CA1184495A - Process of producing pharmaceutical composition of famotidine for injection - Google Patents
Process of producing pharmaceutical composition of famotidine for injectionInfo
- Publication number
- CA1184495A CA1184495A CA000417637A CA417637A CA1184495A CA 1184495 A CA1184495 A CA 1184495A CA 000417637 A CA000417637 A CA 000417637A CA 417637 A CA417637 A CA 417637A CA 1184495 A CA1184495 A CA 1184495A
- Authority
- CA
- Canada
- Prior art keywords
- famotidine
- acid
- injection
- aspartic acid
- aqueous solution
- 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
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
Abstract
ABSTRACT OF THE DISCLOSURE
By the addition of L-aspartic acid, the solubility of Famotidine in water can be effectively improved for providing a stable aqueous solution of Famotidine for injection.
A lyophilized composition of Famotidine for injection is also prepared by lyophilizing an aqueous solution containing Famotidine together with L-aspartic acid and/or L-glutamic acid. Mannitol may be also added to the aqueous solution. as an excipient.
By the addition of L-aspartic acid, the solubility of Famotidine in water can be effectively improved for providing a stable aqueous solution of Famotidine for injection.
A lyophilized composition of Famotidine for injection is also prepared by lyophilizing an aqueous solution containing Famotidine together with L-aspartic acid and/or L-glutamic acid. Mannitol may be also added to the aqueous solution. as an excipient.
Description
A PROCESS OF PRODCING PHARMACEUTICAL COMPOSITION
OF FAMOTIDINE FOR INJECTION
l`his invention relates to a process of producing an injectablèlcomposition of Famot ~ine, and more particularly to a process of producing an aqueous injectable composition of Famotidine (chemical name: 3-[[(2-[(diaminomethYlene)amin ~
4-thiazolyl) methy~thio~ sulfamoylpropionamidine) contain ing L aspar~tic acid. Furthermore, the invention relates to a process of producing a lyophilized injectablecomposition of ;~ Famotidine containing L-aspart ic aci~ and/or L-glutamic acid together with, as the case may be, mannitol.
BAC~C~Nu 01~ ~U =KV-NIION
Famotidine used in ~his invention is a compound useful as gastric acid secretion inhibitors (see, U0 S. Patent No.
4,283,408) ancl oral preparations of the compound preparations have already been developed but the development of the inieCtable/
o~ the compound h~ve delayed since Famotidine is sparingly soluble in water (i. e., thD solubility thereof is less than about 0.1 w/~0). In order to use Famotidine as an injection, the compound must be dissolved in water at a concentration of 10 mg/ml ~1 w/v~/0) and for the purpose, it is required to solubilize Famotidine.
Hitherto, as a means of solubilizing a sparingly soluble medicament, it is known that a base medicament is converted into the salt thereof with a mineral aci~ or an organic acid ~' or an acid medicament is converted lnto the sal~ thereof with an al~ali salt or an organic amine~ and since Famotodine belongs to a basic medicament, it is considered to convert Famotidine into t~e salt thereof with a mineral acid or an organic acid. However, since Famotidine is an unsta~le compound in an acid region as shown in Ta~le 1, it is required not only to solubilize the compound but also to select an acid pro~iding capable of/stable aqueous solution of the salt.and various experiments were pre~ormed using various acids for finding the desired acids.
_ _, . .. _ , . . . . . .
Table 1 Stability of Famotidi~e in aqueous solution(O.1%) at 20 and 50C
k x hr pH
1.23 5.23 x 10 2 8.83 x 10 1
OF FAMOTIDINE FOR INJECTION
l`his invention relates to a process of producing an injectablèlcomposition of Famot ~ine, and more particularly to a process of producing an aqueous injectable composition of Famotidine (chemical name: 3-[[(2-[(diaminomethYlene)amin ~
4-thiazolyl) methy~thio~ sulfamoylpropionamidine) contain ing L aspar~tic acid. Furthermore, the invention relates to a process of producing a lyophilized injectablecomposition of ;~ Famotidine containing L-aspart ic aci~ and/or L-glutamic acid together with, as the case may be, mannitol.
