Package form for bicarbonate-containing powdery pharmaceutical compositions and a method of stabilizing the compositions

The invention provides a method and a package form for insuring a stabilized bicarbonate-containing pharmaceutical composition, the method comprises filling the bicarbonate-containing powdery pharmaceutical composition in a moisture- and gas-permeable plastic container, wrapping the so-filled container in a moisture- and gas-impermeable plastic wrapper and carrying out at least one procedure selected from the group consisting of the procedure of introducing a carbon dioxide gas into a space between the container and wrapper, the procedure of disposing a carbon dioxide-liberating deoxygenating agent in the space and the procedure of disposing a desiccant previously saturated with carbon dioxide gas by way of adsorption in the space. In accordance with the invention, the inherent objects of incorporating the bicarbonate can be accomplished without inducing the aging and degradation of the bicarbonate-containing powdery pharmaceutical composition.

TECHNICAL FIELD 
The present invention relates to a method of stabilizing a 
bicarbonate-containing powdery pharmaceutical composition, particularly a 
novel method of stabilizing a bicarbonate-containing powdery 
pharmaceutical composition which allows the composition in a plastic 
container to remain wholesome without aging or degradation and the object 
of addition of the carbonate to be accomplished without compromise and to 
a package form for such bicarbonate-containing powdery pharmaceutical 
composition. 
BACKGROUND ART 
With very few exceptions such as sodium chloride, drugs are susceptible to 
aging loads such as water, oxygen and light and glass ampules have been in 
use for their storage since many years ago. However, with the recent 
advances in pharmaceutical science, material engineering, production 
methodology, production equipment, etc., these pharmaceutical containers 
are being replaced by glass vials and plastic (such as polyolefins, e.g. 
polyethylene, polypropylene, etc., ethylene-vinyl acetate copolymer, 
polyethylene terephthalate, polyvinyl chloride, etc.) containers which are 
easy for those engaged in medical practice to handle and easy to dispose 
of after use and the utilization of such plastic containers, in 
particular, is rapidly spreading of late. 
However, unlike glass, plastics are inherently permeable to gas and 
moisture and have the disadvantage that containers made thereof cannot be 
used for all kinds of drugs. Recently, materials which are almost as 
impervious to gas and moisture as glass, such as a laminate film carrying 
a vapor-deposited aluminum layer or an aluminum foil, a laminate film 
carrying a vapor-deposited silicon monoxide layer, a multi-layer film 
consisting of plural materials such as polyethylene terephthalate, 
polyvinyl alcohol, polyvinylidene chloride, ethylene-vinyl alcohol 
copolymer, etc. have been developed and today plastics with an oxygen 
permeability rate of not more than 1.0 cc/m.sup.2 .multidot.24 hrs/1 atm. 
and a moisture permeability rate of not more than 1.0 g/m.sup.2 
.multidot.24 hrs/1 atm. are available on the market and finding ever 
broadening usage and application. 
Meanwhile, drugs are generally stable in the bulk form but if they are 
dissolved and administered to patients, the low pH values of the solutions 
would not only damage the local tissue at the administration site but also 
induce systemic disturbances or result in poor absorption. Therefore, a 
variety of pharmaceutical contrivances has so far been made to avoid the 
troubles. By way of illustration, assuming that the pharmaceutical 
composition contains a strongly acidic powdery substance such as the 
hydrochloride or an acidic powdery drug whose neutral salt would be 
unstable, it is common practice to formulate the drug with a bicarbonate 
to insure the proper pH on dissolution or convert it to the neutral salt 
which is more readily absorbed at the time of administration. 
Moreover, drugs which are unstable in solution, for example certain 
antibiotics, are supplied in the powdery form but since these drugs in 
general are sparingly soluble in aqueous vehicles, a bicarbonate as a 
source of carbon dioxide gas, which assists in dissolution, is added as a 
solubilizer. 
On the other hand, sodium hydrogen carbonate is contained as an alkalizing 
agent in dialysis fluid compositions for artificial kidney use and for the 
purpose of insuring the ease of handling and reducing the cost of 
shipment, the recent tread is toward converting such liquid compositions 
to powdery or granular preparations (e.g. Japanese Patent Application 
Kokai H3-38527 and Kokai H3-74331). 
