CA1062721A - Propionic acid derivatives - Google Patents
Propionic acid derivativesInfo
- Publication number
- CA1062721A CA1062721A CA265,001A CA265001A CA1062721A CA 1062721 A CA1062721 A CA 1062721A CA 265001 A CA265001 A CA 265001A CA 1062721 A CA1062721 A CA 1062721A
- Authority
- CA
- Canada
- Prior art keywords
- aluminum
- ibuprofen
- flurbiprofen
- acid
- added
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
- C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
- C07C57/38—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings polycyclic
Abstract
ABSTRACT OF THE DISCLOSURE
Aluminum ibuprofen and flurblprofen salts are eco-nomical, tasteless and more versatile forms of these anti-inflammatory analgetic and anti-pyretic drugs. Pharma-ceutilcal compositions and method of using these aluminum ibuprofen and flurblprofen salts to alleviate inflammatory and pyretic conditions In mammals are disclosed.
Aluminum ibuprofen and flurblprofen salts are eco-nomical, tasteless and more versatile forms of these anti-inflammatory analgetic and anti-pyretic drugs. Pharma-ceutilcal compositions and method of using these aluminum ibuprofen and flurblprofen salts to alleviate inflammatory and pyretic conditions In mammals are disclosed.
Description
INrl'l~DUCTION
This invention relates to 2-(4-isobu-tyl-phenyl)propionlc acid, now known generically as ibuprofen, and
This invention relates to 2-(4-isobu-tyl-phenyl)propionlc acid, now known generically as ibuprofen, and
2~(2-fluoro-4-biphenylyl)propionic acid, now known generically as flurhiprofen, which coMpounds are useful anti-inflam~latory analyesic and anti-pyretic drugs. More particularly, this invention provides improved pharmaceutical forms of these drugs.
BACKGROUND OF T~IE INVENTION
Nicholson et al., U.S. Patent No. 3,385,886 claims 2-(4-isobutylphenyl)propionic acid (ibuprofen) as a compound per se. Nicholson et al. U.S. Patent No. 3,228,831 discloses the use of ibuprofen as a drug to alleviate the symptoms of inflammation in an animal. Flurbiprofen, 2-(2-fluoro-4-biphenylyl)propionic acid, is also a known compound, having anti-inflammatory, analgesic and anti-pyretic activity in mammals.
Various metallic salts of other anti-inflammatory acid compounds, including sodium, calcium, aluminum and various amine salts, are suggested by prior art references such as U.S.
Patent Nos. 3,600,437 and 3,624,142 and Belgian Patent No.
811,810. But none of them discloses the aluminum salts herein disclosed.
For various reasons of concern to the pharmaceu-tical chemists, including the best recoverability from its reaction mixtures, processability in pharmaceutical formula-ti~ns and machinery, chemical and physical stability during transportation and storage, ibuprofen and flurbiprofen have to date been compounded or sold as tablets or gel seals con-taining the free acid ~ se. The material acid taste ' 2 - ;
.. , . ............. , . , . , ................ , . .,: .. .
.. . . .: . . :~ : . .. .
BACKGROUND OF T~IE INVENTION
Nicholson et al., U.S. Patent No. 3,385,886 claims 2-(4-isobutylphenyl)propionic acid (ibuprofen) as a compound per se. Nicholson et al. U.S. Patent No. 3,228,831 discloses the use of ibuprofen as a drug to alleviate the symptoms of inflammation in an animal. Flurbiprofen, 2-(2-fluoro-4-biphenylyl)propionic acid, is also a known compound, having anti-inflammatory, analgesic and anti-pyretic activity in mammals.
Various metallic salts of other anti-inflammatory acid compounds, including sodium, calcium, aluminum and various amine salts, are suggested by prior art references such as U.S.
Patent Nos. 3,600,437 and 3,624,142 and Belgian Patent No.
811,810. But none of them discloses the aluminum salts herein disclosed.
For various reasons of concern to the pharmaceu-tical chemists, including the best recoverability from its reaction mixtures, processability in pharmaceutical formula-ti~ns and machinery, chemical and physical stability during transportation and storage, ibuprofen and flurbiprofen have to date been compounded or sold as tablets or gel seals con-taining the free acid ~ se. The material acid taste ' 2 - ;
.. , . ............. , . , . , ................ , . .,: .. .
.. . . .: . . :~ : . .. .
3~2 ~ ~Z 7 ~ ~
of these products is masked by a coating which permits oral administration without giving the bitter or burning acid taste of the free acid.- Continued research for better modes in which to administer these acids continues both for the purpose of eliminating or reducing the cost of and need for coatings presently used and to overcome as much as possible the dTsagreeable acid taste of the free acid drugs. How-ever, it h~s been found that the usual sodium, calcium and magnesium salt forms of this acid also contain a discernable dîsagreeable taste.
There is a need for an economical, tasteless form of ibuprofen and flurbipro-fen and it is the primary object of this invention to provide such a useful form of these valu-able drug compounds.
It is an additional object of this invention to pro-vide anti-inflammatory pharmaceutiIal compositions of ibu-profen or flurbiprofen suitable for the treatment of inflam-matory conditions in various dosage forms which are more economical and/or palatab~e than presently known forms.
