Sterilization process for sterile liquid pharmaceutical compositions containing ensifentrine

Abstract

The present invention relates to a process for producing a sterile liquid pharmaceutical composition suitable for administration by inhalation comprising ensifentrine particles, the process comprising: (a) heating the ensifentrine particles at a temperature of from 100° C. to 220° C. to obtain sterile ensifentrine particles; and (b) combining the sterile ensifentrine particles with a sterile liquid vehicle to produce a sterile liquid pharmaceutical composition suitable for administration by inhalation. A process for producing an ampule comprising the sterile liquid pharmaceutical composition is also described.

Description

[Technical field]

[0001] Field of the Invention The present invention relates to a process for producing a sterile formulation containing an active pharmaceutical ingredient. [Background technology]

[0002] 2. Background of the Invention Certain pharmaceutical products must meet strict sterility standards before being administered to a patient. Given the importance of sterility to pharmaceutical products, a number of different processes, protocols and techniques have been developed for the sterilization of pharmaceutical products. These include steam sterilization, dry heat sterilization, ionizing radiation sterilization (such as X-ray and gamma sterilization), gas sterilization, sterile filtration and aseptic processing. The selection of a sterilization protocol for a new drug is a complex process that depends on the evaluation of the various available methods and their suitability for the particular product.

[0003] Ensifentrine (N-(2-{(2E)-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl}ethyl)urea; also known as RPL554) is a dual inhibitor of PDE3 / PDE4 and is described in WO00 / 58308A1. Ensifentrine has both bronchodilatory and anti-inflammatory properties and is useful in the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). The structure of ensifentrine is shown below.

[0004] [ka]

[0005] Ensifentrin may be formulated as a suspension of particles in a diluent, as described in WO2016 / 042313A1.

[0006] A suitable method for sterilizing a liquid pharmaceutical composition containing ensifentrine particles has not been described. There is a need to develop a process for producing a sterile ensifentrine suspension. Summary of the Invention

[0007] The inventors have found that, of all the available sterilization techniques, dry heat sterilization of particles of active agent followed by aseptic compounding is particularly suitable for the formulation of ensifentrin as a suspension. Other techniques, such as terminal sterilization and dry gamma sterilization, have been found to cause degradation of the formulation.

[0008] The present invention therefore provides a process for producing a sterile liquid pharmaceutical composition suitable for administration by inhalation comprising ensifentrine particles, the process comprising: (a) heating the ensifentrine particles at a temperature of from 100° C. to 220° C. to obtain sterile ensifentrine particles; and (b) combining the sterile ensifentrine particles with a sterile liquid vehicle to produce a sterile liquid pharmaceutical composition suitable for administration by inhalation.

[0009] The present invention further provides a process for producing ampoules containing a sterile liquid pharmaceutical composition suitable for administration by inhalation, the process comprising: (i) producing a sterile liquid pharmaceutical composition suitable for administration by inhalation comprising ensifentrine particles by a process defined herein; and (ii) filling an ampoule with the sterile liquid pharmaceutical composition suitable for administration by inhalation.

[0010] Detailed Description of the Invention The process of the present invention produces a sterile liquid pharmaceutical composition. The sterile liquid pharmaceutical composition is suitable for administration by inhalation. The sterile liquid pharmaceutical composition comprises sterile ensifentrine particles.

[0011] The term "sterile" refers to a composition that is essentially free of viable microorganisms. Thus, a sterile composition is typically one that is substantially free of viable bacteria or fungi. The term "sterile" is well known in the art.

[0012] The sterility assurance level (SAL) of a sterile liquid pharmaceutical composition is 10 -3 Below, 10 -6 Less than or equal to 10 -9 For example, if SAL is 10 -6 means there is a 1 in 10 chance that the final product is non-sterile 6 The total bioburden limit of a sterile liquid pharmaceutical composition may be less than or equal to 10 CFU / mL, or less than or equal to 1 CFU / mL. "CFU" is colony forming unit. Bioburden is defined as the bioburden limit defined in USP31. <61> The amount of erythrocyte spheroids may be measured using a plate count method, for example the pour-plate method, as described in US Pat.