The bicarbonate contained in such pharmaceutical compositions liberates 
water and carbon dioxide gas with time but it is well known that in a 
closed system there is established an equilibrium among the bicarbonate, 
carbonate, water and carbon dioxide as indicated by the following relation 
(1). 
EQU 2HCO.sub.3.sup.- .revreaction.CO.sub.3.sup.2- +H.sub.2 O+CO.sub.2( 1) 
However, when a bicarbonate-containing powdery pharmaceutical composition 
is supplied in a plastic (such as polyolefins, e.g. polyethylene, 
polypropylene, etc., ethylene-vinyl acetate copolymer, polyvinyl chloride, 
etc.) container, the carbon dioxide gas and water liberated from the 
bicarbonate find their way out through the plastic container which is 
permeable to gas and moisture. As a result, the balance of the above 
relation (1) is tipped to the right to yield the carbonate so that when 
the composition is dissolved for administration, the intrinsic objects of 
adding the bicarbonate, namely supply of HCO.sub.3.sup.-, neutralization 
of the drug, and assistance in dissolution, cannot be accomplished. 
Moreover, the solution after reconstitution undergoes increase of pH to 
affect the stability of the drug solution. For the protection of a powdery 
pharmaceutical composition containing a drug liable to decompose on 
absorption of moisture and a bicarbonate, as supplied in a plastic 
container, from the decomposition due to moisture, it might be 
contemplated to dispose a desiccant externally of the plastic container 
and wrapping the plastic container and desiccant together in a wrapping 
material with proven performance qualities, e.g. an oxygen permeability 
rate of not more than 1.0 cc/m.sup.2 .multidot.24 hrs/ 1 atm. and a water 
permeability rate of not more than 1.0 g/m.sup.2 .multidot.24 hrs/1 atm., 
such as a laminate film carrying a vapor-deposited silicon oxide layer, a 
composite laminate film comprising a plurality of materials such as 
polyethylene terephthalate, polyvinyl alcohol, polyvinylidene chloride, 
ethylene-vinyl alcohol copolymer, etc. or a laminate film having a 
vapor-deposited aluminum layer or an aluminum foil which is equivalent to 
glass in barrier performance. In such cases, there still occur events 
similar to those encountered when a bicarbonate-containing powdery 
composition is simply filled into a plastic container. Thus, the water and 
carbon dioxide gas liberated from the bicarbonate are adsorbed on the 
included desiccant so that the balance of said relation (1) is tipped to 
the right to cause the formation of carbonate and, hence, an elevation of 
pH of the solution after reconstitution. 
The present invention provides a new technology which overcomes all the 
above-mentioned problems associated with the provision of a 
bicarbonate-containing powdery pharmaceutical preparation in a plastic 
container which is permeable to moisture and gas by insuring an increased 
carbon dioxide concentration in the container, allowing the moisture to be 
dissipated to the extent not affecting the quality of the drug, and 
inhibiting decomposition of the bicarbonate and formation of the carbonate 
to suppress the increase of pH after reconstitution and allow the inherent 
objects of incorporation of the carbonate, namely supply of 
HCO.sub.3.sup.-, neutralization of the drug and assistance in dissolution, 
to be accomplished without compromise. 
DISCLOSURE OF INVENTION 
In accordance with the present invention there is provided a method of 
stabilizing a bicarbonate-containing powdery composition characterized in 
that the placement of a bicarbonate-containing powdery pharmaceutical 
composition in a plastic container permeable to moisture and gas is 
followed by at least one procedure selected from among the procedure of 
introducing carbon dioxide gas into a space between the container and a 
wrapper and the procedure of disposing a carbon dioxide-liberating 
deoxygenating agent in said space and the procedure of disposing a 
desiccant previously saturated with carbon dioxide gas by way of 
adsorption, particularly such a method of stabilizing a 
bicarbonate-containing powdery pharmaceutical composition for dialysis. 
The present invention further provides the above stabilizing method wherein 
not only a carbon dioxide-liberating deoxygenating agent but also a 
desiccant is disposed in said space between the container and wrapper, 
which is applicable with particular advantage to the case in which said 
bicarbonate-containing powdery pharmaceutical composition is an 
antibiotic-containing composition. 
