester of N- methyl-3-hydroxypiperidine, non-toxic methonium derivatives thereof, and pharmaceutical compositions of the same.
This application is a continuation-in-part of application Serial No. 2l7,4l3, filed March 24, 1951 which in turn is a continuation-impart of application Serial No. 180,295 filed August 18, 1950, now abandoned.
The reduction of smooth muscle spasm, whether of musculotropic or neurotropic origin, by atropine and by various synthetic compounds related in structure to atropine or papaverine, is well known. While many of these compounds will effectively abolish one or the other type of spasm, they are not capable of relieving both types of muscle spasm. Furthermore, the action of the known compounds is usually accompanied by undesirable side effects such as dilation of the pupil of the eye, dryness of the mouth, large increase in rate of heart beat, hypertension, nausea, and vomiting.
Some esters of N-alkyl-4-piperidinol have been found to be active anti-spasmodics or spasmolytics, but such esters have never been put into use. It is well known that changes in the positions of certain substituents on the piperidine ring may produce profound differences in the physiological activity and effects of such compounds, which differences are not predictable. Thus, N-methyl- 4-phenyl-4-propionoxypiperidine is a potent analgesic whereas the corresponding N-methyl-2-phenyl-2-propionoxy-piperidine has only slight anagesic properties and beta4-methyl-piperidine-ethyl benzoate has considerable anesthetic action while the 2 and 3-methyl derivatives have no such action. Hence, it will be seen that shifting a group from the 4-position of the piperidine ring may cause complete loss of activity.
It is, therefore. an object of the present invention to provide a compound for pharmaceutical purposes and having the effect of reducing either involuntary muscle or nervous spasm.
Another object of the invention is to provide a compound having an anti-spasmodic effect in humans, which compound is long-lasting in action and which will have only a few undesirable side reactions of minor importance.
A further object of the invention is to provide a series of substituted acetic acid esters of N-methyl-3-piperidinol having longer activity and side reactions both less in numher and of lower intensity than other compounds now in use for reducing spasm of human muscle or nerves.
I have found that N-methyl-3-piperidyl benzilate of the formula in the form of non-toxic methonium salts is effective as an anti-spasmodic in both musculotropic and 'n'eurotropic spasms and has long duration of action with fewer undesirable side effects than various other anti-spasmodic; now used.
Surprisingly, N-methyl-3-piperidyl benzilate methonium compounds have a unique, highly selective antispasmodic action in the lower part of the gastro-intestinal tract, i.e., the colon. N-methyl-3-piperidyl benzilate methyl bromide is the first spasmolytic product which has ever been approved by the Food and Drug Administration as an agent which is selective for colonic disorders.
Such unexpected activity in the colon is even more surprising because the next adjacent homolog N-ethyl-3- piperidyl benzilate, as the methyl bromide, does not display activity in the colon but is a selective agent for peptic ulcer in the stomach and duodenum because of its action in suppressing gastric secretion and motility in this area.
The N-methyl-3-piperidyl benzilate methyl bromide salt has been established by thorough clinical investigations to be selective in the colon. Thus, it has been found to restore normal tone and motility in ulcerative colitis, irritable colon, mucous colitis, spastic colitis, diverticulitis, diverticuloses, and diarrhea following gastrointestinal surgery, and rectospasm while relieving pain, cramp, bloating and spasm avoiding urinary retention, dry mouth and visual difiiculties.
N-methyl-3-piperidyl benzilate may be prepared by preparing a mixture N-methyl of 3-chloro-piperidine and benzilic acid in isopropanol and refluxing the mixture. After filtering and concentrating the reaction mixture in vacuo it is added to water, acidified and the unreacted acid removed with ether. After neutralizing the aqueous layer, the product is extracted with ether and the solution dried. After removing the ether the free base is obtained by vacuum distillation.