BAC~C~Nu 01~ ~U =KV-NIION
Famotidine used in ~his invention is a compound useful as gastric acid secretion inhibitors (see, U0 S. Patent No.
4,283,408) ancl oral preparations of the compound preparations have already been developed but the development of the inieCtable/
o~ the compound h~ve delayed since Famotidine is sparingly soluble in water (i. e., thD solubility thereof is less than about 0.1 w/~0). In order to use Famotidine as an injection, the compound must be dissolved in water at a concentration of 10 mg/ml ~1 w/v~/0) and for the purpose, it is required to solubilize Famotidine.
Hitherto, as a means of solubilizing a sparingly soluble medicament, it is known that a base medicament is converted into the salt thereof with a mineral aci~ or an organic acid ~' or an acid medicament is converted lnto the sal~ thereof with an al~ali salt or an organic amine~ and since Famotodine belongs to a basic medicament, it is considered to convert Famotidine into t~e salt thereof with a mineral acid or an organic acid. However, since Famotidine is an unsta~le compound in an acid region as shown in Ta~le 1, it is required not only to solubilize the compound but also to select an acid pro~iding capable of/stable aqueous solution of the salt.and various experiments were pre~ormed using various acids for finding the desired acids.
_ _, . .. _ , . . . . . .
Table 1 Stability of Famotidi~e in aqueous solution(O.1%) at 20 and 50C
k x hr pH
1.23 5.23 x 10 2 8.83 x 10 1
2.21 3.54 x 10 3 5.70 x 10 2 4.00 9.25 x 10 5 7.26 x 10 4 7.03 __5.80 x 10 5 2.62 x 10 4 ~k: decomposition rate constant of Famotidine.
Famotidine clecomposes according to 1st order reaction.J
The results obtained are shown in Table 2.
Table 2 Solubility test.
AcidpH of aq. Solubility and pH Solubility acid soln. within 5 hours within 24 hr8.
Solubility pH
Hydrochloric 1 58 soluble 4.28 precipitate acid produced (low temp.) Oxalic acid 1.73 soluble 2.95 precipitate produced Malonic acid 2.24 soluble 4.13 precipitate produced Succinic acid 2.89 soluble 4.17 precipitate produced Maleic acid 2.06 insoluble 4.83 Fumaric acid 2.34 soluble 3.62 precipitate produced .. . . .. _ .... _ . _ . _ . _ . _ .. ... _ _ .. _ _ .. _ _ _ ... .. _ Table 2 (cont. ) Tartaric acid 2~ 29 insoluble 2 . 91 Citric acid . 2.23 soluble 3.73 soluble Phthalic acid 2.46 insoluble 5.18 ~ Acid solutions were added to Famotidine so that they may be : eq~imolar amoun~ to Famotidine on the assumption that ~amo-_ tidine i9 dessolved at a concentrat~on of 10 mg/ml As is clear from the results snown in Table 2, hydro-chloric acid, oxalic acid, malonic acid, succinic acid, fumaric acid, and citric acid can solubilize Famotidine ~ut maleic acid, ~artaric acid, and phthalic acid which have the extent of a~most/same/acid strength as the foregoing acids ~ut cannot solubilize Famotidine, which shows that the solubility of the does salt of Famotidine and an acid/not always depend upon the acid strength of the acid. Also, as to the acids capable of solubilizing Famotidine, in the cases of using oxalic acid~
each oi malonic acid, succinic acid~ and fumaric acid, when/the solution is allowed to stand at rocm temperature, many cr~stals precipitate wlthin 24 hours and also in the case of using hydrochloric acid, when the solution is preserved over-night in a cold place tin a refrigerator), crystals precipitate.
Citric acid solubilizes Famotidine and the solution form0d precipitates does not produce /but since th~eare such faults that the so pH of the solution is/low to reduce the stability of Famotidine and when the solution is administered as injection (intra-muscular), it givesa pain , the solution is unsuitable for practical use. Tnus, it is unaerstood that ord~ry acids cannot provide an aqueous solution of Famotldlne which can be used as an ineJction.
