CA1292944C - Preparation process for an aqueous pharmaceutical solution of an active principle constituted by an organic acid - Google Patents
Preparation process for an aqueous pharmaceutical solution of an active principle constituted by an organic acidInfo
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- CA1292944C CA1292944C CA000535901A CA535901A CA1292944C CA 1292944 C CA1292944 C CA 1292944C CA 000535901 A CA000535901 A CA 000535901A CA 535901 A CA535901 A CA 535901A CA 1292944 C CA1292944 C CA 1292944C
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Abstract
Company named: Laboratoires CHAUVIN-BLACHE
Inventors: - MAURIN Florence - COQUELET Claude - TOURNOUX Alain Preparation process for an aqueous pharmaceutical solution of an active principle constituted by an organic acid ABSTRACT
The subject of the invention is a preparation process for an aqueous pharmaceutical solution of an active principle constituted by an organic acid, characterized in that:
a) the organic acid is dissolved in a first aqueous solution contain-ing a sufficient quantity of at least a fraction of the basic part of a buffer mixture b) this solution is lyophilized in order to obtain a product in a dry state and c) at the time of use the product in a dry state is dissolved in a second aqueous solution containing the remainder of the buffer mixture, this remainder being such that the pH of the resulting solution is of a physiologically acceptable value.
Fig. None
Inventors: - MAURIN Florence - COQUELET Claude - TOURNOUX Alain Preparation process for an aqueous pharmaceutical solution of an active principle constituted by an organic acid ABSTRACT
The subject of the invention is a preparation process for an aqueous pharmaceutical solution of an active principle constituted by an organic acid, characterized in that:
a) the organic acid is dissolved in a first aqueous solution contain-ing a sufficient quantity of at least a fraction of the basic part of a buffer mixture b) this solution is lyophilized in order to obtain a product in a dry state and c) at the time of use the product in a dry state is dissolved in a second aqueous solution containing the remainder of the buffer mixture, this remainder being such that the pH of the resulting solution is of a physiologically acceptable value.
Fig. None
Description
The present invention is concerned with a preparation process for an aqueous pharmaceutical solution of an active principle constituted by an organic acid normally considered as very slightly soluble or insoluble in water.
The present invention is concerned more particularly with a prep-aration process ~or an aqueous pharmaceutical solution which contains notable quantities of such an active principle (generally from 0.05 to 5% by weight) and which is stable for at least one month in nonmal conditions of use. It is concerned in particular with a preparation process for ophthalmic solutions.
Yarious attempts have already been made to make soluble active principles which are very slightly soluble or insoluble in water.
There can be cited in particular the following methods:
1) Micellar system of making soluble The micellization system allows hydrophobic substances to be made soluble in water but the active principle dissolved in this way risks being much less stable (alteratlon or hydrolysis) than ~n systems where it is insoluble. Furthermore the active principle is susceptible to losing a part of its biological activity. This system therefore does not resolve the general pharmaceutical problem of administration of a product insoluble in water in normal conditions.
The present invention is concerned more particularly with a prep-aration process ~or an aqueous pharmaceutical solution which contains notable quantities of such an active principle (generally from 0.05 to 5% by weight) and which is stable for at least one month in nonmal conditions of use. It is concerned in particular with a preparation process for ophthalmic solutions.
Yarious attempts have already been made to make soluble active principles which are very slightly soluble or insoluble in water.
There can be cited in particular the following methods:
1) Micellar system of making soluble The micellization system allows hydrophobic substances to be made soluble in water but the active principle dissolved in this way risks being much less stable (alteratlon or hydrolysis) than ~n systems where it is insoluble. Furthermore the active principle is susceptible to losing a part of its biological activity. This system therefore does not resolve the general pharmaceutical problem of administration of a product insoluble in water in normal conditions.
2) Making soluble by co-solvent (see for example application PCT WO
85/0410~) Hydrophobic products are susceptible to being made soluble by co-solvents of the polyethyleneglycol type (PEG) of various molecularweights or other similar solvents, but the actlve principle is then susceptible to forming complexes of the ester type of PEG or to become hydrolized by the traces of water present in the co-solvent, therefore not guaranteeing the stability required for the formulation of a pharmaceutical speciality.
