US3709995A - Method of producing gastrointestinal spasmolytic activity with alkylphenoxypoly(ethyleneoxy)ethanols - Google Patents
Method of producing gastrointestinal spasmolytic activity with alkylphenoxypoly(ethyleneoxy)ethanols Download PDFInfo
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- US3709995A US3709995A US00105721A US3709995DA US3709995A US 3709995 A US3709995 A US 3709995A US 00105721 A US00105721 A US 00105721A US 3709995D A US3709995D A US 3709995DA US 3709995 A US3709995 A US 3709995A
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- spasmolytic activity
- polyoxyethylene
- ethyleneoxy
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- spasmolytic
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- 230000002048 spasmolytic effect Effects 0.000 title abstract description 24
- 238000000034 method Methods 0.000 title abstract description 17
- 239000000410 digestive tract spasmolytic agent Substances 0.000 title abstract description 11
- 235000019441 ethanol Nutrition 0.000 title 1
- -1 POLYOXYETHYLENE Polymers 0.000 abstract description 22
- 229920003171 Poly (ethylene oxide) Polymers 0.000 abstract description 14
- 229920000642 polymer Polymers 0.000 abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 239000000812 cholinergic antagonist Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 235000019483 Peanut oil Nutrition 0.000 description 4
- 230000001078 anti-cholinergic effect Effects 0.000 description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000312 peanut oil Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical class C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 3
- 235000021355 Stearic acid Nutrition 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 239000008117 stearic acid Substances 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- 206010052406 Gastric hypermotility Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 208000006550 Mydriasis Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 235000011950 custard Nutrition 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000030135 gastric motility Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000035873 hypermotility Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 230000003170 musculotropic effect Effects 0.000 description 1
- 230000002911 mydriatic effect Effects 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001141 propulsive effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
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
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
Definitions
- compositions having gastrointestinal spasmolytic activity containing a polyoxyethylene polymer of an alkylphenol in which the polyoxyethylene groups are present from about to about 80% of the molecule and a method of producing gastrointestinal spasmolytic activity.
- This invention relates to pharmaceutical compositions having spasmolytic activity and to a method of producing gastrointestinal spasmolytic activity using said compositions. More specifically, this invention relates to a method of producing spasmolytic activity without the concomitant limiting or anticholinergic side effects common to prior art spasmolytic compositions.
- novel pharmaceutical compositions and methods of this invention are unique in that they promptly and consistently depress or completely eliminate abnormal gastric motility. These compositions are not only useful in the treatment of spasticity or hypermotility of the gastrointestinal tract, but are also free of systemic side eifects. Such biological activity has never been reported for com pounds of the chemical class described hereinafter.
- compositions of this invention are in dosage unit form and comprise a nontoxic pharmaceutical carrier and a nonionic polyoxyethylene polymer of an alkylphenol. More specifically the compositions of this invention comprise polymers of alkylphenols having the following structural formula:
- R is an alkyl group comprising from 4 to 16 carbon atoms and n is a positive integer such that the polyoxyethylene groups are present from about 10% to about 80% of the molecule.
- the above compounds of Formula I are those having an alkyl group containing from 8 to 12 carbon atoms and the polyoxyethylene units are present from about 20% to about 70% of the molecule.
- compositions of this invention comprise an oral dosage unit containing the above compounds of Formula I wherein the alkyl group contains 12 carbon atoms and the polyoxyethylene content is from about 63% to about 66% of the molecule.
- the amount of antimotility or musculotropic activity of the above noted novel spasmolytic compounds varies according to the length of the aliphatic substituent on the hydrophobic phenolic nucleus and the percent of the hydrophilic ethylene oxide units present in the molecule.
- polyoxyethylene ethers as illustrated in Formula I and present in these novel compositions are prepared by methods well known to the art. For example, an excess of ethylene oxide is reacted with an alkylphenol under moderate conditions of temperature and pressure in the presence of an alkaline catalyst. This method of preparation is set forth in the textbook Surface Active Agents, Their Chemistry and Technology, Schwartz-Perry, 1949.