SUMMAl~Y ~F '~'HE INVENrrION
As the result of fur~her ad~ancing the investigations, the inventor~havediscovered that L aspar tic acid which is sparingly soluble in water and one of aci~ Cmino acids having low acidity (showlng a high pH when ~issolved) has unexpectedly an excellent solubilizing e~fect for Famotidine.
~ l'hus, according ~o this invention, there is provided a process of producing an aqueous injectablecomposition of Famotidine which comprises adding water to L-aspartic acid and Famotidine, then stirring the mixture. In other embodiment - compounded of this invention, L-aspartic acid is /together with L-glutamic acid and ~hen the aqueous solution of Famotidine thus obtained is lyophilized.
D _ ILED ~ESCRIP'rION OF 'l`H~ INV~N'1'I~N
In spite of that L-aspar tic acid itself is ~paringly soluble in water (solubility: 0.45 w/~/O at 20 C), a stable aqueous solution of L-aspar tic acid is obtained when Famotidine exists in the solution, thereby Famotidine is sufficiently solubilized, and when the solution is allowe~
to stand for 24 hours in a cold place, no precipitation of crystals is observed ~in fact, Famotidine can be solubilized to about 4%). As the result incidental to the solubilizing effect ~y L-aspar tic acid, it is expected ~hat since the aqueous solution of Famotidine thus solubilized has a high ~, - 4 _ pH (about 5.3), a good result will be obtained as to the stabi-lity. In fact, the result shows an excellent stability as shown in Table 3, which shows the decomposition rate constants of aqueous solutlon of 1 w/v~ Famotidine containing L-aspartic acid.
That is, the result shown in Table 3 is astonishingly stabilized more than 10 times the result shown in Table 1 at 20C.
Table 3 Stability ofOFamotidine in aqueous solution(l~) at 20 and 50 C in the presence of aspartic acid pH k x hr 1 5.3 5.16 x 10 6 9.46 x 10 5 ... _ ~ . ... _ ~, . _ _ ............ . _ _ _ .
Also, aspar tic acid does not give any pain and harm to when a~ninistered the human body~as an injection and in this point, the aqueous solution of this invention can be suitably used as an injection.
~ urthermore, as the results of investigating other acidic amino acidsS it has been found that L-glutamic acid s~ows unexpectedly a high solubilizing effect as L-aspart^ic acid and also shows a comparatively high stabilizing effect.
That is, it has been confirmed that in spite of the fact that L-glutamic acid its~lf is sparingly soluble in water (solu-bility: 0.86 w/~0 at 25C), L-glutamic acid gives a consider-ably stable aqueous solution if it exists together with Famotidine and thus sufficiently solubilizes Famotidine. Also, when a~ninistered L-glutamic acid gives no pain and harm to the human body/as an injection as in the case of L-aspar tic acid and hence the aqueous solution is also suitable as injection.
decornpositiQn ll'he /rate constant of the aqueous solution of Famotidine at 100C in each case o~ use o~ L-aspar~ acid, as a solubility agent are L-glutamic acid, or hydrochloric acid /shown in Table 4.
Stability of Famotidine in aqueous solution(1%) at lOO C
Table 4 in the presence ~f L-aspartic acid, L-glutamic acid or ~ = .. __ Solubilizing pH k x hr l agent L-Aspar tic acid ~.~3 2.~9 x lO 2 L-Glutamic acid 506~ 2.91 x lO 2 Hydrochloric acid 5.39 ~ 3 x lO
" 4.31~.87 x l~ 2 _ _ , ~
The above results suggest that even in the case of` using L-glutamic acid, the solution can be preparated as an injection of Famotidine i~ the solution is lyophilized ~there is no problem about the stability of the preparation and it is also stable after reconstitution with~ater). Therefore, various lyophilized products were investigated and as the result thereof, it has been confirmed that in the case of using citric acid, etc., the products show poor solu~ility w~-~when they are reconstituted/water to form a sticky lump or form precipitates, thereby the products canno~ be practically used, while in ~he case o~ using L-aspar tic acid and/or L~
glutamic acid as a solubilizing agent, there are no problems about the solubility and the stability of the solutions.