85/0410~) Hydrophobic products are susceptible to being made soluble by co-solvents of the polyethyleneglycol type (PEG) of various molecularweights or other similar solvents, but the actlve principle is then susceptible to forming complexes of the ester type of PEG or to become hydrolized by the traces of water present in the co-solvent, therefore not guaranteeing the stability required for the formulation of a pharmaceutical speciality.
3) Putting the active principle in suspension (see for example US
patent US 4 087 538) The stablllzlng of a suspenslon of an active principle ln a micro-nized form is obtained by the presence of a suspension agent, namely one or more tensio-active agents of mono-oleate type of polyoxyethylene sorbitan (Tween 80) or other esters Of sorbitan, particularly of laurlc ' 1;Z~ 9 4~
acid and of stearic acid, which enables the fraction made soluble by water to become micellised. Such suspensions, by the presence of the micronized particles, cause an ocular intolerance and are not suitable in the field of ophthalmics.
The present invention is concerned with remedying these inconven-iences.
The present invention is based on the discovery that it is possible to dissolve an organic acid which is normally very slightly soluble in water such as indomethacin in an aqueous solution containing a sufficient quantity of at least the basic part of a buffer mixture and that the quantity of organic acid that can be dissolved is the greater, the larger the quantity of the basic part of the buffer mixture.
The subject cf the present invention is therefore a preparation process for an aqueous pharmaceutical solution with an active principle constituted by an organic acid, characterized in that a) the organic acid is dissolved in à first aqueous solutisn containing a sufficient quantity of at least a fraction of the basic part of a buffer mixture, b) this solution is Iyophilized in order to obtain a product in a dry state and c) at the time of use the product in a dry state is dissolved in a second aqueous solution containing the remainder of the buffer mixture, this remainder being such that the pH of the resulting solution is of a physiologically acceptable value.
Thus in the first stage of the process according to the present invention the organic acid is dissolved in a first aqueous solution containing a sufficient quantity of at least d fraction of the basic part of the buffer mixture. This first solution generally also con-tains a fraction of the acid part of the buffer mixture in such a wayas to be close to neutrality and to avoid pH values which are too basic and capable of affecting the stabilitY Of the active principle, whilst the second solution contains the remainder of the acid part of the buffer mixture and can also contain a fraction of the basic part of the buffer mixture.
At the limit, the first solution could even contain the total Z9~4 amount o~ the constituents of the buffer mixture. However, in this case, the solubility of the organic acid remains fairly weak. In addition it it advantageous to be able to adjust the pH of the final solution to the desired value for administration, thanks to the pre-sence of th~ remainder o~ the acid part of the buffer mixture in thesecond solution. Generally the pH values close to neutrality (pH of 6.5 to7.5) are desirable for administration to man and to animals.
rhe buffer mixtures that can be used in the present invention are in particular the following:
- Boric acid-sodium borate buffer - Monosodium phosphate-disodium phosphate buffer - Monopotassium phosphate-dipotassium phosphate buffer - Acetic acid-sodium acetate buffer - Citric acid-sodium citrate acid and mixtures of these buffers. The first three buffers are preferred.
In order to decrease the global quantity of the buffer mixture, volatile co-solvents such às ethanol can be added to the first solu-tion. Such an addition of ethanol (not exceeding in general 10% by volume) is useful especially when it is desired to obtain solutions to be lyophilized having significant concentrations of active principle (for example of more than 2% by weight).
The first solution can in addition contain any antibacterial agent capable of guaranteeing the bacteriologicaI quality of the solutions.
as for example esters of parahydroxybenzoic acid, and/or any stabilizer of antioxidant type such as sodium sulphites and derivatives, or edetic acid and its salts, as well as any other active principle soluble in water which is capable of completing or improving the therapeutic activity of the first. In addition for ophthalmic applications the solution can contain any product capable of prolonging the contact time and/or of improving the corneal penetration of the active principle, and in particular compounds of dextran typé, cellulose derivatives or other thickening agents compatible with the ophthalmic form of the speciality.
The solution thus prepared is sufficiently stable to allow its Iyophilization, which is carried out according to the usual methods.
Lyoph~lization presents the advantage of produc~ng a product which 129Z9.~
can be kept for a long time. The absence of water and of any co-sol-vent such dS a polyethyleneglycol avoids in effect any degradation or mDdification of the active principle. In addition the co-solvents which can be used are eliminated by sublimation during lyophilization, so that these co-solvents do not interfere even for an ophthalmic application.