- the polyoxyethylene polymers of alkylphenols of this invention have been demonstrated as having gastrointestinal spasmolytic activity without the corresponding anticholinergic side effects in a standard animal pharmacological test procedure reported in The Physiologist, vol. 12, No. 3, August 1969. Briefly, the test comprises implanting a cannula in the stomach of an animal. The animals are fasted for eighteen hours prior to testing and the stomach lavaged with saline to remove traces of food. A miniature rubber ballon is placed in the stomach via the cannula and the balloon is connected to a pressure transducer by a polyethylene tube to record gastric contractions. The system is filled with water and 0.5 ml. of
- test compounds are administered via a cannula in aqueous solution in a dose volume of 1 ml./ kg.
- the post drug motility is recorded for three hours after drug administration.
- Spasmolytic activity is expressed as the duration in minutes of inhibition of propulsive gastric contractions.
- the above standard pharmacological animal test procedure demonstrates the gastrointestinal spasmolytic activity of the polyethoxylated ethers of alkylphenols present in the pharmaceutical compositions of this invention.
- the results further indicate that when the aliphatic chain substituent is increased and the polyoxyethylene content is held relatively constant, spasmolytic potency increased.
- particularly significant in these test results is that they demonstrated the .compounds as represented by Formula I produced spasmolytic activity without the concomitant limiting or anticholinergic side effects.
- compositions of this invention are in dosage unit form and comprise a nontoxic pharmaceutical carrier and the polyoxyethylene polymers of alkylphenols of Formula I in an amount sufficient to produce gastrointestinal spasmolytic activity.
- the composition will contain the polymer ingredient in an amount of from about 50 mg. to about 1000 mg. per dosage unit.
- the compositions will contain the polyoxyethylene polymer ingredient in an amount of from about 250 mg. to about 500 mg. per unit dose.
- the pharmaceutical carrier employed may be, for example, either a solid or liquid.
- solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, sugar seeds, acacia, magnesium stearate, stearic acid, and the like.
- liquid carriers are syrup, peanut oil, olive oil, water and the like.
- the carrier or diluent may include any time delay material well known to the art, such as, for example, glyceryl monostearate or glyceryl distearate alone or with a wax.
- a wide variety of pharmaceutical forms can be em ployed.
- a solid carrier the preparation can be tableted, placed in a hard gelatin capsule in powder or sustained release pellet form or in the form of a troche or lozenge.
- the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 gm.
- a liquid carrier the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or an aqueous or nonaqneous liquid suspension.
- the method in accordance with this invention comprises administering internally to animals, preferably humans, in an amount sufiicient to produce gastrointestinal spasmolytic activity a compound as represented by Formula I combined with a pharmaceutical carrier.
- the polyoxyethylated alkylphenol active ingredient will be present in dosage unit form in an amount of from about 50 mg. to about 1,000 mg. Preferably the above active ingredient will be present from about 250 mg. to about 500 mg. per unit dose.
- the administration may be parenterally or orally.
- the administration of the unit doses is preferably orally to animals sufiering from gastric hypermotility or other similar gastrointestinal abnormalities.
- Advantageously equal doses will be administered one to four times daily.
- the daily dosage will be from 50 mg. to about 4.0 gm. and most advantageously from 250 mg. to about 1.0 gm. of active ingredient.
- spasmolytic activity is achieved without the concomitant mydriatic and antisalivary side efi'ects common to known antispasmodic medicaments.
- EXAMPLE 1 Ingredients: Mg./capsule Octylphenoxypoly(ethyleneoxy)ethanol (68% polyoxyethylene) 1000 Peanut oil 100 Disperse the peanut oil in the polymer and place in a soft gelatin capsule.
- One capsule is administered orally twice a day.
- EXAMPLE 2 Ingredients: Mg. tablet Dodecylphenoxypoly(ethyleneoxy)ethanol (63% polyoxyethylene) 50 Calcium sulfate dihydrate 150 Sucrose 25 Starch l5 Talc 5 Stearic acid 3
- the sucrose, calcium sulfate and the dodecylphenoxypoly(ethyleneoxy)ethanol are thoroughly mixed and granulated with hot 10% gelatin solution.
- the wetted mass is passed through a #16 US. Standard mesh screen directly onto drying trays.
- the granules are dried at F. and passed through a #20 US. Standard Mesh screen. These granules are then mixed with starch, talc and stearic acid, passed through a #60 US. Standard mesh screen and compressed into tablets.
- One tablet is administered four times a day.