The methonium salts of N-methyl-3piperidyl benzilate are readily formed by contacting the free base with a methylating agent in the presence of a suitable solvent such as an hydrous ether. The desired salt forms quickly and generally precipitates from solution. In this way, the methyl iodide, methyl bromide, methyl chloride and methyl sulfate salts may be formed. The methonium salts which may be formed have the formula distillation in vacuo, the residue treated with dilute aqueous hydrochloric acid and the aqueous acid mixture exitracted repeatedly with ether. The aqueous phase was separated, made 'strongly alkaline with 20% aqueous sodium hydroxide and extracted with ether. The ether extracts" were dried with potassium carbonate and distilled; the product was collected at 175176 C. (0.03 mm.), yield 11.5 g. (59%). The hydrochloride salt analyzed as follows:
Analysis.Calcd. for C H ClNO Cl, 9.78-; N, 3.87. Found: Cl, 9.73; N, 3.76.
The ester base of Example 1 was dissolved in. 75 cc. of isopropyl alcohol and 3.4 g. (0.037 mole) methyl bromide added. The reaction mixture was allowed to stand at 30 C. for two days and the product isolated by filtration, yield, 13 g. (87%), MP. 228-229 C. dec.
Analysis.Calcd. for C H BrNO Br, 19.05; N, 3.34. Found: Br, 18.91;N, 3.33.
The anti-spasmodic activity of methonium salts of N- methyI-B-piperidyl benzilate is about equal to atropine but is free of the side effects normally inherent with atropine therapy. The therapeutic dose of methonium salts of N-methyl-3-piperidyl benzilate is generally in the range of to 50 mgm. per dose and may be administered at intervals throughout the day as needed although four doses a day are usually found to be highly satisfactory. The optimum dosage from all viewpoints appears to be 25 mgm. four times a day. Such dosages are of course administered orally, and preferably in tablet, capsule, or
some other convenient pharmaceutical form in conventional use. Standard carriers like starch and sugar may be used as well as the ordinary lubricants, binders, and
disintegrating agents as are required to form tablets.
Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of this invention, they are intended to be included within the scope of the appended claims.
What is claimed is:
1. An anti-spasmodic pharmaceutical composition in unit dosage form adapted for human treatment without causing significant dryness of the mouth and dilation of the eye pupil comprising a compound of the formula wherein Y is a non-toxic anion, and a pharmaceutical carrier.
2. A pharmaceutical composition in unit dosage form adapted for human anti-spasmodic treatment without causing significant dryness of the mouth and dilation of the eye pupil comprising a member of the group consisting of N-methyl-3-piperidyl benzilate and compounds of the formula 1 ad p for-human pas diaucatmentwi hout sai s- 4 ing significant dryness of the mouth and dilation of the eye pupil comprising N-methyl-3-piperidyl benzilate methyl bromide and a pharmaceutical carrier.
4. A pharmaceutical composition in unit dosage form 5 adapted for human anti-spasmodic treatment without caus ing significant dryness of the mouth and dilation of the eye pupil comprising N-methyl-3-piperidyl benzilate methyl chloride and a pharmaceutical carrier.
5. An anti-spasmmodic pharmaceutical composition in unit dosage form adapted for human anti-spasmodic treatment without causing significant dryness of the mouth and dilation of the eye pupil comprising N-methyl-3- piperidyl benzilate methyl iodide and a pharmaceutical carrier.
6. An anti-spasmodic pharmaceutical composition in unit dosage form adapted for human anti-spasmodic treatment without causing significant dryness of the mouth and dilation of the eye pupil comprising N-methyl-3- piperidyl benzilate methyl sulfate and a pharmaceutical carrier.
7. The process which comprises administering a compond to a human for its therapeutic anti-spasmodic elfect, without casing significant dryness of the mouth and 'dilation of the eye pupil, said compound being of the forwherein Y is a non-toxic anion.
8. The process which comprises administering N- methyl-3-piperidyl benzilate methyl bromide to a human for its therapeutic anti-spasmodic effect, without causing significant dryness of the mouth and dilation of the eye pupil.