It is also an object of this invention to provide an improved method for treating inflammation and for alleviat-ing the symptoms of fever and pain by the administration of these more useful forms of ibuprofen or flurbiproFen~
it is also an object ot this invention to provide ibuprofen and flurbiprofen in a useful, less volatile drug form, as the aluminum salts thereof.
Other objects, aspects and advantages of this in- 1 vention will be seen from reading the remaining specifica-tion and claims which rOl low.
SUMMARY OF THE INVENTION
~3~
~ 7 ~ ~
BrieFly according to this invention, tt has been dis-covered that aluminum salts of ibuprofen and flurbiprofen provide an effective pharmaceutical form of these anti-in~lammatory anal~esic and anti-pyretic drug acids. These aluminum salts are essentially tasteless and can be com-pounded economically into pharmaceutical liquid suspension and solid formula~ions for administration in unit dosage form. ~anufacture and use of these aluminum salt forms of these acids obviates the coating operation previously re-quired, and provide the desired dosage of the respective drug acid upon dissociation o~ the salt in the alimentary tract of the animal patient.
DETAILED DESCR ! PT!ON_OF THE INVENT!ON
This invention provides new compounds which are alu-minum salts of ibuprofen and flurbiprofen. They can be described chemically by use of the formula ~ R ~ CH- COO 1 AL~ OH
Y . -: .
' wherein R denotes an isobutyl group or phenyl, x is O to ~ -?3 Y is 1 to 3, so that the sum of x and y is equal to 3, the trivalent state of aluminum, and n i5 0 or 1, and is 1 only when R is phenyl. This invention also includes the concept of mixtures of these salts such that the average sum of x and y in a particular ibuprofen or flurbiprofen sal~ composition of these salts can be between 1 and 3, ~ 7 ~ ~
e.g., 0.9, 1.3 or 2.5. For example, the preferred molar ratio of ibuprofen acid moiety to aluminum ion is in the range of from 1:1 to 3~
This invention includes pharmace~tica1 preparations in dosage unit form adapted for administration to obtain an anti-inflammatory effect comprising per dosage unit, an anti-inflammatory effective, non-toxic amount within the range of from about 5.0 to about 500 mg. of an aluminum ibuprofen compound defined above, or mixtures thereof. The invention also includes a method of treating inflammatory conditions in warm blooded mammals, including humans, which comprises administering to a mammalian subject from 0.1 to 75 mg./!<g. of body weight daily an aluminum ibuprofen or flurbiprofen compound defined above, or mixtures thereof.
The new aluminum salts can be prepared by suspending or dispersing the ibuprofen or flurbiprofen acid in water, adding base to the mixture to effect dissolution of the acid in the mixtures. Then this drug acid solution can be added to or otherwise blended with a solution of a phar-maceutical grade aluminum acid salt, e.g. aluminum nitrate, chloride or sulfate. Precipication of the respective alu-minum salt commences almost immediately~ After the selected proportion of the drug acid or dissolved salt thereof has - been mixed with the alumin~m salt solution, the mixture can be stirred or otherwise agitated to insure complete reaction.
The solid aluminum drug acid salt can be separated by fil-tration washed with water, drled in vacuo at 50 - 60 C.
: ' to constant weight. Thereafter the aluminum salt is ready for compounding into various appropriate pharmaceutical forms such~as,suspensions, elixirs, tablets, or capsules - ' ,~ , ' , , .
~ ~ ~2 ~
mixed with appropriate diluents.
These aluminum salts of these anti-inflammatory and anti-pyretic and analgesic acids are tasteless and can be compounded into pharmaceutical unit dosage form without ~he coating that is necessary for the free acid drug. These aluminum drug acid salt forms in pharmaceutical suspension forms are of particular interest for administration to geriatric and pediatric patients.
The invention is further described by the following examples which exemplify how these`salts can be prepared, how they can be formulated, and how they rate in taste tests over other salts of the same drug acid.
ExamPle 1 A. Calcium Salt of Ibuprofen Ibuprofen (5.0 gm., 0.024 mole) was suspended in 50 ml. of water. To this was added 25 ml. of 1 N NaOH. The mixture was stirred until solution occurred. 1.345 gm. of calcium chloride (0.012 mole) was added and precipitation 2 occurred immediately. The solid was collected, washed with water and dried.
The dried solid was recrystallized from 95% ethanol (70 mol.~ and water (30 ml.) and dried at 60 C.~ melting point 250 + C. `
.
Anal~ses:
Theory (~): C, 69 .30J H, 7.60, Ca, 8.87~.
Found: C, 69~15? H~ 7.58, Ca, 9.17.
B. ~ ~
ibuprofen (100 gm., o.485 mole) was suspended in 300 ml. of water. To this suspension was added 500 ml. of lN
NaOH (0.500 mole) with good stirring. Dissolve 90.8 gm.
'-..':
, ~ 72 1 ,'b~ ' (0.242 mole~ of A1 (NO3)3 9H20 in 300 ml. of water and si-multaneously add the solu~ion of sodium ibuprofen to 200 ml.
of NaHCO3 (20.362 gm., 0.242 mole). Precipitation occurs immediately. Stir for one hour, filter the solids, and wash 5 with water. Dried in vacuo a~ 50 C., melting point 240 +
o C.
AnalYses:
Theory (~): C, 68.70, H, 7.76, Al, 5.94.
