FR3137274A1 - PLASTIC CONTAINER INCLUDING SUFENTANIL INJECTABLE SOLUTION - Google Patents

Abstract

PLASTIC CONTAINER COMPRISING SUFENTANIL INJECTABLE SOLUTION Plastic container containing sufentanil injectable solution with a pH between 2.5 and 4.5.

Description

PLASTIC CONTAINER INCLUDING SUFENTANIL INJECTABLE SOLUTION

The present invention relates to a plastic container containing an injectable solution of sufentanil.

Sufentanil, or N-[4-(methoxymethyl)-1-(2-thiophen-2-ylethyl)-4-piperidyl]-N-phenyl-propanamide, is a fat-soluble opioid analgesic first synthesized in 1974. It is approximately 5 to 10 times more potent than its parent drug, fentanyl, and 500 times more potent than morphine.

Sufentanil is notably marketed in the form of an injectable solution for intravenous (IV) or epidural administration, both in adults and in pediatrics, for the following indications:

• in IV administration, as an analgesic agent for the induction and/or maintenance of balanced general anesthesia; And
• in epidural administration, for postoperative analgesia following a general, thoracic or orthopedic surgery procedure.

Sufentanil injectable solutions are currently marketed at two distinct concentrations: 5µg/ml and 50µg/ml. These solutions contain, in addition to sufentanil, an osmotic agent (sodium chloride) and pH adjusters (sodium hydroxide and hydrochloric acid). Furthermore, according to the pharmacopoeia (see for example USP Monograph Sufentanil citrate injection), the pH of these solutions can vary from 3.5 to 6.

At the date of the present invention, injectable solutions of sufentanil are exclusively stored and marketed in glass containers (ampoules or vials). This is explained in particular by the stability problems of sufentanil solutions when they are stored in plastic containers.

Thus, in “Stability of sufentanil and levobupivacaine solutions and a mixture in a 0.9% sodium chloride infusion stored in polypropylene syringes”, European Journal of Pharmaceutical Sciences 19 (2003) 31–36, the authors Jäppinen et al. evaluated the chemical and microbiological stability of sufentanil injectable solutions in a polypropylene syringe after 7, 14, 21 and 28 days of storage at 4°C, 21°C or 36°C, and found that the solution was unstable or even very unstable as storage time and temperature increased. A loss of 15% of the active ingredient in 1 to 3 days was, for example, observed when the polypropylene syringe containing the sufentanil solution was stored at 36°C.

This increasing short-term instability of sufentanil injectable solutions contained in plastic containers as temperatures rise poses even more difficulties as health authorities such as the EMA (European Medicines Agency) recommend, for a for better conservation, carry out a terminal sterilization of the container once it has been filled with the solution it contains. However, such terminal sterilization is carried out at high temperatures (generally 121°C when this is carried out using steam), which has the consequence of accelerating and amplifying the loss of sufentanil when the solution is contained in a polypropylene container.

In “Stability of sufentanil citrate in a portable reservoir pump, a glass container and a polyethylene container”, Pharmaceutish Weekblad Sientific edition 14(4) (1992) 196-200, authors Roos et al. reported the 21-day stability of a sufentanil solution with a pH significantly greater than 4.5 (4.87) when stored in a polyethylene container. However, the stability of these solutions has not been evaluated beyond 21 days and the polyethylene containers containing the sufentanil solution have not undergone terminal sterilization. Furthermore, the authors also reported great instability of the same sufentanil solution when it was contained in a PVC tank.

At the date of the present invention, there is therefore no injectable solution of sufentanil which allows its long-term storage in a plastic container. However, plastic containers, especially when it comes to syringes pre-filled with a solution ready to be injected, have a certain number of advantages compared to glass containers. Thus, plastic containers make it possible to avoid the release of metal ions which is observed with glass containers, they are less fragile and easier to produce/mold, in particular, when it comes to syringes (connectors Luer-Lock type being easier to mold when they are made of polypropylene).

There is therefore a need for such a composition.

However, it was discovered, completely unexpectedly, an injectable solution of sufentanil that is stable in the short, medium and long term when stored in a plastic container, whether or not it is subject to terminal sterilization. , such a solution notably having a loss of active ingredient of less than 6%, preferably less than 3% after terminal sterilization.