At the time of use the lyophilized product is dissolved in the second solution containing the remainder of the buffer ~ixture, that is to say in ~eneral the remainder of the acid part of the buffer.
This second solution comprises in general from 75 to 98% by weight of water. It can contain any water soluble antibacterial agent, any water soluble antioxidant substance; any other active principle soluble and stable in water; any substance capable of stabilizing the pH at a value compatible with the ocular tolerance: any product having an 1~ influence on the tonicity of the solution like sodium chloride, glyco-coll, glucose; any substance capable of stabilizing the active principle in an aqueous solution. As stabilizers there can be used in particular polyethyleneglycols of which the molecular weight can be from 200 to 1500 and in particular from 200 to 600, at a rate of O to 25~ by weight.
The risks of modification of the active principle by the PEG
contained in the second solution, and this after reconstitution, are thus much less significant than for a solution in pure PEG because of the large proportion of water in the second solution. Other stabili-zers can also be used such as propylene glycol, tetrahydrofurfurylpolyethyleneglycol.
The present invention applies to the preparation of aqueous solutions of active principles constituted by organic acids and in particular aryl or heterocyclic compounds with a carbo~ylic acid group H~ 30 such as indomethacin, aspirin, niflumic acid, ibuprofen, pranoprofen, ketcprofen, alminoprofen, naproxen, sulindac.
The present invention finds a particularly useful application in the preparation of aqueous ophthalmic solutions of indomethacin.
In the case of aqueous ophthalmlc solutions of indomethacin there is advantageously prepared in a first stage a solution containing from 0.1 to 7.5% by weight of indomethacin and a sufficient quantity of a l~r~d~ ~ ~rK
lZ9Z944 fraction of a buffer mixture containing at least a fraction of the basic part of the buffer mixture and in general a fraction of the acid part of this mixture, this solution having a pH of 6.5 to 7.5 and preferably of 6.8 to 7.2. Such a pH is favourable to the stability of the indomethacin. A co-solvent such as ethanol can be added in a quantity which can go up to 10% by weight when the concentration of indomethacin is greater than 2% by weight in the solution. This solution is lyophilized and in addition a second solution is prepared containing the remainder of the buffer mixture. This second solution generally has a pH of 4.5 to 6.5 and, by the aissolYing of the lyophil-ized product in this second solution, enables a resultant solution to be obtained, which has a final pH compatible with the eye, generally fron 6.5 to 7.5 and advantageously from 6.8 to 7.3. This ophthalmic solution can generally have a concentration of indomethacin of 0.05 to 1% by weight.
It should be noted that if the boric acid-sodium borate buffer is used the quantity by weight of indomethacin that can be dissolved in the first solution is approximately equal to the quantity (by weight) of sodium borate.
The present invention applies not only to the preparation of ophthalmic solutions but also to the preparation of nasal solutions, of injectable solutions and of drinkable solutions.
The following examples illustrate the present invention.
Example 1 - Preparation of a collyrium c?ntaining 0.1% by weight of ndomethacin and a borate buffer A first solution of indomethacin is prepared by agitation at ambient temperature of the following constituents:
indomethacin 0.250 9 sodium borate 0.255 9 boric acid 1.405 9 dextran 1.000 9 water q.s. for 100.000 ml This solution has a pH of 7Ø
This solution is lyophilized immediatelys after having divided it into flasks each containing 2 ml of solution.
A second solution is prepared in addition by mixing at ambient temperature the following constituents:
boric acid 1.149 g nipagin (preservative) 0.050 9 PEG 400 (stabilizer) 24.850 g water q.s. for 100.000 ml The pH o~ this solution is 5.65.
This solution is divided into flasks each containing 5 ml.
At the time of use 5 ml of the second solution contained in one flask of solution is added to the lyophilized product contained in another flask. A collyrium containing 0.1% by weight of indomethacin is obtained, having a pH of 7.1.
This solution has, remarkably, a preservation time of at least one month at ambient temperature.