Found: C, 67.22, H, 7.78, Al, 7.88.
KF water - 5.41%
C. Aluminum Salt of 3bupr,ofen (1:1~
Ibuprofen (20.6~ gm., 0.1 mole) was suspended in 20 ml. of water and 100 ml. of lN NaOH added. In 150 ml. of water was dissolved 37.5 gm. (0.1 mole) of Al (NO3)3 9H20.
The solutions of sodium ibuprofen and Al(NO9) 3 were slowly added simultaneously to 450 ml. of NaHCO3 (16.8 gm., 0.2 mole) with stirring. PrecipitatiorI commenced immediately.
Addition took approximately 10 minutes. The resulting pre-cip7tate was stirred for one hour and filtered, The solids 20 were placed In ~acuQ at 50 C-Analyses:
Theory (1~): C, 58.64~ Hg 7.19, Al, 10.13.
Found: C,, 58.06, H, 7.12, Al, 11.4~.
KF water - 5.39%
Melting point 240 ~ C.
D. Maqn~esium Salt of Ibu~rofen Ibuprofen (41.26 gm., 0.2 mole) was suspended in 20 ml. of water. Add 200 ml. of 1 N NaOH (0.2 mole) to the ~ , suspension. A solution of 20.3 gm. (0.1 mole) of MgCl2 9H20 '~
3o was slowly added to the sodium ibuprofen and the resulting ''' ~7- , , 3~32 ~ 7 ~
precipitate filtcred and dried in vacuo, melting point ~ 160 C.
Analyses:
__ T~eory (%): C, 71.81, H3 7.88, Mg, 5.59.
Found: C, 72.12, H, 8.21, Mg, 5.68.
KF water - 3.81%
Example ?
_luminum Salt of Ibuprofen (3:1) Ibuprofen (150 gm., 0.727 mole) was suspended in 1 !iter of water. Add 750 ml. of lN NaOH (0.727 mole) to the suspension and stir. Slowly add a solution of 90.93 gm.
(0. 242 mole) of Al (NO3)39H20 with good stirring until pre-cipitation is complete. Stir for an additional hour and filter. Dry solids _n vacuo a~ 50 C.
15 Analyses: -Theory (%): C, 72.87, H, 8.00, Al, 4.20.
Found: C, 71.50, H, 8.20, Al J 4.96.
; KF water - 3.53 Example ~
TAST PROPERTIES OF VARIOUS IBUPROFEN SALTS
. Suspensions of the various salts were made by ultra-son i f i cat i on and çontained: -Drug: 200 mg.
Pluronic F-681: 20 mg.
Wat~r qs.: 10 ml.
each ml. o~ suspension contains 20 mg. of drug.
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~, ~ ~ o C ~ C ~ ~
_C .-- u~
I c u~ ~ c ~- '-- CL E
CO
~O ~
O Q
L~ O
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._ O D
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-- ~ O I O l-CO ~ ~ CO LL ~ ~ Q - : `
:
--~ : ' a) E
Z U~
q~ a~ E
C ,_ _ ~~1 a) co ~ ~ co O ~ ~ ~ ._ o C
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E ~ 3 .~, ~ 3 ~ ~ ~n o c c ---- .--a) ~ :
on P~ U E E C Q
3 ~ ~ ~
CC S _ , '' .
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t-~ ~ O ~ `
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tn : ~ '-~n O Q : .
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The taste score has the following meaning:
O = poor taste characteristics 9 - excellent taste characteristics Example 4 Pediatric Suspension A pediatric suspension containing 50 mg. of ibuprofen per teaspoonful (5 ml.) is made from the following types and amounts of ingredients.
Aluminum ibuprofen ~1:1) 13.0 gm.
Tragacanth 10.0 gm.
Benzoic Acid 2.0 gm.
Sodium Saccharin 1.0 gm. ;~
Glycerin 10.0 ml.
Peppermint Oil 0.75 ml.
Purified water~ q.s. 1000 ml.
The aluminum ibuprofen Ts mixed with 500 ml. of the water. The tragacanth J saccharin and glycerin are triturated and added to the water. ~he benzalic acid and peppermint oil are added to the mixture in a small amount oF water. Puri-fied water is added to volume. One teaspoon of this suspen-sion is administered to children 1-4 times a day.
Suspension Aluminum ibuprofen (I:1) 104 gm.
Microcrystalline ~ellulose 12 gm.
Sodium Carboxymethylcellulose 10 gm.
Cherry Flavor 0.5 gm-Purified water, q.s. 1000 ml.
Each teaspoonful (5 ml.) contains 400 mg. of ibuprofen free acid. The microcrysta!line cellulose is dispensed in the water with a high-shear mixer. The sodium carboxymethyl-cellulose is added and dissolved by means oF a high-shear ;~ ' .
3~2 ~ ~ 27 ~
mixer. The aluminum ibuprofen and ~lavor are added and mixed and the whole homogenized.
Dose: 1 teaspoonful 1-4 times a day. -Example 6 ' Each '~ablet equiv.
Chewable tablets, to 100 mg. ibuprofen Aluminum ibuprofen (1:1) 65 gm.
Soluble saccharin .3 gm.
Dry orange flavor .7 gm.
Mannitol 2~5 gm.
Acacia 6.5 gm.
