CA1230056A - Packaged stable enema solution or suspension containing 5-aminosalicyclic acid - Google Patents
Packaged stable enema solution or suspension containing 5-aminosalicyclic acidInfo
- Publication number
- CA1230056A CA1230056A CA000462442A CA462442A CA1230056A CA 1230056 A CA1230056 A CA 1230056A CA 000462442 A CA000462442 A CA 000462442A CA 462442 A CA462442 A CA 462442A CA 1230056 A CA1230056 A CA 1230056A
- Authority
- CA
- Canada
- Prior art keywords
- solution
- suspension according
- packaged
- enema solution
- bottle
- 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
Landscapes
- Medicinal Preparation (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A packaged enema solution or suspension consisting essentially of an effective amount of 5-ASA or a pharmaceu-tically acceptable salt or ester thereof, a chelating agent, an antioxidant and a buffer, the solution or suspension having a pH value of from 4 to 7 and being contained in a plastic bottle under an inert gas, the plastic bottle being packaged in a diffusion-tight light-impervious package in the same inert gas as is present in the bottle.
A packaged enema solution or suspension consisting essentially of an effective amount of 5-ASA or a pharmaceu-tically acceptable salt or ester thereof, a chelating agent, an antioxidant and a buffer, the solution or suspension having a pH value of from 4 to 7 and being contained in a plastic bottle under an inert gas, the plastic bottle being packaged in a diffusion-tight light-impervious package in the same inert gas as is present in the bottle.
Description
2~
This invention concerns an enema solution or suspension which is suitable for rectal administration of 5- aminosalicylic acid (5-ASA) in mammals. The present enema solutions are useful in the treatment of bowel diseases, in particular, ulcerative colitis, Crohn's disease located in the colon and proctosigmoiditis.
Salicylazosulfapyridine (SASP) has for a long period ox time been a cornerstone in the treatment of ulcerative colitis and has been used in various pharmaceu-tical dosage forms including enemas. When SASP reaches the colon, it is split by bacteria into sulfapyridine ASP) and 5-ASA and, as explained in detail in Canadian Application No. 426,446, filed April 21, 1983, most experts now hold the active moiety of SASP to be 5-ASA.
Azad Khan et al, Lancet, 1977, pp~892-95, compared suspensions of SASP, SP and 5-ASA administered rectally and concluded that the therapeutic active moiety was 5-ASA and that SP only acts as a carrier to ensure that 5-ASA is not released until it has reached the colon.
Stability tests showed that SASP and SP suspensions were stable at room temperature while the 5-ASA suspension showed some decay and had to be made up in fresh batches every three months and stored in a refrigerator until used.
,., I.:
~36~6 Similar observa-tions were made by Campieri et al, Lancet, August 8, 1981, pp. 220-21, who carried out a comparison trial between 5-ASA and hydrocortisone.
Since 5-ASA turned brown in solution, they added charcoal to the hydrocortisone as coloring agent in order to ensure double-blindness.
While enemas containing 5-ASA have thus proved useful in the treatment of ulcerative colitis, their limited stability is a major problem and a solution to this problem would be of great advantage.
It has now been discovered that the desired stability can be obtained by packaging an aqueous solution or suspension of 5-ASA or a pharmaceutically acceptable salt or ester thereof being contained in a sealed plastic bottle under an inert gas in a diffusion-tight package impervious to light in the same inert gas as was used in the plastic bottle The 5-ASA solution or suspension should further contain a chelating agent, an antioxidant and a buffer in order to provide a pH value of from 4 to 7.
The presence of the same inert gas on both sides of the plastic bottle provides an equilibrium which effectively cooperates with the various stabilizers and the diffusion-tight light-impervious package and provides a stability of a year or more.
Optionally the package may be evacuated to provide a vacuum within the package. The important feature is that the atmosphere around the bottle should be oxygen-free.
Hence, the invention concerns a packaged enema solution or suspension consisting essentially of an effective amount of 5-ASA or a pharmaceutically acceptable salt or es-ter thereof, a chelating agent, an antioxidant and a buffer, said solution or suspension having a pH value of from 4 to 7 and being contained in v~7 l 3~C3 rl~i a plastic bo-ttle under an inert gas, said plastic bottle being packaged in a cliffusion-tight light-impervious package in -the same inert gas as is present in the bo-ttle.