[0013] Typically, the sterility of a liquid pharmaceutical composition is determined according to the USP <71> or Ph Eur 2.6.1. Liquid pharmaceutical compositions are typically prepared according to USP <71> or meets the acceptance criteria defined in Ph Eur 2.6.1.

[0014] The pharmaceutical composition is a liquid pharmaceutical composition and, as such, is liquid under ambient temperature conditions (eg, at a temperature of from 10 to 40° C.).

[0015] The sterile liquid pharmaceutical composition comprises sterile ensifentrine particles. The ensifentrine particles comprise ensifentrine (i.e., ensifentrine free base) or a pharmaceutically acceptable salt thereof. Typically, the ensifentrine particles comprise ensifentrine free base. The ensifentrine particles typically comprise at least 90.0 wt%, preferably at least 95.0 wt% ensifentrine or a pharmaceutically acceptable salt thereof. The ensifentrine particles can consist essentially of ensifentrine or a pharmaceutically acceptable salt thereof, or can consist of ensifentrine or a pharmaceutically acceptable salt thereof. For example, the ensifentrine particles can consist of ensifentrine free base.

[0016] A composition consisting essentially of an ingredient contains only that ingredient and other ingredients that do not materially affect the essential characteristics of the ingredient of which the composition consists essentially. A composition consisting essentially of an ingredient typically contains at least 99.5 wt% of that ingredient, based on the total weight of the composition.

[0017] The sterile ensifentrine particles in the sterile liquid pharmaceutical composition may be suspended in a sterile liquid vehicle. Thus, the sterile liquid pharmaceutical composition typically comprises a suspension of ensifentrine particles. Some or all of the ensifentrine particles in the sterile liquid pharmaceutical composition may be precipitated to the bottom of the container containing the sterile liquid pharmaceutical composition, for example, after a period of storage. The ensifentrine particles may be resuspended by any suitable method, for example, by stirring the sterile liquid pharmaceutical composition.

[0018] Step (a) of the process typically involves heating the ensifentrine particles at a temperature of from 120° C. to 200° C. The process may involve heating the ensifentrine particles at a temperature of from 140° C. to 180° C., such as from 150° C. to 170° C., or from 155° C. to 165° C.

[0019] The ensifentrine particles may be heated for any period of time suitable to produce sterile ensifentrine particles. The process typically involves heating the ensifentrine particles at the temperature for a period of time ranging from 10 minutes to 24 hours. The process may involve heating the ensifentrine particles at the temperature for a period of time ranging from 30 minutes to 360 minutes, for example, from 45 minutes to 160 minutes or from 60 minutes to 140 minutes.

[0020] The process preferably involves heating the ensifentrine particles at a temperature of from 145° C. to 175° C. for a time period of from 45 to 160 minutes. For example, the process may involve heating the ensifentrine particles at a temperature of from 155° C. to 165° C. for a time period of from 110 to 130 minutes.

[0021] Heating ensifentrine particles at a certain temperature range for a certain time means that the temperature of ensifentrine particles is maintained at a temperature within that range for the entire time.Ensifentrine particles are typically heated for the relevant time in one heating step, but heating may alternatively be carried out in two or more separate heating steps.For example, heating at a temperature of 140°C to 180°C for 60 minutes may include a single heating step with a duration of 60 minutes, or may include two separate heating steps with a duration of 30 minutes each.Typically, ensifentrine particles are heated in a single heating step at the temperature for the time.

[0022] Step (a) is typically a dry heat sterilization process. The ensifentrine particles are typically in the form of a dry powder. Thus, the process may include heating a dry powder containing ensifentrine particles at a temperature of 100°C to 220°C to obtain a sterile dry powder containing ensifentrine particles. Typically, the ensifentrine particles are subjected to dry heat treatment themselves. The process may include heating a dry powder of ensifentrine particles (i.e., a dry powder essentially consisting of ensifentrine particles) at a temperature of 100°C to 220°C to obtain a sterile dry powder of ensifentrine particles. The dry powder is typically a powder having a moisture content of less than 5.0 wt%, less than 1.0 wt%, or less than 0.1 wt%.

