CA1186227A - Pharmaceutical composition for injection - Google Patents
Pharmaceutical composition for injectionInfo
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- CA1186227A CA1186227A CA000442797A CA442797A CA1186227A CA 1186227 A CA1186227 A CA 1186227A CA 000442797 A CA000442797 A CA 000442797A CA 442797 A CA442797 A CA 442797A CA 1186227 A CA1186227 A CA 1186227A
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Abstract
ABSTRACT OF THE DISCLOSURE
There is disclosed a stable pharmaceutical preparation which comprises a compound of the formula
There is disclosed a stable pharmaceutical preparation which comprises a compound of the formula
Description
This applicati~n is a division ~f Canadian Application No. 389,484 filed November 5, 1981 for Pharmaceutical Composition ~or Injection.
The present invention relate~ to pharmaceutical preparations comprising9 as a main ingredient, 4-carbamoyl-imidazolium-5-oleate or its salt or hydrate thereof (here-inafter referred to as "Compound A") and to a method for the productio~ thereof.
It has been known that the Compound A can be prepared by the method described, for example, in J. Am.
Chem. Soc. Vol. 74, 2892 (1952), and that the Compound A i~
useful as a therapeutic agent for the treatment of tumor, rheumatism and nephritis (U.S. Patent No. 4,181,731;
French Patent No. 77271~4; Canadian Patent No. 1,078,736).
It is also known that the Compound A can be formu-lated into various dosage forms such as tablets, capsules, and injections.
It has now been foundg however, that the Compound A is so unstable that it is easily colored upon expo~ure to oxygen, heat, or light, and that, when the Compound A
i9 formulated into pharmaceutical preparations such as in~ections, oral dosage forms or suppository, the coloration o~ the ~ompound A i ~urther increased presu~ably due to the interaction of the Compound A with some other components such as solvents, diluents or baseq t}~ough co~plicated reaction.
In addition, the Compound ~ has a poor solubility in water ~about 4.7 mg/ml at ?5~ as free base form3.
Thi~ poor solubility o~ the oompound creates difficultie~
in the prsduction of in~ections of the compound in that the ~olumes o~ the in~ection~ become too large to be practical for intra~enous or intramu~cular in~ection, local ln~ection to tumor and the like.
_ 1 _ ;9~
In order to overcome above mentioned difficultles9 we have extensively studied, and as the results, have found that sulfur compolnd~ capable of producing ~S03 , S032 or S2052 ions are very effective for the control or prevention of coloration. A~ shown in the Experimental Example 1 below9 various stabilizers were examined in expectation of anticoloration by their antioxidative effectR
or chelating of heavy metal ions therewith, but the material~
tested proved to have no e~fect or even increase said colora-10 tion. ~e have found that the sulfur compounds capable of producing ~S03 , S032 or S2052 ions can effectively prevent the coloration of the co~pound. ~en the prepara-tions containing said sulfur compounds were prepared and tested, it was found that excellent stabilization effect was realized in addition to the anti-coloration effect.
For further improvement in a long period stabi-lity thereo~, studies were continued and the following wa~
found out. That is, an excellent anti-coloration effect ~as obtained by the combination of sodium metabisulfite 20 and ~-cysteins hydrochloride. ~his was indeed a surpris-ing finding, because the effect is synergistic only in this particular combination. Furtherm~re, an aqueous injection of the compound in combination with sodium metabisulfite and ~-cysteine hydrochloride did not show any coloration after storing at a room temperature for a long period of time even under severe conditions, as shown in Experimental ~xample 5.
From these facts~ the inventors have also found that by the addition of sulfur compound capable of produc-30 ing one ions selected from HS03 9 S032 and S2052 in com-
The present invention relate~ to pharmaceutical preparations comprising9 as a main ingredient, 4-carbamoyl-imidazolium-5-oleate or its salt or hydrate thereof (here-inafter referred to as "Compound A") and to a method for the productio~ thereof.
It has been known that the Compound A can be prepared by the method described, for example, in J. Am.
Chem. Soc. Vol. 74, 2892 (1952), and that the Compound A i~
useful as a therapeutic agent for the treatment of tumor, rheumatism and nephritis (U.S. Patent No. 4,181,731;
French Patent No. 77271~4; Canadian Patent No. 1,078,736).
It is also known that the Compound A can be formu-lated into various dosage forms such as tablets, capsules, and injections.
It has now been foundg however, that the Compound A is so unstable that it is easily colored upon expo~ure to oxygen, heat, or light, and that, when the Compound A
i9 formulated into pharmaceutical preparations such as in~ections, oral dosage forms or suppository, the coloration o~ the ~ompound A i ~urther increased presu~ably due to the interaction of the Compound A with some other components such as solvents, diluents or baseq t}~ough co~plicated reaction.