The -therapeutically active ingredient 5-ASA
may be present in the form of the free acid or a pharmaceutically acceptable salt or ester thereof.
The salts of 5-ASA may be acid addition salts, in particular, -the hydrochloride, but any pharmaceutically acceptable, non-toxic organic or inorganic acid may be used.
Also, salts formed with the carboxylic acid group may be used. As examples may be mentioned alkali metal salts (k, Na), alkaline earth metal salts (Ca, Mg), but again any pharmaceutically acceptable, non-toxic salt may be used. The Na- and Ca- salts are preferred.
In German Offenlegungsschrift No. 2,712,934, a number of esters of ortho-, meta- and para-salicyclic acid are disclosed. Said esters are effective as ultraviolet ray screening compounds thereby rendering themselves useful in preventing solar burning. The disclosed meta- (or 5-) aminosalicyclic esters and a number of related esters are also applicable in the enema according to the invention.
Applicable esters are, e.g., straight chain or branched-Cl-C18 alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, and stearyl, etc.; straight chain or branched C2-C18 alkenyl esters, e.g., vinyl, allyl, undecenyl, oleyl, linolenyl, etc.; C3-C8 cycloalkyl esters, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and ~3~ 5~
cyclooctyl, etc.; aryl esters, e.g., phenyl, toluyl, xylyl, naphthyl, etc.; alicyclic esters, e.g., menthyl, etc.; or aralkyl esters, e.g., benzyl, phenethyl, etc.
Generally spearing, the proper selection of the active ingredient depends on the selected type of formulation, the disease pattern, especially the site and type of the disease, and the desired release of the active ingredient, - 3a -i ,, , A
~;23~6 as shall be further expounded below together with the concept "e f give amount".
The physical state and sol~bility characteristlcs of thP 5-ASA derivatives mus be taken into accsunt when selecting a suitable carrier composition for the ingredient.
The preferred active ingredient at present is the free acid, S-ASA.
Preferably, the 5-ASA is extremely pure in order to prevent autooxidation. The purity is manifested by the absence ox additional high pressure liquid chromatography tHPLc) peaks (both determined ~luospectrophotometrically and spectrophotometrically in general).
The effective amount of the 5-ASA ox ester or salt thereof contained in the enema depend upon the extent ox the disease and for adults generally in amounts ox prom 0.~ to 4 g 5-ASA per 100 ml enema will be used. Whether or not the enema is a suspension or solution i.a. depends on the amount of 5-ASA and the pH. The solubility 5~ASA in water is about 2 g/100 ml at pH 7, but only about 0.2 g/l~O ml at pi 4.8.
By administering an enema susp~nsionl which might be pxovided at the more acidic pH values in the xange prom 4 to 7, a kind of slow-release of the 5-ASA might be obtained.
Since 5-ASA is assumed to be topically effective at the ulcer site in case ox colitis such slow release us believed Jo be the most beneficial to the patient.
The enema solutîon or suspension also contains a chelating agent to avoid autooxida~ion catalyzed by metal ions which may be present even in. analyt1~ grade chemicals.
Any of the classic chelating agents may be used, but the preferred chelating agents are polymethylene dia~.inet~tra-acetic acid, in particular, ethylene diaminetetraacetic acid (EDTA) and its alkali metal salts, The preferred amount of ~2~5~
chelating agent i9 prom 5 Jo 30 mg/100 ml ~olutlon or suspension, prefexably ab~uk 20 mg/100 ml.
Further, the solution or suspension contains an antioxidant Jo prevent oxidation of the 5-ASA. Preferred antloxidan~s art sodium or potassium pyrosulfite, jut other well-knswn antioxidants might be used, e.g., ascorbic acid.
The preferred amount is 50-200 mg/100 ml suspension or sDlution, preerably about 100 mg/100 ml.
urther, the enema solution contains a suitable bu~er in order to maintain thy desired pH value in the range of from 4 to 7. The preferred pH is from 4.5 to 5, in particular, about 4.8. This pH is advantageously established by means of a citric acid buffer since citric acid has a pka of 4.77.
Other applicable buffers are bicarbonate buffer6 if a pH of 6 to 7 is desired ice the pea for bicarbonate if 6.5. "
Generally speaking, any buffer system might be used which provideR the proper pH and does no interfere w;~th the o~-her components ox enema.
