FR2740338A1 - Stable, liquid dobutamine compositions - Google Patents

Abstract

Stable, liquid pharmaceutical compositions comprise dobutamine (I) and ascorbic acid (II) or a salt to preserve stability.

Description

STABILIZED PHARMACEUTICAL COMPOSITIONS
CONTAINING DOBUTAMINE
The present invention relates to novel liquid formulations based on dobutamine.

It is known, according to the article by Bishara RH and Long HB Dobutamine hydrochloride published in Analytical Profiles of Drug Substances, Academic
Press (1979), Vol. 8, pp. 139-158, that solutions of dobutamine in water are not stable on the one hand during sterilization by heat and on the other hand during their preservation.

 The degradation of dobutamine appears in the form of a pink color that gradually changes to gray and may even result in a precipitate. Degradation products are derivatives that are not currently identified. Only the color of the solution can detect their presence.

To solve this problem, it has long been known to stabilize said solutions by adding sulfite. Thus dobutamine is currently marketed in ready-to-use liquid solution according to the following composition:
e dobutamine HCl 280.2 mg
sodium metabisulphite 4.5 mg
HCl or NaOH qsp pH 4.0
water qs 20 ml
These solutions are then packaged under nitrogen to prevent oxidation of dobutamine as much as possible during storage.

 It is known that sulphites pose problems of pharmacovigilance and toxicity in humans.

 The pharmaceutical industry has therefore long sought to prepare ready-to-use dobutamine solutions having sufficient stability criteria to allow the sterilization of said solutions by heat and / or their preservation for periods of several months but free of sulphites. .

 The present invention has achieved this objective and relates to liquid pharmaceutical compositions containing dobutamine and ascorbic acid or a derivative thereof in an amount sufficient to maintain its stability.

 The liquid pharmaceutical composition is preferably an aqueous injectable composition. The preferred ascorbic acid derivative which is used in these compositions is sodium ascorbate.

 The amount of ascorbic acid or ascorbic acid derivative which is used by weight is preferably greater than 1% relative to dobutamine and even more preferably between 1.5 and 90%. It is obvious that higher amounts could be used since this derivative is not toxic to humans, but since ascorbic acid or its derivative is used to stabilize dobutamine, sufficient amounts to maintain stability are preferred.

 Thus, even more limited weight quantities of 2 and 20% ascorbic acid or one of its derivatives per 100 g of dobutamine are sufficient to achieve this objective, it is most particularly preferred to use weight amounts of between 3, 5 and 10%.

 Since dobutamine and ascorbic acid or its derivative have variable stabilities with the nature of the pH, it is recommended to maintain the pH of the solution in acid form. Thus, a pH of said solution of between 4 and 7 is preferred. Below pH 4, the solutions are difficult to use for injectable use. Above pH 7, dobutamine is not stable. It is thus clearly expressed in the preparation conditions as described for example in the VIDAL dictionary not to mix dobutamine solutions with 5% sodium bicarbonate solutions or strongly alkaline solutions.

 The preferred solutions according to the invention will be set at a pH in the region of 5.5. In the case where the pH is set at around 5.5 weight quantities of sodium ascorbate calculated relative to dobutamine of between 1 and 3% are sufficient to stabilize the dobutamine during sterilization. It is thus advantageous to add to the solution of dobutamine and ascorbic acid or a derivative thereof a pH stabilizing agent such as sodium monoacid phosphate.

 The composition thus prepared can be sterilized by heat treatment, for example at 1200C for a few minutes or by sterilizing filtration.

The preferred composition according to the invention has the composition
next:
dobutamine hydrochloride 280.2 mg
Na2HPO4 150mg
Sodium ascorbate 25 mg
HCI IN qsp pH 5.5
water qs 20 ml
1 COMPARATIVE TRIAL
Protocol
The first test was carried out with a composition identical to that of DobutrexX but without sulfite:
Dobutamine, HCI 280.2 mg
HCI or NaOH QSP pH 4.0
water for injection. QSP20 ml
nitrogen QS

Results:
The product degrades with heat. A gray precipitate is formed during sterilization.

2nd COMPARATIVE TRIAL
Protocol:
The composition is identical to that of DobutrexE but without sulfite; the solution is sterilized by filtration.

Dobutamine, HCI 280.2 mg
HCI or NaOH QSP pH 4.0
water for injection QSP20 ml
nitrogen QS

Results:
The product is not stable. Just after manufacture, the content of dobutamine, HCl is 268 mg / 20 ml for a lower limit of 266 mg / 20 ml. After 1 month of storage at room temperature, a pink color or a gray precipitate appears.