9. A member of the group consisting of N-methyl-3- piperidyl benzilate and compounds of the formula wherein Y is a nontoxic anion.
10. N-methyl-3-piperidyl benzilate l1. N-methyl- 3 -piperidyl benzilate methyl halide, where the methyl halide is a member selected from the group consisting of methyl bromide, methyl chloride and methyl iodide.
12. N-methyl-3-piperidyl benzilate methyl chloride.
13. N-methyl-3-piperidyl benzilate methyl bromide.
14. N-methyl-3-piperidyl benzilate methyl iodide.
15. N-methyl-3-piperidyl benzilate methyl sulfate.
. References Cited in the file of this patent UNITED STATES PATENTS Wolfes et al. Aug. 23, 1938 Feldkamp Dec. 5, 1950 OTHER REFERENCES Burtner et al.: J.A.C.S., vol. 65, pp. 262-267 (1943).
Grant: Hackhs Chem. Dictionary, 3rd ed., 1944, p. 594, McGraw-l-lill.
Blicke et al.: J .A.C.S., vol. 64, 1942, pp. 428-431.
McElvain et al.: J.A.C.S., vol 70, pp. 1826-28, January 1948.
Ford-Moore et al.: J. Chem. Soc. (London), 1947, pp.
U.S, Disp, 25th ed., 1955, pp. 1783-1790, Lippincott CO:
V f w UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTWN Patent No. 2,918,408 December 22 1959 John H. Biel It is hereby certified that error appears in the-printed specification of the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.
Column l, line 40, for "anagesic" read analgesic column 2, line 38 for "an hydrous" read anhydrous line 50, after "such" insert as column 4 line 9 for "ant1- spasmlrnochic read anti-spasmodic line 23,; for "casing" read causing same column 4, line 50, after "benz1late insert a period.
(SEAL) Attest:
KARL H. AXLINE Attesting Officer ROBERT C. WATSON Commissioner of Patents

Claims (1)

1. AN ANTI-SPASMODIC PHARMACEUTICAL COMPOSITION IN UNIT DOSAGE FORM ADAPTED FOR HUMAN TREATMENT WITHOUT CAUSING SIGNIFICANT DRYNESS OF THE MOUTH AND DILATION OF THE EYE PUPIL COMPRISING A COMPOUND OF THE FORMULA
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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2995560A (en) * 1959-09-11 1961-08-08 Lakeside Lab Inc Acetates of 3-piperidinol
US2995492A (en) * 1957-12-23 1961-08-08 Lakeside Lab Inc Piperidine derivatives with psychotogenic activity
US3031456A (en) * 1959-10-22 1962-04-24 Upjohn Co Nu-phenethyl-piperidyl-4-alpha-ethyl-isovalerates
US3077433A (en) * 1959-10-22 1963-02-12 Upjohn Co Composition and method of controlling fungi
US3117976A (en) * 1958-11-12 1964-01-14 Beecham Res Lab Nu-alkyl-pyrrolidine-2-methanol, alpha cyclohexyl mandelates
US3240784A (en) * 1966-03-15 Esters of quaternary z-hydroxy methyl piperidinium compounds
US3301869A (en) * 1960-05-16 1967-01-31 Robins Co Inc A H Methobromide and hydrochloride of 1-ethyl-3-pyrrolidyl benzilate
WO2005014089A1 (en) 2003-07-24 2005-02-17 Glaxo Group Limited Medicament dispenser
US20060148771A1 (en) * 2003-02-14 2006-07-06 Keith Biggadike Medicinal compounds
US20060205790A1 (en) * 2002-10-22 2006-09-14 Coe Diane M Medicinal arylethanolamine compounds
