WO2024025486A1 - A process for the preparation of suspensions for inhalation by nebulization - Google Patents

A process for the preparation of suspensions for inhalation by nebulization Download PDF

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Publication number
WO2024025486A1
WO2024025486A1 PCT/TR2022/050794 TR2022050794W WO2024025486A1 WO 2024025486 A1 WO2024025486 A1 WO 2024025486A1 TR 2022050794 W TR2022050794 W TR 2022050794W WO 2024025486 A1 WO2024025486 A1 WO 2024025486A1
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Prior art keywords
process according
solution
budesonide
mixture
sodium
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PCT/TR2022/050794
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French (fr)
Inventor
Yelda TIGCI EKRAM
Devrim CELIK SAKIZCI
Emine Yilmaz
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Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
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Priority to PCT/TR2022/050794 priority Critical patent/WO2024025486A1/en
Publication of WO2024025486A1 publication Critical patent/WO2024025486A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants

Definitions

  • the invention relates to a simple, rapid, cost effective, timesaving and industrially convenient process for the preparation of a sterile, homogeneous suspension of budesonide or a pharmaceutically acceptable salt thereof for inhalation by nebulization to prevent, treat, or alleviate the symptoms of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease. Further, the present invention also relates to a new inhalation composition comprising budesonide, dispersing or suspending agents, buffering agents, isotonic agents and water for injection.
  • the respiratory tract comprises mainly the lungs and the entirety of the ducts and sacs from the mouth and nose to the alveoli.
  • the respiratory tract has a direct functional relation with the muscle and skeletal system (primarily the diaphragm muscle) providing mechanical ventilation, as well as the cardiovascular system providing blood circulation within the respiratory tract.
  • the factors causing respiratory tract diseases include genetic factors, age, gender, race, infections, as well as environmental factors such as smoking or exposure to cigarette smoke, air pollution, seasonal factors, geographical conditions, professional factors, etc.
  • Drugs such as beta-adrenergic agonists or corticosteroids used in the treatment of respiratory tract diseases are administered through various routes (e.g. inhalation, oral, or parenteral routes).
  • routes e.g. inhalation, oral, or parenteral routes.
  • the preferred route of administration of these drugs is inhalation, since the drugs are directly delivered to the affected sites (airways) in high doses via this route, have a short onset time, and they lack or have minimal systemic side effects.
  • main the inhalation devices, nebulizers, metered dose inhalers, and dry powder inhalers have a widespread use.
  • DPIs dry Powder Inhaler
  • Nebulizers have a relatively simple usage technique compared to metered dose inhaler and dry powder inhaler devices. Nebulizer devices can be selected for patients who cannot use these two devices effectively. The medicine produced in the form of nebules from these devices can be delivered to the lungs by inhaling and exhaling with a mouthpiece or mask.
  • Corticosteroids also known as glucocorticosteroids, glucocorticoids or just steroids
  • corticosteroids are among the most widely used drugs in the world and are effective in many inflammatory and immune diseases.
  • the most common use of corticosteroids is in the treatment of asthma, where inhaled corticosteroids have become first-line therapy and by far the most effective antiinflammatory treatment.
  • Inhaled corticosteroids are now used as first-line therapy for the treatment of persistent asthma in adults and children in many countries, as they are the most effective treatments for asthma currently available.
  • corticosteroids The predominant effect of corticosteroids is to switch off multiple inflammatory genes (encoding cytokines, chemokines, adhesion molecules, inflammatory enzymes, receptors and proteins) that have been activated during the chronic inflammatory process. (Barnes (2003) Ann Stajyer Med139:359-370)
  • Budesonide sold under the brand name Pulmicort®, is a medication of the corticosteroid type. It is available as an inhaler, nebulization solution, pill, nasal spray, and rectal forms. The inhaled form is used in the long-term management of asthma and chronic obstructive pulmonary disease. Interim results from a randomized open-label UK study using the inhaled steroid budesonide reported faster recovery and reduced hospitalization in people with mild COVID-19 at higher risk of progression.
  • budesonide 1617-Butylidenebis(oxy)-11 ,21-dihydroxypregna-1 ,4- diene-3, 20-dione, has the following chemical structure of Formula I.
  • Effective delivery of the inhaler formulations to the lungs is achieved by optimizing the formulation and process steps with the device, active agent and pharmaceutical excipients.
  • the pharmaceutical excipients included in the drug formulation must be properly selected, quantified, and included in the process in determining steps.
  • the dispersing or suspending agents, buffering agents, isotonic agents and water for injection used in a certain order in the process steps and their weight ratio are important in terms of increased stability, delivery rate, and total active agent values. Also, the type of all these pharmaceutical excipients has a critical effect on these quality parameters and accordingly, the performance of the suspension product.
  • the weight ratios of the said pharmaceutical excipients used in the process and the steps of adding them to the process are of great importance in terms of ensuring homogenization and preventing losses in the process.
  • EP 1 494 647 B1 relates a process for the preparation of aqueous suspensions of sterile micronized drug particles, in particular corticosteroid, to be administered by inhalation, which produces homogenous dispersions of particles characterized by optimal size and size distribution is disclosed.
  • the process is carried out by using a turbo-emulsifier equipped with a high-power turbine and connected to a loading hopper.
  • the present invention provides a new process for the preparation of a sterile, homogeneous suspension of budesonide or a pharmaceutically acceptable salt thereof for inhalation by nebulization to prevent, treat, or alleviate the symptoms of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease.