In addition, the Compound ~ has a poor solubility in water ~about 4.7 mg/ml at ?5~ as free base form3.
Thi~ poor solubility o~ the oompound creates difficultie~
in the prsduction of in~ections of the compound in that the ~olumes o~ the in~ection~ become too large to be practical for intra~enous or intramu~cular in~ection, local ln~ection to tumor and the like.
_ 1 _ ;9~
In order to overcome above mentioned difficultles9 we have extensively studied, and as the results, have found that sulfur compolnd~ capable of producing ~S03 , S032 or S2052 ions are very effective for the control or prevention of coloration. A~ shown in the Experimental Example 1 below9 various stabilizers were examined in expectation of anticoloration by their antioxidative effectR
or chelating of heavy metal ions therewith, but the material~
tested proved to have no e~fect or even increase said colora-10 tion. ~e have found that the sulfur compounds capable of producing ~S03 , S032 or S2052 ions can effectively prevent the coloration of the co~pound. ~en the prepara-tions containing said sulfur compounds were prepared and tested, it was found that excellent stabilization effect was realized in addition to the anti-coloration effect.
For further improvement in a long period stabi-lity thereo~, studies were continued and the following wa~
found out. That is, an excellent anti-coloration effect ~as obtained by the combination of sodium metabisulfite 20 and ~-cysteins hydrochloride. ~his was indeed a surpris-ing finding, because the effect is synergistic only in this particular combination. Furtherm~re, an aqueous injection of the compound in combination with sodium metabisulfite and ~-cysteine hydrochloride did not show any coloration after storing at a room temperature for a long period of time even under severe conditions, as shown in Experimental ~xample 5.
From these facts~ the inventors have also found that by the addition of sulfur compound capable of produc-30 ing one ions selected from HS03 9 S032 and S2052 in com-
- 2 -bination with ~-cysteine hydrochloride to the compound, it is possible to obtain a stable preparation showing no coloration even storing for a long period of time) and have succeeded in attaining the anti-coloration and stabilization in full.
Though the invention has been explained in con-nection with aqueous injection which is believed to be most difficult to be stabilized, the invention can likewise be applied to various other pharmaceutical preparations includ-ing oral dosage form, o.intment, suppository and the like.
Examples of said sulfur compounds include bisul-fites (e.g. alkali metal bisulfite as sodium bisulfite ~Ta~S03~, potassium bisulfite (KHS03) or the like, and ammonium bisulfite (NH4HS03)), aqueous sulfurous acid or sulfites (e.g. alkali metal sulfite as sodium sulfite (~a2SO~), potassium sulfite (K2S03) and the like, and alkaline earth metal sulfite as calcium sulfite (CaS03), barium sulfite (BaS0~) and the like), metabisulfites (e.g.
alkali metal metabisulfite as potassium metabisulfite (E2S205~, sodium ~etabisulfite (Na2S205)) and the likeO
A~ to the weight ratio of sulfur compound capable of producing ions selected from HS03 , S032 and S2052 and L-cysteine hydrochloride in the prepar~tion of thi~
invention, it is preferred ~rom the standview of stabili~a-tion effect de~ired and safety use of additives, to use 0.001 to 0.500 part of the sulfur compound and 0.01 to 0.50 part of ~-cysteine hydrochloride per one part of the Compound A.
In ca~e of injection, a daily dose of the Compound A is 50 to 2000 mg for an adult person Next, studies have been continued to find out means to improve solubility of the compound. Various surfactants usually employed as solubilizing means, additives in anticipation of intramolecular action, and non-aqueous vehicles have been tried, but failed to attain the de~ired effect, but very surprisingly, we have found that marked improvement in solubility of the compound i9 obtained by the addition of basic subs-tance. On the basis of this finding, improving solubility which is another object of this invention has been attained in full, thereby succeeding in providing an injection of the compound with wide applicability.
The term "basic material" as used herein may include alkali metal hydro~ides such as NaOH and the like;
alkali metal ca:rbonate such as Na2CO3 and the like; alka-line earth meta:L hydroxides such as Ca(OH)2 and the like;
compound~ having alkali metal or alkaline earth metal ion as cation, for example, borax and the like; and organic amine3 such as ethanolamine, trishydroxymethyl amino methane, basic amino acid (e.g. ~-arginine, ~-lysine) and the like. Anyone of the abovesaid basic materials are successfully used, but from a p~actical sense of view, organic amines are preferable.
The solubility of the compound tends to be in-creased with the amount of said basic material added and the increase in pH. However, at the same time, cares shoula be paid to the safety i~ connection with the absolute adding amount of the basic material, and to select optimum pH range of the injection solution giving no local stimula-tion and the like. In thi~ regard, the most desirable pH
ran~e of the injection solution is 8.0 to 9.5 and undersuch condition~, the preferable basic material~ are organic amines because of easiness in handling and quality of the product obtained. Among them~ the most preferable one ~ arginine since.it ha~ an excellent 301ubility, safety factor as additive and operational easiness in handling thereof. If desired, said basic materials may be used in the form ~f mixture thereof.
