Title: Water soluble powder form compositions and their applications thereof
United States Patent: 5,935,603
Inventors: Derrieu; Guy (Cagnes-sur-Mer, FR); Pougnas; Jean-Luc (Saint Laurent du Var, FR); Broussaud; Olivier (Nice, FR)
Assignee: Virbac SA (Carros, FR)Appl. No.: 945246
Filed: December 22, 1997Water soluble, powder form compositions suitable for completely and rapidly dissolving active ingredients which usually only dissolve in water in the presence of base salts, such as antibiotics of the betalactamide family, for example penicillins and their derivatives, cephalosporins and their derivatives, or other active ingredients such as sulphamides and quinolones, for oral absorption thereof and their applications. The water soluble powder form compositions contain, in combination and in powder form, at least one water soluble active ingredient, not in salt form, and with an exclusively alkaline pH, an excess of one or more strong base salts, and one or more buffers comprising one or more substances and capable of maintaining the pH of the medium at a level below the normal solubilization pH of said active ingredient. Aqueous solution compositions obtained from said powder form compositions are also described.
Example 1 of the Patent
Soluble
Composition Containing 10 Percent Amoxicillin (Composition A)
1) Preparation of a pulverulent composition according to the
invention:
Amoxicillin (in trihydrate form) (10 g, that is 27.4 mmol) is
mixed mechanically with anhydrous sodium carbonate (3 g, that is
28.3 mmol), monosodium phosphate dihydrate (13 g), disodium
phosphate (1 g) and anhydrous glucose, which is a soluble filler
which enables the concentrations to be adjusted so as to obtain a
composition containing 10% (w/w) of active ingredient (71.2 g)
(=composition A).
2) Preparation of the aqueous solution:
40 g of composition A are dissolved in 1000 ml of tap water.
3) Study comparing the properties of the compositions according to
the invention with those of compositions of the prior art:
a) Solubility test.
The speeds at which composition A, described above, and sodium
amoxicillin dissolved were compared:
The same quantities of amoxicillin, that is:
(1) 40 g of composition A, equivalent to 4 g of amoxicillin (in
trihydrate form), and
(2) 4 g of amoxicillin (in sodium form), were dissolved in 1000 ml
of tap water; the time for dissolution and the pH of each of the
solutions obtained were noted.
______________________________________
Product Time for dissolution
Final pH
______________________________________
(1) Composition A
45 sec 7.7
(40 g)
(2) Amoxicillin 42 sec 8.7
(Na) (4 g)
______________________________________
The solubility of composition
A is comparable to that of the sodium salt of amoxicillin, which
is the most soluble form of this antibiotic. The fact should be
noted that, even if the speeds of dissolution are equivalent, the
pH values of the solutions obtained were different.b) Role of each constituent of the composition: study of the appearance of the solution or suspension obtained, of its solubility and of its pH.
The same quantities of amoxicillin (in trihydrate form), that is 4 g, were added to solutions consisting of:
in the first case: sodium carbonate (3 g) and water (1000 ml);
in the second case: monosodium phosphate dihydrate (13 g), disodium phosphate (1 g) and water (1000 ml), and
in the third case: sodium carbonate (3 g), monosodium phosphate dihydrate (13 g), disodium phosphate (1 g) and water (1000 ml), equivalent to the salt of a strong base/buffer combination which is used in composition A. The appearance, the time for dissolution and the pH of each of the solutions obtained were noted.
______________________________________
Appearance
of the Time for
Solvent solution dissolution
Final pH
______________________________________
1st solvent
Solution 45 sec. 8.5
Na carbonate
2nd solvent
Presence of Not 6.5
buffer insoluble determined
material
3rd solvent
Solution 45 sec. 7.6
Na carbonate
and buffer
______________________________________
c) Study comparing the stability of amoxicillin (in trihydrate form) which is employed in composition A, of amoxicillin (in trihydrate form) which is combined solely with a salt of a strong base, and of sodium amoxicillin.
c-1 "normally used solution" assay:
The same quantities of amoxicillin, that is:
(1) 0.8 g of composition A (that is 80 mg of amoxicillin (in trihydrate form)),
(2) 80 mg of amoxicillin (in trihydrate form) combined with 24 mg of sodium carbonate, and
(3) 80 mg of amoxicillin (in sodium form) were dissolved in 1000 ml of tap water (effective dose required for treating poultry).