Thus, the present invention relates to a plastic container comprising an injectable solution of sufentanil whose pH is between 2.5 and 4.5.

Sufentanil injection solution stored in a plastic container with a pH of 2.5 to 4.5 was observed to be stable in the short, medium and long term, whether or not the container underwent terminal sterilization. .

In the context of the present invention:

- the term “injectable solution” means any solution that can be injected parenterally, in particular intravenously (IV), epidural, intramuscular (IM), subcutaneous, or intrathecal, whether it is ready to be injected or requires prior dilution;

- “sufentanil” means N-[4-(methoxymethyl)-1-(2-thiophen-2-ylethyl)-4-piperidyl]-N-phenyl-propanamide, with CAS number 56030-54-7 and chemical structure :

as well as its pharmaceutically acceptable salts, in particular its citrate salt;

- the term “pharmaceutically acceptable salt” of an active principle is understood to mean any addition salt of said active principle with a mineral or organic acid by the action of such an acid in an organic or aqueous solvent such as an alcohol, a ketone, an ether or a chlorinated solvent, and which is acceptable from a pharmaceutical point of view; And

- the term “buffer agent” means any compound or combination of compounds making it possible to maintain the pH of a solution at a stable value (+/- 1, preferably +/- 0.5). As an example of a buffer agent, mention may in particular be made of citrate, phosphate, acetate, glutamate, tartrate, benzoate, lactate, malate, gluconate, succinate, aspartate, glycine, TRIS , histidine and HEPES as well as associated salts.

The present invention therefore relates to a plastic container comprising an injectable solution of sufentanil whose pH varies from 2.5 to 4.5. Preferably, the present invention relates to a plastic container comprising an injectable solution of sufentanil having the following characteristics, taken alone or in combination:

- the container is chosen to be a sealed container. More preferably, the container is chosen to be a bottle, an ampoule, an infusion bag or a syringe. Most preferably, the container is chosen to be a syringe;

- the container is made of polyethylene (PE), polypropylene (PP), PVC, cyclic olefin copolymer (COC), or cyclic olefin polymer (COP). More preferably, the container is made of polypropylene, cyclic olefin copolymer (COC) or cyclic olefin polymer (COP). Very preferably, the container is made of polypropylene;

- the container has been subjected to terminal sterilization;

- sufentanil is present in the solution in the form of sufentanil citrate;

- the sufentanil solution contains 1 µg/ml to 100 µg/ml sufentanil. More preferably, the sufentanil solution contains from 1 μg/ml to 50 μg/ml of sufentanil. Most preferably, the sufentanil solution contains from 5 µg/ml to 50 µg/ml of sufentanil;

- the sufentanil solution is ready to be injected;

- the pH of the sufentanil solution is less than 4.5. More preferably, the pH of the sufentanil solution is between 2.5 and 4. More preferably, the pH of the sufentanil solution is between 3 and 4. Very preferably, the pH of the solution sufentanil is between 3 and less than 4;

- sufentanil solution contains a buffering agent. More preferably, the sufentanil solution contains a buffer agent chosen from citrate or one of its salts, phosphate or one of its salts, acetate or one of its salts, glutamate or one of its salts, tartrate or one of its salts, benzoate or one of its salts, lactate or one of its salts, malate or one of its salts, gluconate or one of its salts, histidine or one of its salts, succinate or one of its salts, aspartate or one of its salts and glycine or one of its salts. Very preferably, the sufentanil solution contains a buffer agent chosen to be citrate or one of its salts;

- the sufentanil solution contains 0.1 mM to 50 mM buffering agent. More preferably, the sufentanil solution contains from 1 mM to 20 mM of buffering agent. Very preferably, the sufentanil solution contains from 5 mM to 15 mM of buffering agent;

- the sufentanil solution contains a tonic agent. More preferably, the sufentanil solution contains a toning agent chosen from dextrose, glycerin, mannitol, potassium chloride, sodium chloride. Very preferably, the sufentanil solution contains a toning agent chosen to be sodium chloride;

- the sufentanil solution contains a tonic agent in proportions suitable to obtain an isotonic solution whose osmolarity is between 200-400mOsm/kg, preferably between 250-350mOsm/kg. The sufentanil solution can thus contain from 1 g/l to 50 g/l of toning agent. More preferably, the sufentanil solution contains from 5 g/l to 10 g/l of sodium chloride or from 40 g/l to 50 g/l of glucose; and or

- the volume of the container varies from 1 ml to 500 ml. More preferably, the volume of the container varies from 1 ml to 100 ml. Most preferably, the volume of the container varies from 1 ml to 50 ml.