Th~ amount of basic material is to be determined princi.paly by the amount of the active ingredient, the Compound A and the total quality evaluation of the prepa-ration thus obtained including safety factor, but prefer-ably it i~ in a range of 0.9 to 3 ~oles per mole of the c ompound .
Thus, the present invention makes it possible to provide pharmaceutical preparation~ of the Compound A
with improved anti-coloration and stabilization effects by the addition o~ sulfur compound capable of producing at least one of the ions selected from HS0~ , S032 and S2052 ; to attain more complete anti-coloration and stabili~ation e~fects even in the preparation which is very liable to be colored, and which is unstable like an aqueous injection by the addition of ~-cysteine hydrochloride in combination with the said sulfur com?ounds; and to improve solubility of the compou~d by the addition of basic material and especially L-arginine, thereby furnish-ing wide variety of injections with up to higher concent-ration.
In preparing the present preparations, the above~
said stabili er and/or solubilizer is used depending on 6~7 the requirements of the respective dosage form and using other pharmacologically permissible additives as diluents, bases, solvent or the like as occasion demands, various dosage forms are formulated following conventional means.
Unique properties and usefulness of the invention shall be now explained in the following Experimental Examples.
perime ~
To an aqueous solution of the Compound A (lO mg/ml) containing ~-arginlne, was added each of the stabilizers listed in the following Table l in a concentration of 0.2 %. ~ach 5 ml of the solution was taken in a 8 ml ampule, and after replacing the remaining air with nitro-gen gas, the ampule was stored at 50 C. for l week and the degree of coloration of the content was measured by light absorbance at 420 nm (layer length lO mm). In Table l, was also ~iven color which was determined following JIS Z
QlO2-l457 "Color name", Kogyo-yo Shikimeicho, K.K. Nihon Shikisai Sha by visual inspeotion.
Table Sample material ~ ght Color ~ _ . ~
control 0.383 pale yellowish 0.2% sodi.um sulfite 0.038 colorles~
0.2~ sodium bisulfite 0.040 colorless 0.2% sodium metabisulfite 0.035 colorless Table l (cont'd) 0.2~ ED~A-2Na 0.520 bright yellowish green 0.2~ L-ascorbic acid 0.092 faint yellowish green 0.2~ Erysorbic acid 2.7~6 yellow ocher 0.2% thiourea 1.016 light yellowish green 0.2~ Taurine 0.903 light yellowish green 0.2~ acetylthiourea 0.726 light yellowish green Experimental Example 2 -Freeze~dried preparation containing 20 mg/vial of the compound A alone (control) and together with 10 mg/vial of sodium bisulfite were prepared. After storing at 40C. or 50 C~ under light shielding condition or room temperature under 1000 Lux, for 2 months, the degree of coloration was measured by visual inspection and shown in Table 2, in conformity to JIS Z 8102-1957 "Color name", Kogyoyo Shikimeicho, K. K. Nihon Shikisai Sha.
Table 2 Storing condition Sample Light Light 1000 Lux 20material shielding shielding room temp.
at 40C. at 50C.
.
control white - faint faint faint bluish purple bluish purple bluish green 10 mg sodium white white white bisulfite ~x~erimental Exam~le 3 Freeze dried preparation containing 100 mg of the Compound A, 200 mg of I,arginine as solubilizer and 5 mg of sodium bisulfite per vial and being placed in a vial, the inner air of which ~as replaced with nitroge~ gas, was prepared and after storing at 503C.
under light shielding condition for 2 months, the conte~t of the compound was measured by using light absorbance ratio at 276 nm. The results are shown~in Table 3.
Table Sample material ~-oleate originall idazolium co~trol (not added with 10 sodium bisul~ite) 89 added with 5 mg of sodium bisul~ite 95 ~xperimental EXample 4 . . _ To an aqueous solution of the Compound A
(10 mg/ml) containing I,arginine~ various stabilizers were added each alone or in the combination formt in an amount o~ 0.2 %. Each 5 ml of these solutions wer~
taken in the respective 18 ml vial, applied with stopper, stored at 50C. for 24 hours, and the degree of coloration was measured by light absorbance at 420 nm (layer length 10 mm). A1SO, the final color ~Jas determined in conformity to JIS Z 8102-1957 "Color name", Kogyoyo Shikimeicho, K.K. I~Tihon Shikisai Sha, by visual inspection.
