SUXAMETHONIUM COMPOSITION AND PREFILLED SYRINGE THEREOF

Abstract

A suxamethonium pharmaceutical composition including suxamethonium chloride and a succinic acid buffer. Also, a prefilled syringe thereof and a process of sterilizing the suxamethonium prefilled syringe. The composition and the prefilled syringe are useful as ready-to-use formulations, especially in emergency conditions, and present long shelf lives, even at room temperature.

Claims

1-14. (canceled)

15. An aqueous pharmaceutical composition for parenteral administration, comprising: suxamethonium chloride at a concentration ranging from 8 mg/ml to 12 mg/ml; and succinic acid at a concentration ranging from 5 mM to 20 mM; and having a pH ranging from 3.0 to 4.5.

16. The aqueous pharmaceutical composition according to claim 15, wherein the concentration of suxamethonium chloride in the composition corresponds to 10 mg/ml of suxamethonium chloride anhydrous.

17. The aqueous pharmaceutical composition according to claim 15, wherein succinic acid is present at a concentration of 6 mM.

18. The aqueous pharmaceutical composition according to claim 15, wherein the pH is ranging from 3.4 to 3.8.

19. The aqueous pharmaceutical composition according to claim 15, wherein the composition has an osmolality ranging from 250 mOsm/kg to 350 mOsm/kg.

20. The aqueous pharmaceutical composition according to claim 15, wherein the composition has an osmolality of about 300 mOsm/kg.

21. The aqueous pharmaceutical composition according to claim 15, comprising sodium chloride.

22. The aqueous pharmaceutical composition according to claim 21, wherein sodium chloride is at a concentration of about 7 mg/ml.

23. The aqueous pharmaceutical composition according to claim 15, further comprising a pH adjusting agent.

24. The aqueous pharmaceutical composition according to claim 23, wherein the pH adjusting agent is selected from hydrochloric acid, sodium hydroxide and mixtures thereof.

25. The aqueous pharmaceutical composition according to claim 15, wherein the water used to form the aqueous composition is water for injection grade.

26. The aqueous pharmaceutical composition according to claim 15, being sterile.

27. The aqueous pharmaceutical composition according to claim 26, wherein the sterility is obtained by heat sterilization.

28. A suxamethonium prefilled syringe comprising an aqueous pharmaceutical composition according to claim 15.

29. The suxamethonium prefilled syringe according to claim 28, wherein the syringe is a plastic syringe.

30. The suxamethonium prefilled syringe according to claim 28, wherein the syringe is made of polypropylene, cyclic olefin copolymer and/or cyclic olefin polymer.

31. The suxamethonium prefilled syringe according to claim 28, wherein the syringe has a total volume selected from 5 ml, 10 ml, 20 ml and 50 ml.

32. The suxamethonium prefilled syringe according to claim 28, being sterilized by terminal heat sterilization.

33. A process for sterilizing a suxamethonium prefilled syringe, comprising: providing a suxamethonium prefilled syringe according to claim 28; and subjecting the suxamethonium prefilled syringe to steam sterilization at a temperature ranging from 118° C. to 125° C., with F0 ranging from 8 to 30.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0106] FIGS. 1A and 1B are graphs representing the evolution overtime of the concentrations in suxamethonium (FIG. 1A) and in succinylmonocholine (FIG. 1B) upon storage of the composition of Example 1 at 2-8° C. up to 24 months.

[0107] FIGS. 2A and 2B are graphs representing the evolution overtime of the concentrations in suxamethonium (FIG. 2A) and in succinylmonocholine (FIG. 2B) upon storage of the composition of Example 1 at 25° C. up to 6 months.

EXAMPLES

[0108] The present invention is further illustrated by the following examples.

Abbreviations

[0109] g: grams; [0110] L: liter; [0111] mg: milligrams; [0112] ml: milliliters; [0113] mM: millimolar; [0114] PFS: prefilled syringe; [0115] Qs: quantum sufficiat; [0116] RH: relative humidity.

Example 1: Suxamethonium Composition and Prefilled Syringe (PFS)

[0117] Purpose: Manufacturing a suxamethonium composition comprising a target concentration of 10 mg/ml of suxamethonium chloride anhydrous after sterilization. In order to compensate the degradation of suxamethonium chloride during the step of sterilization, a composition comprising 5% overage suxamethonium chloride is first prepared.