In addition, at performing the l~yophilization, an excipient such as mannitol generally ,_-~-~~' . ' ~o~n be, if necesary, added.
From the above investigations, the inventorshavediscovered that an aqueous injectable solution of Famotidine is obtained by using L-aspar tiC acid and also a lyphilized product for injection o~ F`amotidine is obtained by using L-aspar^tic acid and!or L-glutamic ~cid and has attained this invention based on the discovery.
The aqueous injec~ablè~composition of Famotidine can be obtained by mixing ~amotidine and L-aspartic acid of an amount of 1-2 mole times that of Famotidine in water accord-ing to this invention. Practically, the aqueous inejCtable composition of Famotidine is perpared by placing necessary amounts of Famotidine and L-aspartic acid in a vessel and after adding thereto water, sufficiently stirring the mixture until Famotidine and L-aspartic acid are dissolved in water.
Also, the lyophilized composition of Famotidine for inejction can be obtained by mixing Famotidine with L-aspartic acid and/or L-glutamic acid in an amount of 1-2 mole times the amount of Famotidine in water until they are dissolved in water and, after, if desired, dissolving a proper amount of mannitol in the solution, lyophilizing the aqueous solution.
Then, the invention will further be explained in more detail by the following e~amples.
Example 1 To 1 g of Famotidine and 0.4 g of L-aspar tic acid was dded 90 ml of water and after sufficiently stirring the water was added to the solution mixture for 15-30 minutes/so that the total ~olume became 100 ml.
Example 2 To 2 g of Famotidine and 0.8 g of L-aspartic acid was added about 90 ml of water and after sufficiently stirring the mixture for 15-30 minutes to dissol~e them, water was added to the solution so that the total volume became 100 ml.
Example 3 To 1 g of Famotidine and 0.4 g of L-aspar tic acid was sufficiently added about 90 ml of water and after/stirring the mixture for 15-30 minutes to dissolve the components, water was added to the solution so that the total volume became 100 ml. The aqueous solution was lyophilized to provide a lyophilized composition of Famotidine for injection.
Example 4 To 1 g of Famotidine and 0.4 g of L-aspar tic acid was added about 90 ml of water and the mixture was sufficiently stirred for 15-30 mintues to dissolve the components. In the aqueous solution thus obtained was dissolved 2 g of D-mannitol and then after adding thereto water so that the total volume became 100 ml, the aqueous solution was lyophilized to provide a lyophilized composition of Famotidine for injection.
~xample 5 To 1 g of Famotidine and 0~45 g of L-glutamic acid was added about 90 ml of water and after sufficiently stirring the mixture for 15-30 minutes to dissolve the components, water was added to the solution so that the total volume became 100 ml. The aqueous solution was lyophilized ~ to provide a lyophilized composition of Famotidine for injection.
Example 6 To 1 g o~ Famotodine and 0.45 g of L-glutamic acid was added about 90 ml of water and the mixture was sufficiently stirred for 15-30 minutes to dissolve the components. In the solution was dissolved 4 g of D-mannitol and after adding water to the solution so that the total volume became 100 ml, the aqueous solution was lyophilized to provide a lyophilized composition of Famotidine for injection.
Example 7 To 1 g of Famotidine, 0.2~ g of L-aspar tic acid, and 0 22 g of L-glutamic acid was added about 90 ml of water and the mixture was sufficiently stirred for 15-30 minutes to dissolve the components. In the solution was dissolved 4 g of D-mannitol and after adding water to the solution so that the total volume became 100 ml, the aqueous solution was lyophilized to provide a lyophilized composition of Famotidine for injection.
Famotidine clecomposes according to 1st order reaction.J
The results obtained are shown in Table 2.
Table 2 Solubility test.
AcidpH of aq. Solubility and pH Solubility acid soln. within 5 hours within 24 hr8.