Table 4 Sa~ple material ~ight Color control 2.392 golden color C.2~ sodium sulfite 1.472 bright yellow 0.2~ sodium bisulfite 1.120 bright yellow 0.2~ sodium ~etabisulfite 1.532 bright yellow 0.2~ ~DTA-2Na 1.832 golden color 0.2% ~-ascorbic acid 1.582 dark yellow 0.2~ ~-cysteine hydro-chloride 1.683 golden color 0.2% sodium metabisulfite plus 0.2% EDTA-2Na 0.833 brlght yellow 0.2~ sodium metabisulfite plu3 O. 601 pale yellow 0.2% l-ascorbic acid 0.2~ sodium metabisfulfite 0.2% ~-cysteine hydroch- 0.286 faint yellow loride ~xperlmental_ ~
Aqueous injection each containing the following in indicated amount~ per ampule were prepared and stored under severe condition of 50C., 1000 ~UX 9 or at room tem-perature, and the degree of coloration ~as determined by measuring light absorbance at 420 nm (layer length 10 ~m), and compared with each other. In this example, in prepar~
ing the injection solution, oxygen-free water was used and the inner space of the ampule was replaced with nitrogen gas.
_ g _ Prescription (per æm ule~
4-carbamoyl-imidazolium-5-oleate100 mg ~-arginine 200 mg -sodium metabisulfite 4 mg ~-cysteine hydrochloride 10 mg benzyl alcohol 50 mg sterilized distilled water for injection to make 5 ml Tab e 5 Storing condition ~lght absorbance initial 0.020 50Co - 2 months 0.002 1000 ~ux 2 months 0.007 room temp. - 6 months 0.015 Experimental Exam le 6 Excess amounts of the Compound A were dispersed in aqueous solutions containing various surfactants and additives, respectively. In each case, solubility of the compound was determined by measuring li~ht absorbance at 277 nm with the filtrate. For non-aqueous vehicles marked with *, the corresponding solubility of the compound was judged by eye-measurement.
Ta~le 6 Solubility Solubility mg/ml of 4- mg/ml o~ 4-Solvent carbamoyl- Solvent carbamoyl-imldazolium- imidazolium-5-oleate 5-oleate ~ _ . _ _ . _ .
5% Amycol No. 1 water 4 7 (manufactured by Nichiden 5.1 Kagaku K.K.) 5~o polyoxyethy-nated YCaStgr oil 4 5 deoxycholate white gel 5% polyoxyethy-lene sorbitan 4.6 saturated glu-monooleate tamic acid 5-3 5% sod um lauryl 4 7 saturated aspartic 5.4 * ethanol less than 2 saiUdrated gentisic whit * propylene glycol about 5 5C~ levul.inic acid 6.
~o * polyethylene less glycol than 2 5~o tartaric acid 7.0 * glycerine about 3 lOC/o mannitol 4.6 * N,N-dimethyl- less acetamide than 2 5,~ sodium salicylate 6.5 * sesame oil less 5~o nicotinic amide 7.2 than 2 * cotton seed_ less 5~ ethylurea 5.6 * corn oil less than 2 ~e~ac~
Using the same procedures as stated in EXperi-mental Example 6~ solubility measurement was carried out.
, ~able 7 . .
Solubilit~ of 4-carbamoyl-imi- PH of Solvent dazolium-5- solvent oleate, mg~ml 1% ethanolamine 24~9 8.64 50thrishydroxy methylamino 25-7 8.56 5% Irarginine 33.5 8.69 5% Irlysine 10.7 8.20 0.5% NaOH 21.4 8.50 NaHC03 Na2C03 buffer 26.7 8.42 5% borax 22.2 8.44 The invention shall be now more fully explained in the following examples, which, however, should not be taXen as being limitative in any sense.
Example A mixture of 4-carbamoyl-imidazolium-5-oleate (100 g), sodium bisulfite (5 g) and l,arginine (200 g) was dissolved in distilled water for injection to give the total ~olume 10 Q of the solution. The solution was fil-tered to remove bacteria, filled in each 10 ml into vials (24 ml in volume) and freeze-dried (the inner space of vial being replaced with nitrogen gas) to obtain freeze-dried injection, which was stable and capable of being reconstituted in higher concentration in less than 10 ml of distilled water for injectio~ before use.
~B~i~7 Exam~le 2 ~ he same procedures as stated in Example 1 ~rere repeated, excepting substituting sodium sulfite for sodium bisulfite, to obtain freeze-dried injec~ion, which was stable and capable of being reconstituted in higher concentration in less than 10 ml of distilled water for injection before use.
~ he sa~e procedures as stated in ~xample 1 were repeated, excepting substituting sodium metabisulfite for sodium bisulfite, to obtain freeze-dried injection~
which was stable and capable of being reconstituted in higher concentration in less than 10 ml of distilled ~ater for injection before use.