[0023] The ensifentrin particles typically have a particle size distribution with Dv50 of 0.5 μm to 5.0 μm. Preferably, the ensifentrin particles have Dv50 of 1.0 μm to 2.0 μm. Typically, the ensifentrin particles have Dv10 of 0.2 μm to 1.0 μm, and the ensifentrin particles have Dv90 of 2.5 μm to 6.0 μm. For example, the ensifentrin particles may have Dv10 of 0.4 μm to 0.6 μm, and the ensifentrin particles may have Dv90 of 2.8 μm to 4.2 μm.

[0024] Particle size is described herein with reference to the Dv50 value, which is the median particle size of the volume distribution. Thus, half of the particle volume has a diameter less than the Dv50 value, and half of the particle volume has a diameter greater than the Dv50 value. This is a well-known way of expressing particle size distribution. The parameters Dv10 and Dv90 may also be used to characterize the particle size distribution of a sample. 10% of the particle volume has a diameter less than the Dv10 value. 90% of the particle volume has a diameter less than the Dv90 value.

[0025] The technique used to measure the Dv50 (and Dv10 and Dv90) values ​​referred to herein is typically laser diffraction. The particle size distribution of ensifentrine particles may be measured by laser diffraction using a wet powder dispersion system. For example, the particle size distribution can be measured by laser diffraction using a Malvern Spraytec in combination with a wet dispersion cell. Typically, the instrument parameters for the Malvern Spraytec are as follows: · Particles – standard opaque particles; · Refractive index particles - 1.50; · Refractive index (imaginary) - 0.50; · Particle density - 1.00; · Refractive index of dispersant - 1.33; Control unit - 1000RPM; Measurement type - timed; Initial sampling time - 30s; Decay rate - 20%~30%; Dispersant- 1% Polysorbate 20 in deionized water.

[0026] The ensifentrine particles may be produced by any pharma- ceutically acceptable size reduction or particle size controlled manufacturing process. For example, the particles may be produced by spray drying a solution of ensifentrine, by controlled crystallization, or by size reduction of a solid form of ensifentrine, for example, by air jet milling, mechanical micronization, or media milling.

[0027] The process further includes combining the sterile ensifentrine particles with a sterile liquid vehicle to produce a sterile liquid pharmaceutical composition suitable for administration by inhalation. Combining the sterile ensifentrine particles with a sterile liquid vehicle typically includes mixing the sterile ensifentrine particles with the sterile liquid vehicle.

[0028] A sterile liquid vehicle typically includes one or more diluents. The diluent may be any suitable liquid diluent. For example, a sterile liquid vehicle typically includes water as a diluent. A sterile liquid vehicle may include one or more additional diluents, or a sterile liquid vehicle may include a single diluent. A sterile liquid vehicle may include water as a single diluent.

[0029] A sterile liquid vehicle containing water may be used to prepare a sterile liquid pharmaceutical composition suitable for use in a nebulizer. The sterile liquid vehicle typically further comprises one or more additional excipients selected from a surfactant, a buffer, and an isotonicity agent.

[0030] The sterile liquid vehicle typically further comprises an isotonicity agent. Examples of the isotonicity agent include sodium chloride, potassium chloride, glucose, glycerin and mannitol. Preferably, the isotonicity agent is sodium chloride.

[0031] The concentration of the tonicity agent in the sterile liquid vehicle is typically 1.0 mg / mL or more (e.g., 1.0 to 50.0 mg / mL). Preferably, the tonicity agent concentration is 4.0 to 20.0 mg / mL or 6.0 to 12.0 mg / mL.

[0032] The sterile liquid vehicle typically further comprises one or more surfactants. The one or more surfactants may comprise a non-ionic surfactant, an anionic surfactant, a cationic surfactant, a zwitterionic surfactant, or a mixture thereof. Typically, the one or more surfactants comprise a non-ionic surfactant.

