US2899357A - Oral pharmaceutical composition for - Google Patents
Oral pharmaceutical composition for Download PDFInfo
- Publication number
- US2899357A US2899357A US2899357DA US2899357A US 2899357 A US2899357 A US 2899357A US 2899357D A US2899357D A US 2899357DA US 2899357 A US2899357 A US 2899357A
- Authority
- US
- United States
- Prior art keywords
- bis
- quaternary
- active
- pharmaceutical composition
- trimethylammonium
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Lifetime
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- 239000008203 oral pharmaceutical composition Substances 0.000 title 2
- 239000000203 mixture Substances 0.000 claims description 32
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 230000003000 nontoxic Effects 0.000 claims description 6
- 231100000252 nontoxic Toxicity 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 description 22
- 230000001077 hypotensive Effects 0.000 description 16
- 239000001294 propane Substances 0.000 description 16
- 150000003839 salts Chemical group 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- 230000001225 therapeutic Effects 0.000 description 12
- 238000010521 absorption reaction Methods 0.000 description 10
- 230000036772 blood pressure Effects 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 10
- GETQZCLCWQTVFV-UHFFFAOYSA-O trimethylammonium Chemical compound C[NH+](C)C GETQZCLCWQTVFV-UHFFFAOYSA-O 0.000 description 10
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- -1 (4 methylmorpholinium)- propane Chemical compound 0.000 description 6
- 210000004369 Blood Anatomy 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- 208000001953 Hypotension Diseases 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 230000003389 potentiating Effects 0.000 description 6
- 125000000129 anionic group Chemical group 0.000 description 4
- 150000001450 anions Chemical class 0.000 description 4
- 239000002220 antihypertensive agent Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- SOWZZZARRXSFKR-UHFFFAOYSA-M 1-cyclohexyl-3-(1-methylpyrrolidin-1-ium-1-yl)-1-phenylpropan-1-ol;methyl sulfate Chemical compound COS([O-])(=O)=O.C1CCCCC1C(O)(C=1C=CC=CC=1)CC[N+]1(C)CCCC1 SOWZZZARRXSFKR-UHFFFAOYSA-M 0.000 description 2
- CODNYICXDISAEA-UHFFFAOYSA-N Bromine monochloride Chemical class BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 description 2
- PRJYGTXIVBWUGB-UHFFFAOYSA-O CCC.[NH+]1=CC=CC=C1 Chemical compound CCC.[NH+]1=CC=CC=C1 PRJYGTXIVBWUGB-UHFFFAOYSA-O 0.000 description 2
- QDBWXYRWVGRLPO-UHFFFAOYSA-N CN(C(C(C)(C)C)(CC)C)C(C)CC Chemical compound CN(C(C(C)(C)C)(CC)C)C(C)CC QDBWXYRWVGRLPO-UHFFFAOYSA-N 0.000 description 2
- 210000001168 Carotid Artery, Common Anatomy 0.000 description 2
- DXXUGBPKQDTBQW-UHFFFAOYSA-L Chlorisondamine Chemical compound [Cl-].[Cl-].ClC1=C(Cl)C(Cl)=C(Cl)C2=C1C[N+](CC[N+](C)(C)C)(C)C2 DXXUGBPKQDTBQW-UHFFFAOYSA-L 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 210000000936 Intestines Anatomy 0.000 description 2
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229960002214 Methantheline bromide Drugs 0.000 description 2
- FUFVKLQESJNNAN-UHFFFAOYSA-M Methylhomatropine Chemical compound [Br-].C[N+]1(C)C(C2)CCC1CC2OC(=O)C(O)C1=CC=CC=C1 FUFVKLQESJNNAN-UHFFFAOYSA-M 0.000 description 2
- 229940051875 Mucins Drugs 0.000 description 2
- 102000015728 Mucins Human genes 0.000 description 2
- 108010063954 Mucins Proteins 0.000 description 2
- ALWKGYPQUAPLQC-UHFFFAOYSA-N Neostigmine Chemical class CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 ALWKGYPQUAPLQC-UHFFFAOYSA-N 0.000 description 2
- 210000000826 Nictitating Membrane Anatomy 0.000 description 2
- 206010039424 Salivary hypersecretion Diseases 0.000 description 2
- NPRHVSBSZMAEIN-UHFFFAOYSA-N Tridihexethyl Chemical compound C=1C=CC=CC=1C(O)(CC[N+](CC)(CC)CC)C1CCCCC1 NPRHVSBSZMAEIN-UHFFFAOYSA-N 0.000 description 2
- 229950008407 Tridihexethyl iodide Drugs 0.000 description 2
- ZVTLLNNZNVVFHC-UHFFFAOYSA-N [Br-].[Br-].C[NH+]1CCOCC1.C[NH+]1CCOCC1 Chemical compound [Br-].[Br-].C[NH+]1CCOCC1.C[NH+]1CCOCC1 ZVTLLNNZNVVFHC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000001154 acute Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- ZILVEYQJZUAJRX-UHFFFAOYSA-O azanium;butane Chemical compound [NH4+].CCCC ZILVEYQJZUAJRX-UHFFFAOYSA-O 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 239000001273 butane Substances 0.000 description 2