Solubility pH
Hydrochloric 1 58 soluble 4.28 precipitate acid produced (low temp.) Oxalic acid 1.73 soluble 2.95 precipitate produced Malonic acid 2.24 soluble 4.13 precipitate produced Succinic acid 2.89 soluble 4.17 precipitate produced Maleic acid 2.06 insoluble 4.83 Fumaric acid 2.34 soluble 3.62 precipitate produced .. . . .. _ .... _ . _ . _ . _ . _ .. ... _ _ .. _ _ .. _ _ _ ... .. _ Table 2 (cont. ) Tartaric acid 2~ 29 insoluble 2 . 91 Citric acid . 2.23 soluble 3.73 soluble Phthalic acid 2.46 insoluble 5.18 ~ Acid solutions were added to Famotidine so that they may be : eq~imolar amoun~ to Famotidine on the assumption that ~amo-_ tidine i9 dessolved at a concentrat~on of 10 mg/ml As is clear from the results snown in Table 2, hydro-chloric acid, oxalic acid, malonic acid, succinic acid, fumaric acid, and citric acid can solubilize Famotidine ~ut maleic acid, ~artaric acid, and phthalic acid which have the extent of a~most/same/acid strength as the foregoing acids ~ut cannot solubilize Famotidine, which shows that the solubility of the does salt of Famotidine and an acid/not always depend upon the acid strength of the acid. Also, as to the acids capable of solubilizing Famotidine, in the cases of using oxalic acid~
each oi malonic acid, succinic acid~ and fumaric acid, when/the solution is allowed to stand at rocm temperature, many cr~stals precipitate wlthin 24 hours and also in the case of using hydrochloric acid, when the solution is preserved over-night in a cold place tin a refrigerator), crystals precipitate.
Citric acid solubilizes Famotidine and the solution form0d precipitates does not produce /but since th~eare such faults that the so pH of the solution is/low to reduce the stability of Famotidine and when the solution is administered as injection (intra-muscular), it givesa pain , the solution is unsuitable for practical use. Tnus, it is unaerstood that ord~ry acids cannot provide an aqueous solution of Famotldlne which can be used as an ineJction.
SUMMAl~Y ~F '~'HE INVENrrION
As the result of fur~her ad~ancing the investigations, the inventor~havediscovered that L aspar tic acid which is sparingly soluble in water and one of aci~ Cmino acids having low acidity (showlng a high pH when ~issolved) has unexpectedly an excellent solubilizing e~fect for Famotidine.
~ l'hus, according ~o this invention, there is provided a process of producing an aqueous injectablecomposition of Famotidine which comprises adding water to L-aspartic acid and Famotidine, then stirring the mixture. In other embodiment - compounded of this invention, L-aspartic acid is /together with L-glutamic acid and ~hen the aqueous solution of Famotidine thus obtained is lyophilized.
D _ ILED ~ESCRIP'rION OF 'l`H~ INV~N'1'I~N
In spite of that L-aspar tic acid itself is ~paringly soluble in water (solubility: 0.45 w/~/O at 20 C), a stable aqueous solution of L-aspar tic acid is obtained when Famotidine exists in the solution, thereby Famotidine is sufficiently solubilized, and when the solution is allowe~
to stand for 24 hours in a cold place, no precipitation of crystals is observed ~in fact, Famotidine can be solubilized to about 4%). As the result incidental to the solubilizing effect ~y L-aspar tic acid, it is expected ~hat since the aqueous solution of Famotidine thus solubilized has a high ~, - 4 _ pH (about 5.3), a good result will be obtained as to the stabi-lity. In fact, the result shows an excellent stability as shown in Table 3, which shows the decomposition rate constants of aqueous solutlon of 1 w/v~ Famotidine containing L-aspartic acid.
That is, the result shown in Table 3 is astonishingly stabilized more than 10 times the result shown in Table 1 at 20C.
Table 3 Stability ofOFamotidine in aqueous solution(l~) at 20 and 50 C in the presence of aspartic acid pH k x hr 1 5.3 5.16 x 10 6 9.46 x 10 5 ... _ ~ . ... _ ~, . _ _ ............ . _ _ _ .