Example 2 - Preparation of a collyrium containing 0.1% by weight of indomethacin The operatlng method is as for example 1, uslng the following solutlons:
- first solution (to be lyophilized) divided into flasks each ccntain-20 ing 2 ml.
indomethacin 0.250 g dextran 1.000 g monosodium phosphate0.612 9 disodium phosphate 6.400 g nipagin 0.125 g water q.s. for 100.000 ml pH 7.25 - Second solution, divided into flasks each containing 5 ml monosodium phosphate 0.874 9 PEG 400 10.000 9 water ~.s. for 100.000 ml pH 5.1 The finaI collyrium has a pH of 7.1 and is stable for at least one month.
, 129Z94~, Example 3 - Preparation of a collyrium containing 0.4X by weight of indomethacin The operating method is as for example l, using the following solutions:
- First solution (to be lyophilized) divided into flasks each containing 2 ml indomethacin l.000 9 dextran 1.000 9 boric acid 2.180 9 sodium borate l.000 g water q.s. for lO0.000 ml pH 7.0 - Second solution (divided into flasks each containing 5 ml) boric acid 1.500 g PEG 400 25.000 9 water q.s. for lO0.000 ml pH 5.55 The f~nal collyrium has a pH of 7.1 and is stable for at least two months.
~ - Preparation of a collyrium containing 0.1% by weight of lbuprofen The operating method is as for example 1, using the following solutions:
- First solution (to be lyophilized) divided into flasks each contain-25 ing 2 ml ibuprofen (acid) 0.250 9 : nipagin 0.125 9 boric acid 2.190 9 sodium borate 0.500 9 dextran 1.000 9 water q.s. for 100.000 ml ; pH 7.0 : - Second solution (divided into flasks each containlng 5 ml) boric acid 1.224 9 PEG 400 25.000 9 water q.s. for lO0.000 g 1~9Z944 pH 5.6 The final collyrium has a pH of 7.0 and is stable for at least one month.
Examp!e 5 - Collyrium containing 0.l% by weight of indomethacin The operating method is dS for example l.
- First solution:
indomethacin 0.250 9 ethanol 5.000 ml sodium borate 0.1315 9 boric acid 0.450 9 nipagin 0.125 9 dextran 5.000 9 water q.s. for lO0.000 ml pH 7.0 - Second solution:
sodi~m borate 0.018 9 boric acid 0.727 9 PEG 400 24.85 9 water q.s. for lO0.000 ml pH 7.2 pH of final collyrium 7.2 Example 6 - Collyrium containing 0.4% by weight of indomethacin The operating method is as for example 1.
25 - First solution:
indomethacin 1.000 9 sodium borate 1.000 9 boric acid 2.180 9 dextran 1.000 9 water q.s. for 100.000 ml pH 7.0 - Second solution:
boric acid 1.500 9 nipagin 0-050 9 PEG 600 25.000 9 water q.s. for 100.000 ml lZ92944 pH 5.5 pH of final collyrium 7.0 Example 7 - Collyrium containing 0.1% by weight of indomethacin The operating method is as for example 1.
5 - First solution:
indomethacin 0.250 g sodium borate 0.255 g boric acid 1.405 g dextran 1.000 g water ~.s. for lO0.000 ml pH 7.0 - Second solution:
boric acid 1.149 g nipagin 0.050 g PEG 400 5.000 g water q.s, for lO0.000 ml pH 5.7 pH of ftnal collyrtum 7.0 Example 8 - Collyrium containing 2Z by weight of indomethacin The operatlng method is as for example 1.
- First solution:
indomethacin 5.000 g ethanol 5.000 ml sodium borate 5.000 9 boric acid 2.140 g ; dextran 1,000 g water q.s. for 100.000 g pH 7.2 - Second solution:
boric acid 2.452 g PEG 400 25.000 g nipagin 0.050 g water q.s. for lO0.000 ml pH 5.2 pH of final collyrtum 7.0 lZ92944 Example 9 - Preparation of a collyrium contain ng O.l% of indomet acln The operating method is dS for example 1, in such a way as to obtain per flask the following formula of the lyophilisate.