Magnesium stearate 6.5 gm.''' -'' Talc 7.0 gm.
The clrug~ mannitol and acacia are mixed with water and granulated to give a wet mass which is passed through a 8 ,~
mesh sieve and dried. The flavor, magnesium stearate and talc are added and mixed well. Tablets are compressed using , a tablet machine. This batch will make about 1000 tablets.
Example ~
Suspension 200 mg./ml. "
Aluminum ibuprofen (1:1) 52 gm.
Orange flavor 0.5 gm.
- Polysorbate 80 12.0 gm. -Sodium benzoate 0.5 gm.. . .
Purified water, qs. ' ,1000 ml,.
'25 Blend ingredients and prepare suspension using ultra- ~
sonlfication. ~ , Each teaspoonful gives 200 mg. of ibuprofen. Dos3ges can be given 1-4 times a day.
E_ample 8 ~0 Suppositor~ formulation . .
~332 7 Z ~
Percent ibuproFen, Al salt (1:1) ---------------------- 15.5 White wax, USP -------------------------------- 4.0 Theobroma 80.5 Footnote: 1 = By weight.
White wax is rnixed with the aluminum ibuprofen with the acid of gentle heat to melt the wax. Theobroma oil is shaved and added to the mixture slowly. After the theo-broma oil has been completely melted~ with the aid of addi-tional heat as required, the mixture may be poured into suppository molds of suitable size for the desired dose;
e.g., a 2.58 9. suppository of the above mixture yields a 400 mg. dose of aluminum ibuprofen (1:1) Example ~ Aluminum flurbiprofen (1:1) (0.004 mole) A 1 9, portion of flurbiprofen is suspended in 100 ml.
of water, to this suspension 4,,09 mol. of 1.0 N sodium hydroxide solution is added, and the mixture is heated un-til all of the flurbiprofen is in a solution as a sodium flurbiprofen. In a separate container 1.53 9. (0.004 mole) of a pharmaceutical grade of aluminum nitrate 9H2o is dis-solved in 40 ml. of water. A solution of o.688 g. (0.0081 mole) sodium bicarbonate in 30 ml. of water is also pre-pared. The sodium flurbiprofen solution and the aluminum ; nitrate solution are added simultaneously to the sodium .
; 25 biearbonate solu~ion with good stirring. Solid form of aluminum flurbiprofen salt forms immediately. The mixture is stirred for one-half hour after addition is completed to insure complete reaction. The aluminum flurbiprofen salt is separated from the aqueous medium by filtration and air dried, 3~32 ~ ~ ~ Z7 ~ ~
In a taste test of this aluminum flurbiprofen salt compared with the flurbiprofen acid and ibuprofen acid, the aluminum flurbiprofen salt gave essentially no drug taste. The test was conducted as follows:
The three compounds tested were A - The above aluminum flurbiprofen salt;
B - Flurbiprofen, acid;
C - Ibuprofen, acid.
Each test compound was suspended, at a concentration of 80 mg./ ml. in a standard, common vehicle containing ~orbitol solution, glycerin, sorbic acid, polysorbate 80 ~ - .
(TWEEN 80 ), orange-lemon flavor, 95 percent ethanol, deionized water and sodium saccharin.
Each composition was tested and rated on a 0 to 9 number scale where 0 is strong acid taste to 9 no taste.
The results were as follows:
A - 7, mild; no drug taste B - 1, intense burning C - 1, intense burning.
. ~, -
of these products is masked by a coating which permits oral administration without giving the bitter or burning acid taste of the free acid.- Continued research for better modes in which to administer these acids continues both for the purpose of eliminating or reducing the cost of and need for coatings presently used and to overcome as much as possible the dTsagreeable acid taste of the free acid drugs. How-ever, it h~s been found that the usual sodium, calcium and magnesium salt forms of this acid also contain a discernable dîsagreeable taste.
There is a need for an economical, tasteless form of ibuprofen and flurbipro-fen and it is the primary object of this invention to provide such a useful form of these valu-able drug compounds.
It is an additional object of this invention to pro-vide anti-inflammatory pharmaceutiIal compositions of ibu-profen or flurbiprofen suitable for the treatment of inflam-matory conditions in various dosage forms which are more economical and/or palatab~e than presently known forms.
It is also an object of this invention to provide an improved method for treating inflammation and for alleviat-ing the symptoms of fever and pain by the administration of these more useful forms of ibuprofen or flurbiproFen~
it is also an object ot this invention to provide ibuprofen and flurbiprofen in a useful, less volatile drug form, as the aluminum salts thereof.
Other objects, aspects and advantages of this in- 1 vention will be seen from reading the remaining specifica-tion and claims which rOl low.
SUMMARY OF THE INVENTION
~3~
~ 7 ~ ~
BrieFly according to this invention, tt has been dis-covered that aluminum salts of ibuprofen and flurbiprofen provide an effective pharmaceutical form of these anti-in~lammatory anal~esic and anti-pyretic drug acids. These aluminum salts are essentially tasteless and can be com-pounded economically into pharmaceutical liquid suspension and solid formula~ions for administration in unit dosage form. ~anufacture and use of these aluminum salt forms of these acids obviates the coating operation previously re-quired, and provide the desired dosage of the respective drug acid upon dissociation o~ the salt in the alimentary tract of the animal patient.