The invention further provides a method of stabilizing a 
bicarbonate-containing powdery pharmaceutical composition characterized by 
filling the bicarbonate-containing powdery composition into a plastic 
container which is impermeable to moisture and gas and introducing carbon 
dioxide gas into said container, which method is applicable with 
particular advantage to the case in which said bicarbonate-containing 
powdery pharmaceutical composition is a powdered dialysate. 
Furthermore, the present invention provides a package form contributory to 
the stabilization of a bicarbonate-containing powdery pharmaceutical 
composition which comprises a plastic container permeable to moisture and 
gas and adapted to contain the bicarbonate-containing powdery 
pharmaceutical composition and a plastic packaging wrapper as implemented 
by following at least one procedure selected from the group consisting of 
the procedure of filling the space between said container and wrapper with 
carbon dioxide gas, the procedure of disposing a carbon dioxide 
gas-liberating deoxygenating agent in said space and the procedure of 
disposing a desiccant saturated with carbon dioxide gas by way of 
adsorption in said space. 
The moisture- and gas-permeable plastic container used for accommodating a 
bicarbonate-containing powdery pharmaceutical composition for the use of 
the present invention may be made of various materials which are permeable 
to moisture and gas including but not limited to polyolefins such as 
polyethylene, poly-propylene, ethylene-.alpha.-olefin copolymers, etc., 
ethylene-vinyl acetate copolymer, polyvinyl chloride, polyamides, etc., 
inclusive of multi-layer films comprising such materials in various 
combinations. 
The moisture- and gas-impermeable plastic wrapper for use in the present 
invention includes, among others, moisture- and gas-impermeable 
aluminum-laminated films, laminate films carrying a vapor-deposited 
aluminum or silicon monoxide layer and multi-layer films comprising such 
materials as polyethylene terephthalate, polyvinyl alcohol, polyvinylidene 
chloride, ethylene-vinyl alcohol copolymer, etc. in suitable combinations. 
Among the various materials mentioned above, transparent materials through 
which the contents of the container can be visually inspected, such as a 
laminate film carrying a vapor-deposited silicon monoxide layer or a 
multi-layer film comprising a combination of polyethylene terephthalate, 
polyvinyl alcohol, polyvinylidene chloride, ethylene-vinyl alcohol 
copolymer and/or the like, are preferred. 
The bicarbonate for use in the present invention includes sodium hydrogen 
carbonate, potassium hydrogen carbonate, ammonium hydrogen carbonate and 
other bicarbonates. As representative examples of said 
bicarbonate-containing powdery pharmaceutical composition may be mentioned 
various powdery preparations for dialysis use (powdered dialysate 
preparations for artificial kidney use and powdery preparations for 
peritoneal dialysis) and antibiotic preparations. 
The antibiotics for use as active ingredients of said antibiotic-containing 
pharmaceutical compositions may be any known antibiotics such as 
cephalosporins antibiotics, e.g. cefazolin sodium, ceftizoxime sodium, 
cefotiam hydrochloride, cefmenoxime hydrochloride, cefacetrile sodium, 
cefamandole sodium, cefaloridine, cefotaxime sodium, cefotetan sodium, 
cefoperazone sodium, cefsulodin sodium, ceftezole sodium, cefpiramide 
sodium, cefmetazole sodium, cefuroxime sodium, ceftazidime, etc., 
penicillin antibiotics such as ampicillin sodium, carbenicillin sodium, 
sulbenicillin sodium, ticarcillin sodium, cloxacillin sodium, piperacillin 
sodium, etc., monobactam antibiotics such as carumonam sodium, and 
carbapenem antibiotics such as imipenem and so on. 
In the present invention which comprises introducing carbon dioxide gas 
into the space between said container accommodating a 
bicarbonate-containing powdery pharmaceutical composition and said 
wrapper, disposing a carbon dioxide gas-liberating deoxygenating agent in 
said space or disposing a desiccant saturated with carbon dioxide gas by 
way of adsorption in said space, the concentration of carbon dioxide gas 
in the container can be maintained at the proper level. For stabilizing a 
hygroscopic pharmaceutical composition, a desiccant can be further 
disposed in said space to attain a more satisfactory stabilizing effect. 