- 229950002565 chlorisondamine Drugs 0.000 description 2
- 230000001713 cholinergic Effects 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- GNVRJGIVDSQCOP-UHFFFAOYSA-O diethyl(methyl)azanium Chemical compound CC[NH+](C)CC GNVRJGIVDSQCOP-UHFFFAOYSA-O 0.000 description 2
- PQMWYJDJHJQZDE-UHFFFAOYSA-M diethyl-methyl-[2-(9H-xanthene-9-carbonyloxy)ethyl]azanium;bromide Chemical compound [Br-].C1=CC=C2C(C(=O)OCC[N+](C)(CC)CC)C3=CC=CC=C3OC2=C1 PQMWYJDJHJQZDE-UHFFFAOYSA-M 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940083122 ganglion-blocking antiandrenergic Bisquaternary ammonium compounds Drugs 0.000 description 2
- 230000000574 ganglionic Effects 0.000 description 2
- 150000004676 glycans Polymers 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000000968 intestinal Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000009114 investigational therapy Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000004804 polysaccharides Polymers 0.000 description 2
- 230000001179 pupillary Effects 0.000 description 2
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000036633 rest Effects 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 230000001052 transient Effects 0.000 description 2
- 229960003167 tridihexethyl Drugs 0.000 description 2
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 2
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/13—Amines
- A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
Definitions
- the present invention resides in the concept of a composition containing a therapeutically active quaternary ammonium salt'in combination with a therapeutically inactive quaternary ammonium salt. Excipients permitting proper dosage requirements and imparting pharmaceutical elegance are employed in compounding the finished preparation in a form suitable for dispensing.
- hypotensive agents of which a number have been developed in the recent past. In'varying degree these are therapeutically useful by injectiontherapy, but absorption by the oral route is generally insufiicient to permit administration in practical or economical. dosage form.
- the amount of the active hypotensive quaternary can be varied from about 25 to about 400 milligrams per dose and the amount of the relatively inactive quaternary employed should be between about 0.5 and about 3.0 milligrams per milligram of the active component in each dose. Above the ratio of about 3.0 parts of inactive quaternary per part of hypotensive quaternary, little advantage is apparent.
- the composition is preferably tabletted or capsulated in a manner following usual pharmacy prac- States Patent 9 ticebecause the taste of the quaternaries lessens the desirability of use in solution form.
- The'potentiating quaternaries are the bis-quaternaries of C through C ditertiaryaminoalkanes wherein the tertiaryamino-forming substituents are lower-aliphatic radicals, such as C through C lower-alkyl groups, which can be joined to form a saturated or unsaturated heterocyclic ring.
- Compounds of this type have frequently been described in the literature and the processes for their preparation are well-known. The precise nature of the quaternising moiety is not critical.
- the onium groups of the potentiator be relatively small and that it have no substantial biological activity.
- the nature of the anion is. not critical, but should be small since the potentiator is the cation and the smaller the anion, the greater is the concentration of the cation per unit of molecular weight.
- suitable compounds are the dichlorides, dibromides, or chlorobromides of any 0 the following:
- Oral administration of such compound produces no eiiect on the blood pressure.
- the compound When administered intraperitoneally in a dosage of 2.0 mg./kg. to an unanesthetised cat, the compound produced no noticeable ellects upon careful observation for evidence of ganglionic stimulation or blockade as oifered by relaxation of the nictitating mem-- brane, pupillary dilation, salivation, et cetera.