The gas used in the bottle and the package should ye inert with relation to the solution Gr suspension.
Preferred inext gases are nitrogen or argon, but also carbon dioxide may be used if the solution or 3uspension contains a bicarbonate for The plastic bottle is preferably mada by blow forming prom a polyethylene granulate which has been deoxidized by alternating vacuum and nitrogen treatments.
he dif~usi~n-~ight l~ght-impervious package material it pre~era~ly made from a heat-sealable plastic-metal laminate, ~.g., plastic-aluminum laminate, where any heat-sealable plastic material, e.g., polyethylene, might be used.
A packaged suspension according to the invention may be prepared as follows:
1. Prepara-tion of a 5-ASA suspension 5-ASA* 1 g/100 ml EDTA 20 mg Sodium pyrosulfite 0.2 g Citric acid 1 g Sodium hydroxide g.s. (up to pH = 4.8 about 0.35 g) Sterile water up to 100 ml * 5-ASA is extremely pure to avoid autooxidation -no additional HPLC peaks (both fluospectrophoto-metrically and spectrophometrically in general).
The suspension is prepared and dispensed in an inert gas, e.g., nitrogen or argon.
2. Filling of 5-ASA suspension in a plastic bottle The polyethylene granulate is deoxidized by alternating vacuum and nitrogen treatments. The deoxidized granulate is extruded, formed by blowing and the 5-ASA suspension is filled into a plastic bottle blower/pac~ing machine, wherein the bottle is sealed after filling. The inert gas used for dispensing also constitutes the supporting air, blowing air and the air in the chamber in which the filling and forming procedures are taking place.
The bottle is conveyed directly to a packing chamber containing the same inert gas in which the bottles are packed in aroma-tight, light-impervious (plastics aluminum laminate) bags which are sealed by welding before they drop into the atmosphere.
r i .. - . .. . . . .
~z~
Enema suspensions contain 1 g and 2 9 5 ASA per 100 ml prepared in analogy witI- the above procedure have been tested for stability by fluospectrophotometry and HPLC.
After storage at room temperature for more than a year, no significant change W3S observed neither with regard to color or 5-ASA content.
This is shown in the following tables l and 2 showing stability tests on enema suspensions after storage at room temperature and humidity for 24 months and 12 months reapectively.
The 24 months tests are made on packages filled and se&led by hand. Dnly one bottle was tested each month, which may account for the minor variations.
It is also to be understood thct the following claims are intended to cover all oF the generic and specific features of the invention herein described, and all statements of thP scope oF thy invention which as a matter of language, might be said to fall therebetween.
l 30 0 5 6.
Q~
Jo Us o o . ~,~ o so O N--~ N 0 ~~3 l . O ~~J C3C~`
V . . . . . .
c O E I E f OD O
to J ox Jo O
Vl'C E O
~0 Q Cl~O O _l OO It I`
_l O O -I-I O Us E ~1 tJ . OO O O 0 V _~~ _l O C E I E ~~ I1~ 0C~ O
I
U'~ E ~3O E
Ox _~ ::C ox = C f C O
I.`
J ~:0 . l I N
to out o o a o o oo o .
1--_ O r_l f 1 l I`
Al E
Q~ l t + +.~ +
I_ O
.u :3 O I O
Q l on v ,~ Ul E t + + + to +
~3 QL C
T O
I_ U
Us S Us Lo _I I
O S C
~).~ O
~3C~6 -! `
_~ O O O O Ox C O E 0~ _I O
r a T E O
O o E v v I E O O O
E r O
++++
I_ O
I_ O N
V~ 2 ~2~ )51~i The invention will be further illustrated with reference to the accompanying singlc figure of drawing which shows a partly torn away package containing a liquid-filled enema bottle.
The drawing shows a laminated foil package 1 enclosing a squeezable enema bottle 2 containing Pentasa~ suspension 3.
The laminated foil package 1 is heat-sealed along each edge at la and along the bottom at lb and the top at lc respectively.
Preferably the package is formed from a heat-sealable plastic-metal laminate e.g. an inner polyethylene layer 4 and an outer aluminum layer 5.
The bottle is constituted by a container part 6, a neck part 7 and a sealed closure part 8, which may be broken simply by turning the leaflet 9.
. . ,~
.