The present invention may also be carried into practice by using a 
moisture- and gas-impermeable plastic container and filling a powdery 
pharmaceutical composition, such as a powdered dialysate composition, 
directly into the container. In this mode, the object of the invention can 
be accomplished by filling carbon dioxide gas in the container. However, 
the carbon dioxide gas-liberating deoxygenating agent and the desiccant 
adsorptively saturated with carbon dioxide gas cannot be disposed in the 
container because it would result in a direct contact of them with the 
bicarbonate-containing powdery composition. 
Filling of the container with carbon dioxide gas can be carried out by any 
of the conventional methods. For example, when said wrapper is employed, 
the space between the wrapper and the plastic container can be filled with 
carbon dioxide gas or a mixture gas of carbon dioxide and nitrogen. When a 
container impermeable to moisture and gas is employed, the container may 
be filled with carbon dioxide gas or said mixture gas in the same manner. 
In either procedure, it is preferable to evacuate the air from the 
container beforehand, i.e. preceding said filling with carbon dioxide gas. 
The carbon dioxide gas-liberating deoxygenating agent which can be used in 
the present invention can be any substance having both deoxygenating and 
carbon dioxide gas-liberating activities but is preferably a substance 
which is capable of removing oxygen from said space and insuring a high 
output of carbon dioxide gas. Such deoxygenating agent includes those 
which contain, as the principal active ingredient, at least one member 
selected from the group consisting of iron powder; reducing inorganic 
salts such as dithionites, sulfites, ferrous salts, etc.; polyphenols such 
as hydroquinone, catechol, etc., reducing polyhydric alcohols such as 
ascorbic acid, erythorbic acid and their salts. The dithionites absorb 
oxygen in the presence of water and, at the same time, react with a 
bicarbonate or carbonate to yield carbon dioxide gas. The agents 
comprising sodium ascorbate and ferrous sulfate as main ingredients absorb 
oxygen and generate carbon dioxide gas in the presence of water. 
Commercial products among such carbon dioxide gas-liberating deoxygenating 
agents include Ageless G (registered trademark, Mitsubishi Gas Chemical) 
and Sendo-Hojizai (Keep-Fresh) Type C (Toppan Printing), among others. 
The desiccant saturated with carbon dioxide gas for use in the present 
invention includes silica gel, various aluminum silicates, crystalline 
hydrated alkali metal or alkaline earth metal aluminosilicates and 
zeolites which have been saturated with carbon dioxide gas by way of 
adsorption. To let said desiccant adsorb carbon dioxide gas to saturation, 
the desiccant is allowed to stand in a carbon dioxide atmosphere at room 
temperature or a lower temperature, preferably not higher than about 
15.degree. C., for several hours. For example, when the commercial product 
Zeolum (registered trademark) A4 (Tosoh), is subjected to the above 
procedure, the desired desiccant saturated with carbon dioxide gas is 
easily obtained. Zeolum (registered trademark) A3RG (Tosoh), which is 
comparatively low in carbon dioxide adsorption potential, can also be 
saturated with carbon dioxide gas in the same manner. When the desiccant 
saturated with carbon dioxide gas is disposed in the space between the 
plastic container and wrapper, carbon dioxide gas is liberated from the 
desiccant saturated with carbon dioxide gas so that a carbon dioxide 
atmosphere is established within the space. Moreover, since such desiccant 
has a high adsorptive affinity for water vapor than carbon dioxide gas, it 
adsorbs not only moisture and adherent water from the powdery 
pharmaceutical composition within the plastic container but, depending on 
conditions, the water which may be liberated by decomposition of the 
bicarbonate for some cause or other to release carbon dioxide gas so that 
the carbon dioxide partial pressure within the container is elevated to 
inhibit decomposition of the bicarbonate. 
It should be understood that when the relative humidity in the container is 
to be maintained at a level not exceeding 1% at 25.degree. C. in the 
present invention, zeolites having high dehydrating agents are preferably 
employed. 
In the present invention, a desiccant saturated with carbon dioxide gas and 
a deoxygenating agent which absorbs oxygen by way of oxidation reaction, 
such as said iron powder, dithionites, sulfites, ferrous salts, etc., can 
be used in combination. In this mode, when a moisture-containing 
self-reacting type deoxygenating agent (e.g. Ageless Z from Mitsubishi Gas 
Chemical) is used as said deoxygenating agent, the carbon dioxide 
concentration and moisture level within the container can be adequately 
maintained without causing degradation of the bicarbonate-containing 
powdery pharmaceutical composition. 