[0118] Method: A solution comprising the components listed in Table 1 was prepared by dissolution of suxamethonium chloride dihydrate, sodium chloride and succinic acid in water:

TABLE-US-00001 Suxamethonium composition Product Composition per liter of composition Suxamethonium chloride dihydrate (Equivalent to Suxamethonium chloride anhydrous) 11.55 g (10.5 g) Sodium chloride 7 g Succinic acid 720 mg NaOH 1N Qs pH 3.6 HCl 1N Qs pH 3.6 Water for injection (WFI) 1 L

[0119] The original concentration of suxamethonium chloride anhydrous in the composition was thus 10.5 mg/ml, corresponding to an overage of 5%. The concentration of succinic acid in the composition is 6 mM.

[0120] After dissolution, the pH of the solution was adjusted to 3.6 using NaOH and/or HCl. The solution was filtered, filled in a 10 ml polypropylene syringe. After plugging the syringe, the PFS was sterilized by autoclaving (121° C., F0≥ 15). The composition of the sterilized PFS was analyzed by HPLC.

[0121] HPLC conditions. HPLC analyses were conducted on HPLC system Waters Alliance (with column heater and DAD 2998 detector). The chromatographic conditions are described below:

TABLE-US-00002 Column Symmetry C18 250*4.6 mm 5 .Math.m (WATERS ref WAT054275) Mobile phase composition Buffer sodium pentanesulfonate and sodium chloride with 1% v/v sulfuric acid (filtered at 0.45 .Math.m) Acetonitrile Composition % Buffer % Acetonitrile 93 7 Needle wash Purified water / acetonitrile 90/10 (V/V) Flow rate 1 ml/min Column temperature 25° C. Sample temperature 5° C. Injection volume 10 .Math.L Detection 214 nm Integration mode Area Run time 10 minutes sample injected such as Results: The concentration in suxamethonium chloride in the sterilized prefilled syringe was measured just after sterilization and was found to correspond to the targeted dose, i.e. 10 mg/ml in suxamethonium chloride anhydrous.

Example 2: Stability of the Suxamethonium Composition

[0122] Purpose: Determining the stability overtime of the composition present in the sterilized PFS obtained in Example 1.

[0123] Method: Sterilized PFS obtained as described in Example 1 were stored at 5° C. or 25° C. The concentrations in suxamethonium and its degradation products, succinylmonocholine and choline, were measured by HPLC at different time points, up to 24 months of storage.

TABLE-US-00003 Storage conditions: Test Temperature Relative Humidity 5° C. 5° C. ± 2° C. N.A. 25° C./60%RH 25° C. ± 2° C. 60%

TABLE-US-00004 Stability time points: Time (in months) Test 0 1 2 3 6 9 12 18 21 24 5°C x x x x x x x x 25° C./60%RH x x x x x Time T=0 corresponds to the composition just after sterilization.

[0124] HPLC analytical conditions and equipment are identical to those of Example 1.

[0125] Results: The evolution of the concentration in suxamethonium, succinylmonocholine and choline upon storage at 2-8° C. or 25° C. is reported in Tables 2 and 3 respectively. The evolution of the concentration in suxamethonium and succinylmonocholine upon storage of the composition at 2-8° C. up to 24 months is reported in FIGS. 1A and 1B respectively. The evolution of the concentration in suxamethonium and succinylmonocholine upon storage of the composition at 25° C. up to 6 months is reported in FIGS. 2A and 2B respectively.

TABLE-US-00005 Stability results for storage at 5° C. Shelf life specifications T0 T3 T6 T9 T12 T18 T21 T24 pH 3.0-4.5 3.6 3.5 3.5 3.6 3.5 3.5 3.5 3.5 Suxamethonium chloride anhydrous mg/ml 9.00-10.50 10.10 10.09 9.90 9.76 9.72 9.50 9.31 9.35 %/Theory 90.0 - 105.0 101.0 100.9 99.0 97.6 97.2 95.0 93.1 93.5 Succinylmonocholine HCl (%w/w.sub.suxa .sub.HCl) ≤ 8.0 2.6 3.0 3.4 4.1 4.5 5.5 6.3 6.0 Choline HCl (%w/w.sub.suxa .sub.HCl) ≤ 8.0 1.7 2.1 2.4 3.1 3.3 4.3 4.9 4.5