indomethacin 5 mg borax 5.1 mg boric acid 28.096 mg dextran 20 mg In addition the following solution is prepared:
PEG 400 1242.5 mg nipagin 2.5 mg EDTA 2.5 mg boric acid 99.75 mg borax 7.45 mg purified water q.s. for 5 ml At the time of use the solution constituting the solvent is added to the lyophilisate and a reconstituted collyrium is obtained having the following percentage formula:
indoemthàcin 0.1 g bordx 0.25l 9 boric acid 2.5569 9 nipagin 0.05 9 EDTA 0.05 9 PEG 400 24.85 9 dextran 0.4 9 purified water q.s. for 100 ml :
patent US 4 087 538) The stablllzlng of a suspenslon of an active principle ln a micro-nized form is obtained by the presence of a suspension agent, namely one or more tensio-active agents of mono-oleate type of polyoxyethylene sorbitan (Tween 80) or other esters Of sorbitan, particularly of laurlc ' 1;Z~ 9 4~
acid and of stearic acid, which enables the fraction made soluble by water to become micellised. Such suspensions, by the presence of the micronized particles, cause an ocular intolerance and are not suitable in the field of ophthalmics.
The present invention is concerned with remedying these inconven-iences.
The present invention is based on the discovery that it is possible to dissolve an organic acid which is normally very slightly soluble in water such as indomethacin in an aqueous solution containing a sufficient quantity of at least the basic part of a buffer mixture and that the quantity of organic acid that can be dissolved is the greater, the larger the quantity of the basic part of the buffer mixture.
The subject cf the present invention is therefore a preparation process for an aqueous pharmaceutical solution with an active principle constituted by an organic acid, characterized in that a) the organic acid is dissolved in à first aqueous solutisn containing a sufficient quantity of at least a fraction of the basic part of a buffer mixture, b) this solution is Iyophilized in order to obtain a product in a dry state and c) at the time of use the product in a dry state is dissolved in a second aqueous solution containing the remainder of the buffer mixture, this remainder being such that the pH of the resulting solution is of a physiologically acceptable value.
Thus in the first stage of the process according to the present invention the organic acid is dissolved in a first aqueous solution containing a sufficient quantity of at least d fraction of the basic part of the buffer mixture. This first solution generally also con-tains a fraction of the acid part of the buffer mixture in such a wayas to be close to neutrality and to avoid pH values which are too basic and capable of affecting the stabilitY Of the active principle, whilst the second solution contains the remainder of the acid part of the buffer mixture and can also contain a fraction of the basic part of the buffer mixture.
At the limit, the first solution could even contain the total Z9~4 amount o~ the constituents of the buffer mixture. However, in this case, the solubility of the organic acid remains fairly weak. In addition it it advantageous to be able to adjust the pH of the final solution to the desired value for administration, thanks to the pre-sence of th~ remainder o~ the acid part of the buffer mixture in thesecond solution. Generally the pH values close to neutrality (pH of 6.5 to7.5) are desirable for administration to man and to animals.
rhe buffer mixtures that can be used in the present invention are in particular the following:
- Boric acid-sodium borate buffer - Monosodium phosphate-disodium phosphate buffer - Monopotassium phosphate-dipotassium phosphate buffer - Acetic acid-sodium acetate buffer - Citric acid-sodium citrate acid and mixtures of these buffers. The first three buffers are preferred.
In order to decrease the global quantity of the buffer mixture, volatile co-solvents such às ethanol can be added to the first solu-tion. Such an addition of ethanol (not exceeding in general 10% by volume) is useful especially when it is desired to obtain solutions to be lyophilized having significant concentrations of active principle (for example of more than 2% by weight).
The first solution can in addition contain any antibacterial agent capable of guaranteeing the bacteriologicaI quality of the solutions.
as for example esters of parahydroxybenzoic acid, and/or any stabilizer of antioxidant type such as sodium sulphites and derivatives, or edetic acid and its salts, as well as any other active principle soluble in water which is capable of completing or improving the therapeutic activity of the first. In addition for ophthalmic applications the solution can contain any product capable of prolonging the contact time and/or of improving the corneal penetration of the active principle, and in particular compounds of dextran typé, cellulose derivatives or other thickening agents compatible with the ophthalmic form of the speciality.
The solution thus prepared is sufficiently stable to allow its Iyophilization, which is carried out according to the usual methods.