- EXAMPLE 3 Ingredients: Mg./capsule Nonylphenoxypoly (ethyleneoxy ethanol (23 polyoxyethylene) 500 Peanut oil 200 The ingredients are thoroughly mixed and filled into a soft gelatin capsule.
- phenoxypoly(ethyleneoxy)ethanol are dissolved in the distilled water and the syrup added. The mixture is filtered. The oil of orange and oil of custard flavor are then added and the mixture thoroughly stirred.
- One teaspoonful is administered four times a day.
- a method ofproducing gastrointestinal spasmolytic activity which comprises administering orally to animals suffering from gastric hypermotility an amout sufiicient to produce said activity of a polyoxyethylene polymer of an alkylphenol having the formula:
- R is an alkyl group comprising from 8 to 12 carbon atoms and n is a positive integer such that the polyoxyethylene groups are present from about 20% to about 70% of the molecule.
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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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
PHARMACEUTICAL COMPOSITIONS HAVING GASTROINTESTINAL SPASMOLYTIC ACTIVITY CONTAINING A POLYOXYETHYLENE POLYMER OF AN ALKYLPHENOL IN WHICH THE POLYOXYETHYLENE GROUPS ARE PRESENT FROM ABOUT 10% TO ABOUT 80% OF THE MOLECULE AND A METHOD OF PRODUCING GASTROINSTESTINAL SPASMOLYTIC ACTIVITY.
Description
United States Patent Office 3,709,995 Patented Jan. 9, 1973 3,709,995 METHOD OF PRODUCING GASTROINTESTINAL SPASMOLYTIC ACTIVITY WITH ALKYLPHE- NOXYPOLY(ETHYLENEOXY)ETHANOLS William G. Groves, Blue Bell, Pa., and William J. Tillman, Cherry Hill, N.J., assignors to Smith Kline & French Laboratories, Philadelphia, Pa. No Drawing. Filed Jan. 11, 1971, Ser. No. 105,721 Int. Cl. A61k 27/00 US. Cl. 424-341 5 Claims ABSTRACT OF THE DISCLOSURE Pharmaceutical compositions having gastrointestinal spasmolytic activity containing a polyoxyethylene polymer of an alkylphenol in which the polyoxyethylene groups are present from about to about 80% of the molecule and a method of producing gastrointestinal spasmolytic activity.
This invention relates to pharmaceutical compositions having spasmolytic activity and to a method of producing gastrointestinal spasmolytic activity using said compositions. More specifically, this invention relates to a method of producing spasmolytic activity without the concomitant limiting or anticholinergic side effects common to prior art spasmolytic compositions.
Prior to the present invention, there has been a great need for compounds and compositions which produce spasmolytic activity without the usual anticholinergic side effects, such as, for example, dry mouth and mydriasis which are common to known anticholinergic-antispasmodic compounds. The need of a safe and effective composition devoid of the above noted side effects and having spasmolytic activity has been great.
The novel pharmaceutical compositions and methods of this invention are unique in that they promptly and consistently depress or completely eliminate abnormal gastric motility. These compositions are not only useful in the treatment of spasticity or hypermotility of the gastrointestinal tract, but are also free of systemic side eifects. Such biological activity has never been reported for com pounds of the chemical class described hereinafter.
Most advantageously the compositions of this invention are in dosage unit form and comprise a nontoxic pharmaceutical carrier and a nonionic polyoxyethylene polymer of an alkylphenol. More specifically the compositions of this invention comprise polymers of alkylphenols having the following structural formula:
FORMULA I R-o omomomemomon wherein R is an alkyl group comprising from 4 to 16 carbon atoms and n is a positive integer such that the polyoxyethylene groups are present from about 10% to about 80% of the molecule.
Preferably, the above compounds of Formula I are those having an alkyl group containing from 8 to 12 carbon atoms and the polyoxyethylene units are present from about 20% to about 70% of the molecule.
Most advantageously, the compositions of this invention comprise an oral dosage unit containing the above compounds of Formula I wherein the alkyl group contains 12 carbon atoms and the polyoxyethylene content is from about 63% to about 66% of the molecule.
The amount of antimotility or musculotropic activity of the above noted novel spasmolytic compounds varies according to the length of the aliphatic substituent on the hydrophobic phenolic nucleus and the percent of the hydrophilic ethylene oxide units present in the molecule.