[0033] Examples of surfactants include lecithin, oleic acid, polyoxyethylene glycol alkyl ethers (e.g., PEG 300, PEG 600, PEG 1000, Brij 30, Brij 35, Brij 56, Brij 76 and Brij 97), polypropylene glycol (e.g., PPG 2000), glucoside alkyl ethers, polyoxyethylene glycol octylphenol ethers, polyoxyethylene glycol alkylphenol ethers, glycerol alkyl esters, polyoxyethylene glycol sorbitan alkyl esters (polysorbates, e.g., polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 97), and the like. Examples of surfactants include sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80) and sorbitan trioleate (Span 85), cocamide MEA, cocamide DEA, dodecyl dimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (poloxamer), block copolymers of polyethylene glycol and polypropylene oxide (e.g., Pluronic surfactants), polyvinylpyrrolidone K25, polyvinyl alcohol, oligolactic acid, sodium dioctyl sulfosuccinate and polyethoxylated tallow amine (POEA).

[0034] Preferably, the one or more surfactants include polysorbate and / or sorbitan alkyl ester. The one or more surfactants may include, for example, polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) or polysorbate 80 (polyoxyethylene (20) sorbitan monooleate). The one or more surfactants may include, for example, sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80) or sorbitan trioleate (Span 85). Preferably, the sterile liquid vehicle includes polysorbate 20 and / or sorbitan monolaurate (Span 20).

[0035] The sterile liquid vehicle may include two or more surfactants, or the sterile liquid vehicle may include a single surfactant. For example, the composition may include a single surfactant polysorbate, such as polysorbate 20. The sterile liquid vehicle may include two or more surfactants. For example, the sterile liquid vehicle may include polysorbate 20 and sorbitan monolaurate (Span 20).

[0036] The total concentration of one or more surfactants in the sterile liquid vehicle is typically from 0.01 to 2.0 mg / mL. Preferably, the total concentration of surfactants is from 0.1 to 1.0 mg / mL. For example, the total concentration of surfactants in the sterile liquid vehicle may be from 0.25 to 0.75 mg / mL. The sterile liquid vehicle may, for example, contain polysorbate at a concentration of from 0.1 to 1.0 mg / mL, and optionally sorbitan alkyl ester at a concentration of from 0.01 to 0.1 mg / mL.

[0037] Sterile liquid vehicles typically further comprise one or more buffers. Buffers can be used to control the pH of liquid pharmaceutical compositions. Buffers typically comprise a weak acid and its conjugate base. Examples of buffers include citrate buffer, phosphate buffer, acetate buffer and bicarbonate buffer.

[0038] Preferably, the buffer is a phosphate buffer. For example, the sterile liquid vehicle may contain sodium dihydrogen phosphate dihydrate and / or disodium phosphate dihydrate.

[0039] The pH of the sterile liquid vehicle is typically from 6.0 to 7.5, for example from 6.2 to 7.2. The pH of the sterile liquid vehicle may be from 6.5 to 6.9. The pH of the sterile liquid vehicle is typically the pH measured at a temperature of 20° C. The pH of the sterile liquid vehicle may be measured by any suitable technique. For example, the pH may be measured using a potentiometric pH meter.

[0040] The total concentration of one or more buffering agents in the sterile liquid vehicle is typically from 0.1 to 20.0 mg / mL. Preferably, the buffer concentration is from 1.0 to 2.0 mg / mL. The buffer concentration includes both the acid and conjugate base components of the buffer.

[0041] Typically, the sterile liquid vehicle comprises: water, one or more isotonicity agents, one or more buffers, and one or more surfactants. For example, the sterile liquid vehicle may comprise: water, sodium chloride, sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, polysorbate 20, and sorbitan laurate.