This invention concerns an enema solution or suspension which is suitable for rectal administration of 5- aminosalicylic acid (5-ASA) in mammals. The present enema solutions are useful in the treatment of bowel diseases, in particular, ulcerative colitis, Crohn's disease located in the colon and proctosigmoiditis.
Salicylazosulfapyridine (SASP) has for a long period ox time been a cornerstone in the treatment of ulcerative colitis and has been used in various pharmaceu-tical dosage forms including enemas. When SASP reaches the colon, it is split by bacteria into sulfapyridine ASP) and 5-ASA and, as explained in detail in Canadian Application No. 426,446, filed April 21, 1983, most experts now hold the active moiety of SASP to be 5-ASA.
Azad Khan et al, Lancet, 1977, pp~892-95, compared suspensions of SASP, SP and 5-ASA administered rectally and concluded that the therapeutic active moiety was 5-ASA and that SP only acts as a carrier to ensure that 5-ASA is not released until it has reached the colon.
Stability tests showed that SASP and SP suspensions were stable at room temperature while the 5-ASA suspension showed some decay and had to be made up in fresh batches every three months and stored in a refrigerator until used.
,., I.:
~36~6 Similar observa-tions were made by Campieri et al, Lancet, August 8, 1981, pp. 220-21, who carried out a comparison trial between 5-ASA and hydrocortisone.
Since 5-ASA turned brown in solution, they added charcoal to the hydrocortisone as coloring agent in order to ensure double-blindness.
While enemas containing 5-ASA have thus proved useful in the treatment of ulcerative colitis, their limited stability is a major problem and a solution to this problem would be of great advantage.
It has now been discovered that the desired stability can be obtained by packaging an aqueous solution or suspension of 5-ASA or a pharmaceutically acceptable salt or ester thereof being contained in a sealed plastic bottle under an inert gas in a diffusion-tight package impervious to light in the same inert gas as was used in the plastic bottle The 5-ASA solution or suspension should further contain a chelating agent, an antioxidant and a buffer in order to provide a pH value of from 4 to 7.
The presence of the same inert gas on both sides of the plastic bottle provides an equilibrium which effectively cooperates with the various stabilizers and the diffusion-tight light-impervious package and provides a stability of a year or more.
Optionally the package may be evacuated to provide a vacuum within the package. The important feature is that the atmosphere around the bottle should be oxygen-free.
Hence, the invention concerns a packaged enema solution or suspension consisting essentially of an effective amount of 5-ASA or a pharmaceutically acceptable salt or es-ter thereof, a chelating agent, an antioxidant and a buffer, said solution or suspension having a pH value of from 4 to 7 and being contained in v~7 l 3~C3 rl~i a plastic bo-ttle under an inert gas, said plastic bottle being packaged in a cliffusion-tight light-impervious package in -the same inert gas as is present in the bo-ttle.
The -therapeutically active ingredient 5-ASA
may be present in the form of the free acid or a pharmaceutically acceptable salt or ester thereof.
The salts of 5-ASA may be acid addition salts, in particular, -the hydrochloride, but any pharmaceutically acceptable, non-toxic organic or inorganic acid may be used.
Also, salts formed with the carboxylic acid group may be used. As examples may be mentioned alkali metal salts (k, Na), alkaline earth metal salts (Ca, Mg), but again any pharmaceutically acceptable, non-toxic salt may be used. The Na- and Ca- salts are preferred.
In German Offenlegungsschrift No. 2,712,934, a number of esters of ortho-, meta- and para-salicyclic acid are disclosed. Said esters are effective as ultraviolet ray screening compounds thereby rendering themselves useful in preventing solar burning. The disclosed meta- (or 5-) aminosalicyclic esters and a number of related esters are also applicable in the enema according to the invention.
Applicable esters are, e.g., straight chain or branched-Cl-C18 alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, and stearyl, etc.; straight chain or branched C2-C18 alkenyl esters, e.g., vinyl, allyl, undecenyl, oleyl, linolenyl, etc.; C3-C8 cycloalkyl esters, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and ~3~ 5~
cyclooctyl, etc.; aryl esters, e.g., phenyl, toluyl, xylyl, naphthyl, etc.; alicyclic esters, e.g., menthyl, etc.; or aralkyl esters, e.g., benzyl, phenethyl, etc.