The polyoxyethylene ethers as illustrated in Formula I and present in these novel compositions are prepared by methods well known to the art. For example, an excess of ethylene oxide is reacted with an alkylphenol under moderate conditions of temperature and pressure in the presence of an alkaline catalyst. This method of preparation is set forth in the textbook Surface Active Agents, Their Chemistry and Technology, Schwartz-Perry, 1949.
The polyoxyethylene polymers of alkylphenols of this invention have been demonstrated as having gastrointestinal spasmolytic activity without the corresponding anticholinergic side effects in a standard animal pharmacological test procedure reported in The Physiologist, vol. 12, No. 3, August 1969. Briefly, the test comprises implanting a cannula in the stomach of an animal. The animals are fasted for eighteen hours prior to testing and the stomach lavaged with saline to remove traces of food. A miniature rubber ballon is placed in the stomach via the cannula and the balloon is connected to a pressure transducer by a polyethylene tube to record gastric contractions. The system is filled with water and 0.5 ml. of
water is introduced into the balloon.
A one hour pre-drug control recording is obtained and the test compounds are administered via a cannula in aqueous solution in a dose volume of 1 ml./ kg. The post drug motility is recorded for three hours after drug administration.
Spasmolytic activity is expressed as the duration in minutes of inhibition of propulsive gastric contractions.
The above test was conducted on rats to determine the gastric spasmolytic efiect obtained by altering both the length of the alkyl chain and the polyoxyethylene content of the compounds as represented by Formula I and following are the results obtained:
In summary, the above standard pharmacological animal test procedure demonstrates the gastrointestinal spasmolytic activity of the polyethoxylated ethers of alkylphenols present in the pharmaceutical compositions of this invention. The results further indicate that when the aliphatic chain substituent is increased and the polyoxyethylene content is held relatively constant, spasmolytic potency increased. There is also an increase in spasmolytic potency when the alkyl side chain remains the same with decreasing percentage of polyoxyethylene. However, particularly significant in these test results is that they demonstrated the .compounds as represented by Formula I produced spasmolytic activity without the concomitant limiting or anticholinergic side effects.
The compositions of this invention are in dosage unit form and comprise a nontoxic pharmaceutical carrier and the polyoxyethylene polymers of alkylphenols of Formula I in an amount sufficient to produce gastrointestinal spasmolytic activity. Preferably, the composition will contain the polymer ingredient in an amount of from about 50 mg. to about 1000 mg. per dosage unit. Advantageously, the compositions will contain the polyoxyethylene polymer ingredient in an amount of from about 250 mg. to about 500 mg. per unit dose.
The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, sugar seeds, acacia, magnesium stearate, stearic acid, and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly the carrier or diluent may include any time delay material well known to the art, such as, for example, glyceryl monostearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be em ployed. Thus, if a solid carrier is used the preparation can be tableted, placed in a hard gelatin capsule in powder or sustained release pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 gm. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or an aqueous or nonaqneous liquid suspension.
The method in accordance with this invention comprises administering internally to animals, preferably humans, in an amount sufiicient to produce gastrointestinal spasmolytic activity a compound as represented by Formula I combined with a pharmaceutical carrier. The polyoxyethylated alkylphenol active ingredient will be present in dosage unit form in an amount of from about 50 mg. to about 1,000 mg. Preferably the above active ingredient will be present from about 250 mg. to about 500 mg. per unit dose. The administration may be parenterally or orally. The administration of the unit doses is preferably orally to animals sufiering from gastric hypermotility or other similar gastrointestinal abnormalities. Advantageously equal doses will be administered one to four times daily. Preferably the daily dosage will be from 50 mg. to about 4.0 gm. and most advantageously from 250 mg. to about 1.0 gm. of active ingredient.
When the method of administration described above is carried out, spasmolytic activity is achieved without the concomitant mydriatic and antisalivary side efi'ects common to known antispasmodic medicaments.
The following examples are not limiting but are illustrative of compounds of this invention and the procedures for their preparation. Other variations of this invention will be obvious to those skilled in the art.
EXAMPLE 1 Ingredients: Mg./capsule Octylphenoxypoly(ethyleneoxy)ethanol (68% polyoxyethylene) 1000 Peanut oil 100 Disperse the peanut oil in the polymer and place in a soft gelatin capsule.
One capsule is administered orally twice a day.