Exa,m~ e,,~
A mixl,ure of 4-car'bamo~l-imidazolium-5-oleate (100 g), sodium bisulfite (2.5 g), sodium metabisulfite (2.5 g) and I,arginine (200 g) was dissolved in distilled water for injection to give the total volume '0 ~ of the solution. The solution was filte~ed to remove b~cteria, filled in each 10 ~1 into vials (24 ml in vol-lne), and subjected to ~reeze-drying to obtain freeze-dried injec-tion being stable and capable of being reconstituted inhigher concertration in les~ than 10 ml of distilled ~ater for injection before use.
, - 13 -156 g of 4-carbamoyl-imidazolium-5-oleate hydrochloride, 3.1 Q of 1 % aqueous sodium hydroxide solu-tion and 200 g of L-arginine were dissolved, under stirring, in distilled water for injection, to make the total volume to 10 liters. This was filtered to remove bacteria, filled in each 10 ml into vials (24 ml i~ volume) and subjected to freeze-drying -to obtain freeze-dried injection being stable and capable of being reconstituted in higher con-centration in less than 10 ml of distilled water for injection before use.
Exam~le 6 into 5 liters of oxygen-free, sterilized, distilled water for injection, were dissolved gently 4 g of sodium metabisulfite, 10 g of L-cysteine hy~rochloride and then 100 g of 4-carbc~moyl-imidazolium-5-oleate, 200 g of ~-arginine and 50 g of benzyl alcohol. Thus obtained solution was filtered under sterile condition, each 5 ml of which was then filled into ampules (5 ml in volume), and after replac~
ing air in vessel with nitrogen gas, the a~pule was sealed to obtain an aqueous injection of 4-carbamoyl-imidazolium-5-oleate which was stable for a longer period of time.
Compound ~ 2000 g crystalline cellulose 2400 g ma~nesium stearate 50 g sodium bisulfite 150 g The above-mentioned ingredients were ~ixed together a~d thus obtained powdery mixture was formed into tablets each weighing about 230 mg. This was proven to be very stable for a longer period of time.
B ample 8 Compound A 400 g milk sugar 600 g sodium metabisulfite 20 g l-cysteine h~drochloride 40 g ~ he above-mentioned ingredients were mixed together to obtain uniformly mixed powder, which was 10 stable for a longer period of time.
Though the invention has been explained in con-nection with aqueous injection which is believed to be most difficult to be stabilized, the invention can likewise be applied to various other pharmaceutical preparations includ-ing oral dosage form, o.intment, suppository and the like.
Examples of said sulfur compounds include bisul-fites (e.g. alkali metal bisulfite as sodium bisulfite ~Ta~S03~, potassium bisulfite (KHS03) or the like, and ammonium bisulfite (NH4HS03)), aqueous sulfurous acid or sulfites (e.g. alkali metal sulfite as sodium sulfite (~a2SO~), potassium sulfite (K2S03) and the like, and alkaline earth metal sulfite as calcium sulfite (CaS03), barium sulfite (BaS0~) and the like), metabisulfites (e.g.
alkali metal metabisulfite as potassium metabisulfite (E2S205~, sodium ~etabisulfite (Na2S205)) and the likeO
A~ to the weight ratio of sulfur compound capable of producing ions selected from HS03 , S032 and S2052 and L-cysteine hydrochloride in the prepar~tion of thi~
invention, it is preferred ~rom the standview of stabili~a-tion effect de~ired and safety use of additives, to use 0.001 to 0.500 part of the sulfur compound and 0.01 to 0.50 part of ~-cysteine hydrochloride per one part of the Compound A.
In ca~e of injection, a daily dose of the Compound A is 50 to 2000 mg for an adult person Next, studies have been continued to find out means to improve solubility of the compound. Various surfactants usually employed as solubilizing means, additives in anticipation of intramolecular action, and non-aqueous vehicles have been tried, but failed to attain the de~ired effect, but very surprisingly, we have found that marked improvement in solubility of the compound i9 obtained by the addition of basic subs-tance. On the basis of this finding, improving solubility which is another object of this invention has been attained in full, thereby succeeding in providing an injection of the compound with wide applicability.
The term "basic material" as used herein may include alkali metal hydro~ides such as NaOH and the like;
alkali metal ca:rbonate such as Na2CO3 and the like; alka-line earth meta:L hydroxides such as Ca(OH)2 and the like;
compound~ having alkali metal or alkaline earth metal ion as cation, for example, borax and the like; and organic amine3 such as ethanolamine, trishydroxymethyl amino methane, basic amino acid (e.g. ~-arginine, ~-lysine) and the like. Anyone of the abovesaid basic materials are successfully used, but from a p~actical sense of view, organic amines are preferable.
The solubility of the compound tends to be in-creased with the amount of said basic material added and the increase in pH. However, at the same time, cares shoula be paid to the safety i~ connection with the absolute adding amount of the basic material, and to select optimum pH range of the injection solution giving no local stimula-tion and the like. In thi~ regard, the most desirable pH
ran~e of the injection solution is 8.0 to 9.5 and undersuch condition~, the preferable basic material~ are organic amines because of easiness in handling and quality of the product obtained. Among them~ the most preferable one ~ arginine since.it ha~ an excellent 301ubility, safety factor as additive and operational easiness in handling thereof. If desired, said basic materials may be used in the form ~f mixture thereof.