Lyoph~lization presents the advantage of produc~ng a product which 129Z9.~
can be kept for a long time. The absence of water and of any co-sol-vent such dS a polyethyleneglycol avoids in effect any degradation or mDdification of the active principle. In addition the co-solvents which can be used are eliminated by sublimation during lyophilization, so that these co-solvents do not interfere even for an ophthalmic application.
At the time of use the lyophilized product is dissolved in the second solution containing the remainder of the buffer ~ixture, that is to say in ~eneral the remainder of the acid part of the buffer.
This second solution comprises in general from 75 to 98% by weight of water. It can contain any water soluble antibacterial agent, any water soluble antioxidant substance; any other active principle soluble and stable in water; any substance capable of stabilizing the pH at a value compatible with the ocular tolerance: any product having an 1~ influence on the tonicity of the solution like sodium chloride, glyco-coll, glucose; any substance capable of stabilizing the active principle in an aqueous solution. As stabilizers there can be used in particular polyethyleneglycols of which the molecular weight can be from 200 to 1500 and in particular from 200 to 600, at a rate of O to 25~ by weight.
The risks of modification of the active principle by the PEG
contained in the second solution, and this after reconstitution, are thus much less significant than for a solution in pure PEG because of the large proportion of water in the second solution. Other stabili-zers can also be used such as propylene glycol, tetrahydrofurfurylpolyethyleneglycol.
The present invention applies to the preparation of aqueous solutions of active principles constituted by organic acids and in particular aryl or heterocyclic compounds with a carbo~ylic acid group H~ 30 such as indomethacin, aspirin, niflumic acid, ibuprofen, pranoprofen, ketcprofen, alminoprofen, naproxen, sulindac.
The present invention finds a particularly useful application in the preparation of aqueous ophthalmic solutions of indomethacin.
In the case of aqueous ophthalmlc solutions of indomethacin there is advantageously prepared in a first stage a solution containing from 0.1 to 7.5% by weight of indomethacin and a sufficient quantity of a l~r~d~ ~ ~rK
lZ9Z944 fraction of a buffer mixture containing at least a fraction of the basic part of the buffer mixture and in general a fraction of the acid part of this mixture, this solution having a pH of 6.5 to 7.5 and preferably of 6.8 to 7.2. Such a pH is favourable to the stability of the indomethacin. A co-solvent such as ethanol can be added in a quantity which can go up to 10% by weight when the concentration of indomethacin is greater than 2% by weight in the solution. This solution is lyophilized and in addition a second solution is prepared containing the remainder of the buffer mixture. This second solution generally has a pH of 4.5 to 6.5 and, by the aissolYing of the lyophil-ized product in this second solution, enables a resultant solution to be obtained, which has a final pH compatible with the eye, generally fron 6.5 to 7.5 and advantageously from 6.8 to 7.3. This ophthalmic solution can generally have a concentration of indomethacin of 0.05 to 1% by weight.
It should be noted that if the boric acid-sodium borate buffer is used the quantity by weight of indomethacin that can be dissolved in the first solution is approximately equal to the quantity (by weight) of sodium borate.
The present invention applies not only to the preparation of ophthalmic solutions but also to the preparation of nasal solutions, of injectable solutions and of drinkable solutions.
The following examples illustrate the present invention.
Example 1 - Preparation of a collyrium c?ntaining 0.1% by weight of ndomethacin and a borate buffer A first solution of indomethacin is prepared by agitation at ambient temperature of the following constituents:
indomethacin 0.250 9 sodium borate 0.255 9 boric acid 1.405 9 dextran 1.000 9 water q.s. for 100.000 ml This solution has a pH of 7Ø
This solution is lyophilized immediatelys after having divided it into flasks each containing 2 ml of solution.
A second solution is prepared in addition by mixing at ambient temperature the following constituents:
boric acid 1.149 g nipagin (preservative) 0.050 9 PEG 400 (stabilizer) 24.850 g water q.s. for 100.000 ml The pH o~ this solution is 5.65.
This solution is divided into flasks each containing 5 ml.
At the time of use 5 ml of the second solution contained in one flask of solution is added to the lyophilized product contained in another flask. A collyrium containing 0.1% by weight of indomethacin is obtained, having a pH of 7.1.
This solution has, remarkably, a preservation time of at least one month at ambient temperature.