DETAILED DESCR ! PT!ON_OF THE INVENT!ON
This invention provides new compounds which are alu-minum salts of ibuprofen and flurbiprofen. They can be described chemically by use of the formula ~ R ~ CH- COO 1 AL~ OH
Y . -: .
' wherein R denotes an isobutyl group or phenyl, x is O to ~ -?3 Y is 1 to 3, so that the sum of x and y is equal to 3, the trivalent state of aluminum, and n i5 0 or 1, and is 1 only when R is phenyl. This invention also includes the concept of mixtures of these salts such that the average sum of x and y in a particular ibuprofen or flurbiprofen sal~ composition of these salts can be between 1 and 3, ~ 7 ~ ~
e.g., 0.9, 1.3 or 2.5. For example, the preferred molar ratio of ibuprofen acid moiety to aluminum ion is in the range of from 1:1 to 3~
This invention includes pharmace~tica1 preparations in dosage unit form adapted for administration to obtain an anti-inflammatory effect comprising per dosage unit, an anti-inflammatory effective, non-toxic amount within the range of from about 5.0 to about 500 mg. of an aluminum ibuprofen compound defined above, or mixtures thereof. The invention also includes a method of treating inflammatory conditions in warm blooded mammals, including humans, which comprises administering to a mammalian subject from 0.1 to 75 mg./!<g. of body weight daily an aluminum ibuprofen or flurbiprofen compound defined above, or mixtures thereof.
The new aluminum salts can be prepared by suspending or dispersing the ibuprofen or flurbiprofen acid in water, adding base to the mixture to effect dissolution of the acid in the mixtures. Then this drug acid solution can be added to or otherwise blended with a solution of a phar-maceutical grade aluminum acid salt, e.g. aluminum nitrate, chloride or sulfate. Precipication of the respective alu-minum salt commences almost immediately~ After the selected proportion of the drug acid or dissolved salt thereof has - been mixed with the alumin~m salt solution, the mixture can be stirred or otherwise agitated to insure complete reaction.
The solid aluminum drug acid salt can be separated by fil-tration washed with water, drled in vacuo at 50 - 60 C.
: ' to constant weight. Thereafter the aluminum salt is ready for compounding into various appropriate pharmaceutical forms such~as,suspensions, elixirs, tablets, or capsules - ' ,~ , ' , , .
~ ~ ~2 ~
mixed with appropriate diluents.
These aluminum salts of these anti-inflammatory and anti-pyretic and analgesic acids are tasteless and can be compounded into pharmaceutical unit dosage form without ~he coating that is necessary for the free acid drug. These aluminum drug acid salt forms in pharmaceutical suspension forms are of particular interest for administration to geriatric and pediatric patients.
The invention is further described by the following examples which exemplify how these`salts can be prepared, how they can be formulated, and how they rate in taste tests over other salts of the same drug acid.
ExamPle 1 A. Calcium Salt of Ibuprofen Ibuprofen (5.0 gm., 0.024 mole) was suspended in 50 ml. of water. To this was added 25 ml. of 1 N NaOH. The mixture was stirred until solution occurred. 1.345 gm. of calcium chloride (0.012 mole) was added and precipitation 2 occurred immediately. The solid was collected, washed with water and dried.
The dried solid was recrystallized from 95% ethanol (70 mol.~ and water (30 ml.) and dried at 60 C.~ melting point 250 + C. `
.
Anal~ses:
Theory (~): C, 69 .30J H, 7.60, Ca, 8.87~.
Found: C, 69~15? H~ 7.58, Ca, 9.17.
B. ~ ~
ibuprofen (100 gm., o.485 mole) was suspended in 300 ml. of water. To this suspension was added 500 ml. of lN
NaOH (0.500 mole) with good stirring. Dissolve 90.8 gm.
'-..':
, ~ 72 1 ,'b~ ' (0.242 mole~ of A1 (NO3)3 9H20 in 300 ml. of water and si-multaneously add the solu~ion of sodium ibuprofen to 200 ml.
of NaHCO3 (20.362 gm., 0.242 mole). Precipitation occurs immediately. Stir for one hour, filter the solids, and wash 5 with water. Dried in vacuo a~ 50 C., melting point 240 +
o C.
AnalYses:
Theory (~): C, 68.70, H, 7.76, Al, 5.94.
Found: C, 67.22, H, 7.78, Al, 7.88.
KF water - 5.41%
C. Aluminum Salt of 3bupr,ofen (1:1~
Ibuprofen (20.6~ gm., 0.1 mole) was suspended in 20 ml. of water and 100 ml. of lN NaOH added. In 150 ml. of water was dissolved 37.5 gm. (0.1 mole) of Al (NO3)3 9H20.
The solutions of sodium ibuprofen and Al(NO9) 3 were slowly added simultaneously to 450 ml. of NaHCO3 (16.8 gm., 0.2 mole) with stirring. PrecipitatiorI commenced immediately.
Addition took approximately 10 minutes. The resulting pre-cip7tate was stirred for one hour and filtered, The solids 20 were placed In ~acuQ at 50 C-Analyses:
Theory (1~): C, 58.64~ Hg 7.19, Al, 10.13.
Found: C,, 58.06, H, 7.12, Al, 11.4~.