Generally spearing, the proper selection of the active ingredient depends on the selected type of formulation, the disease pattern, especially the site and type of the disease, and the desired release of the active ingredient, - 3a -i ,, , A
~;23~6 as shall be further expounded below together with the concept "e f give amount".
The physical state and sol~bility characteristlcs of thP 5-ASA derivatives mus be taken into accsunt when selecting a suitable carrier composition for the ingredient.
The preferred active ingredient at present is the free acid, S-ASA.
Preferably, the 5-ASA is extremely pure in order to prevent autooxidation. The purity is manifested by the absence ox additional high pressure liquid chromatography tHPLc) peaks (both determined ~luospectrophotometrically and spectrophotometrically in general).
The effective amount of the 5-ASA ox ester or salt thereof contained in the enema depend upon the extent ox the disease and for adults generally in amounts ox prom 0.~ to 4 g 5-ASA per 100 ml enema will be used. Whether or not the enema is a suspension or solution i.a. depends on the amount of 5-ASA and the pH. The solubility 5~ASA in water is about 2 g/100 ml at pH 7, but only about 0.2 g/l~O ml at pi 4.8.
By administering an enema susp~nsionl which might be pxovided at the more acidic pH values in the xange prom 4 to 7, a kind of slow-release of the 5-ASA might be obtained.
Since 5-ASA is assumed to be topically effective at the ulcer site in case ox colitis such slow release us believed Jo be the most beneficial to the patient.
The enema solutîon or suspension also contains a chelating agent to avoid autooxida~ion catalyzed by metal ions which may be present even in. analyt1~ grade chemicals.
Any of the classic chelating agents may be used, but the preferred chelating agents are polymethylene dia~.inet~tra-acetic acid, in particular, ethylene diaminetetraacetic acid (EDTA) and its alkali metal salts, The preferred amount of ~2~5~
chelating agent i9 prom 5 Jo 30 mg/100 ml ~olutlon or suspension, prefexably ab~uk 20 mg/100 ml.
Further, the solution or suspension contains an antioxidant Jo prevent oxidation of the 5-ASA. Preferred antloxidan~s art sodium or potassium pyrosulfite, jut other well-knswn antioxidants might be used, e.g., ascorbic acid.
The preferred amount is 50-200 mg/100 ml suspension or sDlution, preerably about 100 mg/100 ml.
urther, the enema solution contains a suitable bu~er in order to maintain thy desired pH value in the range of from 4 to 7. The preferred pH is from 4.5 to 5, in particular, about 4.8. This pH is advantageously established by means of a citric acid buffer since citric acid has a pka of 4.77.
Other applicable buffers are bicarbonate buffer6 if a pH of 6 to 7 is desired ice the pea for bicarbonate if 6.5. "
Generally speaking, any buffer system might be used which provideR the proper pH and does no interfere w;~th the o~-her components ox enema.
The gas used in the bottle and the package should ye inert with relation to the solution Gr suspension.
Preferred inext gases are nitrogen or argon, but also carbon dioxide may be used if the solution or 3uspension contains a bicarbonate for The plastic bottle is preferably mada by blow forming prom a polyethylene granulate which has been deoxidized by alternating vacuum and nitrogen treatments.
he dif~usi~n-~ight l~ght-impervious package material it pre~era~ly made from a heat-sealable plastic-metal laminate, ~.g., plastic-aluminum laminate, where any heat-sealable plastic material, e.g., polyethylene, might be used.
A packaged suspension according to the invention may be prepared as follows:
1. Prepara-tion of a 5-ASA suspension 5-ASA* 1 g/100 ml EDTA 20 mg Sodium pyrosulfite 0.2 g Citric acid 1 g Sodium hydroxide g.s. (up to pH = 4.8 about 0.35 g) Sterile water up to 100 ml * 5-ASA is extremely pure to avoid autooxidation -no additional HPLC peaks (both fluospectrophoto-metrically and spectrophometrically in general).
The suspension is prepared and dispensed in an inert gas, e.g., nitrogen or argon.
2. Filling of 5-ASA suspension in a plastic bottle The polyethylene granulate is deoxidized by alternating vacuum and nitrogen treatments. The deoxidized granulate is extruded, formed by blowing and the 5-ASA suspension is filled into a plastic bottle blower/pac~ing machine, wherein the bottle is sealed after filling. The inert gas used for dispensing also constitutes the supporting air, blowing air and the air in the chamber in which the filling and forming procedures are taking place.