______________________________________
Content of amoxicillin in
solution at time (in hours)
Product pH t0 t4 t12 t24 t36
______________________________________
(1) Composition A
(0.8 g) 7.6 100.5 99.2 100.8 101.0 98.7
(2) Amoxicillin 9.2 100.1 87.8 66.2 -- --
(3H.sub.2 O) (80 mg)
Na carbonate (24 mg)
(3) Amoxiciliin 8.7 100.0 92.1 75.4 -- --
(Na) (80 mg)
______________________________________
Composition A, to which the
present invention relates, leads, in solution, to the amoxicillin
being stable, over a period of more than 36 hours, when compared
with sodium amoxicillin, on the one hand, and with amoxicillin
trihydrate which is combined with an inorganic sodium salt
(equivalent to the salt employed in composition A), on the other
hand. Unexpectedly, solubilization at a non-alkaline pH does
indeed improve stability significantly; consequently, the pH
values are one of the keys to the instability or stability of the
aqueous compositions which are obtained.c-2 "concentrated solution" assay:
The same quantities of amoxicillin, that is:
(1) 40 g of composition A (that is 4 g of amoxicillin (in trihydrate form)),
(2) 4 g of amoxicillin (in trihydrate form) combined with 1.2 g of sodium carbonate, and
(3) 4 g of amoxicillin (in sodium form), were separately dissolved in 1000 ml of tap water (concentration employed in order to achieve a preliminary solubilization before diluting for use).
______________________________________
Content of amoxicillin in
solution in % at time (in
hours)
Product pH t0 t4 t12 t24
__________________________________
(1) Composition A
(40 g) 7.7 100.2 99.2 98.3 97.1
(2) Amoxicillin
(3H2 O) 9.4 100.2 80.3 -- --
(4 g)
Na carbonate
(1.2 g)
(3) Amoxicillin
(Na) 8.7 100.0 87.2 -- --
(4 g)
______________________________________
In the same way as in the
preceding paragraph (c-1), the stability of the amoxicillin in a
composition according to the invention is found to be superior, in
solution, to that of sodium amoxicillin and of amoxicillin
trihydrate which is combined with sodium carbonate. In view of the
high content of active ingredient in the concentrated solutions,
the experiment records a shorter period of stability, i.e. 12
hours instead of the 36 hours for the composition A-based solution
described in paragraph c-1. This time is ample for preparing
solutions which are of therapeutic value and which are stable in
solution for more than 24 hours.d) Stability over time
The stabilities, at ambient temperature (25.degree. C.), of composition A, of amoxicillin trihydrate, of a composition A', equivalent to composition A without the buffer, that is 10 g of amoxicillin (in trihydrate form) together with 3 g of anhydrous sodium carbonate and anhydrous glucose (85.2 g), and of sodium amoxicillin, which compounds and compositions were packaged in the sachets which are normally employed for this type of speciality, were studied over a period of 24 months.
______________________________________
Content of amoxicillin in % at
time (in months)
Product t0 t6 t12 t24
______________________________________
Composition A 100.5 99.6 100.2 98.9
Amoxicillin (3H2O)
100.0 99.2 99.6 98.5
Composition A'
99.8 98.8 97.8 93.7
Amoxicillin Na
100.0 97.3 94.8 90.2
______________________________________
The stability of the
amoxicillin which is in the pulverulent state and which is
included in composition A is comparable to that of the active
material on its own, i.e. amoxicillin trihydrate, which is the
reference.By contrast, amoxicillin trihydrate which is combined solely with the solubilizer, i.e. sodium carbonate, exhibits instability beyond 12 months, with this instability appearing at 6 months in the case of sodium amoxicillin, which is the salified soluble form.
Claim 1 of 10 Claims
1. Pulverulent,
water-soluble compositions, comprising, in combination and in
pulverulent form:
at least one non-salified active ingredient which is only soluble
in water at alkaline pH,
at least one salt of a strong base, which is present in excess,
and
at least one buffer, which is formed from one or more substances
which are suitable for maintaining the pH of the medium at a value
which is lower than the normal pH for solubilizing the said active
ingredient.
____________________________________________
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