Also, aspar tic acid does not give any pain and harm to when a~ninistered the human body~as an injection and in this point, the aqueous solution of this invention can be suitably used as an injection.
~ urthermore, as the results of investigating other acidic amino acidsS it has been found that L-glutamic acid s~ows unexpectedly a high solubilizing effect as L-aspart^ic acid and also shows a comparatively high stabilizing effect.
That is, it has been confirmed that in spite of the fact that L-glutamic acid its~lf is sparingly soluble in water (solu-bility: 0.86 w/~0 at 25C), L-glutamic acid gives a consider-ably stable aqueous solution if it exists together with Famotidine and thus sufficiently solubilizes Famotidine. Also, when a~ninistered L-glutamic acid gives no pain and harm to the human body/as an injection as in the case of L-aspar tic acid and hence the aqueous solution is also suitable as injection.
decornpositiQn ll'he /rate constant of the aqueous solution of Famotidine at 100C in each case o~ use o~ L-aspar~ acid, as a solubility agent are L-glutamic acid, or hydrochloric acid /shown in Table 4.
Stability of Famotidine in aqueous solution(1%) at lOO C
Table 4 in the presence ~f L-aspartic acid, L-glutamic acid or ~ = .. __ Solubilizing pH k x hr l agent L-Aspar tic acid ~.~3 2.~9 x lO 2 L-Glutamic acid 506~ 2.91 x lO 2 Hydrochloric acid 5.39 ~ 3 x lO
" 4.31~.87 x l~ 2 _ _ , ~
The above results suggest that even in the case of` using L-glutamic acid, the solution can be preparated as an injection of Famotidine i~ the solution is lyophilized ~there is no problem about the stability of the preparation and it is also stable after reconstitution with~ater). Therefore, various lyophilized products were investigated and as the result thereof, it has been confirmed that in the case of using citric acid, etc., the products show poor solu~ility w~-~when they are reconstituted/water to form a sticky lump or form precipitates, thereby the products canno~ be practically used, while in ~he case o~ using L-aspar tic acid and/or L~
glutamic acid as a solubilizing agent, there are no problems about the solubility and the stability of the solutions.
In addition, at performing the l~yophilization, an excipient such as mannitol generally ,_-~-~~' . ' ~o~n be, if necesary, added.
From the above investigations, the inventorshavediscovered that an aqueous injectable solution of Famotidine is obtained by using L-aspar tiC acid and also a lyphilized product for injection o~ F`amotidine is obtained by using L-aspar^tic acid and!or L-glutamic ~cid and has attained this invention based on the discovery.
The aqueous injec~ablè~composition of Famotidine can be obtained by mixing ~amotidine and L-aspartic acid of an amount of 1-2 mole times that of Famotidine in water accord-ing to this invention. Practically, the aqueous inejCtable composition of Famotidine is perpared by placing necessary amounts of Famotidine and L-aspartic acid in a vessel and after adding thereto water, sufficiently stirring the mixture until Famotidine and L-aspartic acid are dissolved in water.
Also, the lyophilized composition of Famotidine for inejction can be obtained by mixing Famotidine with L-aspartic acid and/or L-glutamic acid in an amount of 1-2 mole times the amount of Famotidine in water until they are dissolved in water and, after, if desired, dissolving a proper amount of mannitol in the solution, lyophilizing the aqueous solution.
Then, the invention will further be explained in more detail by the following e~amples.
Example 1 To 1 g of Famotidine and 0.4 g of L-aspar tic acid was dded 90 ml of water and after sufficiently stirring the water was added to the solution mixture for 15-30 minutes/so that the total ~olume became 100 ml.
Example 2 To 2 g of Famotidine and 0.8 g of L-aspartic acid was added about 90 ml of water and after sufficiently stirring the mixture for 15-30 minutes to dissol~e them, water was added to the solution so that the total volume became 100 ml.