- the inactive propane compound was then tested in combination with an active hypotensive compound, 1-(2- ethyl 1,2,3,4 tetrahydroisoquinolinium) 3 (trimethylammonium)propane dibromide, by injection directly into the upper third of the small intestine of anesthetised dogs, the blood pressure being recorded directly from a common carotid artery, with the following results:
- the potentiators are much less expensive than the therapeutic agents and there is an economic advantage; additionally, the smaller molecular weight of the simple bis-quaternary potentiators provides a high ionic concentration of quaternary groups with a relatively small weight of compound and permits preparing the tablet or oral preparation in a more practical size for administration; and, by permitting smaller doses of the therapeutically active agent, fewer side reactions are obtained than by increasing the quantity of therapeutic agent since some of the therapeutic agents produce side reactions from direct local action on the gastro-intestinal tract.
- cholinergic agents such as carbamyl methylcholine, acctyl-beta-methylcholine, and neostigmine salts
- antispasmodic agents such as homatropine methobromide, methantheline bromide
- a pharmaceutical composition for oral administration including one part by weight of a physiologically active, non-toxic, systemically absorbable quaternary ammonium salt in combination with between about 0.5 and 3.0 parts by weight of a substantially biologically inert bis-quaternary ammonium salt.
- a pharmaceutical composition for oral administration including one part by weight of a non-toxic, systemically absorbable quaternary ammonium compound having hypotensive activity in combination with between about 0.5 and 3.0 parts by weight of a substantially biologically inert bis-quarternary ammonium salt.
- composition of claim 2 wherein the substantially biologically inert salt is of a trimethylene-bis-trimethylammonium cation.
Landscapes
- 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)
Description
Chester John Cavallito and Thomas Beniah ODell, De I catur, llL, assignors to Irwin, Neisler and (Zompany, Decatur, 11]., a corporation of Illinois No Drawing. Application August 20,1956
Serial No. 605,199
3 Claims. (Cl. 167-'55) "This invention relates to pharmaceutical compositions containing a physiologically active quaternary ammonium salt and is more particularly concerned with an improvenient in such compositions whereby the therapeutic effect of the active quaternary salt therein can be realized upon the oral administration of the composition.
The relatively poor absorption rate into the blood stream from the gastro-intestinal tract of quaternary salts having useful therapeutic properties has materially reduced the scope of their application since injection therapy necessarily requires professional administration as opposed tosimple oral therapy following the instructions of a physician.
.The present invention resides in the concept of a composition containing a therapeutically active quaternary ammonium salt'in combination with a therapeutically inactive quaternary ammonium salt. Excipients permitting proper dosage requirements and imparting pharmaceutical elegance are employed in compounding the finished preparation in a form suitable for dispensing.
The theory upon which the invention rests,.as best understood on the basis of extensive investigation, appears to be as follows: absorption of quaternary salts from the gastro-intestinal tract is mediocre because such salts become tightly bound to anionic receptors in the wall of the tract and, as a result, are not readily absorbed. For example, the mucins which form part of the lining of the intestinal tract are polysaccharide acids which apparently retain quaternaries by ionic attraction. The administration of a quaternary having no physiological activity, but having certain structural molecular properties in common with the active agent, in combination therewith, results in-the binding of the inactive quaternary at'many of the anionic sites in the wall of the intestine, leaving fewer of such sites available for binding of the therapeutic quaternaries.
The invention will be illustrated by reference to the administration of hypotensive agents, of which a number have been developed in the recent past. In'varying degree these are therapeutically useful by injectiontherapy, but absorption by the oral route is generally insufiicient to permit administration in practical or economical. dosage form.