EXAMPLE 2 Ingredients: Mg. tablet Dodecylphenoxypoly(ethyleneoxy)ethanol (63% polyoxyethylene) 50 Calcium sulfate dihydrate 150 Sucrose 25 Starch l5 Talc 5 Stearic acid 3 The sucrose, calcium sulfate and the dodecylphenoxypoly(ethyleneoxy)ethanol are thoroughly mixed and granulated with hot 10% gelatin solution. The wetted mass is passed through a #16 US. Standard mesh screen directly onto drying trays. The granules are dried at F. and passed through a #20 US. Standard Mesh screen. These granules are then mixed with starch, talc and stearic acid, passed through a #60 US. Standard mesh screen and compressed into tablets.
One tablet is administered four times a day.
EXAMPLE 3 Ingredients: Mg./capsule Nonylphenoxypoly (ethyleneoxy ethanol (23 polyoxyethylene) 500 Peanut oil 200 The ingredients are thoroughly mixed and filled into a soft gelatin capsule.
phenoxypoly(ethyleneoxy)ethanol are dissolved in the distilled water and the syrup added. The mixture is filtered. The oil of orange and oil of custard flavor are then added and the mixture thoroughly stirred.
One teaspoonful is administered four times a day.
What is claimed is:
1. A method ofproducing gastrointestinal spasmolytic activity which comprises administering orally to animals suffering from gastric hypermotility an amout sufiicient to produce said activity of a polyoxyethylene polymer of an alkylphenol having the formula:
wherein:
R is an alkyl group comprising from 8 to 12 carbon atoms and n is a positive integer such that the polyoxyethylene groups are present from about 20% to about 70% of the molecule.
2. The method of claim 1 wherein said polymer is administered in a daily regimen of from about 50 mg. to about 4.0 gm.
3. The method of claim 1 wherein the alkyl group contains 12 carbon atoms and the polyoxyethylene units are present from about 61% to about 63% and said polymer is administered in a daily dosage regimen of from about 250 mg. to about 1.0 gm.
4. The method of claim 1 wherein a tablet or capsule OTHER REFERENCES containing from about 50 mg. to about 1000 mg. of the Remingtods Practice of Pharmacy, 13 ed, 1965, polymer is administered from one to four times daily.
5. The method of claim 1 wherein a tablet or capsule Chemical Abstracts 53 4 1 1959 containing from about 250 mg. to about 500 mg. of the 5 i l Abstracts 55;675f (1961), polymer is administered from one to four times daily. The Physiologist, v01, 12, No. 3, p. 241 (1969).
References J. Primary Examiner UNITED STATES PATENTS 10 L. SCHENKMAN, Assistant Examiner 3,244,589 4/1966 Sunnen et a1. 42478 X US. Cl. X.R.
3,440,318 4/1969 Polin 424341 X 42478
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10572171A | 1971-01-11 | 1971-01-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3709995A true US3709995A (en) | 1973-01-09 |
Family
ID=22307436
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US00105721A Expired - Lifetime US3709995A (en) | 1971-01-11 | 1971-01-11 | Method of producing gastrointestinal spasmolytic activity with alkylphenoxypoly(ethyleneoxy)ethanols |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3709995A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2528826A1 (en) * | 1982-06-16 | 1983-12-23 | Sanofi Sa | Phenyl and naphthyl polyoxyethylene cpds. - anti:seborrhoea and antiinflammatories applied topically to skin, as lotions, creams, shampoo etc. |
-
1971
- 1971-01-11 US US00105721A patent/US3709995A/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2528826A1 (en) * | 1982-06-16 | 1983-12-23 | Sanofi Sa | Phenyl and naphthyl polyoxyethylene cpds. - anti:seborrhoea and antiinflammatories applied topically to skin, as lotions, creams, shampoo etc. |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AS | Assignment |
Owner name: SMITHKLINE BECKMAN CORPORATION, PENNSYLVANIA Free format text: CHANGE OF NAME;ASSIGNOR:SMITHKLINE CORPORATION;REEL/FRAME:004080/0769 Effective date: 19820304 Owner name: SMITHKLINE BECKMAN CORPORATION Free format text: CHANGE OF NAME;ASSIGNOR:SMITHKLINE CORPORATION;REEL/FRAME:004080/0769 Effective date: 19820304 |