The bottle is conveyed directly to a packing chamber containing the same inert gas in which the bottles are packed in aroma-tight, light-impervious (plastics aluminum laminate) bags which are sealed by welding before they drop into the atmosphere.
r i .. - . .. . . . .
~z~
Enema suspensions contain 1 g and 2 9 5 ASA per 100 ml prepared in analogy witI- the above procedure have been tested for stability by fluospectrophotometry and HPLC.
After storage at room temperature for more than a year, no significant change W3S observed neither with regard to color or 5-ASA content.
This is shown in the following tables l and 2 showing stability tests on enema suspensions after storage at room temperature and humidity for 24 months and 12 months reapectively.
The 24 months tests are made on packages filled and se&led by hand. Dnly one bottle was tested each month, which may account for the minor variations.
It is also to be understood thct the following claims are intended to cover all oF the generic and specific features of the invention herein described, and all statements of thP scope oF thy invention which as a matter of language, might be said to fall therebetween.
l 30 0 5 6.
Q~
Jo Us o o . ~,~ o so O N--~ N 0 ~~3 l . O ~~J C3C~`
V . . . . . .
c O E I E f OD O
to J ox Jo O
Vl'C E O
~0 Q Cl~O O _l OO It I`
_l O O -I-I O Us E ~1 tJ . OO O O 0 V _~~ _l O C E I E ~~ I1~ 0C~ O
I
U'~ E ~3O E
Ox _~ ::C ox = C f C O
I.`
J ~:0 . l I N
to out o o a o o oo o .
1--_ O r_l f 1 l I`
Al E
Q~ l t + +.~ +
I_ O
.u :3 O I O
Q l on v ,~ Ul E t + + + to +
~3 QL C
T O
I_ U
Us S Us Lo _I I
O S C
~).~ O
~3C~6 -! `
_~ O O O O Ox C O E 0~ _I O
r a T E O
O o E v v I E O O O
E r O
++++
I_ O
I_ O N
V~ 2 ~2~ )51~i The invention will be further illustrated with reference to the accompanying singlc figure of drawing which shows a partly torn away package containing a liquid-filled enema bottle.
The drawing shows a laminated foil package 1 enclosing a squeezable enema bottle 2 containing Pentasa~ suspension 3.
The laminated foil package 1 is heat-sealed along each edge at la and along the bottom at lb and the top at lc respectively.
Preferably the package is formed from a heat-sealable plastic-metal laminate e.g. an inner polyethylene layer 4 and an outer aluminum layer 5.
The bottle is constituted by a container part 6, a neck part 7 and a sealed closure part 8, which may be broken simply by turning the leaflet 9.
. . ,~
.
Claims (15)
1. A packaged enema solution or suspension consisting essentially of an effective amount of 5-ASA or a pharmaceutically acceptable salt or ester thereof, a chelating agent, an antioxidant and a buffer, said solution or suspension having a pH value of from 4 to 7 and being contained in a plastic bottle under an inert gas, said plastic bottle being packaged in a diffusion-tight light-impervious package in the same inert gas as is present in the bottle.
2. A packaged enema solution or suspension according to claim 1, wherein the chelating agent comprises EDTA, the antioxidant comprises sodium pyrosulfite and the buffer comprises citric acid and sodium hydroxide.
3. A packaged enema solution or suspension according to claim 2, wherein the pH of said solution is about 4.8.
4. A packaged enema solution or suspension according to claim 1, wherein the buffer is sodium bicarbonate and hydrochloric acid.
5. A packaged enema solution or suspension according to claim 4, wherein the pH of said solution is about 6.5.
6. An enema solution or suspension according to claim 1, wherein the 5-aminosalicyclic acid is sufficiently pure to avoid autooxidation, having no additional HPLC
fluospectrophotometric and spectrophotometric peaks.
fluospectrophotometric and spectrophotometric peaks.
7. A packaged enema solution or suspension according to claim 1, wherein the inert gas is argon, nitrogen or carbon dioxide.
8. A packaged enema solution or suspension according to claim 1 consisting essentially of substantially pure 5-aminosalicyclic acid or a pharmaceutically acceptable salt or ester thereof, ethylenediaminetetraacetic acid, sodium pyrosulfite, citric acid, sodium hydroxide and purified water wherein the pH of said solution is up to about 4.8.