Accordingly, we have compounded simple bis-quater-- nary ammonium alkanes whichare relatively inert biologically with bis-quaternary ammonium compounds having known therapeutically desirable hypotensive activity by the injection route and obtained entirely satisfactory re sults upon clinical evaluation. In general, the amount of the active hypotensive quaternary can be varied from about 25 to about 400 milligrams per dose and the amount of the relatively inactive quaternary employed should be between about 0.5 and about 3.0 milligrams per milligram of the active component in each dose. Above the ratio of about 3.0 parts of inactive quaternary per part of hypotensive quaternary, little advantage is apparent. The composition is preferably tabletted or capsulated in a manner following usual pharmacy prac- States Patent 9 ticebecause the taste of the quaternaries lessens the desirability of use in solution form. The'potentiating quaternaries are the bis-quaternaries of C through C ditertiaryaminoalkanes wherein the tertiaryamino-forming substituents are lower-aliphatic radicals, such as C through C lower-alkyl groups, which can be joined to form a saturated or unsaturated heterocyclic ring. Compounds of this type have frequently been described in the literature and the processes for their preparation are well-known. The precise nature of the quaternising moiety is not critical. It is only necessary that the onium groups of the potentiator be relatively small and that it have no substantial biological activity. The nature of the anion is. not critical, but should be small since the potentiator is the cation and the smaller the anion, the greater is the concentration of the cation per unit of molecular weight. Thus, among suitable compounds are the dichlorides, dibromides, or chlorobromides of any 0 the following:
1,3 -bis-(trin1ethylammonium) propane 1,3 -bisethyldimethylammonium) -p rop ane 1,3 -bis- (diethylmethylammonium) -prop ane 1,3 -bisl -methylpyrollidinium) -prop ane 1,3-bis- (4-methylmorpholinium) -propane 1 trimethylammonium 3 (4 methylmorpholinium)- propane 1-trimethylammonium-3 pyridinium-propane 1,2-bis- (trimethylammonium) -ethane 1,4-bisdiethylmethylammonium) -butane 1,3 -bistrimethyl ammonium -butane A wide variety of therapeutically active compounds having hypotensive properties has likewise been described in the literature and any of such substances can be employed. Illustrative of suitable active compounds. are
' the following:
1,6-bis-(trimethylammonium)-heXane salts 1,5-bis-(trimethylammonium)-pentane salts 1,5-bis-(N-methylpyrrolidinium)-pentane salts, such as the tartrate A I Chlorisondamine Pentamethyl-diethyl-3 -aza-pentane 1,5-diammonium-di I bromide The following description illustrates a specific, embodi rnent of the composition constituting the invention:
' 1,3-bis(trimethylammonium)propane dibromide hav ing an acute toxicity in mice of I.V. LD =83.0 milligrams per kilogram was chosen as the potentiating agent.
The effect of this compound on the blood pressure of; anesthetised dogs upon intravenous administration was determined to be:
A blood pressure fall under such test conditions, with a recovery in less than five minutes, means that the substance tested has no useful hypotensive activity since this is merely an ultra-short, transient acute response. Oral administration of such compound produces no eiiect on the blood pressure. When administered intraperitoneally in a dosage of 2.0 mg./kg. to an unanesthetised cat, the compound produced no noticeable ellects upon careful observation for evidence of ganglionic stimulation or blockade as oifered by relaxation of the nictitating mem-- brane, pupillary dilation, salivation, et cetera.
The inactive propane compound was then tested in combination with an active hypotensive compound, 1-(2- ethyl 1,2,3,4 tetrahydroisoquinolinium) 3 (trimethylammonium)propane dibromide, by injection directly into the upper third of the small intestine of anesthetised dogs, the blood pressure being recorded directly from a common carotid artery, with the following results:
Dosage, mg./kg.
Percent Duration fall in in hours Active Inactive blood greater comcompressure than pound pound The said compounds were then combined in the dosage ratios immediately above, placed in a capsule, and administered orally just prior to anesthetising and setting up dogs for recording blood pressure as above. The time required for setting up was approximately ten minutes. The results are summarized in the table below:
Dosage, rug/kg.
Percent fall in blood Duration Active Inactive pressure in hours comcompound pound In tests conducted in a similar manner with other active hypotensive agents, such as 1-[2-(naphtheneethyDpyridinium] (3 trimethylammonium)propane dibromide, using trimethylene 1,3 bis (trimethylammonium)theophyllinate, trirnethylene 1,3 bis (4 methylmorpholinium)dibromide, and, 1,3-(trimethylammonium)propane dibromide, for example, as potentiating agents, we obtained, upon oral administration in capsules, in every instance at least double the effect resulting from oral administration of the active compound alone.
Following such pharmacological investigations in animals, we have had conducted in humans a clinical evaluation of the tetrahydroisoquinolinum and naphtheneethyltion that results from the oral combination. This further supports the view that the inactive quaternary does not sensitize the organism to the therapeutic agent but rather permits better absorption of the therapeutic agent from the gastro-intestinal tract.
Among the advantages in providing a potentiated composition as herein described, as opposed to merely increasing the dosage of the active component of the composition, are the following: the potentiators are much less expensive than the therapeutic agents and there is an economic advantage; additionally, the smaller molecular weight of the simple bis-quaternary potentiators provides a high ionic concentration of quaternary groups with a relatively small weight of compound and permits preparing the tablet or oral preparation in a more practical size for administration; and, by permitting smaller doses of the therapeutically active agent, fewer side reactions are obtained than by increasing the quantity of therapeutic agent since some of the therapeutic agents produce side reactions from direct local action on the gastro-intestinal tract.