TABLE-US-00006 Stability results for storage at 25° C. Shelf life specifications T0 T1 T2 T3 T6 pH 3.0-4.5 3.6 3.5 3.5 3.4 3.4 Suxamethonium chloride anhydrous mg/ml 9.00-10.50 10.10 9.70 9.52 9.42 8.57 %/Theory 90.0 - 105.0 101.0 97.0 95.2 94.2 85.7 Succinylmonocholine HCl (%w/w.sub.suxa HCl) ≤ 8.0 2.6 3.9 5.1 6.4 9.2 Choline HCl (%w/w.sub.suxa .sub.HCl) ≤ 8.0 1.7 3.1 4.3 5.4 8.6

[0126] Discussion: The stability data at T24 months at 2-8° C. indicates: [0127] suxamethonium content: 93.5% of the initial content in suxamethonium; and [0128] succinylmonocholine content: 4.9% w/w.

[0129] This is well within the maximum specifications of at least 90% suxamethonium content and up to 8% succinylmonocholine. The tested composition thus presents an optimized stability and a targeted shelf life of minimum 24 months at 2-8° C. with this formulation.

[0130] The stability data at T3 months at 25° C. indicates: [0131] suxamethonium content: 94.2% of the initial content in suxamethonium; and [0132] succinylmonocholine content: 6.4% w/w.

[0133] This is also well within the maximum specifications of suxamethonium and succinylmonocholine. The tested composition thus presents an optimized stability and a targeted shelf life of minimum 3 months at 25° C. with this formulation.

Example 3: Degradation During Sterilization and Corresponding Needed Overage

[0134] Purpose: Suxamethonium is known to be a quite unstable molecule and to degrade when exposed to heat. However, terminal heat sterilization of drugs should be privileged in order to ensure a high security for patients and insurance of sterility of the final drug product. Therefore, the degradation of suxamethonium under heat sterilization was studied in order to determine the overage of the composition required before sterilization in order to compensate degradation.

[0135] Method: Several batches of target composition (i.e. comprising 10 mg/ml of suxamethonium chloride anhydrous) have been manufactured and were subjected to steam sterilization at 121.3° C. on a pilot autoclave (Autoclave Lequeux) or on an industrial equipment (Autoclave SBM 58EQ002, model SDR-10.09.50).

[0136] The loss of suxamethonium as well as the formation of the degradation products succinylmonocholine and choline were measured by HPLC at T0, i.e. just after the sterilization step. HPLC analytical conditions and equipment are identical to those of Example 1.

[0137] Results: The results are presented in Table 4:

TABLE-US-00007 Effects of steam sterilization Degradation products Loss in suxamethonium (%) % w/w succinylmonocholine % w/w choline Pilot autoclave: F0 18 3.2 1.2 Not analyzed Pilot autoclave: F0 25 3.3 1.9 Not analyzed Pilot autoclave: F0 26 3.7 2.3 Not analyzed Pilot autoclave: F0 25 3.6 1.8 1.3 Industrial autoclave: mean cycle 3.2 1.8 1.3

[0138] Mean degradation on pilot scale is approximately 3.4%. The degradation with the industrial cycle is of the same order of magnitude. Pilot autoclave cycles were conducted at the upper limit to ensure most stringent conditions. The temperature increase and decrease on the industrial equipment is slightly slower due to thermal inertia. The conducted cycle was conducted at the standard (mean) conditions. If the cycle is conducted at the upper limit, degradation will be slightly higher.

[0139] Discussion: The degradation products of suxamethonium are well identified and the amount of active substance degradation is equivalent to the amount of degradation products appearing upon HPLC and ionic chromatography analysis (sum of succinylmonocholine, choline and succinic acid provides the correct mass balance). These results are in accordance with scientific literature that describes the degradation of suxamethonium upon exposure to heat. It has to be mentioned that the degradation products of suxamethonium are its natural metabolites (upon degradation in vivo). Moreover, a safety assessment has proved (based on bibliographic data) that the degradation products at the maximum concentrations achievable do not present a significant pharmacological or toxicological effect. They are safe and without danger to be injected at these concentrations.

[0140] In order to ensure the right suxamethonium dosage upon batch release, the suxamethonium overage in the composition can be fixed at 5% during manufacture. This overage takes into account the degradation during the step of sterilization, but also the overall degradation that occurs during the cumulated holding time during manufacturing which is performed at a temperature of about 25° C. With this overage, the degradation that can occurs during the 24 months shelf life of the composition stored at 2-8° C., during transportation and during a possible final storage before use for a 4 weeks period at room temperature, in the worst conditions for each situation, will not exceed the minimum specifications of 90% suxamethonium content.