US20070172385A1 (en) * 2003-12-17 2007-07-26 Glaxo Group Limited Benzothiophen and thiochrone containing phenethanolamine derivatives for the treatment of respiratory disorders
US7442839B2 (en) 2002-10-28 2008-10-28 Glaxo Group Limited Phenethanolamine derivative for the treatment of respiratory diseases
EP2042168A1 (en) 2001-09-14 2009-04-01 Glaxo Group Limited Inhalation device comprising phenethanolamine derivatives for treatment of respiratory diseases
WO2011054527A1 (en) 2009-11-06 2011-05-12 Norton Healthcare Limited Airflow adaptor for a breath-actuated dry powder inhaler
EP2436686A1 (en) 2005-03-25 2012-04-04 Glaxo Group Limited Pyrimidopyridine compound used as a CSBP/RK/p38 modulator
EP2799102A2 (en) 2009-06-09 2014-11-05 Ivax Pharmaceuticals Ireland Inhaler
KR20140138880A (en) * 2012-03-14 2014-12-04 가부시키가이샤 엘티티 바이오파마 Ameliorating agent for chronic obstructive pulmonary disease
WO2015181837A3 (en) * 2014-05-30 2016-02-18 Sphaera Pharma Pvt. Ltd. Novel compounds as anti-tubercular agents
WO2018094392A1 (en) 2016-11-21 2018-05-24 Lupin Inc. Medicament dispenser
WO2019053085A1 (en) 2017-09-13 2019-03-21 Lupin Atlantis Holdings Sa Inhaler and mesh for an inhaler
WO2019195711A1 (en) 2018-04-06 2019-10-10 Lupin Inc. Medicament dispenser
WO2020058823A1 (en) 2018-09-17 2020-03-26 Lupin, Inc. Dose indicator assembly for a medicament dispenser
WO2021195353A1 (en) 2020-03-25 2021-09-30 Lupin Inc. Multi-carrier medicament dispensers
WO2022020506A1 (en) 2020-07-23 2022-01-27 Lupin Inc. Dose counter assemblies for medicament dispensers

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2127547A (en) * 1938-08-23 Esters of pseudotropine and proc
US2533002A (en) * 1949-10-29 1950-12-05 Sterling Drug Inc 1-methyl-3-piperidylmethyl phenyl-(2-thienyl) acetate, its salts and production thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2127547A (en) * 1938-08-23 Esters of pseudotropine and proc
US2533002A (en) * 1949-10-29 1950-12-05 Sterling Drug Inc 1-methyl-3-piperidylmethyl phenyl-(2-thienyl) acetate, its salts and production thereof

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3240784A (en) * 1966-03-15 Esters of quaternary z-hydroxy methyl piperidinium compounds
US2995492A (en) * 1957-12-23 1961-08-08 Lakeside Lab Inc Piperidine derivatives with psychotogenic activity
US3117976A (en) * 1958-11-12 1964-01-14 Beecham Res Lab Nu-alkyl-pyrrolidine-2-methanol, alpha cyclohexyl mandelates
US2995560A (en) * 1959-09-11 1961-08-08 Lakeside Lab Inc Acetates of 3-piperidinol
US3031456A (en) * 1959-10-22 1962-04-24 Upjohn Co Nu-phenethyl-piperidyl-4-alpha-ethyl-isovalerates
US3077433A (en) * 1959-10-22 1963-02-12 Upjohn Co Composition and method of controlling fungi
US3301869A (en) * 1960-05-16 1967-01-31 Robins Co Inc A H Methobromide and hydrochloride of 1-ethyl-3-pyrrolidyl benzilate
EP2042168A1 (en) 2001-09-14 2009-04-01 Glaxo Group Limited Inhalation device comprising phenethanolamine derivatives for treatment of respiratory diseases
US20060205790A1 (en) * 2002-10-22 2006-09-14 Coe Diane M Medicinal arylethanolamine compounds