While the invention has been illustrated with reference to quaternary salts possessing hypotensive properties, we have found that other quaternary ammonium salts possessing therapeutic properties are likewise potentiated by combination with the C to C quaternaries of the type hereinbefore described. For example, cholinergic agents, such as carbamyl methylcholine, acctyl-beta-methylcholine, and neostigmine salts; and, antispasmodic agents, such as homatropine methobromide, methantheline bromide,
tricyclamol methosulfate, and tridihexethyl iodide, are increased markedly in effectiveness at reduced dosage levels. The principle of potentiation herein described is not concerned with the qualitative nature of the activity of the therapeutic quaternary, but is related to its chemical characteristics. It will thus be apparent from the foregoing that the inventive concept is of broad application and makes possible the use of substances not otherwise orally administrable in practical dosages by increasing the relative absorption of the therapeutic quaternary.
We claim:
1. A pharmaceutical composition for oral administration including one part by weight of a physiologically active, non-toxic, systemically absorbable quaternary ammonium salt in combination with between about 0.5 and 3.0 parts by weight of a substantially biologically inert bis-quaternary ammonium salt.
2. A pharmaceutical composition for oral administration including one part by weight of a non-toxic, systemically absorbable quaternary ammonium compound having hypotensive activity in combination with between about 0.5 and 3.0 parts by weight of a substantially biologically inert bis-quarternary ammonium salt.
3. The composition of claim 2 wherein the substantially biologically inert salt is of a trimethylene-bis-trimethylammonium cation.
References Cited in the file of this patent U.S. Dispensatory, 25th ed., 1955, pp. 1697-1700, 1701, 1702, 1703.
Barlow: Introduction to Chem. Pharmacology, John Wiley and Sons, N.Y., 1955, pp. 10, 11, 161-163, 179.
Hager et al.: J.A.P.A., Sci. Ed., 42:1, pp. 9, 10, 12, January 1953.
Claims (1)
1. A PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION INCLUDING ONE PART BY WEIGHT OF A PHYSIOLOGICALLY ACTIVE, NON-TOXIC, SYSTEMICALLY ABSORBABLE QUATERNARY AMMONIUM SALT IN COMBINATION WITH BETWEEN ABOUT 0.5 AND 3.0 PARTS BY WEIGHT OF A SUBSTANTIALLY BIOLOGICALLY INERT BIS-QUATERNARY AMMONIUM SALT.
Publications (1)
Publication Number | Publication Date |
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US2899357A true US2899357A (en) | 1959-08-11 |
Family
ID=3448158
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US2899357D Expired - Lifetime US2899357A (en) | Oral pharmaceutical composition for |
Country Status (1)
Country | Link |
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US (1) | US2899357A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3037910A (en) * | 1958-04-18 | 1962-06-05 | Burroughs Wellcome Co | Process for treatment of hypertension |
US3397990A (en) * | 1964-01-30 | 1968-08-20 | Pfizer & Co C | Hexamethonium salts as growth promoters in animal feed compositions |
US20100221354A1 (en) * | 2003-11-04 | 2010-09-02 | Supernus Pharmaceuticals, Inc. | Pharmaceutical composition for once-a-day oral administration of trospium chloride |
-
0
- US US2899357D patent/US2899357A/en not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
---|
None * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3037910A (en) * | 1958-04-18 | 1962-06-05 | Burroughs Wellcome Co | Process for treatment of hypertension |
US3397990A (en) * | 1964-01-30 | 1968-08-20 | Pfizer & Co C | Hexamethonium salts as growth promoters in animal feed compositions |
US20100221354A1 (en) * | 2003-11-04 | 2010-09-02 | Supernus Pharmaceuticals, Inc. | Pharmaceutical composition for once-a-day oral administration of trospium chloride |
US20100222375A1 (en) * | 2003-11-04 | 2010-09-02 | Supernus Pharmaceuticals, Inc. | Pharmaceutical Composition Comprising Trospium Chloride for Once-A-Day Administration |
US20100221355A1 (en) * | 2003-11-04 | 2010-09-02 | Supernus Pharmaceuticals, Inc. | Pharmaceutical composition for once-a-day oral administration of trospium chloride |
US20100221356A1 (en) * | 2003-11-04 | 2010-09-02 | Supernus Pharmaceuticals, Inc. | Pharmaceutical composition for once a day administration of trospium chloride |
US20100221353A1 (en) * | 2003-11-04 | 2010-09-02 | Supernus Pharmaceuticals, Inc. | Pharmaceutical Composition For Once-A-Day Administration of Trospium Chloride |
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