KF water - 5.39%
Melting point 240 ~ C.
D. Maqn~esium Salt of Ibu~rofen Ibuprofen (41.26 gm., 0.2 mole) was suspended in 20 ml. of water. Add 200 ml. of 1 N NaOH (0.2 mole) to the ~ , suspension. A solution of 20.3 gm. (0.1 mole) of MgCl2 9H20 '~
3o was slowly added to the sodium ibuprofen and the resulting ''' ~7- , , 3~32 ~ 7 ~
precipitate filtcred and dried in vacuo, melting point ~ 160 C.
Analyses:
__ T~eory (%): C, 71.81, H3 7.88, Mg, 5.59.
Found: C, 72.12, H, 8.21, Mg, 5.68.
KF water - 3.81%
Example ?
_luminum Salt of Ibuprofen (3:1) Ibuprofen (150 gm., 0.727 mole) was suspended in 1 !iter of water. Add 750 ml. of lN NaOH (0.727 mole) to the suspension and stir. Slowly add a solution of 90.93 gm.
(0. 242 mole) of Al (NO3)39H20 with good stirring until pre-cipitation is complete. Stir for an additional hour and filter. Dry solids _n vacuo a~ 50 C.
15 Analyses: -Theory (%): C, 72.87, H, 8.00, Al, 4.20.
Found: C, 71.50, H, 8.20, Al J 4.96.
; KF water - 3.53 Example ~
TAST PROPERTIES OF VARIOUS IBUPROFEN SALTS
. Suspensions of the various salts were made by ultra-son i f i cat i on and çontained: -Drug: 200 mg.
Pluronic F-681: 20 mg.
Wat~r qs.: 10 ml.
each ml. o~ suspension contains 20 mg. of drug.
' .
' , z~ c o .--x ~7 o ~
u7 ~ ~ - ~ c ~ -- ~ o ~
c u~ C ~ ~ Q tD
~ ._ ~ I
_ ~ Y ~ cn m c c ~ Q,)._ E -- ~n ~:7 c ._ X
~, ~ ~ o C ~ C ~ ~
_C .-- u~
I c u~ ~ c ~- '-- CL E
CO
~O ~
O Q
L~ O
~ C
._ O D
O ~ _ .
C ~ (11>`
E O ~ ~ O
-- ~ O I O l-CO ~ ~ CO LL ~ ~ Q - : `
:
--~ : ' a) E
Z U~
q~ a~ E
C ,_ _ ~~1 a) co ~ ~ co O ~ ~ ~ ._ o C
C
~ ~ ~ O
~ O O
) Ccn Q
~ , ._ c~ ~n ~ E E 3a~
E ~ 3 .~, ~ 3 ~ ~ ~n o c c ---- .--a) ~ :
on P~ U E E C Q
3 ~ ~ ~
CC S _ , '' .
_~ .
.
C _ O
._ ~ ) ~ OILI
11~ ~-1 N
C~ ..
t-~ ~ O ~ `
~ ~ -- O :~!
tn : ~ '-~n O Q : .
u E
~ , ....
,.. .... ... .
z~
Z:~
The taste score has the following meaning:
O = poor taste characteristics 9 - excellent taste characteristics Example 4 Pediatric Suspension A pediatric suspension containing 50 mg. of ibuprofen per teaspoonful (5 ml.) is made from the following types and amounts of ingredients.
Aluminum ibuprofen ~1:1) 13.0 gm.
Tragacanth 10.0 gm.
Benzoic Acid 2.0 gm.
Sodium Saccharin 1.0 gm. ;~
Glycerin 10.0 ml.
Peppermint Oil 0.75 ml.
Purified water~ q.s. 1000 ml.
The aluminum ibuprofen Ts mixed with 500 ml. of the water. The tragacanth J saccharin and glycerin are triturated and added to the water. ~he benzalic acid and peppermint oil are added to the mixture in a small amount oF water. Puri-fied water is added to volume. One teaspoon of this suspen-sion is administered to children 1-4 times a day.
Suspension Aluminum ibuprofen (I:1) 104 gm.
Microcrystalline ~ellulose 12 gm.
Sodium Carboxymethylcellulose 10 gm.
Cherry Flavor 0.5 gm-Purified water, q.s. 1000 ml.
Each teaspoonful (5 ml.) contains 400 mg. of ibuprofen free acid. The microcrysta!line cellulose is dispensed in the water with a high-shear mixer. The sodium carboxymethyl-cellulose is added and dissolved by means oF a high-shear ;~ ' .
3~2 ~ ~ 27 ~
mixer. The aluminum ibuprofen and ~lavor are added and mixed and the whole homogenized.
Dose: 1 teaspoonful 1-4 times a day. -Example 6 ' Each '~ablet equiv.
Chewable tablets, to 100 mg. ibuprofen Aluminum ibuprofen (1:1) 65 gm.
Soluble saccharin .3 gm.
Dry orange flavor .7 gm.
Mannitol 2~5 gm.
Acacia 6.5 gm.
Magnesium stearate 6.5 gm.''' -'' Talc 7.0 gm.
The clrug~ mannitol and acacia are mixed with water and granulated to give a wet mass which is passed through a 8 ,~
mesh sieve and dried. The flavor, magnesium stearate and talc are added and mixed well. Tablets are compressed using , a tablet machine. This batch will make about 1000 tablets.