The container according to the present invention is obtained by filling with a sufentanil solution as defined above followed by crimping. Preferably, the container thus obtained is then subjected to terminal sterilization. This terminal sterilization step is carried out according to any process conventionally used by those skilled in the art. In particular, the terminal sterilization step is carried out in an autoclave, the product being exposed to a temperature of 121°C for at least 15 minutes.

The sufentanil solution included in the plastic container according to the present invention can be prepared according to any method conventionally used by those skilled in the art. As an example of a process for preparing a solution as defined above, we can in particular cite the process comprising the following steps:

• introduction and mixing of each of the ingredients of the solution in a given volume of water;
• pH adjustment; And
• filtration.

The present invention is illustrated in a non-limiting manner by the following examples.

Example 1 – Stability of a sufentanil solution contained in a plastic container following terminal sterilization

1.1 – Preparation of a sufentanil solution

Sufentanil solutions whose compositions are reported in Table 1 below were prepared according to the process described below.

Solutions S1.1 S1.2 S2.1 S2.2 S3.1 S3.2 S4.1 S4.2 S5.1 S5.2 Sufentanil
(µg/ml) 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Citrate buffer (mM) - 6mM - 6mM - 6mM - 6mM - 6mM NaCl (g/l) 9.4 9.0 9.4 9.0 9.4 9.0 9.0 8.5 9.4 9.0 1N HCl / 1N NaOH Qs
pH=5.0 Qs
pH=4.5 Qs
pH=4.0 Qs
pH=3.8 Qs
pH=3.5

Table 1 – Sufentanil Solutions

A stock solution of sufentanil (base) at 50 µg/ml is prepared to avoid errors due to weighing too small quantities.

For solutions containing a buffering agent, sodium citrate dihydrate and citric acid are dissolved with magnetic stirring in 80% of the total volume of water for injections, then the stock solution of sufentanil is added to be diluted tenfold and mixed with magnetic stirring.

Sodium chloride is then added to the solution to adjust the tonicity.

The pH is finally adjusted with hydrochloric acid and/or sodium hydroxide.

The volume is finally completed to 100% with water then the solution is filtered on a 0.22 µm Millipore PVDF disk.

1.2 – Preparation of a plastic container pre-filled with sufentanil solution

Polypropylene (PP) or COC (cyclic olefin copolymer) syringes, as well as glass or COP (cyclic olefin polymer) vials pre-filled with a sufentanil solution whose characteristics are reported in Table 2 below, were prepared. according to the process described below.

Container Sufentanil solution Terminal sterilization GLASS-A1 S1.1 Yes GLASS-A2 S3.1 Yes PP-A1 S1.1 No PP-A2 S1.1 Yes PP-B1 S1.2 Yes PP-C1 S2.1 No PP-C2 S2.1 Yes PP-D1 S3.1 No PP-D2 S3.1 Yes PP-E1 S3.2 Yes PP-F1 S4.1 No PP-F2 S4.1 Yes PP-G1 S4.2 No PP-G2 S4.2 Yes PP-H1 S5.1 No PP-H2 S5.1 Yes COC-A1 S4.1 Yes COC-B1 S4.2 Yes COP-A1 S4.1 Yes COP-B1 S4.2 Yes

Table 2 – Pre-filled plastic containers

A Borealis HD-850MO silicone-coated PP syringe is filled with 5 ml of a sufentanil solution as described above, then capped with an elastomer cap (Aptar chlorobutyl C1797 6422NR 6DDP1). A piston is then added manually.

A COC syringe (Transcoject PFS 10 ml Barrel COC) is filled with 10 ml of a sufentanil solution as described above, then capped with an elastomer cap (Aptar chlorobutyl C1797 6422NR 6DDP1). A piston is then added manually.

A 10 ml type II glass vial is filled with 10 ml of a sufentanil solution as described above, then stoppered with a chlorobutyl stopper (Aptar Stelmi C5394 6422GS 6 DH1).