In the present invention, a carbon dioxide gas-liberating deoxygenating 
agent and a desiccant can be used in combination. In this mode, the use of 
a moisture-containing carbon dioxide gas-liberating deoxygenating agent is 
particularly preferred. Thus, when such a moisture-containing carbon 
dioxide gas-liberating deoxygenating agent is used in combination with a 
desiccant, the deoxygenating agent releases traces of water and the 
desiccant is prevented from adsorbing carbon dioxide gas owing to the 
preferential adsorption of such traces of water so that the carbon dioxide 
gas in the space is maintained at a suitable concentration level. The use 
of said carbon dioxide gas-liberating deoxygenating agent is also 
beneficial when the bicarbonate-containing powdery pharmaceutical 
composition is a composition susceptible to oxidative decomposition. 
Thus, in accordance with the present invention, the bicarbonate-containing 
powdery pharmaceutical composition can be preserved in a plastic container 
without aging and degradation and, at the same time, the object of 
addition of the bicarbonate can be accomplished without compromise.

In the view, (1) stands for a plastic wrapper, (2) for a plastic container, 
(3) for a bicarbonate-containing powdery pharmaceutical composition, and 
(4) for a carbon dioxide gas-liberating deoxygenating agent. 
BEST MODE OF PRACTICING THE INVENTION 
The following examples are intended to illustrate the invention in further 
detail. The materials used in the examples are referred to by the 
following abbreviations. 
______________________________________ 
L-LDPE Linear low-density polyethylene 
KPET Polyvinylidene chloride-coated 
polyethylene terephthalate 
PVDC Polyvinylidene chloride 
______________________________________ 
Example 1 
A bag (175 .mu.m thick, 50.times.50 mm) made of L-LDPE (density 0.920) was 
filled with 20 mg of sodium hydrogen carbonate and 100 mg of sodium 
chloride. Then, this filled bag and one piece of the carbon dioxide 
gas-liberating oxygenating agent (Ageless G15, Mitsubishi Gas Chemical) 
were placed in a laminate-film wrapping bag of KPET (15 .mu.m)/PVDC (25 
.mu.m)/L-LDPE (30 .mu.m) (sized 70.times.70 mm), followed by heat sealing 
to provide a container of the invention as illustrated in FIG. 1. This 
product is used for a carbon dioxide gas-liberating deoxygenating agent 
group. 
Similarly an L-LDPE bag containing said drugs was prepared and placed in 
the same wrapping bag as above. This was followed by filling with a 
mixture gas of 5%, 10% or 20% of carbon dioxide gas and the balance of air 
and the wrapping bag was heat-sealed. This was used for a carbon 
dioxide-filled group. As a control, the same L-DPE bag containing the 
drugs, not packaged in the wrapping bag, was tested. This was used for a 
control group. 
The samples in the above CO.sub.2 -liberating deoxygenating agent group, 
CO.sub.2 gas-filled group and control group were stored at 40.degree. C. 
and 75% RH. The samples immediately after manufacture and after storage 
periods of 1, 2 and 3 months were respectively dissolved in 100 ml of 
physiological saline and the pH of each solution was measured. The results 
are shown in Table 1. 
TABLE 1 
______________________________________ 
Storage at 40.degree. C. and 
Immediately 
75% RH 
after 1 2 3 
Sample groups manufacture 
Month Months 
Months 
______________________________________ 
CO.sub.2 gas-liberating 
8.02 8.05 8.02 8.03 
deoxygenator group 
CO.sub.2 gas-filled group 
CO.sub.2 concentration 5% 
8.02 8.05 8.07 8.04 
CO.sub.2 concentration 10% 
8.02 8.03 8.02 8.05 
CO.sub.2 concentration 20% 
8.04 8.03 8.05 8.02 
Control 8.03 8.23 8.47 8.69 
______________________________________ 
Each value is the mean of n = 3 
It is apparent from Table 1 that the solutions from the carbon 
dioxide-liberating deoxygenator group and carbon dioxide gas-filled group 
showed no pH elevation, indicating that the use of a carbon dioxide 
gas-liberating deoxygenating agent and the procedure of filling with 
carbon dioxide gas, both according to the invention, arrested 
decomposition of the bicarbonate in the plastic container. 