Example ~
Suspension 200 mg./ml. "
Aluminum ibuprofen (1:1) 52 gm.
Orange flavor 0.5 gm.
- Polysorbate 80 12.0 gm. -Sodium benzoate 0.5 gm.. . .
Purified water, qs. ' ,1000 ml,.
'25 Blend ingredients and prepare suspension using ultra- ~
sonlfication. ~ , Each teaspoonful gives 200 mg. of ibuprofen. Dos3ges can be given 1-4 times a day.
E_ample 8 ~0 Suppositor~ formulation . .
~332 7 Z ~
Percent ibuproFen, Al salt (1:1) ---------------------- 15.5 White wax, USP -------------------------------- 4.0 Theobroma 80.5 Footnote: 1 = By weight.
White wax is rnixed with the aluminum ibuprofen with the acid of gentle heat to melt the wax. Theobroma oil is shaved and added to the mixture slowly. After the theo-broma oil has been completely melted~ with the aid of addi-tional heat as required, the mixture may be poured into suppository molds of suitable size for the desired dose;
e.g., a 2.58 9. suppository of the above mixture yields a 400 mg. dose of aluminum ibuprofen (1:1) Example ~ Aluminum flurbiprofen (1:1) (0.004 mole) A 1 9, portion of flurbiprofen is suspended in 100 ml.
of water, to this suspension 4,,09 mol. of 1.0 N sodium hydroxide solution is added, and the mixture is heated un-til all of the flurbiprofen is in a solution as a sodium flurbiprofen. In a separate container 1.53 9. (0.004 mole) of a pharmaceutical grade of aluminum nitrate 9H2o is dis-solved in 40 ml. of water. A solution of o.688 g. (0.0081 mole) sodium bicarbonate in 30 ml. of water is also pre-pared. The sodium flurbiprofen solution and the aluminum ; nitrate solution are added simultaneously to the sodium .
; 25 biearbonate solu~ion with good stirring. Solid form of aluminum flurbiprofen salt forms immediately. The mixture is stirred for one-half hour after addition is completed to insure complete reaction. The aluminum flurbiprofen salt is separated from the aqueous medium by filtration and air dried, 3~32 ~ ~ ~ Z7 ~ ~
In a taste test of this aluminum flurbiprofen salt compared with the flurbiprofen acid and ibuprofen acid, the aluminum flurbiprofen salt gave essentially no drug taste. The test was conducted as follows:
The three compounds tested were A - The above aluminum flurbiprofen salt;
B - Flurbiprofen, acid;
C - Ibuprofen, acid.
Each test compound was suspended, at a concentration of 80 mg./ ml. in a standard, common vehicle containing ~orbitol solution, glycerin, sorbic acid, polysorbate 80 ~ - .
(TWEEN 80 ), orange-lemon flavor, 95 percent ethanol, deionized water and sodium saccharin.
Each composition was tested and rated on a 0 to 9 number scale where 0 is strong acid taste to 9 no taste.
The results were as follows:
A - 7, mild; no drug taste B - 1, intense burning C - 1, intense burning.
. ~, -
Claims (13)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing an aluminum salt of the formula wherein R is an isobutyl or phenyl group, x is 0 to 2, y is 1 to 3, so that the sum of x and y is equal to 3, and n is 0 or 1 and is 1 only when R is phenyl;
which comprises reacting an aqueous suspension or dispersion of an acid selected from 2-(4-isobutylphenyl)propionic acid (ibuprofen) and 2-(2-fluoro-4-biphenylyl)propionic acid (flurbiprofen) with an aqueous solution of an aluminum salt in the presence of a base.
which comprises reacting an aqueous suspension or dispersion of an acid selected from 2-(4-isobutylphenyl)propionic acid (ibuprofen) and 2-(2-fluoro-4-biphenylyl)propionic acid (flurbiprofen) with an aqueous solution of an aluminum salt in the presence of a base.
2. The process according to claim 1 in which sufficient sodium hydroxide is added to an aqueous suspension of the acid in order to dissolve the acid, and an aqueous solution of aluminum nitrate is added to the resultant solution.
3. A process for preparing an aluminum ibuprofen which comprises reacting an aqueous suspension of ibuprofen with an aqueous solution of an aluminum salt, in the presence of a base.
4. The process according to claim 3, wherein ibuprofen is suspended in water, sodium hydroxide is added in an amount sufficient to dissolve the ibuprofen and then aluminum nitrate in water is added in an amount sufficient to form aluminum ibuprofen.
5. The process according to claim 4 wherein 1 mol of aluminum nitrate is reacted with 1 mol of ibuprofen.
6. The process according to claim 4 wherein 1 mol of aluminum nitrate is reacted with 2 mols of ibuprofen.
7. The process according to claim 4 wherein 1 mol of aluminum nitrate are reacted with 3 mols of ibuprofen.
8. A process for preparing an aluminum flurbiprofen which comprises reacting an aqueous suspension of flurbiprofen with an aqueous solution of an aluminum salt, in the presence of a base.
9. A process in accordance with claim 8 wherein flurbiprofen is suspended in water, sodium hydroxide is added in an amount sufficient to dissolve the flurbiprofen and then aluminum nitrate in water is added in an amount sufficient to form aluminum flurbiprofen.