Th~ amount of basic material is to be determined princi.paly by the amount of the active ingredient, the Compound A and the total quality evaluation of the prepa-ration thus obtained including safety factor, but prefer-ably it i~ in a range of 0.9 to 3 ~oles per mole of the c ompound .
Thus, the present invention makes it possible to provide pharmaceutical preparation~ of the Compound A
with improved anti-coloration and stabilization effects by the addition o~ sulfur compound capable of producing at least one of the ions selected from HS0~ , S032 and S2052 ; to attain more complete anti-coloration and stabili~ation e~fects even in the preparation which is very liable to be colored, and which is unstable like an aqueous injection by the addition of ~-cysteine hydrochloride in combination with the said sulfur com?ounds; and to improve solubility of the compou~d by the addition of basic material and especially L-arginine, thereby furnish-ing wide variety of injections with up to higher concent-ration.
In preparing the present preparations, the above~
said stabili er and/or solubilizer is used depending on 6~7 the requirements of the respective dosage form and using other pharmacologically permissible additives as diluents, bases, solvent or the like as occasion demands, various dosage forms are formulated following conventional means.
Unique properties and usefulness of the invention shall be now explained in the following Experimental Examples.
perime ~
To an aqueous solution of the Compound A (lO mg/ml) containing ~-arginlne, was added each of the stabilizers listed in the following Table l in a concentration of 0.2 %. ~ach 5 ml of the solution was taken in a 8 ml ampule, and after replacing the remaining air with nitro-gen gas, the ampule was stored at 50 C. for l week and the degree of coloration of the content was measured by light absorbance at 420 nm (layer length lO mm). In Table l, was also ~iven color which was determined following JIS Z
QlO2-l457 "Color name", Kogyo-yo Shikimeicho, K.K. Nihon Shikisai Sha by visual inspeotion.
Table Sample material ~ ght Color ~ _ . ~
control 0.383 pale yellowish 0.2% sodi.um sulfite 0.038 colorles~
0.2~ sodium bisulfite 0.040 colorless 0.2% sodium metabisulfite 0.035 colorless Table l (cont'd) 0.2~ ED~A-2Na 0.520 bright yellowish green 0.2~ L-ascorbic acid 0.092 faint yellowish green 0.2~ Erysorbic acid 2.7~6 yellow ocher 0.2% thiourea 1.016 light yellowish green 0.2~ Taurine 0.903 light yellowish green 0.2~ acetylthiourea 0.726 light yellowish green Experimental Example 2 -Freeze~dried preparation containing 20 mg/vial of the compound A alone (control) and together with 10 mg/vial of sodium bisulfite were prepared. After storing at 40C. or 50 C~ under light shielding condition or room temperature under 1000 Lux, for 2 months, the degree of coloration was measured by visual inspection and shown in Table 2, in conformity to JIS Z 8102-1957 "Color name", Kogyoyo Shikimeicho, K. K. Nihon Shikisai Sha.
Table 2 Storing condition Sample Light Light 1000 Lux 20material shielding shielding room temp.
at 40C. at 50C.
.
control white - faint faint faint bluish purple bluish purple bluish green 10 mg sodium white white white bisulfite ~x~erimental Exam~le 3 Freeze dried preparation containing 100 mg of the Compound A, 200 mg of I,arginine as solubilizer and 5 mg of sodium bisulfite per vial and being placed in a vial, the inner air of which ~as replaced with nitroge~ gas, was prepared and after storing at 503C.
under light shielding condition for 2 months, the conte~t of the compound was measured by using light absorbance ratio at 276 nm. The results are shown~in Table 3.
Table Sample material ~-oleate originall idazolium co~trol (not added with 10 sodium bisul~ite) 89 added with 5 mg of sodium bisul~ite 95 ~xperimental EXample 4 . . _ To an aqueous solution of the Compound A
(10 mg/ml) containing I,arginine~ various stabilizers were added each alone or in the combination formt in an amount o~ 0.2 %. Each 5 ml of these solutions wer~
taken in the respective 18 ml vial, applied with stopper, stored at 50C. for 24 hours, and the degree of coloration was measured by light absorbance at 420 nm (layer length 10 mm). A1SO, the final color ~Jas determined in conformity to JIS Z 8102-1957 "Color name", Kogyoyo Shikimeicho, K.K. I~Tihon Shikisai Sha, by visual inspection.