Example 3 To 1 g of Famotidine and 0.4 g of L-aspar tic acid was sufficiently added about 90 ml of water and after/stirring the mixture for 15-30 minutes to dissolve the components, water was added to the solution so that the total volume became 100 ml. The aqueous solution was lyophilized to provide a lyophilized composition of Famotidine for injection.
Example 4 To 1 g of Famotidine and 0.4 g of L-aspar tic acid was added about 90 ml of water and the mixture was sufficiently stirred for 15-30 mintues to dissolve the components. In the aqueous solution thus obtained was dissolved 2 g of D-mannitol and then after adding thereto water so that the total volume became 100 ml, the aqueous solution was lyophilized to provide a lyophilized composition of Famotidine for injection.
~xample 5 To 1 g of Famotidine and 0~45 g of L-glutamic acid was added about 90 ml of water and after sufficiently stirring the mixture for 15-30 minutes to dissolve the components, water was added to the solution so that the total volume became 100 ml. The aqueous solution was lyophilized ~ to provide a lyophilized composition of Famotidine for injection.
Example 6 To 1 g o~ Famotodine and 0.45 g of L-glutamic acid was added about 90 ml of water and the mixture was sufficiently stirred for 15-30 minutes to dissolve the components. In the solution was dissolved 4 g of D-mannitol and after adding water to the solution so that the total volume became 100 ml, the aqueous solution was lyophilized to provide a lyophilized composition of Famotidine for injection.
Example 7 To 1 g of Famotidine, 0.2~ g of L-aspar tic acid, and 0 22 g of L-glutamic acid was added about 90 ml of water and the mixture was sufficiently stirred for 15-30 minutes to dissolve the components. In the solution was dissolved 4 g of D-mannitol and after adding water to the solution so that the total volume became 100 ml, the aqueous solution was lyophilized to provide a lyophilized composition of Famotidine for injection.
Claims (3)
1. A process of producing an aqueous injectable com-position of Famotidine which comprises adding L aspartic acid to an aqueous composition of Famotidine.
2. A process of producing a lyophilized composition of Famotidine for injection which comprises preparing an aqueous solution of Famotidine by adding thereto L-aspartic acid and/or L-glutamic acid and lyophilizing the aqueous solu-tion.
3. A process of producing a lyophilized composition of Famotidine for injection which comprises dissolving Famoti-dine in water by adding thereto L-aspartic acid and/or L-glu-tamic acid, further dissolving mannitol in the solution, and then lyophilizing the aqueous solution.
4. An aqueous injectable composition of Famotidine comprising Famotidine and L-aspartic acid in an aqueous solu-tion.
5. The composition of claim 4, wherein the L-aspartic acid is present in an amount 1 to 2 mole times that of Famo-tidine.
6. A lyophilized composition of Famotidine for injec-tion which comprises Famotidine and L-aspartic acid and/or glutamic acid when prepared by the process of claim 2.
7. A lyophilized composition of Famotidine for injec-tion which comprises Famotidine, L-aspartic acid and/or glu-tamic acid and mannitol when prepared by the process of
3. A process of producing a lyophilized composition of Famotidine for injection which comprises dissolving Famoti-dine in water by adding thereto L-aspartic acid and/or L-glu-tamic acid, further dissolving mannitol in the solution, and then lyophilizing the aqueous solution.
4. An aqueous injectable composition of Famotidine comprising Famotidine and L-aspartic acid in an aqueous solu-tion.
5. The composition of claim 4, wherein the L-aspartic acid is present in an amount 1 to 2 mole times that of Famo-tidine.
6. A lyophilized composition of Famotidine for injec-tion which comprises Famotidine and L-aspartic acid and/or glutamic acid when prepared by the process of claim 2.