While a mixed powder of sodium hydrogen carbonate and sodium chloride was 
used as the bicarbonate-containing powdery pharmaceutical composition in 
this example, the method described in this example of the invention can be 
applied with advantage to any other powdery composition comprising a 
varying type of electrolyte other than sodium chloride in combination with 
sodium hydrogen carbonate, for example a powdered dialysate composition. 
Example 2 
A laminate film bag of KPET (15 .mu.m)/PVDC (25 .mu.m)/L-LDPE (30 .mu.m) 
(sized 90.times.90 mm) was filled with 20 mg of sodium hydrogen carbonate 
and 100 mg of sodium chloride. The bag was then filled with a mixture gas 
of 5%, 10% or 20% of carbon dioxide gas and the balance of air and 
heat-sealed to provide a package form of the invention. 
The above package form was stored at 40.degree. C./75% RH and samples 
immediately after manufacture and after storage periods of 1, 2 and 3 
months were respectively dissolved in 100 ml of physiological saline and 
the pH of each solution was measured. 
As a result, the solution from the above package form was as stable as that 
in the CO.sub.2 gas-filled group of Example 1. Moreover, the method and 
package form described in this example were suited for powdered dialysate 
compositions. 
Example 3 
Using a pharmaceutical composition (hereinafter referred to as Drug A) 
comprising one gram (potency) of a crystalline powder of cefalexin 
(hereinafter referred to as CEX), a cephem antibiotic, and 20 mg of sodium 
hydrogen carbonate, the following experiment was carried out. 
Thus, Drug A was filled into a glass vial (.o slashed.26 mm, Nichiden Rika 
Glass), stoppered with a butyl rubber stopper and clinched with an 
aluminum band (Sample 1, control). 
Then, Drug A was filled into a bag (175 .mu.m thick, 50.times.50 mm) made 
of L-LDPE (density 0.920) and the filled bag was placed in a laminate-film 
wrapping bag of KPET (15 .mu.m)/PVDC (50 .mu.m)/L-LDPE (50 .mu.m) (sized 
70.times.70 mm) and heat-sealed (Sample 2, comparative example). Samples 
were prepared in the same manner except that 6 g of silica gel (Fuji Gel 
Industry) was inserted before said heat-sealing (Sample 3, comparative 
example), 2 g of a zeolite (Zeolum A4, Tosoh) was placed before said 
heat-sealing (Sample 4, comparative example), 2 g of a zeolite (Zeolum 
A3RG, Tosoh) previously saturated with carbon dioxide gas was inserted 
(Sample 5, this invention), 2 g of a zeolite (Zeolum A3RG, Tosoh) and one 
piece of a CO.sub.2 gas-liberating deoxygenating agent (Ageless G20, 
Mitsubishi Gas Chemical) were inserted (Sample 6, this invention), and 2 g 
of a zeolite (Zeolum A4, Tosoh) and one piece of a CO.sub.2 gas-liberating 
deoxygenating agent were inserted (Ageless G20, ditto) (Sample 7, this 
invention). 
The above samples were stored at 40.degree. C. and 75% RH. 
In a preliminary experiment in which the respective samples were stored at 
40.degree. C. and 75% RH, elevations of pH were observed after 2 months of 
storage at 40.degree. C./75% RH. Based on this result, the samples prior 
to the beginning of storage and those after 3 months of storage were 
examined for the pH of Drug A (as dissolved in 100 ml of physiological 
saline), water content, potency (calculated on the anhydrous basis), 
carbon dioxide concentration in the bag, and appearance (color). 
The results are shown in Table 2. 