8th TEST
Goal:
Make a solution with sulfite, sterilized by filtration or by heat.

Protocol:
The composition is identical to that of Dobutrex:
Dobutamine, HCI 280.2 mg
Sodium metabisulfite 4.5 mg
HCI or NaOH QSP pH 4.0
water for injection QSP20 ml
nitrogen QS

 Part of the batch was autoclaved at 121 ° C for 20 minutes (277 flasks) to give batch A. The other non-autoclaved portion (592 flasks) was batch B. Batches were stored at 250C, 40 "C and 50" C.

Results
After manufacture, lot A has a slight pale yellow color.

Both lots are not stable; sulphites are consumed during manufacturing and storage, as shown by the values presented in the table below.

<tb><SEP> PRODUCT <SEP> TIME / <SEP> PERCENT
<tb><SEP> TEMPERATURE <SEP> FROM <SEP> SO2
<tb><SEP> Dobutrex- <SEP> Lot <SEP> 2.56
<tb> commercial
<tb><SEP> Test <SEP> A <SEP> Time <SEP> 0 <SEP> 1.16
<tb><SEP> 1 <SEP> months / 25 C <SEP> 0.49
<tb><SEP> 1 <SEP> months / 40 C <SEP> 0.00
<tb><SEP> 1 <SEP> month / 50 C <SEP> 0.00
<tb><SEP> Test <SEP> B <SEP> Time <SEP> 0 <SEP> 1.60
<tb><SEP> 1 <SEP> month / 25 "C <SEP> 0.70 <SEP>
<tb><SEP> 1 <SEP> months <SEP> 0.40
<tb><SEP> 1 <SEP> months <SEP> 0.00
<Tb>

For both batches, after 3 months of storage at 25 ° C., the solutions have a pink color or a gray precipitate.
Dobutamine, however, remains within + 5 percent of the theoretical value.

1 "TEST ACCORDING TO THE INVENTION
Solutions with sodium ascorbate by varying the pH.

Protocol:
The solution is prepared by adding an amount of sodium ascorbate (19 ml of 0.05-0.10 or 0.15 percent solution per 20 ml of finished product) and varying the pH (3 , 5 - 4.0 or 4.5). There is no sulphite.

 The solutions are prepared under nitrogen and autoclaved at 121 ° C / 20 minutes.

 The solutions are analyzed after sterilization and are stored at 50 ° C.

Results:
Immediately after sterilization nar the heat:
there is no degradation of dobutamine to heat,
the chromatographic profile reveals secondary peaks whose importance increases with the amount of ascorbate provided, for the same pH value. The importance of these peaks decreases from pH 3.5 to 4.5,
the yellow color increases with the amount of ascorbate added, for the same pH. This coloration decreases from pH 3.5 to 4.5.

After 1 month and a half at 50 C:
The values are grouped in the table below.

<Tb>

Concentration <SEP><SEP> Dobutamine <SEP>% <SEP> of <SEP> peaks <SEP>
<tb><SEP> ascorbate <SEP> Initial pH <SEP><SEP> Absorbance <SEP> (% <SEP> of <SEP> the <SEP> secondary
<tb><SEP> in <SEP><SEP> to <SEP> 308 <SEP> nm * <SEP> initial <SEP> value <SEP>(<SEP> report)
<tb> solution <SEP> final <SEP> surfaces)
<tb><SEP> 0.1425 <SEP>% <SEP> 3.5 <SEQ> 2.6910 <SEP> 98 <SEQ> 4.68
<tb><SEP> 4.0 <SEP> 1.1669 <SEP> 100 <SEP> 2.47
<tb><SEP> 4.5 <SEP> 0.6230 <SEQ> 102 <SEP> 0.43
<tb><SEP> 0.095 <SEP>% <SEP> 3.5 <SEP> 2.4669 <SEP> 98 <SEP> 2.44
<tb><SEP> 4.0 <SEP> 0.9400 <SEP> 99 <SEP> 1.36
<tb><SEP> 4.5 <SEP> 0.8960 <SEP> 96 <SEP> 0.78
<tb><SEP> 0.0475 <SEP>% <SEP> 3.5 <SEP> Disorder <SEP> 103 <SEP> 2.29
<tb><SEP> 4.0 <SEP> Disorder <SEP> 103 <SEP> 0.93
<tb><SEP> 4.5 <SEP> Disorder <SEP> 103 <SEP> 0.24
<tb> * of the solution against the non-autoclaved solution.

Solutions made with 0.0475 percent ascorbate are not stable. PH 4.5 gives the best results. With this pH, the coloration and the secondary peaks are the weakest
2G TEST ACCORDING TO THE INVENTION
The variation in the amount of ascorbate added was studied at a pH of 4.5.

 Solutions are prepared with the following sodium ascorbate concentrations: 45; 54; 63; 72; 81; 90; 135; 271 mg per 100 ml of final solution from 19 ml of sodium ascrobate solutions at the following concentrations: 48; 57; 67; 76; 86; 95; 142; 285 mg per 100 ml which are supplemented to 20 ml.

 The solutions are prepared under nitrogen and autoclaved at 120 ° C / 20 minutes.

Solutions are analyzed after sterilization.

<Tb>

concentration <SEP> in <SEP> pH <SEP> after <SEP> Absorbance <SEP> content <SEP> in <SEP> sum <SEP> of
<tb> ascorbate <SEP> in <SEP> sterilization <SEP> to <SEP> 308 <SEP> nm * <SEP> dobutamine <SEP> peaks
<tb><SEP> 0.045 <SEP> 4.9 <SEP> 0.618 <SEP> 1.43 <SEP> 0.98
<tb><SEP> 0.054 <SEP> 4.9 <SEP> 0.471 <SEP> 1.46 <SEP> 0.63
<tb><SEP> 0.063 <SEP> 4.7 <SEP> 0.584 <SEP> 1.47 <SEP> 0.74
<tb><SEP> 0.072 <SEP> 4.7 <SEP> 0.569 <SE> 1.47 <SEP> 0.70
<tb><SEP> 0.081 <SEP> 4.7 <SEP> 0.594 <SEP> 1.46 <SEP> 0.72
<tb><SEP> 0.090 <SEP> 4.7 <SEP> 0.710 <SEP> 1.48 <SEP> 0.92
<tb><SEP> 0.135 <SEP> 4.6 <SEP> 0.804 <SEP> 1.50 <SEP> 0.95
<tb><SEP> 0,271 <SEP> 4,6 <SEP> 1,136 <SEP> 1,44 <SEP> 1,46
<Tb>
The minimum concentration of sodium ascorbate at pH 4.5 that protects dobutamine is approximately 54 mg / 100 ml which corresponds to a weight ratio relative to dobutamine of approximately 3.8%.

 Unsterilized and air-maintained solutions are pink in 24 hours, except for ascorbate concentrations of 135 and 271 mg / 100 ml. The concentration of 135 mg / 100 ml is the minimum concentration that protects dobutamine for 24 hours after opening the vial, the solution remaining in the open air. This concentration corresponds to a weight ratio relative to dobutamine of 9.6%.

3rd TRIAL ACCORDING TO THE INVENTION
Goal:
Optimize stability by varying the pH
Protocol:
The solutions are all manufactured with a sodium ascorbate concentration per 100 ml of 0.135% solution.

 The pH is adjusted to 4.5 - 5.0 - 5.5 - 6.0 - 6.5 - 7.0 with hydrochloric acid.

 There is no sulphite.

 The manufacturing is done under nitrogen.

 The vials are sterilized at 120 ° C / 20 minutes.

Results:
Immediately after sterilization by heat:
dobutamine is stable to heat,
staining decreases from pH 4.5 to 5.5 and then increases
with the pH.

secondary peaks (from ascorbate) decrease from pH 4.5 to
5.5.

<tb> pH <SEP> initial <SEP> Absorbance <SEP> to <SEP> Dobutamine, <SEP> HCI <SEP> Sum <SEP> of <SEP> peaks
<tb><SEP> 308 <SEP> nm * <SEP> (g / 100ml) <SEP> secondary
<tb><SEP> 4.5 <SEP> 0.823 <SEP> 1.46 <SEP> 1.19
<tb><SEP> 5.0 <SEP> 0.691 <SEP> 1.44 <SEP> 0.56
<tb><SEP> 5.5 <SEP> 0.644 <SEP> 1.45 <SEP> 0.37
<tb><SEP> 6.0 <SEP> 0.741 <SEP> 1.45 <SEP> 0.35
<tb><SEP> 6.5 <SEP> 0.762 <SEP> 1.43 <SEP> 0.36
<tb><SEP> 7.0 <SEP> 0.895 <SEP> 1.51 <SEP> 0.33
<Tb>

* diluted 1/2 solution against water
Minimal absorbance of the solution is obtained with a pH of 5.5. The dobutamine content is not affected by the pH change in the range studied.

After one month at 50 "C
dobutamine is stable,
secondary peaks (from ascorbate) decrease by
pH 4.5 to 5.5. At pH 5.5 their sum is 0.11 percent.

<Tb>

<SEP> Dobutamine <SEP> Percentage <SEP> of <SEP> Absorbance <SEP> to
<tb> Initial pH <SEP><SEP>(<SEP> percentage of <SEP> secondary <SEP> peaks <SEP> 308 <SEP> nm *
<tb><SEP> the <SEP> initial <SEP> content
<tb><SEP> 4.5 <SEP> 100 <SEP> 0.97 <SEP> 1.033
<tb><SEP> 5.0 <SEP> 100 <SEP> 0.32 <SEP> 0.572
<tb><SEP> 5.5 <SEP> 99 <SEP> 0.11 <SEP> 0.313
<tb> * diluted 1/2 solution against water.

4th TRIAL ACCORDING TO THE INVENTION
Aim: to optimize the minimum amount of sodium ascorbate as a function of pH.

Operating procedure

<tb> dobutamine, <SEP> HCl <SEP> 1.4 <SEP> 1.4 <SEP> 1.4 <SEP> 1.4 <SEP> 1.4 <SEP> 1.4 <SEP> 1, 4 <SEP> 1.4
<tb> Ascorbate <SEP> of <SEP> Na <SEP> 95 <SEP> ml <SEP> 95 <SEP> ml
<tb> (0.0480 <SEP> g / 100 <SEP> ml) <SEP>
<tb> Ascorbate <SEP> of <SEP> Na <SEP> 95 <SEP> ml <SEP> 95 <SEP> ml <SEP>
<tb> (0.0383g / 100 <SEP> ml) <SEP>
<tb> Ascorbate <SEP> of <SEP> Na <SEP> 95 <SEP> ml <SEP> 95 <SEP> ml
<tb> (0.0292 <SEP> 9/100 <SEP> ml)
<tb> Ascorbate <SEP> of <SEP> Na <SEP> 95 <SEP> ml <SEP> 95 <SEP> ml <SEP>
<tb> (0.0106 <SEP> g / 100 <SEP> ml) <SEP>
<tb><SEP> HCl <SEP> 0.1 <SEP> N <SEP> or <SEP> pH5.5 <SEP> pH6.5 <SEP> pH5.5 <SEP> pH6.5 <SEP> pH5, <SEP> pH 6.5 <SEP> pH 5.5 <SEP> pH 6.5
<tb> NaOH <SEP> 0, <SEP> QSP
<tb><SEP> H20 <SEP> QSP <SEP> 100ml <SEP> 100ml <SEP> 100ml <SEP> 100ml <SEP> 100ml <SEP> 100ml <SEP> 100ml <SEP> 100ml <SEP>
<tb> Prenarations sterilized under nitrogen 120 C / 20 min
Results

<tb> Concentration <SEP> pH <SEP> before <SEP> pH <SEP> after <SEP> Absorbance <SEP> content <SEP> in <SEP> Sum <SEP> of
<tb> in <SEP> ascorbate
<tb><SEP> of <SEP> Sodium <SEP> HCl <SEP> Secondary
<tb><SEP> (g / 100 <SEP> ml)
<tb><SEP> 0.0456 <SEP> 5.5 <SEP> 5.9 <SEP> 0.383 <SEP> 1.4 <SEP> 0.06
<tb><SEP> 6.5 <SEP> 6.4 <SEP> 0.405 <SEP> 1.4 <SEP> 0.03
<tb><SEP> 0.0364 <SEP> 5.5 <SEP> 5.8 <SEP> 0.326 <SEP> 0.04
<tb><SEP> 6.5 <SEP> 6.3 <SEW> 0.355 <SEP> Not <SEP> of <SEP> 0.03
<tb><SEP> 0.0277 <SEP> 5.5 <SEP> 5.7 <SEP> 0.238 <SEP> variation <SEP> 0.05
<Tb>

<tb><SEP> 6.5 <SEP> 6.3 <SEP> 0.317 <SEP> significant <SEP> 0.02
<tb> 0.0101 <SEP> 5.5 <SEP> 5.8 <SEP> 0.252 <SEP> 0.02
<tb><SEP> 6.5 <SEP> 6.4 <SEP> 0.340 <SEP> 0.03
<tb><SEP> 0 <SEP> 5.5 <SEP> 3.99 <SEP> 0.635 <SEP> no <SEP> determined
<tb><SEP> 6.5 <SEP> 6.21 <SEP> 0.909
<tb> * diluted solution half against water
5th TEST ACCORDING TO THE INVENTION
Goal:
Stabilize the pH.

Protocol:
Taking into account the results obtained in the test 3 according to the invention, a pH value of 5.5 is retained. To stabilize the pH, disodium phosphate is added. The optimum amount is determined by judging the buffering effect of solutions at various concentrations of disodium phosphate.

Results:
The buffering effect is maximum at a concentration of 150 mg / 20 ml
6th TEST ACCORDING TO THE INVENTION
Goal:
Predict the importance of secondary peak formation during storage by increasing the ascorbate content. It can be envisaged that the less concentrated solutions will have secondary peaks in the long term, the importance of which will be at most equal to that determined during this test.

Protocol:
The solution is prepared according to the following formulation:
Dobutamine, HCI 280.2 mg
NaHPO4.2H20 150mg
Sodium ascorbate 250 mg (weight / dobutamine ratio = 89%)
HCI 1 N QSP pH 5.5
Water for injection QSP 20 ml
nitrogen QS

 The ascorbate is brought to a concentration approximately 10 times higher than that selected for test 3. The solution is kept at 25 ° C. and 40 ° C. for 6 months.

Some of the solutions have been sterilized by heat:
121 "C / 20 minutes
124 "C / 10 minutes
125 "C / 8 minutes
126 "C / 6 minutes
Results:
All heat sterilized solutions are yellow but the dobutamine content remains unchanged.

For non autoclaved solutions:
dobutamine is stable at 25 ° C but decreases at 40 ° C,
Ascorbic acid is stable at 25 C but decreases to 40 C
the disodium phosphate makes it possible to stabilize the pH,
the color increases only at 40 ° C,
after 6 months secondary peaks (from ascorbate)
account for 0.79 percent at 25 C and 2.14 percent at 4000.

The results after 6 months of storage are summarized in the table below.

<tb><SEP> Dobutamine <SEP>% <SEP> of <SEP> peaks <SEP> Content <SEP> in <SEP> Absorbance
<tb> Temperature <SEP> pH <SEP> (% <SEP> content <SEP> secondary <SEP> ascorbate <SEP> to <SEP> 308 <SEP> nm *
<tb><SEP> initial) <SEP> (%)
<tb><SEP> 25 "C <SEP> 5.5 <SEP> 100 <SEP> 0.79 <SEP> 1.13 <SEP> 2.53
<tb><SEP> 40 "C <SEP> 5.7 <SEP> 100 <SEP> 2.14 <SEP> 0.98 <SEP> 2.99
<Tb>

* diluted 1/2 solution against water
The following wording can be used:
Dobutamine, HCI 280.2 mg
NaHPO4.2H20 150mg
Sodium ascorbate 27 mg
HCI 1 N QSP pH 5.5
Water for injection QSP 20 ml
nitrogen QS

 Immediately prior to sterilization the absorbance of the solution (half dilution against water) at 308 nm is 0.54. After sterilization it is 0.64. This low increase shows the good stability of the preparation to heat. It is however possible to dispense with sterilization by heat, in favor of a preparation in aseptic conditions with double sterilizing filtration.

Claims (6)

 1 - Liquid and stable pharmaceutical compositions containing dobutamine and ascorbic acid or a derivative thereof in an amount sufficient to preserve its stability.  2- pharmaceutical compositions according to claim 1 characterized in that the amount of ascorbic acid used relative to dobutamine is greater than 1% by weight.  3- pharmaceutical compositions according to claim 2 characterized in that the amount of ascorbic acid used relative to dobutamine is between 1.5 and 90% by weight and preferably between 2 and 20% by weight and even more preferably between 3.5 and 10%.  4- Pharmaceutical compositions according to any one of the preceding claims characterized in that the pH of the solution is adjusted between 4 and 7 and preferably about 5.5.  5 - Compositions according to claim 4 characterized in that, when the amount of ascorbic acid used relative to dobutamine is between 1 and 3% by weight, the pH is set at about 5.5.  6. Pharmaceutical compositions according to any one of the preceding claims, corresponding to the following formula:  Dobutamine hydrochloride 280.2 mg  Na2HPO4 150mg  Sodium ascorbate 27 mg  HCI IN q.s.p pH 5.5  water q.s.p 20 ml