Example 2 - Preparation of a collyrium containing 0.1% by weight of indomethacin The operatlng method is as for example 1, uslng the following solutlons:
- first solution (to be lyophilized) divided into flasks each ccntain-20 ing 2 ml.
indomethacin 0.250 g dextran 1.000 g monosodium phosphate0.612 9 disodium phosphate 6.400 g nipagin 0.125 g water q.s. for 100.000 ml pH 7.25 - Second solution, divided into flasks each containing 5 ml monosodium phosphate 0.874 9 PEG 400 10.000 9 water ~.s. for 100.000 ml pH 5.1 The finaI collyrium has a pH of 7.1 and is stable for at least one month.
, 129Z94~, Example 3 - Preparation of a collyrium containing 0.4X by weight of indomethacin The operating method is as for example l, using the following solutions:
- First solution (to be lyophilized) divided into flasks each containing 2 ml indomethacin l.000 9 dextran 1.000 9 boric acid 2.180 9 sodium borate l.000 g water q.s. for lO0.000 ml pH 7.0 - Second solution (divided into flasks each containing 5 ml) boric acid 1.500 g PEG 400 25.000 9 water q.s. for lO0.000 ml pH 5.55 The f~nal collyrium has a pH of 7.1 and is stable for at least two months.
~ - Preparation of a collyrium containing 0.1% by weight of lbuprofen The operating method is as for example 1, using the following solutions:
- First solution (to be lyophilized) divided into flasks each contain-25 ing 2 ml ibuprofen (acid) 0.250 9 : nipagin 0.125 9 boric acid 2.190 9 sodium borate 0.500 9 dextran 1.000 9 water q.s. for 100.000 ml ; pH 7.0 : - Second solution (divided into flasks each containlng 5 ml) boric acid 1.224 9 PEG 400 25.000 9 water q.s. for lO0.000 g 1~9Z944 pH 5.6 The final collyrium has a pH of 7.0 and is stable for at least one month.
Examp!e 5 - Collyrium containing 0.l% by weight of indomethacin The operating method is dS for example l.
- First solution:
indomethacin 0.250 9 ethanol 5.000 ml sodium borate 0.1315 9 boric acid 0.450 9 nipagin 0.125 9 dextran 5.000 9 water q.s. for lO0.000 ml pH 7.0 - Second solution:
sodi~m borate 0.018 9 boric acid 0.727 9 PEG 400 24.85 9 water q.s. for lO0.000 ml pH 7.2 pH of final collyrium 7.2 Example 6 - Collyrium containing 0.4% by weight of indomethacin The operating method is as for example 1.
25 - First solution:
indomethacin 1.000 9 sodium borate 1.000 9 boric acid 2.180 9 dextran 1.000 9 water q.s. for 100.000 ml pH 7.0 - Second solution:
boric acid 1.500 9 nipagin 0-050 9 PEG 600 25.000 9 water q.s. for 100.000 ml lZ92944 pH 5.5 pH of final collyrium 7.0 Example 7 - Collyrium containing 0.1% by weight of indomethacin The operating method is as for example 1.
5 - First solution:
indomethacin 0.250 g sodium borate 0.255 g boric acid 1.405 g dextran 1.000 g water ~.s. for lO0.000 ml pH 7.0 - Second solution:
boric acid 1.149 g nipagin 0.050 g PEG 400 5.000 g water q.s, for lO0.000 ml pH 5.7 pH of ftnal collyrtum 7.0 Example 8 - Collyrium containing 2Z by weight of indomethacin The operatlng method is as for example 1.
- First solution:
indomethacin 5.000 g ethanol 5.000 ml sodium borate 5.000 9 boric acid 2.140 g ; dextran 1,000 g water q.s. for 100.000 g pH 7.2 - Second solution:
boric acid 2.452 g PEG 400 25.000 g nipagin 0.050 g water q.s. for lO0.000 ml pH 5.2 pH of final collyrtum 7.0 lZ92944 Example 9 - Preparation of a collyrium contain ng O.l% of indomet acln The operating method is dS for example 1, in such a way as to obtain per flask the following formula of the lyophilisate.