A COP vial (Gerresheimer 390050002 vial 50ml RTS MONO) is filled with 20 ml of a sufentanil solution as described above, then closed with an elastomer cap (Aptar Stelmi C5394 6422GS 6 DH1).

When the container is subjected to terminal sterilization, it is then placed in an autoclave at 121°C (inside the product using a sample in which a temperature probe is inserted) for at least 15 minutes.

The containers are then stored at room temperature and protected from light until the analyzes reported in point 1.3 below are carried out.

1.3 – Stability assessment 1.3.1 – Protocol

The solutions contained in the syringes prepared above are evaluated visually (color, turbidity and presence of particles).

The pH of the solution is measured and the sufentanil concentration of the solution is also evaluated by HPLC (UHPLC with PDA detector / Supelco Ascentis Express Phenyl Hexyl column (2 µm) 100x2.1 mm / mobile phases A: Perchloric acid 0.05%, B: Acetonitrile / Detection 230 nm (PDA 200 – 400 nm)).

1.3.2 - Results

The results of these analyzes are reported in the following Table 3.

Container pH Sufentanil concentration
(in µg/ml) Sufentanil loss from original concentration (%) Visual observations GLASS-A1 5.08 4.95 1 Colorless
Clear
No particles visible GLASS-A2 4.06 4.97 0.6 PP-A1 5.03 5.01 - PP-A2 5.01 3.88 22.4 PP-B1 4.99 3.95 21 PP-C1 4.57 5.04 - PP-C2 4.6 4.56 8.8 PP-D1 4.09 5.04 - PP-D2 4.04 4.82 3.6 PP-E1 3.98 4.91 1.8 PP-F1 3.69 5.07 - PP-F2 3.69 4.77 4.6 PP-G1 3.61 5.11 - PP-G2 3.61 4.96 0.8 PP-H1 3.65 4.99 - PP-H2 3.61 4.77 4.6 COC-A1 3.69 4.88 2.4 COC-B1 3.61 5.03 0.0 COP-A1 3.69 4.91 1.8 COP-B1 3.61 5.06 0.0

Table 3 – Stability of sufentanil solutions contained in plastic containers

1.3.3 – Conclusions

We note that, unlike the glass container (GLASS-A1 and GLASS-A2) for which terminal sterilization has no (or very little) impact on the stability of the solution, we observe a strong loss of active ingredient for solutions contained in a plastic container when the pH is greater than 4.5 (PP-A2 and PP-B1). Reducing the pH of the solution to a level less than or equal to 4.5 makes it possible to significantly limit the loss of active ingredient (PP-C2, PP-D2, PP-E1, PP-F2, PP-G2, PP -H2 COC-A1, COC-B1, COP-A1 and COP-B2).

In addition, it is observed that, when the pH is less than or equal to 4.5, the presence of a buffer agent makes it possible to further improve the stability of the solution contained in a plastic container following terminal sterilization (PP- E1, PP-G2, COC-B1 and COP-B1). On the other hand, the presence of a buffering agent in a solution whose pH is greater than 4.5 does not significantly reduce the loss of active ingredient (PP-B1).

Example 2 – Stability over time of a sufentanil solution contained in a PP syringe

2.1 – Preparation of a sufentanil solution

Sufentanil solutions whose compositions are reported in the following Table 4 were prepared according to the process described in point 1.1 above.

Solutions S6 S7 S8 Sufentanil (µg/ml) 5.0 5.0 5.0 Citrate buffer (mM) - 3mM 6mM NaCl (g/l) 9.0 9.0 9.0 1N HCl / 1N NaOH Qs pH=3.65 Qs pH=3.61 Qs pH=3.60

Table 4 – Sufentanil Solutions

2.2 – Preparation of a polypropylene syringe pre-filled with sufentanil solution

Syringes pre-filled with a sufentanil solution whose characteristics are reported in Table 5 below were prepared according to the process described in point 1.2 above.

Syringe Material Sufentanil solution Terminal sterilization PP-A1 PP S6 No PP-A2 PP S6 Yes PP-B1 PP S7 No PP-B2 PP S7 Yes PP-C1 PP S8 No PP-C2 PP S8 Yes

Table 5 – Prefilled polypropylene syringes

2.3 – Stability assessment 2.3.1 – Protocol

Once filled with the sufentanil solution (and after possibly having undergone terminal sterilization), the pre-filled syringes are placed in a climatic chamber.