[0042] The process typically further comprises producing a sterile liquid vehicle. The sterile liquid vehicle may be produced by sterilizing the liquid vehicle, for example, by sterile filtration, heat treatment or gamma radiation treatment of the liquid vehicle. The sterile liquid vehicle is typically produced by sterile filtration of the liquid vehicle. Sterile filtration typically comprises filtering the liquid vehicle through a filter having a nominal pore size of 0.5 μm or less, or 0.3 μm or less (e.g., about 0.2 μm).

[0043] The process of the present invention produces a sterile liquid pharmaceutical composition through aseptic processing and compounding.As such, the process typically does not further include the additional step of terminal sterilization, which has been found to cause the presence of impurities in the composition.For example, the process typically does not further include heating the sterile liquid pharmaceutical composition suitable for administration by inhalation, which contains ensifentrine particles, at a temperature of 100°C or higher.

[0044] The concentration of ensifentrine particles in the sterile liquid pharmaceutical composition produced by the process can be any suitable concentration, for example, from 0.01 to 400 mg / mL. Typically, the concentration of ensifentrine particles is from 0.1 to 5.0 mg / mL. Preferably, the concentration of ensifentrine particles is from 0.1 to 2.5 mg / mL. For example, the concentration of ensifentrine particles can be from 0.15 to 0.5 mg / mL, or from 1.0 to 2.0 mg / mL.

[0045] For example, a sterile liquid pharmaceutical composition may include: ·water; Particles consisting of ensifentrine free base in a concentration ranging from 0.1 to 20 mg / mL; ·One or more tonicity agents with a total concentration between 1.0 and 15 mg / mL; one or more buffering agents with a total concentration between 0.1 and 4 mg / mL; and ·One or more surfactants at a total concentration between 0.05 and 3 mg / mL.

[0046] A sterile liquid pharmaceutical composition may include: ·water; Particles containing ensifentrine free base in a concentration of 0.5 to 6 mg / mL; · Sodium chloride in concentrations from 5 to 12 mg / mL; · Sodium dihydrogen phosphate dihydrate in concentrations from 0.3 to 2 mg / mL; · Disodium phosphate dihydrate in concentrations from 0.3 to 2 mg / mL; Polysorbate 20 in concentrations from 0.1 to 1.5 mg / mL; and Sorbitan laurate in concentrations from 0.01 to 0.5 mg / mL.

[0047] The present invention also provides a process for producing ampoules containing a sterile liquid pharmaceutical composition suitable for administration by inhalation. The process includes: (i) producing a sterile liquid pharmaceutical composition suitable for administration by inhalation comprising ensifentrine particles by a process defined herein; and (ii) filling an ampoule with the sterile liquid pharmaceutical composition suitable for administration by inhalation. The ampoule may be a glass ampoule or a plastic ampoule. The ampoule is typically a polyethylene plastic ampoule. The ampoule may be individually overwrapped with an aluminum foil pouch after filling.

[0048] The ampoule may be a blow-fill-seal ampoule. For example, the process may be a process for manufacturing an ampoule using blow-fill-seal technology, the ampoule containing a sterile liquid pharmaceutical composition suitable for administration by inhalation, the process comprising: (i) manufacturing a sterile liquid pharmaceutical composition suitable for administration by inhalation, comprising ensifentrine particles, by a process defined herein; and (ii) manufacturing a blow-fill-seal ampoule filled with the sterile liquid pharmaceutical composition suitable for administration by inhalation. EXAMPLES

[0049] method Assay tests were performed in duplicate using the key high performance liquid chromatography (HPLC) parameters shown in Table 1.

[0050] [Table 1]

[0051] Quantitation of impurities was performed in duplicate using the key high performance liquid chromatography (HPLC) parameters shown in Table 2.

[0052] [Table 2]

[0053] Test Product The effectiveness of different sterilization techniques was evaluated: (i) a suspension formulation containing ensifentrin particles (terminally sterilized); and (ii) Ensifentrin particles prior to formulation as a suspension (sterile blend and fill).

[0054] Three aqueous suspensions were prepared having the formulations shown in Tables 3 to 5.

[0055] [Table 3]

[0056] [Table 4]

[0057] [Table 5]

[0058] Unformulated ensifentrine particles were evaluated as a dry powder.

[0059] sterilization technology The sterilization techniques shown in Table 6 were evaluated.

[0060] [Table 6]

[0061] The sterilized micronized ensifentrin obtained by techniques C through F can then be combined with a sterile vehicle to obtain a suspension formulation.

[0062] result The assay and related substances of the products obtained from each of the sterilization techniques A through F were evaluated by the HPLC method described above, and the results are summarized in Table 7.

[0063] [Table 7]

[0064] conclusion The results in Table 7 showed that terminal heat treatment (Technique A), terminal gamma irradiation (Technique B) and dry gamma irradiation (Technique F) caused some degradation when used to prepare sterile suspensions of ensifentrin particles.

[0065] However, ensifentrin particles are found to be highly resistant to sterilization by dry heat treatment, with no significant change in purity or assay observed when treated at temperatures between 150° C. and 170° C. Dry heat treatment at 160° C. for at least 120 minutes is preferred. The sterilized ensifentrin particles obtained by dry heat treatment can be combined with a suspension vehicle in a sterile compounding and processing procedure to obtain a sterile suspension formulation containing ensifentrin.

Claims

1. 1. A process for producing a sterile liquid pharmaceutical composition suitable for administration by inhalation comprising ensifentrine particles, the process comprising: (a) heating the ensifentrine particles at a temperature of from 100°C to 220°C to obtain sterile ensifentrine particles; and (b) combining the sterile ensifentrine particles with a sterile liquid vehicle to produce a sterile liquid pharmaceutical composition suitable for administration by inhalation.

2. 10. The process of claim 1, comprising heating the ensifentrine particles at a temperature of from 120°C to 200°C.

3. 10. The process of claim 1, comprising heating the ensifentrine particles at a temperature of from 140°C to 180°C.

4. 10. The process of claim 1, comprising heating the ensifentrine particles at said temperature for a period of from 10 minutes to 24 hours.

5. 10. The process of claim 1, comprising heating the ensifentrine particles at said temperature for a time period of from 30 minutes to 360 minutes.

6. 10. The process of claim 1, comprising heating the ensifentrine particles at a temperature of from 145°C to 175°C for a time period of from 45 to 160 minutes.

7. 10. The process of claim 1, comprising heating the ensifentrine particles at a temperature of from 155°C to 165°C for a time period of from 110 to 130 minutes.

8. 2. The process of claim 1, wherein the ensifentrine particles comprise at least 95% by weight of ensifentrine or a pharmaceutically acceptable salt thereof, based on the total weight of the ensifentrine particles.

9. 10. The process of claim 1, wherein the ensifentrine particles are in the form of a dry powder.

10. 2. The process of claim 1, wherein the ensifentrine particles have a particle size distribution with a Dv50 of 0.5 to 5.0 μm.

11. The process of claim 1 , wherein the sterile liquid vehicle comprises a diluent.

12. The process of claim 1, wherein the sterile liquid vehicle comprises a diluent and one or more additional excipients selected from surfactants, buffers, and isotonicity agents.

13. 10. The process of claim 1, wherein the sterile liquid vehicle comprises water as a diluent.

14. 10. The process of claim 1, wherein the sterile liquid vehicle comprises a single diluent, water.

15. 15. The process of claim 14, wherein the sterile liquid vehicle comprises: water, sodium chloride, sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, polysorbate 20, and sorbitan laurate.

16. 10. The process of claim 1, further comprising producing a sterile liquid vehicle by sterile filtration of the liquid vehicle.

17. 10. The process of claim 1, further comprising heating the sterile liquid pharmaceutical composition suitable for administration by inhalation to a temperature of 100°C or greater.

18. 1. A process for producing ampoules containing a sterile liquid pharmaceutical composition suitable for administration by inhalation, the process comprising: (i) producing a sterile liquid pharmaceutical composition suitable for administration by inhalation comprising ensifentrine particles according to the process defined in any one of claims 1 to 17; and (ii) Filling ampoules with a sterile liquid pharmaceutical composition suitable for administration by inhalation.