US7442839B2 (en) 2002-10-28 2008-10-28 Glaxo Group Limited Phenethanolamine derivative for the treatment of respiratory diseases
US20060148771A1 (en) * 2003-02-14 2006-07-06 Keith Biggadike Medicinal compounds
US7538127B2 (en) 2003-02-14 2009-05-26 Glaxo Group Limited Medicinal compounds
WO2005014089A1 (en) 2003-07-24 2005-02-17 Glaxo Group Limited Medicament dispenser
US20070172385A1 (en) * 2003-12-17 2007-07-26 Glaxo Group Limited Benzothiophen and thiochrone containing phenethanolamine derivatives for the treatment of respiratory disorders
US7294650B2 (en) 2003-12-17 2007-11-13 Glaxo Group Limited Benzothiophen and thiochrone containing phenethanolamine derivatives for the treatment of respiratory disorders
EP2436686A1 (en) 2005-03-25 2012-04-04 Glaxo Group Limited Pyrimidopyridine compound used as a CSBP/RK/p38 modulator
EP2447266A1 (en) 2005-03-25 2012-05-02 Glaxo Group Limited Pyrimidopyridine compound used as a CSBP/RK/p38 modulator
EP2799102A2 (en) 2009-06-09 2014-11-05 Ivax Pharmaceuticals Ireland Inhaler
US8931476B2 (en) 2009-06-09 2015-01-13 Ivax Pharmaceuticals Ireland Inhaler
EP2596827A2 (en) 2009-11-06 2013-05-29 Norton Healthcare Limited Airflow adaptor for a breath-actuated dry powder inhaler
WO2011054527A1 (en) 2009-11-06 2011-05-12 Norton Healthcare Limited Airflow adaptor for a breath-actuated dry powder inhaler
EP3002022A1 (en) 2009-11-06 2016-04-06 Norton Healthcare Limited Airflow adaptor for a breath-actuated dry powder inhaler
KR20140138880A (en) * 2012-03-14 2014-12-04 가부시키가이샤 엘티티 바이오파마 Ameliorating agent for chronic obstructive pulmonary disease
US20150038719A1 (en) * 2012-03-14 2015-02-05 Ltt Bio-Pharma Co., Ltd. Agent for Ameliorating Chronic Obstructive Pulmonary Disease
EP2826479A4 (en) * 2012-03-14 2015-11-11 Ltt Bio Pharma Co Ltd Ameliorating agent for chronic obstructive pulmonary disease
KR101995612B1 (en) 2012-03-14 2019-07-02 가부시키가이샤 엘티티 바이오파마 Ameliorating agent for chronic obstructive pulmonary disease
US9539248B2 (en) 2012-03-14 2017-01-10 Ltt Bio-Pharma Co., Ltd. Agent for ameliorating chronic obstructive pulmonary disease
US10100012B2 (en) 2014-05-30 2018-10-16 Sphaera Pharma Pvt. Ltd. Compounds as anti-tubercular agents
US10207993B2 (en) 2014-05-30 2019-02-19 Sphaera Pharma Pvt. Ltd. Compounds as anti-tubercular agents
WO2015181837A3 (en) * 2014-05-30 2016-02-18 Sphaera Pharma Pvt. Ltd. Novel compounds as anti-tubercular agents
WO2018094392A1 (en) 2016-11-21 2018-05-24 Lupin Inc. Medicament dispenser
WO2019053085A1 (en) 2017-09-13 2019-03-21 Lupin Atlantis Holdings Sa Inhaler and mesh for an inhaler
WO2019195711A1 (en) 2018-04-06 2019-10-10 Lupin Inc. Medicament dispenser
WO2020058823A1 (en) 2018-09-17 2020-03-26 Lupin, Inc. Dose indicator assembly for a medicament dispenser
WO2021195353A1 (en) 2020-03-25 2021-09-30 Lupin Inc. Multi-carrier medicament dispensers
WO2022020506A1 (en) 2020-07-23 2022-01-27 Lupin Inc. Dose counter assemblies for medicament dispensers

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