9. A packaged enema solution or suspension according to claim 1, wherein the plastic bottle is polyethylene.
10. A packaged enema solution or suspension according to claim 9. wherein a polyethylene granulate used for producing the polyethylene bottle is deoxidized by alternately evacuating the granulate and flooding the granulate with nitrogen gas.
11. A packaged enema solution or suspension according to claim 10, wherein the deoxidized granulate is extruded, formed into a bottle by means of an inert gas, and the bottle is filled with said enema solution.
12. A packaged enema solution or suspension according to claim 11, wherein the filled bottle is conveyed directly to a packing chamber wherein the bottle is packed into an aroma-tight bag under an inert gas, said bag being sealed by welding before being contacted with air.
13. A packaged enema solution or suspension according to claim 12, wherein the aroma-tight bag is a plastic aluminum laminate.
14. A packaged enema solution or suspension according to claim 13, containing per 100 ml of solution about 0.2 to 4.0 g 5-aminosalicyclic acid, about 50 mg to 200 mg of sodium pyrosulfite, about 0.5 to 1.5 g citric acid, about 0.5 to 2 g sodium hydroxide, about 5 to 30 mg sodium EDTA, and purified water.
15. A packaged enema solution or suspension according to claim 14, containing per 100 ml of solution about 1 g of 5-aminosalicyclic acid, about 200 mg of sodium pyrosulfite, about 1 g citric acid, about 20 mg sodium EDTA, and sufficient sodium hydroxide and purified water to maintain a pH of 4.8.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US52976983A | 1983-09-06 | 1983-09-06 | |
| US529,769 | 1983-09-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1230056A true CA1230056A (en) | 1987-12-08 |
Family
ID=24111185
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000462442A Expired CA1230056A (en) | 1983-09-06 | 1984-09-05 | Packaged stable enema solution or suspension containing 5-aminosalicyclic acid |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1230056A (en) |
-
1984
- 1984-09-05 CA CA000462442A patent/CA1230056A/en not_active Expired
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4664256A (en) | Packaged stable enema solution or suspension containing 5-aminosalicyclic acid | |
| US5610170A (en) | Package form for bicarbonate-containing powdery pharmaceutical compositions and a method of stabilizing the compositions | |
| EP0764121B1 (en) | Package | |
| AU597254B2 (en) | Impervious packaging in the form of a card having compartments and permitting gaseous exchange between the compartments | |
| US6113927A (en) | Package and packaging method for aqueous liquid materials | |
| JP3060133U (en) | Eye perfusion / wash bag package | |
| USRE33239E (en) | Packaged stable enema solution or suspension containing 5-aminosalicyclic acid | |
| KR20090036606A (en) | Packaging comprising pharmaceutical forms | |
| RU2005114485A (en) | STABILIZED PHARMACEUTICAL PRODUCT INCLUDING AMORPHIC ACTIVE SUBSTANCE | |
| US20210015776A1 (en) | Methods of stabilization of levothyroxine sodium tablets | |
| KR100260976B1 (en) | Divided package of adsorbent for internal use and process for producing the same | |
| KR20020081293A (en) | Pharmaceutical Composition Comprising Pemetrexed Together With Monothioglycerol L-Cystein or Thioglycolic Acid | |
| CA1230056A (en) | Packaged stable enema solution or suspension containing 5-aminosalicyclic acid | |
| CA2110376C (en) | Pharmaceutical enema preparation | |
| CA2345014A1 (en) | Packaged cosmetic effervescent cleansing pillow | |
| GB1485832A (en) | Package | |
| CN220431019U (en) | Semi-permeable container packaging system | |
| CN2603785Y (en) | Medicine wrapper | |
| JPH1015032A (en) | Stabilized 5-aminosalycilic acid solid pharmaceutical | |
| JPH06190021A (en) | Divided package of internally taking adsorbent and preparation thereof | |
| JPH11262514A (en) | Bicarbonate containing chemical container package and carbon dioxide gas partial pressure controlling agent | |
| JPS59176247A (en) | Method for preventing decomposition of water-soluble azunole | |
| JPS6451043A (en) | Method for keeping freshness of eggplant | |
| JPH06339512A (en) | Novel use of carbon dioxide generation type deoxidation scavenger | |
| JPH0129767B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |