AP998A - Stabilised pharmaceutical compositions, with quinupristine and dalfopristine base and their preparation. - Google Patents

Abstract

A stabilised pharmaceutical composition comprisi quinupristine of the formula and dalfopristine of the formula: wherein the composition further comprises an at.least stoichimetric amount of methanesulphonic acid.,or hydrochloric acid and has a pH in the range 3.5 to 5. The coraposition is prepared by a process which comprises simultaneously or successively dissolving the quinupristine, dalfopristine and said acid in water and adjusting the pH.

Description

STABILIZED PHARMACEUTICAL COMPOSITIONS BASED ON

QUINUPRISTINE AND ON DALFOPRISTINE AND THEIR

PREPARATION

The present invention relates to stabilized 5 pharmaceutical. compositions intended for the parenteral administration of quinupristine and of dalfopristine components of Synercid®.

A description has been given in Patent Application EP 248,703 of pristinamycin I derivatives of general formula:

AP/F/ 99/01530

and of their combinations with pristinamycin II derivatives of structure:

AP 00998

Quinupristine, a derivative of pristinamycin I, and dalfopristine, a derivative of pristinamycin II, are the components of Synercid®:

dalfopristine β £ 9 I 0. β ΰ ,ΰ/dV

Synercid® (quinupristine/dalfopristine) is an injectable 30/70 combination, the antibacterial activity of which, in particular, with respect to vancomycin-resistant germs, is cited in numerous publications [The Annals of Pharmacotherapy, 29., 102210 1026 (1995); Microbial Drug resistance, 1, 223-234 (1995)] .

The solubilization of the isolated components quinupristine or dalfopristine can be obtained in the

AP 00998 salt state.

However, the fact of having to dissolve a combination poses numerous problems, in particular the problem of finding a salifying agent capable of being suitable for each of the components. Moreover, it is necessary to make sure that the pharmaceutical composition exhibits a stability such that the dosage of active principle initially fixed is constant during the lifetime of the medicament. The constitution of stabilized pharmaceutical compositions comprising the quinupristine/dalfopristine combination, the stability of solutions and/or of lyophilisates prepared from solutions, have posed serious problems of preparation which can bring into question the possibility of using them to make a medicament which can be stored and thus marketed. This is due in particular to the significant appearance of degradation impurities.

It has now been found that it is possible to J stabilize pharmaceutical compositions comprising the quinupristine/dalfopristine combination by use of at least stoichiometric amounts of methanesulphonic acid or of hydrochloric acid, at a pH within the range [3.5 ; 5]. Thus, solutions based on methanesulphonic or hydrochloric acid having a pH in the range [3.5 ; 5] are sufficiently stable for the production of an industrial preparation and result, depending on the situation, in lyophilisates, in reconstituted solutions after lyophilization and/or in frozen solutions which

AP/F/ 9 9 / 0 1 5 30

AP 00998 are stable and thus storable with a view to marketing and/or a therapeutic use.

The stabilized pharmaceutical compositions according to the invention are in particular aqueous solutions comprising:

dalfopristine and quinupristine; methanesulphonic or hydrochloric acid, in an at least stoichiometric amount with respect to the sum of the 10 dalfopristine and of the quinupristine introduced;

if necessary, an.excess of methanesulphonic or hydrochloric acid intended to adjust the pH of the solution thus formed in the range [3.5 ; 5] ;

optionally, an isotonizing agent and/or other pharmaceutically acceptable adjuvants;

- an amount of water suitable for adjusting the concentration of the solution.

The solutions thus obtained exhibit the advantage of being stabilized.

According to another aspect of the invention, they can be lyophilized by application of the usual techniques, after lowering the temperature and removing the water. They can be taken up again in water at the

AP 00998 time of injection. According to yet another aspect of the invention, they can also be frozen.

When the composition obtained is lyophilized, the latter can be taken up in solution again at the time of use in any compatible and pharmaceutically acceptable injectable medium. The lyophilisate can advantageously be taken up again, for example, in water for injectable preparations or in infusion solutions (glucose solution or sodium chloride, in particular).

When the solution has been frozen (frozen bag, for example), it can be defrosted at the time of use. In another alternative, the lyophilisates can also be taken up again in dilute solution (preferably containing less than 20 mg/ml of active principle), the said solution being stored until the time of use.

It is understood that the present invention can also be applied to other soluble pristinamycin derivatives. For example, it can also be applied to derivatives as described in European Patents EP

133,097, EP 135,410, EP 191,662 and EP 248,703.

The stabilized pharmaceutical compositions according to the invention preferably contain concentrations of quinupristine/dalfopristine active principle of between 5 and 250 mg/ml or, in the case of a lyophilisate, in proportions of between 5 and 95%, a proportion of 20 to 90% being more preferred. It is clearly understood that stabilized pharmaceutical compositions of lower concentration can also be

AP/P/ 99/01530

AP 00998 produced and clinically used; these solutions also come within the scope of the present invention.

The amount of acid depends on the amount of dalfopristine and quinupristine. It is determined so as to have at least stoichiometric proportions and in such a way as to obtain solutions for which the pH is within the range [3.5,-5].

According to a preferred aspect of the invention, the pH of the starting solution is fixed in a range of [3.5 ; 4.5], preferably 3.5.

According to another preferred aspect of the invention, in the case of a lyophilized composition, the pH of the solution to be lyophilized is fixed in a range of [4.5 ; 5].

When the stabilized pharmaceutical compositions according to the invention contain a pharmaceutically acceptable adjuvant, the latter can be chosen, for example, from cosolvents, stabilizers,

') cryoprotective agents, desiccating agents, fillers and isotonizing agents.

Without implied limitation, the cosolvents and the solubilizing agents can be chosen from polyethylene glycols (polyethylene glycols 300 and 400), propylene glycol, ethanol and surface-active agents, such as, for example, polysorbate 80 or polyoxyethylenated derivatives (cremophors); the fillers and the cryoprotective agents can in particular be chosen from simple sugars (for example glucose,

AP/P/99/0 1 53 0

AP 00998 mannitol, fructose or sorbitol), disaccharides (for example sucrose, lactose, trehalose or maltose) or water-soluble polymers (for example dextrans, carboxymethylcellulose, polyvinylpyrrolidone or gelatin); the stabilizing agents can in particular be chosen from antioxidizing agents, and the like; the isotonizing agents can in particular be chosen from glucose, sodium chloride, glycerol, sorbitol, mannitol, fructose or dextrans 40 and 70. When the pH of the solution is high (pH = 5 or in the region of 5), if it is desired to prepare a concentrated solution, it is preferable to choose an isotonizing agent other than sodium chloride.

The stabilized pharmaceutical compositions according to the invention are more especially intended for administration by the parenteral route. They can also be used by the oral, ocular or auricular route or in local application on the skin and mucous membranes.

The stabilized pharmaceutical compositions according to the invention are prepared by simultaneously or successively dissolving quinupristine, dalfopristine, methanesulphonic acid or hydrochloric acid in water and then adjusting the pH in the range [3.5 ; 5] and/or adding an isotonizing agent and/or adding other pharmaceutically acceptable adjuvants and, if appropriate, lyophilizing and/or freezing.

AP/P/' 99/01530

According to a preferred aspect, the

AP 00998 compositions according to the invention are prepared bydissolving the quinupristine component and then the dalfopristine component in water acidified by methanesulphonic acid or hydrochloric acid, followed, if appropriate, by the adjustment of the pH in the range [3.5 ; 5] and/or by the addition of an isotonizing agent and/or of other pharmaceutically acceptable adjuvants. They are, if appropriate, lyophilized and/or frozen.

The solution is generally prepared and divided up from 0°C to room temperature, preferably at low temperatures, this temperature depending on the duration of the preparation and on the pH. The operations are carried out in particular at a temperature of less than 10°C.

The stabilized pharmaceutical compositions according to the invention can optionally be sterilized. Sterilization is advantageously carried out by sterilizing filtration.

The stabilized pharmaceutical compositions according to the invention, in the liquid, lyophilized or frozen state, exhibit the advantage of an optimum physicochemical stability which makes possible preservation for a period of time which is sufficient for them to be used to prepare a medicament which can be stored and thus marketed.

According to a preferred aspect of the invention, stabilized pharmaceutical compositions is

AP/P/ 9 9 / 0 1 5 30

0 9 9 8 understood, to mean compositions exhibiting not more than:

2.0¾ increase in the level of each of the major degradation impurities (A and B) after preservation for 24 months at 4°C or for 12 months at 20°C, in the case of a lyophilisate,

2.0% increase in the level of each of the major degradation impurities (A and B) after preservation for 18 hours between 0 and 6°C, in the case of concentrated solutions before or after lyophilization,

2.0% increase in the level of each of the major degradation impurities (A and B) after preservation for 3 months at -20°C, in the case of a frozen composition,

5% increase in the level of each of the major degradation impurities (A and B) after preservation for 6 hours at room temperature or ) for 72 hours at 4°C, in the case of dilute solutions for infusion.

The following examples, given without implied limitation, illustrate the present invention.

Example 1

One litre of a 125 mg/ml solution of quinupristine/dalfopristine (30/70), salified by methanesulphonic acid (= 16.7 mg/ml), at a pH of 4.75, is prepared by introducing 810 g of water for

AP/P/ 9 9/015 3 0

AP 00998 injectable preparations into a dissolution vessel equipped with a cooling unit. The solution is cooled at a temperature of between 0 and 6°C throughout the manufacturing. 16.4 g of methanesulphonic acid are added and then 37.5 g of quinupristine, which are dissolved by mechanical stirring, and 87.5 g of dalfopristine, which are also dissolved by mechanical stirring, are successively introduced. The pH of the solution is adjusted to 4.75 by a IN methanesulphonic acid solution. The solution is made up to 1 litre (1030 g) with water for injectable preparations.

This solution is sterilized by sterilized filtration (0.22 gm) and divided up into bottles [500 mg of quinupristine/dalfopristine (30/70) per bottle] and then lyophilized [freezing: temperature 30°C to -50°C; freezing rate approximately 0.5°/min,sublimation: pressure 0.5 mbar; secondary desiccation: pressure (= 30 gbars) temperature 40°C].

The quality and the stability during storage of the lyophilisates or of the reconstituted solution are evaluated by a reverse-phase high performance liquid chromatography (HPLC) method which makes it possible to determine the content of dalfopristine and quinupristine and the content of degradation impurities.

AP/P/ 9 9 / 0 1 5 30

HPLC analysis:

AP 00998

Stationary phase	Octadecylsilane-grafted silicon, Lichrospher-100 RP18, 5 μπι
Detection	254 nm U.V.
Dimensions of the column	125 x 4 mm
Temperature of the column	40°C
Mobile phase A	Phosphate buffer pH 2.9.......80 V Acetonitrile........20 V
Mobile phase B	Phosphate buffer pH 2.9.......35 V Acetonitrile........65 V
Gradient	from 0% mobile phase B to 66% mobile phase B over 42.5 min, followed by a return to 0% mobile phase B over 1.5 min and reequilibrating for 5 min
Flow rate of the mobile phase	1.1 ml/min

AP/P/ 99/01530

The method of analysis by HPLC makes it possible to determine the contents of quinupristine and dalfopristine with an accuracy of 2% and the degradation impurities are determined to within about

0.1%.

Two lyophilized batches of quinupristine/

AP 00998 « k μ dalfopristine (30/70), composed of bottles containing 500 mg of active principle (batch la and batch lb), were manufactured according to the above process and their stability studied at 4°C during storage for a period of 2 years. The results of the stability study on each of these 2 batches shows good preservation of the assays of the active principles and very little degradation (see Tables I and II) .

Quinupristine/dalfopristine (30/70) solutions 10 are reconstituted from these lyophilisates by taking up again in 5.0 ml of 5% glucose. Under these conditions, the stability of the concentrated solution thus constituted (premix), studied over a period of 60 minutes, is judged largely satisfactory for allowing subsequent dilution in an infusion bag (see Table III).

Under the dilution conditions anticipated for a clinical administration (500 mg of quinupristine/dalfopristine (30/70) in a 250 ml bag containing 5% glucose), the formulation ensures satisfactory stability over a period of at least 72 hours at 4°C or 6 hours at 25°C (see Tables IV and V) .

AP/r/ 9 9 / 0 1 5 30

AP 00998

Stability results for the lyophilisates over 2 years:

Stability study on batch la over a period of months at 4°C

	Batch la	TO	3 months	6 months	9 months	12 months	18 months	24 months
5	Assay (mg/bottle) Dalfopristine	350	347	343	343	345	358	342
	Quinupristine	149	145	147	149	145	153	144
	i impurities (A)	1.0	1.0	1.0	0.9	0.9	1.0	0.8
10	(B)	0.5	0.5	0.7	0.4	0.6	0.6	0.5
	(C)	0.2	0.1	0.2	0.1	0.1	0.1	0.1
	(D)	0.5	0.5	0.5	0.4	0.4	0.5	0.3
	(E)	0.3	0.2	-	0.1	0.2	0.1	0.1

Table I

Stability study on batch lb over a period of 24 months at 4°C

AP/P/ 9 9 / 0 1 5 30

	Batch lb	TO	6 months	9 months	12 months	18 months	24 months
	Assay (mg/bottle) Dalfopristine	349	340	343	343	340	340
20	Quinupristine	148	144	146	142	143	142
	% impurities (A)	1.0	0.8	0.8	0.9	0.9	0.8
	(B)	0.5	0.6	0.4	0.6	0.4	0.5
	(C)	0.2	0.2	0.1	0.2	0.1	0.2
25	(D)	0.4	0.4	0.4	0.4	0.4	0.3
	(E)	0.1	-	0.2	0.2	0.2	0.1

AP 00998

Table II

Stability results for the concentrated solution reconstituted from lyophilisates (premix):

)

Premix	TO	15 min	30 min	45 min	60 min
Assay (% with respect to TO)
Dalfopristine	100.0	99.7	100.2	99.0	99.0
Quinupristine	100.0	100.2	100.7	99.6	101.1
f impurities
(A)	0.74	0.89	1.02	1.12	1.28
(B)	0.51	0.62	0.69	0.72	0.78
'' (D)	0.47	0.49	0.46	0.53	0.61
Sum of the other impurities	0.28	0.30	0.32	0.33	0.38

AP/P/99/0 1 5 3 0 ) 15

Table III

Stability results for the solutions for infusion:

Three batches of lyophilisates manufactured as described above (batch lc, batch Id, batch le) were used to test the stability of solutions diluted under clinical conditions (500 mg of lyophilized quinupristine/dalfopristine (30/70) diluted in 250 ml of 5% glucose).

AP 00998

Stability of dilute solutions for infusion over a period of 72 hours at 4°C

Batches tested	Batch Ic	Batch Id	Batch le
TO	72h at 4°C	TO	72h at 4°C	TO	72h at 4°C
(mg/250 ml)
Dalfopristin	313	297	314	301	318	306
e	135	127	134	129	136	131
Quinupristin
e
f impurities
(A)	1.5	4.2	1.1	4.1	1.6	4.5
(B)	0.7	0.9	0.6	0.8	0.8	1.0
(C)	0.2	0.3	0.1	0.3	0.2	0.3
(D)	0.3	0.4	0.4	0.5	0 -.4	0.4
(E)	0.3	0.3	0.2	0.2	0.6	0.3

AP/P/ 9 9 / 0 1 5 30

Table IV

AP 00998

Stability of dilute solutions for infusion over a period of 6 hours at room temperature

Batches tested	Batch lc	Batch ld	Batch le
TO	6h at room temperature	TO	6h at room temperature	TO	6h at room temperature
(mg/250 ml)
Dalfopristin	314	304	321	311	319	313
e	134	132	137	136	137	136
Quinupristin
e
i impurities
(A)	1.3	4.5	1.1	4.2	1.7	4.7
(B)	0.7	0.8	0.6	0.7	0.6	0.7
(C)	0.2	0.5	0.2	0.4	0.2	0.5
(D)	0.2	0.3	0.3	0.4	0.2	0.3
(E)	0.3	0.3	0.2	0.2	0.3	0.3

Table V

Example 2

125 mg/ml solutions of quinupristine/dalfopristine (30/70), at a pH of 4.50, salified either by hydrochloric acid or by methanesulphonic acid, are prepared according to the following protocol:

350 g of water for injectable preparations are introduced into a dissolution beaker. 30.0 g of quinupristine are dispersed in the water at room temperature using a mechanical stirrer. A IN solution of methanesulphonic acid or of hydrochloric acid is

AP/P/ 9 9 / 0 1 5 30

AP 00998 added until dissolution is complete and a pH of 4.50 has been obtained. 70.0 g of dalfopristine are dispersed in the water using a mechanical stirrer and then a IN solution of methanesulphonic acid or of hydrochloric acid is added until dissolution is complete and a pH of 4.50 has been obtained. Homogenization is carried out for 10 minutes.

The solution is made up to 0.8 litre (824 g) with water for injectable preparations.

The lyophilization of this solution according to the protocol described in Example 1 makes it possible to obtain lyophilisates with a satisfactorystability during storage. A stability study in the course of storage at 4°C and at room temperature (RT) confirms the good stability of the formulations (cf. Tables VI and VII).

Stability of lyophilisates based on methanesulphonic acid over a period of 1 year at 4°C and at room temperature:

AP/P/ 9 9 / 0 1 5 30

AP 00998

Methane- sulphonic acid	TO	6 months	9 months	1 year
4°C	R.T.	4°C	R.T.	4°C	R.T.
Assay
(mg/bottle)	332	322	299	328	319	324	310
Dalfopristin	143	150	135	149	145	146 -	143
e
Quinupristin
e
t impurities
(A)	3.7	4.0	3.9	3.4	3.3	4.3	4.4
(B)	1.9	1.7	1.7	1.6	2.2	1.9	2.8
(C)	0.3	0.5	0.9	0.3	0.3	0.3	0.3
(D)	1.4	1.4	1.5	1.2	1.2	1.4	1.4

Table VI

S

.)

AP/P/ 9 9 / 0 1 5 30

AP 00998

Stability of lyophilisates based on hydrochloric acid over a period of 6 months at 4°C and at room temperature :

	Hydrochloric acid	TO	6 months
4°C	R.T.
5	Assay (mg/bottle)
	Dalfopristine	327	333	313
1	Quinupristine	156	150	145
	f impurities
	(A)	1.7	1.6	1.4
10	(B)	1.6	1.6	2.4
	(C)	0.3	0.2	0.2
	(D)	0.9	0.4	0.4

Table VII

Example 3

125 mg/ml solutions of quinupristine/dalfopristine (30/70) are prepared respectively according to Example 1 or 2 at various pH values by addition of a variable amount of IN methanesulphonic acid; these solutions are intended for lyophilization or for freezing. The pH of the solutions for lyophilization is fixed in a range of between 4.5 and 4.8. The pH of the solutions intended for freezing is fixed in a range of between 3.5 and 4.5.

The stability study on the batches of lyophilisates (prepared under the conditions for

AP/P/ 99/01530

AP 00998 ²⁰ dissolution of the active principles described in Example 1 but on a scale of 600 ml, by introducing 150 ml of water and 35 to 50 ml of a IN solution of methanesulphonic acid before dispersion of the active principles) shows, over a period of 4 years, an optimum stability (see Table VIII).

Stability of lyophilisates in a pH range from 4.3 to 4.8 over a period of 4 years at 4 °C.

	Batch 3a	Batch 3b	Batch 3c’	Batch 3d
PH	= 4.3	PH	= 4.5	PH	= 4.7	PH	= 4.8
	TO	4	TO	4	TO	4	TO	4
		years		years		years		years
		4°C		4°C		4°C		4°C
Assay
(mg/bottle)
Quinupristine	175	148	159	154	152	153	159	149
Dalfopristine	384	291	343	313	331	321	351	328
% impurities
(A)	0.6	0.5	0.6	0.8	0.8	0.9	1.1	1.1
(B)	1.0	3.3	0.8	2.1	0.9	1.2	1.0	1.1
(C)	0.5	0.5	0.4	0.4	0.4	0.4	0.3	0.5
(D)	0.8	0.7	0.9	0.6	0.7	0.6	0.8	0.5

AP/ P/99/01530 batch prepared with adjustment of the pH by addition of 6.5 ml of 0.5N NaOH (under the conditions described below in Example 5).

Table VIII

Stability of solutions intended for freezing, during manufacture, under the conditions of Example 2 (Table IX):

AP 00998

Analysis after dissolution of the active principles, after filtration and before freezing.

	Solution pH 3.5	Solution pH 4.0	Solution pH 4.5
	Batch 3e	Batch 3f	Batch 3g
	(1)	(2)	(3)	(1)	(2)	(3)	(1)	(2)	(3)
	Assay
	(mg/bottle)
5	Quinupristine	147	148	152	147	153	148	144	136	144
	Dalfopristine	339	328	335	320	336	331	334	313	334
	%· impurities
	(A)	2.0	1.9	2.0	1.8	1.8	2.0	2.6	3.3	3.6
	(B)	0.9	1.1	1.3	1.0	1.0	1.6	1.0	1.5	1.7
10	(C)	0.3	0.3	0.3	0.3	0.4	0.4'	0.2	0.4	0.2
	(D)	0.9	1.0	1.1	1.1	1.0	1.0	1.4	1.4	1.4

(1) (2) (3)

After dissolution

After filtration Table IX

Before freezing

AP/P/ 9 9 / 0 1 5 3 0

Example 4

Quinupristine/dalfopristine (30/70) solutions at a pH of 4.75 and at various concentrations of between 125 mg/ml and 250 mg/ml are prepared according to Example 1. These solutions are used to produce 500 mg lyophilisates. The most concentrated solutions (200 and 250 mg/ml) are slower to employ because of the time for dissolution of the dalfopristine and of the period of time for adjustment of the pH. The study shows that the degradation profiles during manufacture are not

AP 00998 modified, only the times for redissolving lyophilisates are increased when the concentration of the solution is increased (see Table X).

Degradation profile for solutions during manufacture (after filtration and after lyophilization). Conditions for redissolving the lyophilisates .

	Batch 4a 125 mg/ml	Batch 4b 143 mg/ml	Batch 4c 167 mg/ml	Batch 4d 200 mg/ml	Batch 4e 250 mg/ml
(1)	(2)	(1)	(2)	(1)	(2)	(1	(2)	(1)	(2)
% impurities (A)	1.10	0.99	0.66	1.13	0.58	0.74	0.54	0.58	0.38	0.56
(B)	0.78	0.83	0.61	0.92	0.58	0.72	0.65	0.76	0.52	0.80
(C)	0.26	0.25	0.24	0.28	0.24	0.29	0.25	0.26	0.24	0.24
CD)	0.52	0.55	0.58	0.60	0.58	0.62	0.54	0.62	0.49	0.51
Total known	2.66	2.62	2.09	2.93	1.98	2.37	1.98	2.22	1.63	2.11
impurities Sum of the	2.38	2.37	2.18	2.22	2.27	2.44	2.29	2.13	2.24	2.09
unknown impurities Total	5.04	4.99	4.27	5.15	4.25	4.81	4.27	4.35	3.87	4.20
impurities

AP/r/ 9 9/01530

AP 00998

	Batch 4a	Batch 4b	Batch 4c	Batch 4d	Batch 4e
	125 mg/ml	143 mg/ml	167 mg/ml	200	mg/ml	250 mg/ml
	(1)	(2)	(1)	(2)	(1)	(2)	(1	(2)	(1)	(2)
	REDISSOLUTION
	Time for
	redissolving
	in 4 ml of 5i	-	40 S	-	50 S	-	50 s	-	2 min	-	3 min
5	glucose								30 s
	pH of the
	solution
	reconstituted	-	4.54	-	4.56	-	4.56	-	4.55	-	4.44
	in 4 ml of 5%
10	glucose

(1) : Solution after filtration (2) : Lyophilisate (T12H)

Table X

Example 5

125 mg/ml solutions of quinupristine/dalfopristine (30/70) are prepared according to Example 1 for which the adjustment of the pH to 4.75 is carried out by variable amounts of IN methanesulphonic acid (1 to 9 ml/1) and of 0.5N sodium hydroxide (0 to 15 ml/1).

Conditions for adjustment of the pH (per litre of solution)

AP 00998

	Batch 5a	Batch 5b	Batch 5c	Batch 5d	Batch 5e	Batch 5f
Starting amount of methanesulphonic acid (g/D	16.36	16.36	16.36	16.36	16.36	16.36
Adjustment of the pH:
Addition of IN methanesulphonic acid (ml/1)	1.0	2.0	4.0	4.4	8.0	9.0
Addition of 0.5N NaOH (ml/1)	0	0	7.0	6.2	15.0	14.0

Table XI

The stability of the solutions manufactured (studied at 3°C over a period of 2 0 hours) shows no difference according to the conditions for adjustment of the pH.

)

Stability of the lyophilisates obtained:

AP/P/ 9 9 / 0 1 5 30

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AP/P/ 9 9 / 0 1 5 30 in o

AP 00998

Example 6

Frozen quinupristine/dalfopristine (30/70) solutions, salified by methanesulphonic acid or by hydrochloric acid, are prepared in a concentration range of 5 and 20 mg/ml and at pH values of 3.5 and 5.0 and in the presence of isotonizing agents, such as NaCl and glucose. The stability of the solutions stored in the frozen form is judged satisfactory.

(a) 800 g of water for injectable preparations are ) 10 introduced into a dissolution vessel equipped with a cooling unit. The solution is cooled at a temperature of between 0 and 6°C throughout the manufacture. 98% of the amount of methanesulphonic acid necessary for the dissolution and for the adjustment of the pH are added.'

1.5 g of quinupristine are introduced and dissolved with mechanical stirring. 3.5 g of dalfopristine are introduced and dissolved with mechanical stirring. The solution is isotonized with glucose. The pH of the _! solution is adjusted to 5.0 by a 0. IN solution of methanesulphonic acid. This solution is made up to 1 litre with water for injectable preparations.

Stability of the batch prepared above in (a) during a period of 3 months at -22°C:

AP/P/ 9 9 / 0 1 5 30

AP 00998

	TO	3 months
	Assay (mg/ml) Dalfopristine	3.37	3.38
	Quinupristine	1.41	1.37
5	% impurities (A)	2.42	2.55
	(B)	0.32	0.37
	(C)	0.18	0.29
	(D)	0.32	0.37
	(S)	-	0.12

Table XIII (b) The preparation is carried out as described above but introducing 6 g of quinupristine and 14 g of dalfopristine. The pH of the solution is adjusted to 3.5 by a 0. IN solution of methanesulphonic acid. The solution is made up to 1 litre with water for injectable preparations.

Stability of the batch prepared above in (b) during a period of 3 months at -22°C:

AP/P/ 9 9 / 0 1 5 30

AP 00998

	TO	3 months
	Assay (mg/ml) Dalfopristine	14.0	16.8
	Quinupristine	5.5	6.6
5	f impurities (A)	0.29	0.74
	(B)	0.26	0.30
')	(C)	0.27	0.28
	(D)	0.31	0.40

Table XIV (c) The preparation is carried out as described above in (a) but isotonizing the solution with sodium chloride and adjusting the pH to 3.5 by a 0. IN solution of methanesulphonic acid. The solution is made up to 1 litre with water for injectable preparations.

Stability of the batch prepared above in (c) during a period of 3 months at -22°C:

AP/P/ 9 9/01530

AP 00998 j 15

	TO	3 months
Assay (mg/ml)
Dalfopristine	3.57	3.90
Quinupristine	1.42	1.57
% impurities
(A)	0.25	0.56
(B)	0.20	0.21
(C)	0.21	0.15
(D)	0.30	0.35

Table XV (d) The preparation is carried out as described above in (c) but adjusting the pH to 5.0 by a 0. IN solution of hydrochloric acid. The solution is made up to 1 litre with water for injectable preparations.

Stability of the batch prepared above in (d) during a period of 3 months at -22°C:

AP/P/ 9 9 / 0 1 5 3 0

AP 00998

	TO	3 months
	Assay (mg/ml) Dalfopristine	3.41	3.89
	Quinupristine	1.45	1.63
5	f impurities (A)	2.77	2.64
	(B)	0.32	0.35
	(C)	0.21	0.15
	(D)	0.32	0.37

Table XVI in o

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AP 00998

Having now pariicularly described and ;·>. enained my/our said ir.xcalinii and In v. bai manner the same is be periormed 1/we declare that what I/we claim is -·

Claims (13)

1. Stabilized pharmaceutical composition based on the quinupristine/dalfopristine combination, characterized in that it comprises an at least stoichiometric amount of methanesulphonic acid or of hydrochloric acid and in that its pH is within the range [3.5 ; 5].

2. Stabilized pharmaceutical composition according to claim 1, characterized in that it can be lyophilized, frozen or in the liquid state.

3. Stabilized pharmaceutical composition according to claim 1 or 2, characterized in that it comprises:

dalfopristine and quinupristine; methanesulphonic or hydrochloric acid, in an at least stoichiometric amount with respect to the dalfopristine and the quinupristine introduced;

if appropriate, an excess of methanesulphonic or hydrochloric acid intended to adjust the pH of the solution thus formed in the range [3.5 ; 5] ;

optionally, an isotonizing agent and/or other pharmaceutically acceptable adjuvants; an amount of water suitable for adjusting the concentration of the solution, and in that the water is removed in the case of a lyophilisate .

AP/P/ 9 9 / 0 1 5 30

AP 0 0 9 9 8

4. Stabilized pharmaceutical composition according to claim 3, characterized in that the concentration of quinupristine/dalfopristine active principle is between 5 and 250 mg/ml and, when it is a

5 lyophilisate, the proportion of active principle is between 5 and 95%.

5. Stabilized pharmaceutical composition according to claim 4, characterized in that the concentration of quinupristine/dalfopristine active

10 principle in the lyophilisate is between 20 and 90%.

6. Stabilized pharmaceutical composition according to one of claims 1 to 4, characterized in that the pH is within the range [3.5 ; 4.5] .

7. Stabilized pharmaceutical composition 15 according to claim 6, characterized in that the pH is

3.5.

8. Stabilized pharmaceutical composition according to one of claims 1 to 4, characterized in that the pH is within the range [4.5 ; 5].

20

9. Use of a lyophilized or frozen stabilized pharmaceutical composition according to claim 2, for the preparation of a stabilized ready-foruse solution.

10. Process for the preparation of a

25 pharmaceutical composition according to claim 1, characterized in that quinupristine, dalfopristine, methanesulphonic acid or hydrochloric acid are simultaneously or successively dissolved in water and

AP/P/ 9 9 / 0 1 5 30

AP 00998 then the pH is adjusted in the range [3.5 ; 5].

11. Preparation process according to claim 10, characterized in that quinupristine and then dalfopristine are dissolved successively in water

5 acidified by methanesulphonic acid or hydrochloric acid and then the pH is adjusted in the range [3.5 ; 5].

12. Process according to claim 10 or 11 for the preparation of a pharmaceutical composition according to claim 2, characterized in that, if

10 appropriate, the solution obtained is subsequently lyophilized and/or frozen.

13. Use of methanesulphonic acid or of hydrochloric acid for the preparation of stabilized pharmaceutical compositions according to one of claims