7. A lyophilized composition of Famotidine for injec-tion which comprises Famotidine, L-aspartic acid and/or glu-tamic acid and mannitol when prepared by the process of
claim 3.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56201934A JPS58103312A (en) | 1981-12-15 | 1981-12-15 | Aqueous solution for injection of hardly soluble drug and its preparation |
| JP201934/1981 | 1981-12-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1184495A true CA1184495A (en) | 1985-03-26 |
Family
ID=16449204
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000417637A Expired CA1184495A (en) | 1981-12-15 | 1982-12-14 | Process of producing pharmaceutical composition of famotidine for injection |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS58103312A (en) |
| KR (1) | KR880001632B1 (en) |
| CA (1) | CA1184495A (en) |
| ES (1) | ES8405613A1 (en) |
| GR (1) | GR77823B (en) |
| MX (1) | MX7581E (en) |
| PT (1) | PT75985B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002051411A1 (en) * | 2000-12-22 | 2002-07-04 | Yamanouchi Pharmaceutical Co., Ltd. | Famotidine injections |
| CN111904936A (en) * | 2020-08-28 | 2020-11-10 | 开封康诺药业有限公司 | Famotidine freeze-dried powder injection |
| CN114028342A (en) * | 2021-12-08 | 2022-02-11 | 广东彼迪药业有限公司 | Famotidine rapidly disintegrating particles, famotidine tablets and preparation method |
| CN114681409A (en) * | 2021-10-20 | 2022-07-01 | 海南倍特药业有限公司 | Famotidine for injection and preparation method thereof |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES8703865A2 (en) * | 1985-06-28 | 1987-03-16 | Barisintex Sa | Process for preparing H2 receptor antagonist ascorbate compounds |
| CA2426925A1 (en) * | 2000-11-24 | 2003-04-25 | Yamanouchi Pharmaceutical Co., Ltd. | Water-soluble liquid internal medicine |
| JP4828040B2 (en) * | 2001-04-27 | 2011-11-30 | テルモ株式会社 | Famotidine injection |
| AU2002360025A1 (en) * | 2001-12-27 | 2003-07-15 | Terumo Kabushiki Kaisha | Famotidine injection |
| AU2003235236A1 (en) * | 2002-05-13 | 2003-11-11 | Daiichi Pharmaceutical Co., Ltd. | Lyophilization product |
-
1981
- 1981-12-15 JP JP56201934A patent/JPS58103312A/en active Granted
-
1982
- 1982-12-14 CA CA000417637A patent/CA1184495A/en not_active Expired
- 1982-12-14 GR GR70069A patent/GR77823B/el unknown
- 1982-12-14 PT PT75985A patent/PT75985B/en unknown
- 1982-12-14 ES ES518199A patent/ES8405613A1/en not_active Expired
- 1982-12-15 MX MX82101115U patent/MX7581E/en unknown
- 1982-12-15 KR KR8205621A patent/KR880001632B1/en not_active IP Right Cessation
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002051411A1 (en) * | 2000-12-22 | 2002-07-04 | Yamanouchi Pharmaceutical Co., Ltd. | Famotidine injections |
| US7094414B2 (en) | 2000-12-22 | 2006-08-22 | Astellas Pharma Inc. | Famotidine injections |
| CN111904936A (en) * | 2020-08-28 | 2020-11-10 | 开封康诺药业有限公司 | Famotidine freeze-dried powder injection |
| CN114681409A (en) * | 2021-10-20 | 2022-07-01 | 海南倍特药业有限公司 | Famotidine for injection and preparation method thereof |
| CN114028342A (en) * | 2021-12-08 | 2022-02-11 | 广东彼迪药业有限公司 | Famotidine rapidly disintegrating particles, famotidine tablets and preparation method |
| CN114028342B (en) * | 2021-12-08 | 2023-04-28 | 广东彼迪药业有限公司 | Famotidine Ding Su disintegrating particles, famotidine tablet and preparation method |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6365047B2 (en) | 1988-12-14 |
| ES518199A0 (en) | 1984-06-16 |
| KR880001632B1 (en) | 1988-09-03 |
| PT75985A (en) | 1983-01-01 |
| MX7581E (en) | 1989-11-24 |
| GR77823B (en) | 1984-09-25 |
| KR840002654A (en) | 1984-07-16 |
| JPS58103312A (en) | 1983-06-20 |
| PT75985B (en) | 1985-12-05 |
| ES8405613A1 (en) | 1984-06-16 |
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