Table 4 Sa~ple material ~ight Color control 2.392 golden color C.2~ sodium sulfite 1.472 bright yellow 0.2~ sodium bisulfite 1.120 bright yellow 0.2~ sodium ~etabisulfite 1.532 bright yellow 0.2~ ~DTA-2Na 1.832 golden color 0.2% ~-ascorbic acid 1.582 dark yellow 0.2~ ~-cysteine hydro-chloride 1.683 golden color 0.2% sodium metabisulfite plus 0.2% EDTA-2Na 0.833 brlght yellow 0.2~ sodium metabisulfite plu3 O. 601 pale yellow 0.2% l-ascorbic acid 0.2~ sodium metabisfulfite 0.2% ~-cysteine hydroch- 0.286 faint yellow loride ~xperlmental_ ~
Aqueous injection each containing the following in indicated amount~ per ampule were prepared and stored under severe condition of 50C., 1000 ~UX 9 or at room tem-perature, and the degree of coloration ~as determined by measuring light absorbance at 420 nm (layer length 10 ~m), and compared with each other. In this example, in prepar~
ing the injection solution, oxygen-free water was used and the inner space of the ampule was replaced with nitrogen gas.
_ g _ Prescription (per æm ule~
4-carbamoyl-imidazolium-5-oleate100 mg ~-arginine 200 mg -sodium metabisulfite 4 mg ~-cysteine hydrochloride 10 mg benzyl alcohol 50 mg sterilized distilled water for injection to make 5 ml Tab e 5 Storing condition ~lght absorbance initial 0.020 50Co - 2 months 0.002 1000 ~ux 2 months 0.007 room temp. - 6 months 0.015 Experimental Exam le 6 Excess amounts of the Compound A were dispersed in aqueous solutions containing various surfactants and additives, respectively. In each case, solubility of the compound was determined by measuring li~ht absorbance at 277 nm with the filtrate. For non-aqueous vehicles marked with *, the corresponding solubility of the compound was judged by eye-measurement.
Ta~le 6 Solubility Solubility mg/ml of 4- mg/ml o~ 4-Solvent carbamoyl- Solvent carbamoyl-imldazolium- imidazolium-5-oleate 5-oleate ~ _ . _ _ . _ .
5% Amycol No. 1 water 4 7 (manufactured by Nichiden 5.1 Kagaku K.K.) 5~o polyoxyethy-nated YCaStgr oil 4 5 deoxycholate white gel 5% polyoxyethy-lene sorbitan 4.6 saturated glu-monooleate tamic acid 5-3 5% sod um lauryl 4 7 saturated aspartic 5.4 * ethanol less than 2 saiUdrated gentisic whit * propylene glycol about 5 5C~ levul.inic acid 6.
~o * polyethylene less glycol than 2 5~o tartaric acid 7.0 * glycerine about 3 lOC/o mannitol 4.6 * N,N-dimethyl- less acetamide than 2 5,~ sodium salicylate 6.5 * sesame oil less 5~o nicotinic amide 7.2 than 2 * cotton seed_ less 5~ ethylurea 5.6 * corn oil less than 2 ~e~ac~
Using the same procedures as stated in EXperi-mental Example 6~ solubility measurement was carried out.
, ~able 7 . .
Solubilit~ of 4-carbamoyl-imi- PH of Solvent dazolium-5- solvent oleate, mg~ml 1% ethanolamine 24~9 8.64 50thrishydroxy methylamino 25-7 8.56 5% Irarginine 33.5 8.69 5% Irlysine 10.7 8.20 0.5% NaOH 21.4 8.50 NaHC03 Na2C03 buffer 26.7 8.42 5% borax 22.2 8.44 The invention shall be now more fully explained in the following examples, which, however, should not be taXen as being limitative in any sense.
Example A mixture of 4-carbamoyl-imidazolium-5-oleate (100 g), sodium bisulfite (5 g) and l,arginine (200 g) was dissolved in distilled water for injection to give the total ~olume 10 Q of the solution. The solution was fil-tered to remove bacteria, filled in each 10 ml into vials (24 ml in volume) and freeze-dried (the inner space of vial being replaced with nitrogen gas) to obtain freeze-dried injection, which was stable and capable of being reconstituted in higher concentration in less than 10 ml of distilled water for injectio~ before use.
~B~i~7 Exam~le 2 ~ he same procedures as stated in Example 1 ~rere repeated, excepting substituting sodium sulfite for sodium bisulfite, to obtain freeze-dried injec~ion, which was stable and capable of being reconstituted in higher concentration in less than 10 ml of distilled water for injection before use.
~ he sa~e procedures as stated in ~xample 1 were repeated, excepting substituting sodium metabisulfite for sodium bisulfite, to obtain freeze-dried injection~
which was stable and capable of being reconstituted in higher concentration in less than 10 ml of distilled ~ater for injection before use.