Example 4: Effect of the Amount of Succinic Acid on the Stability of the Composition

[0141] Purpose: Determining the effect of the amount of succinic acid present in the composition on its stability overtime.

Methods and Results

[0142] 1) Need of a pH buffer:

[0143] Two formulations at 10 mg/ml suxamethonium chloride, with and without 20 mM succinic acid buffer, were prepared and adjusted to pH 4.5. After steam sterilization, samples were stored at 25° C. for two weeks. The unbuffered solution exhibits a significant pH drop in less than 2 weeks, contrary to the succinic acid buffered composition (results in Table 5). This will thus lead to out of specification pH before reaching the shelf life. Thus, a pH buffer is required to maintain the target pH during the whole shelf life.

TABLE-US-00008 pH of unbuffered composition compared to succinic acid buffered composition, after 2 weeks storage at 25° C. Without pH buffer With 20 mM succinic acid buffer pH t0 4.5 4.5 pH t14 days 4.02 4.43

[0144] 2) Comparison of compositions comprising 20 mM or 50 mM of succinic acid at three different pH values:

[0145] Formulations at 10 mg/ml suxamethonium chloride, comprising 20 mM or 50 mM of succinic acid were prepared and adjusted at pH 3.0, 3.5 or 4.5. After steam sterilization, samples were stored at 25° C. for one week and the suxamethonium content was measured by HPLC (results in Table 6).

TABLE-US-00009 Suxamethonium content (%), depending on pH and succinic acid concentration, after 1-week storage at 25° C. pH 3.0 pH 3.5 pH 4.5 Without succinic acid 99.1 99.3 99.0 20 mM succinic acid 98.9 98.5 97.7 50 mM succinic acid 97.8 96.8 90.5

[0146] After one-week storage at 25° C., stability of suxamethonium is similar at pH 3.0 and 3.5, while stability decreases at pH 4.5. In these conditions, chemical stability is similar with and without 20 mM succinic acid. However, as evidenced above, succinic acid is required to maintain pH stability beyond one week of storage at 25° C. 50 mM succinic acid leads to faster degradation rate. Thus, the amount of succinic acid was adjusted to a maximum at 20 mM. The succinic acid content can be minimized and should enable a proper control of pH value all over the product shelf life.

[0147] 3) Comparison of compositions comprising 4 mM or 6 mM of succinic acid:

[0148] Formulations at 10 mg/ml suxamethonium chloride, comprising 4 mM or 6 mM of succinic acid were prepared and adjusted at pH 3.6. After steam sterilization, samples were stored at 25° C. up to 4 months and the pH was monitored (Table 7).

TABLE-US-00010 pH of composition comprising 4 mM or 6 mM of succinic acid upon storage at 25° C. 4 mM succinic acid buffer 6 mM succinic acid buffer pH adjustment 3.6 3.6 T0 after steam sterilization 3.4 3.5 T1 month 3.3 3.5 T2 months 3.2 3.4 T4 months 3.2 3.4

[0149] Above data demonstrate that the pH decrease with 4 mM succinic acid is faster than with 6 mM succinic acid. Consequently, a concentration of 4 mM of succinic acid is not sufficient to control the pH decrease (especially if the initial pH is at the lower end of the specification).

[0150] Discussion: The degradation of suxamethonium chloride proceeds through a hydrolysis of the ester bonds. The hydrolysis yields succinylmonocholine, choline and succinic acid. The formation of succinic acid upon hydrolysis leads to pH decrease. The Applicant found that buffering the composition enables to avoid an out of specification pH at shelf life and an acceleration of the degradation upon pH drop.

[0151] The buffer chosen for the composition of the invention is succinic acid. It was selected at least for the following reasons: [0152] succinic acid is an approved and widely accepted pharmaceutical excipient; [0153] succinic acid has a high buffer capacity around the targeted pH value of pH 3.6; [0154] succinic acid is also one of the degradation products and metabolites of suxamethonium chloride.

[0155] The above results show that the concentration of succinic acid has to be carefully selected: the composition should comprise enough but not too much succinic acid in order to achieve expected stability during the shelf life. A range of 5 mM to 20 mM was found to provide expected effects. Higher succinic acid content increases the degradation kinetic of suxamethonium. Lower succinic acid content negatively impacts the buffering of the composition and the degradation of suxamethonium.