The solutions contained in the syringes prepared above are evaluated visually (color, turbidity and presence of particles) at t ₀ (ie after preparation and possible terminal sterilization) t ₀ +1 month and t ₀ +3 months after storage in the protected from light at 25°C and 40°C.

The pH of the solution is measured and the sufentanil concentration of the solution is also evaluated by HPLC.

2.3.2 - Results

The results of these analyzes are reported in Tables 6 and 7 below.

Syringe Storage duration Sufentanil concentration
(in µg/ml) Loss of sufentanil compared to the original concentration (in %) Visual observations PP-A1 t ₀ 4.96 0.0 Colorless
Clear
No particles visible PP-A2 t ₀ 4.84 3.2 t ₀ + 1 month 4.81 3.8 t ₀ + 3 months 4.80 4.0 PP-B1 t ₀ 5.04 - PP-B2 t ₀ 4.91 1.8 t ₀ + 1 month 4.92 1.6 t ₀ + 3 months 4.89 2.2 PP-C1 t ₀ 5.00 - PP-C2 t ₀ 4.92 1.6 t ₀ + 1 month 4.92 1.6 t ₀ + 3 months 4.95 1.0

Table 6 – Stability of sufentanil solutions contained in polypropylene syringes at 25°C

Syringe Storage duration Sufentanil concentration
(in µg/ml) Loss of sufentanil compared to original concentration (in %) Visual observations PP-A1 t ₀ 4.96 0.0 Colorless
Clear
No particles visible PP-A2 t ₀ 4.84 3.2 t ₀ +1 month 4.75 5.0 t ₀ + 3 months 4.63 7.4 PP-B1 t ₀ 5.04 - PP-B2 t ₀ 4.92 1.6 t ₀ + 1 month 4.89 2.2 t ₀ + 3 months 4.7 6.0 PP-C1 t ₀ 5.00 - PP-C2 t ₀ 4.92 1.6 t ₀ + 1 month 4.87 2.6 t ₀ + 3 months 4.79 4.2

Table 7 – Stability of sufentanil solutions contained in polypropylene syringes at 40°C

2.3.3 – Conclusions

These results highlight that the presence of a buffering agent makes it possible to further improve the short, medium and long term stability of a sufentanil solution whose pH is less than 4.5 contained in a plastic container, which whether or not it has undergone terminal sterilization.

Claims (13)

Plastic container containing an injectable solution of sufentanil with a pH between 2.5 and 4.5. Container according to claim 1, characterized in that it is a bottle, an ampoule, an infusion bag or a syringe. Container according to claim 1 or 2, characterized in that it is made of polyethylene (PE), polypropylene (PP), PVC, cyclic olefin copolymer (COC), or cyclic olefin polymer ( COP). Container according to claim 3, characterized in that it is made of polypropylene (PP), cyclic olefin copolymer (COC) or cyclic olefin polymer (COP). Container according to any one of claims 1 to 4, characterized in that the sufentanil is present in the solution in the form of sufentanil citrate. Container according to any one of Claims 1 to 5, characterized in that the sufentanil solution contains from 1 µg/ml to 100 µg/ml of sufentanil. Container according to any one of claims 1 to 6, characterized in that the pH of the sufentanil solution is strictly less than 4.5. Container according to claim 7, characterized in that the pH of the sufentanil solution is between 2.5 and 4 Container according to any one of claims 1 to 8, characterized in that the sufentanil solution contains a buffering agent. Container according to claim 9, characterized in that the buffering agent is chosen from citrate or one of its salts, phosphate or one of its salts, acetate or one of its salts, glutamate or one of its salts, tartrate or one of its salts, benzoate or one of its salts, lactate or one of its salts, malate or one of its salts, gluconate or one of its salts, phosphate or one of its salts, histidine or one of its salts, succinate or one of its salts, aspartate or one of its salts and glycine or one of its salts. Container according to claim 9 or 10, characterized in that the sufentanil solution contains from 0.1 mM to 50 mM of buffering agent. Container according to any one of claims 1 to 11, characterized in that the sufentanil solution contains a tonic agent. Container according to any one of claims 1 to 12, characterized in that it has been subjected to terminal sterilization.