Exa,m~ e,,~
A mixl,ure of 4-car'bamo~l-imidazolium-5-oleate (100 g), sodium bisulfite (2.5 g), sodium metabisulfite (2.5 g) and I,arginine (200 g) was dissolved in distilled water for injection to give the total volume '0 ~ of the solution. The solution was filte~ed to remove b~cteria, filled in each 10 ~1 into vials (24 ml in vol-lne), and subjected to ~reeze-drying to obtain freeze-dried injec-tion being stable and capable of being reconstituted inhigher concertration in les~ than 10 ml of distilled ~ater for injection before use.
, - 13 -156 g of 4-carbamoyl-imidazolium-5-oleate hydrochloride, 3.1 Q of 1 % aqueous sodium hydroxide solu-tion and 200 g of L-arginine were dissolved, under stirring, in distilled water for injection, to make the total volume to 10 liters. This was filtered to remove bacteria, filled in each 10 ml into vials (24 ml i~ volume) and subjected to freeze-drying -to obtain freeze-dried injection being stable and capable of being reconstituted in higher con-centration in less than 10 ml of distilled water for injection before use.
Exam~le 6 into 5 liters of oxygen-free, sterilized, distilled water for injection, were dissolved gently 4 g of sodium metabisulfite, 10 g of L-cysteine hy~rochloride and then 100 g of 4-carbc~moyl-imidazolium-5-oleate, 200 g of ~-arginine and 50 g of benzyl alcohol. Thus obtained solution was filtered under sterile condition, each 5 ml of which was then filled into ampules (5 ml in volume), and after replac~
ing air in vessel with nitrogen gas, the a~pule was sealed to obtain an aqueous injection of 4-carbamoyl-imidazolium-5-oleate which was stable for a longer period of time.
Compound ~ 2000 g crystalline cellulose 2400 g ma~nesium stearate 50 g sodium bisulfite 150 g The above-mentioned ingredients were ~ixed together a~d thus obtained powdery mixture was formed into tablets each weighing about 230 mg. This was proven to be very stable for a longer period of time.
B ample 8 Compound A 400 g milk sugar 600 g sodium metabisulfite 20 g l-cysteine h~drochloride 40 g ~ he above-mentioned ingredients were mixed together to obtain uniformly mixed powder, which was 10 stable for a longer period of time.
Claims (11)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Injection which comprises a compound of the formula (I) (I) its salt or hydrate thereof, and a basic substance.
2. Injection according to Claim 1 which is characterized by that said basic substance is an organic amine.
3. Injection according to Claim 2 which is characterized by that said organic amine is L-arginine.
4. Stable injection according to any one of the preceding Claims 1 to 3, which is characterized by that one or more of the sulfur compound capable of producing at least one of the ions selected from HSO3-, SO32- and S2O52- are further added.
5. Injection stable for a long period of time according to any one of the preceding Claims 1 to 3, which is characterized by containing the sulfur compound capable of producing one of the ions selected from HSO3-, SO32- and S2O52-, and L-cysteine hydrochloride.
6. A process for enhancing water-solubility of a compound of the formula (I) (I) its salt or hydrate thereof which comprises combining a basic substance with the said compound.
7. A process for producing an injection of the compound of the formula (I) (I) its salts or hydrate thereof, which comprises dissolving the said compound in combination with a basic substance in an injectable aqueous solution.
8. The process according to Claim 7 which is characterized by that said basic substance is an organic amine.
9. The process according to Claim 8 which is characterized by that said organic amine is L-arginine.
10. The process according to any one of the preceding claims 7 to 9 which is characterized by that one or more of the sulfur compound capable of producing at least one of the ions selected from HSO3-, SO32- and S2O52- are further added.
11. The process according to any one of the preceding claims 7 to 9 which is characterized in that the sulfur compound capable of producing one of the ions selected from HSO3-, SO32- and S2O52-, and L-cysteine hydrochloride are added to the said compound.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP15617380A JPS5780317A (en) | 1980-11-05 | 1980-11-05 | Preparation of pharmaceutical composition for injection |
JP156173/80 | 1980-11-05 | ||
JP156795/80 | 1980-11-06 | ||
JP15679580A JPS5780328A (en) | 1980-11-06 | 1980-11-06 | Preparation of stable pharmaceutical preparation |
CA000389484A CA1186999A (en) | 1980-11-05 | 1981-11-05 | Pharmaceutical composition for injection |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000389484A Division CA1186999A (en) | 1980-11-05 | 1981-11-05 | Pharmaceutical composition for injection |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1186227A true CA1186227A (en) | 1985-04-30 |
Family
ID=27167165
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000442797A Expired CA1186227A (en) | 1980-11-05 | 1983-12-07 | Pharmaceutical composition for injection |
Country Status (1)
Country | Link |
---|---|
CA (1) | CA1186227A (en) |
-
1983
- 1983-12-07 CA CA000442797A patent/CA1186227A/en not_active Expired
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