indomethacin 5 mg borax 5.1 mg boric acid 28.096 mg dextran 20 mg In addition the following solution is prepared:
PEG 400 1242.5 mg nipagin 2.5 mg EDTA 2.5 mg boric acid 99.75 mg borax 7.45 mg purified water q.s. for 5 ml At the time of use the solution constituting the solvent is added to the lyophilisate and a reconstituted collyrium is obtained having the following percentage formula:
indoemthàcin 0.1 g bordx 0.25l 9 boric acid 2.5569 9 nipagin 0.05 9 EDTA 0.05 9 PEG 400 24.85 9 dextran 0.4 9 purified water q.s. for 100 ml :
Claims (9)
1) Process for the preparation of an aqueous pharmaceutical solution containing an active principle constituted by an organic acid in which process:
a) the organic acid is dissolved in a first aqueous solution contain-ing a sufficient quantity of at least a fraction of the basic portion of a buffer mixture, b) the resultant solution is lyophilized in order to obtain a dry product, and c) at the time of use the dry product is redissolved in a second aqueous solution containing the remainder of the buffer mixture, this remainder being such that the pH of the resultant aqueous pharmaceut-ical solution is of a physiologically-acceptable value.
a) the organic acid is dissolved in a first aqueous solution contain-ing a sufficient quantity of at least a fraction of the basic portion of a buffer mixture, b) the resultant solution is lyophilized in order to obtain a dry product, and c) at the time of use the dry product is redissolved in a second aqueous solution containing the remainder of the buffer mixture, this remainder being such that the pH of the resultant aqueous pharmaceut-ical solution is of a physiologically-acceptable value.
2) Process according to claim 1, in which the first solution also contains a fraction of the acid portion of the buffer mixture and the second solution contains the reminder of the buffer mixture,
3) Process according to claim 1 or claim 2, in which the buffer mixture employed is selected from the group consisting of the following buffer mixtures, namely boric acid-sodium borate, monosodium phosphate-disodium phosphate and monopotassium phosphate-dipotassium phosphate.
4) Process according to claim 1 or 2, in which the first solution contains a volatile co-solvent.
5) Process according to claim 4, in which the co-solvent is ethanol.
6) Process according to claim 1, 2 or 5, in which the second solution contains a stabilizer.
7) Process according to claim 6, in which the stabilizer is a polyethyleneglycol having a molecular weight in the range of from 200 to 1500.
8) Process according to claim 1, 2, 5 or 7; in which the active principle is selected from the group consisting of indomethacin, aspirin, niflumic acid, ibuprofen, pranoprofen, ketoprofen, amino-profen, naproxen and sulindac.
9) Process according to claim 1, 2, 5 or 7, for the prepa-tion of an ophthalmic solution of indomethacin, in which:
a) the first solution is prepared containing 0.1 to 7.5% by weight of indomethacin and d sufficient quantity of at least a fraction of the basic portion of the buffer mixture, this first solution having a pH
value in the range of from 6.5 to 7.5, b) the resultant solution is lyophilized in order to obtain a dry product, and c) at the time of use the dry product is redissolved in the second solution which contains the remainder of the buffer mixture, this remainder being such that the pH of the resultant aqueous ophthalmic solution is in the range of from 6.5 to 7.5.
a) the first solution is prepared containing 0.1 to 7.5% by weight of indomethacin and d sufficient quantity of at least a fraction of the basic portion of the buffer mixture, this first solution having a pH
value in the range of from 6.5 to 7.5, b) the resultant solution is lyophilized in order to obtain a dry product, and c) at the time of use the dry product is redissolved in the second solution which contains the remainder of the buffer mixture, this remainder being such that the pH of the resultant aqueous ophthalmic solution is in the range of from 6.5 to 7.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000535901A CA1292944C (en) | 1987-04-29 | 1987-04-29 | Preparation process for an aqueous pharmaceutical solution of an active principle constituted by an organic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000535901A CA1292944C (en) | 1987-04-29 | 1987-04-29 | Preparation process for an aqueous pharmaceutical solution of an active principle constituted by an organic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1292944C true CA1292944C (en) | 1991-12-10 |
Family
ID=4135537
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000535901A Expired - Lifetime CA1292944C (en) | 1987-04-29 | 1987-04-29 | Preparation process for an aqueous pharmaceutical solution of an active principle constituted by an organic acid |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1292944C (en) |
-
1987
- 1987-04-29 CA CA000535901A patent/CA1292944C/en not_active Expired - Lifetime
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