TABLE 2 
______________________________________ 
CO.sub.2 - 
liberating 
No. Container Desiccant deoxygenator 
______________________________________ 
1 Glass vial + -- -- 
rubber stopper 
2 Plastic bag + -- -- 
laminate film wrapper 
3 Plastic bag + Silica gel, 6 g 
-- 
laminate film wrapper 
4 Plastic bag + Zeolum A4, 2 g 
-- 
laminate film wrapper 
5 Plastic bag + Zeolum A3RG*, 2 g 
-- 
laminate film wrapper 
6 Plastic bag + Zeolum A3RG, 2 g 
Ageless G20 
laminate film wrapper 
7 Plastic bag + Zeolum A4, 2 g 
Ageless G20 
laminate film wrapper 
______________________________________ 
Before storage 
Potency of 
antibiotic 
Moisture (.mu.g CO.sub.2 con- 
content (potency)/ 
centration 
No. pH (%) mg) (ppm) Appearance 
______________________________________ 
1 7.24 4.35 994 291 White 
2 7.28 4.27 1018 275 White 
3 7.32 4.11 1001 230 White 
4 7.30 4.24 1031 0 White 
5 7.31 4.18 992 254 White 
6 7.26 4.20 1007 2825 White 
7 7.25 4.21 1012 0 White 
______________________________________ 
After 3 months of storage at 40.degree. C./75% RH 
Potency of 
antibiotic 
Moisture (.mu.g CO.sub.2 con- 
content (potency)/ 
centration 
No. pH (%) mg) (ppm) Appearance 
______________________________________ 
1 7.26 4.34 998 2141 White 
2 6.35 5.15 723 2180 Pale 
yellow 
3 7.80 4.15 1009 824 White 
4 8.02 4.18 1002 0 White 
5 7.43 4.14 1015 1521 White 
6 7.18 4.22 999 9891 White 
7 7.23 4.15 1002 7368 White 
______________________________________ 
Zeolum A3RG* in Sample No. 5 in Table 2 was previously saturated with 
carbon dioxide gas. 
Referring to the combination of an L-LDPE container and a laminate film 
wrapper, Sample 2 (comparative example) which contained neither of the 
desiccant and carbon dioxide gas-liberating deoxygenating agent was 
affected by external moisture to show a decrease in potency of the 
antibiotic and a change in appearance. The pH was also fairly depressed 
and it was considered attributable to decomposition products of CEX. 
Sample 3 (comparative example) which contained a silica gel having no high 
desiccating power showed no loss of potency or an increase in moisture 
content because CEX is not so hygroscopic. However, the pH of its solution 
showed an increase of about 0.5 from the value prior to storage. The cause 
of this increase is that because the desiccant adsorbed moisture, the 
sodium hydrogen carbonate was partially decomposed to sodium carbonate. 
Sample 4 (comparative example) in which Zeolum A4, a potent desiccant, was 
used, there was no decrease in potency but because of the marked 
adsorption of carbon dioxide gas on the desiccant, the pH exceeded 8 at 3 
months of storage, an increase of about 0.7. This result suggested that 
the use of a potent desiccant alone is not effective enough for the 
stabilization of powdery antibiotic products. 
On the other hand, Sample 5, Sample 6 and Sample 7 (all of the invention) 
showed findings comparable to those of Sample 1 (control) employing the 
glass vial which is the ordinary container for antibiotics, in potency, 
moisture level and pH. 
Sample 5, in which the low CO.sub.2 -adsorbing Zeolum A3RG was previously 
saturated with carbon dioxide gas, showed a lesser change of pH and no 
remarkable difference in carbon dioxide concentration as compared with 
Sample 1. 
On the other hand, Sample 6 and Sample 7, in which a CO.sub.2 -liberating 
deoxygenating agent was employed, showed somewhat higher CO.sub.2 
concentrations than Sample 1 and Sample 5 but no changes of significance 
in potency, moisture level and pH. 
Thus, the bicarbonate-containing pharmaceutical composition in a plastic 
container could be well maintained by means of a moisture- and 
gas-impermeable wrapper, a desiccant and a carbon dioxide gas-liberating 
deoxygenating agent without causing the aging and degradation of the 
active ingredient(s) and without inducing the formation of carbonate from 
bicarbonate. 
INDUSTRIAL APPLICABILITY 
The method of the present invention for stabilizing a 
bicarbonate-containing powdery pharmaceutical composition insures an 
increased carbon dioxide gas concentration in the container, prevents 
aging and degradation of the drug over a long period of time with great 
effectiveness and helps accomplish the objectives of incorporation of the 
bicarbonate, namely the supply of HCO.sub.3.sup.-, neutralization of the 
drug, and assistance in dissolution. 
Furthermore, the invention enables the supply of containers for such 
stabilized bicarbonate-containing powdery pharmaceutical compositions.