10. The process of claim 9 wherein 1 mol of aluminum nitrate is reacted with 1 mol of flurbiprofen.
11. An aluminum salt selected from the group con-sisting of aluminum salts of 2-(4-isobutylphenyl)propianic and 2-(2-fluoro-4-biphenylyl)propionic acids, whenever prepared or produced by the process defined in claim 1 or 2 or by the obvious chemical equivalent.
12. An aluminum salt of ibuprofen, whenever prepared or produced by the process defined in claim 5, 6 or 7 or by the obvious chemical equivalent.
13. An aluminum salt of flurbiprofen, whenever pre-pared or produced by the process defined in claim 8, 9 or 10 or by the obvious chemical equivalent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US64043175A | 1975-12-15 | 1975-12-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1062721A true CA1062721A (en) | 1979-09-18 |
Family
ID=24568211
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA265,001A Expired CA1062721A (en) | 1975-12-15 | 1976-11-05 | Propionic acid derivatives |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS5273835A (en) |
| AU (1) | AU503656B2 (en) |
| BE (1) | BE849450A (en) |
| CA (1) | CA1062721A (en) |
| DE (1) | DE2652961A1 (en) |
| FR (1) | FR2335210A1 (en) |
| GB (1) | GB1527563A (en) |
| MX (1) | MX4487E (en) |
| NL (1) | NL7613426A (en) |
| ZA (1) | ZA766709B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4145440A (en) * | 1977-08-18 | 1979-03-20 | The Upjohn Company | Liquid suspension of an aluminum salt of ibuprofen |
| US4361580A (en) * | 1980-06-20 | 1982-11-30 | The Upjohn Manufacturing Company | Aluminum ibuprofen pharmaceutical suspensions |
| EP0070714B1 (en) * | 1981-07-20 | 1986-05-07 | The Upjohn Company | Use of ibuprofen or flurbiprofen for the manufacture of a medicament for treating respiratory disorders |
| US4476248A (en) * | 1983-02-28 | 1984-10-09 | The Upjohn Company | Crystallization of ibuprofen |
| IT1175941B (en) * | 1984-02-16 | 1987-08-12 | Stabil Bioterapico Farmachim | MONO, BI AND TRI-SUBSTITUTED ALUMINUM SALTS OF ARYL-ALCANOIC ACIDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| GB8623557D0 (en) * | 1986-10-01 | 1986-11-05 | Boots Co Plc | Therapeutic agents |
| US4861797A (en) * | 1987-10-15 | 1989-08-29 | Oratech Pharmaceutical Development Corporation | Liquid ibuprofen compositions and methods of making them |
| US5028625A (en) * | 1989-06-20 | 1991-07-02 | American Home Products Corporation | Acid addition salt of ibuprofen and meglumine |
| DE3938227C1 (en) * | 1989-11-17 | 1991-05-02 | Dolorgiet Gmbh & Co Kg, 5205 St Augustin, De | Oral antiinflammatory and analgetic pharmaceutical compsn. - comprises magnesium ibuprofen dissolved in mixt. of water, propane-1,2-diol and glycerol |
| GB9523833D0 (en) * | 1995-11-22 | 1996-01-24 | Boots Co Plc | Medical treatment |
| AU7916798A (en) * | 1997-05-22 | 1998-12-11 | Boots Company Plc, The | Pharmaceutical compositions of flurbiprofen and burn-masking agent for treating sore throat |
| CN111892618A (en) * | 2020-08-24 | 2020-11-06 | 运城鸿博化工有限公司 | Hindered phenol antioxidant with novel structure and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE811810A (en) * | 1974-03-04 | 1974-09-04 | 2-(3-phenoxy-phenyl)-propionyloxy-aluminium - mono-or di-basic salts which form aq. suspensions without objectionable taste |
-
1976
- 1976-11-05 CA CA265,001A patent/CA1062721A/en not_active Expired
- 1976-11-09 ZA ZA766709A patent/ZA766709B/en unknown
- 1976-11-11 AU AU19519/76A patent/AU503656B2/en not_active Expired
- 1976-11-11 MX MX765116U patent/MX4487E/en unknown
- 1976-11-17 GB GB47813/76A patent/GB1527563A/en not_active Expired
- 1976-11-22 DE DE19762652961 patent/DE2652961A1/en not_active Withdrawn
- 1976-12-02 NL NL7613426A patent/NL7613426A/en not_active Application Discontinuation
- 1976-12-14 FR FR7637679A patent/FR2335210A1/en active Granted
- 1976-12-15 JP JP51150676A patent/JPS5273835A/en active Pending
- 1976-12-15 BE BE173300A patent/BE849450A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| BE849450A (en) | 1977-06-15 |
| AU503656B2 (en) | 1979-09-13 |
| FR2335210B1 (en) | 1980-02-29 |
| MX4487E (en) | 1982-05-21 |
| AU1951976A (en) | 1978-05-18 |
| DE2652961A1 (en) | 1977-06-16 |
| ZA766709B (en) | 1977-10-26 |
| GB1527563A (en) | 1978-10-04 |
| FR2335210A1 (en) | 1977-07-15 |
| JPS5273835A (en) | 1977-06-21 |
| NL7613426A (en) | 1977-06-17 |
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