  • the main object of the present invention is to provide a new process for the preparation a sterile, homogeneous suspension of budesonide or a pharmaceutically acceptable salt thereof for inhalation by nebulization which eliminates all aforesaid problems and brings additional advantages to the relevant prior art.
  • Another object of the present invention is to provide a process for the preparation of a sterile, homogeneous suspension of budesonide or a pharmaceutically acceptable salt thereof for inhalation by nebulization to prevent, treat or alleviate, the symptoms of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease.
  • Another object of the present invention is to optimize the formulation and processing steps comprising the active agent and pharmaceutical excipients to ensure effective delivery of inhaler formulations to the lung.
  • Another object of the present invention is to provide a process for the preparation of a sterile, homogeneous suspension of budesonide or a pharmaceutically acceptable salt thereof for inhalation by nebulization with enhanced uniformity and homogeneity.
  • Another object of the present invention is to provide a process for the preparation of suspension to be used in pharmaceutical formulations for inhalation by nebulization with increased stability, enhanced fine particle dose (FPD), fine particle fraction (FPF), delivery rate and total active agent values.
  • FPD fine particle dose
  • FPF fine particle fraction
  • Another object of the present invention is to homogenize the active agent properly and to ensure the formation of a stable colloidal suspension by the production process.
  • a stable, homogeneous and effective suspension to delivery to the lungs is obtained by the said production process.
  • Another object of the present invention is to provide a new drug delivery formulation that allows budesonide or a pharmaceutically acceptable salt thereof to reach the target tissue effectively provided by the above-mentioned process.
  • Another object of the present invention is to provide a process for the preparation of suspension to prevent foam formation by using the peristaltic pump.
  • Another object of the present invention is to provide a sterile active agent that is sterilized by autoclaving.
  • the present invention relates a process for the preparation of a sterile, homogeneous suspension of budesonide or a pharmaceutically acceptable salt thereof for inhalation by nebulization, which comprises the following steps; a- obtaining Solution A
  • the invention defines a sterile, homogeneous suspension for inhalation by nebulization obtained by the process subjected to the invention.
  • a sterile, homogeneous suspension for inhalation by nebulization comprising the active agent, dispersing or suspending agents, buffering agents, isotonic agents and water for injection.
  • the active agent is budesonide or pharmaceutically acceptable salt thereof.
  • the concentration of budesonide in the suspension is 0.1-5 mg/ml, preferably 0.1-3 mg/ml, more preferably 0.1-2.5 mg/ml.
  • a suitable dispersing medium by including the dispersing or suspending agents in the process before the active agents to help disperse the active agents which are easily wetted and sinks to the bottom such as budesonide.
  • the main purpose of dispersing a powder in a liquid is to separate primary particles from aggregates and agglomerates and then stabilize them in the liquid medium. This requires an effective dispersing or suspending agent that adsorbs very quickly at the solid/liquid interface.
  • the key criterion for an effective dispersing or suspending agent is strong adsorption or attachment to the particle surface. This requires the dispersing or suspending agents to be attached to the active agent particle surface at multiple points.
  • dispersing or suspending agents in suspension is to reduce the surface energy of the powder. This facilitates the decomposition and homogeneous dispersion stages of the agglomerates of the particles in the following homogenization.
  • the applied process steps have a direct effect on the blend uniformity, which is one of the first chemical indicators of the product's quality profile. It has been observed that the blend uniformity is increased by adding dispersing or suspending agents to the process. The steps of adding dispersing or suspending agents and their weight ratios of great importance in order to ensure homogenization and prevent losses in the process.
  • the dispersing or suspending agents are selected from the group comprising polysorbate 80, polysorbate 20, sorbitan monolaurate, sorbitan trioleate (SpanR85), sorbitan mono-oleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, glyceryl mono-oleate, polyethylene glycol 400 and glyceryl monolaurate or mixtures thereof.
  • polysorbate 80 polysorbate 20
  • sorbitan monolaurate sorbitan trioleate
  • SpanR85 sorbitan trioleate
  • sorbitan mono-oleate natural lecithin
  • oleyl polyoxyethylene (2) ether stearyl poly
  • dispersing or suspending agent is polysorbate 80.
  • the concentration of polysorbate 80 in the suspension is between 0.01-1 mg/ml.
  • the pharmaceutical suspension comprises one or more buffering agents.
  • the buffering agents may be any buffering agents suitable for use in a liquid pharmaceutical composition for administration by inhalation.
  • the pharmaceutical composition comprises at least two buffering agents in the present invention.
  • the buffering agents are selected from the group comprising disodium edetate, monosodium phosphate dihydrate, dibasic sodium phosphate anhydrous, citric acid anhydrous, phosphate buffers, acetate buffers, acetic acid, sulfuric acid, fumaric acid, lactic acid, malic acid, tartaric acid, phosphoric acid, sodium carbonate, potassium carbonate, ammonium carbonate, sodium sulfate, sodium hydroxide, potassium hydroxide, sodium citrate dihydrate or mixtures thereof.
  • the buffering agents are disodium edetate, sodium citrate dihydrate and citric acid anhydrous.
  • the concentration of disodium edetate in the suspension is between 0.01-1 mg/ml.
  • the concentration of sodium citrate dihydrate in the suspension is between 0.1-5 mg/ml. According to one embodiment, the concentration of citric acid anhydrous in the suspension is between 0.1-5 mg/ml.
  • the pharmaceutical suspension typically comprises isotonic agents.
  • Suspensions will desirably be isotonic.
  • the formulations which are used present process may be adjusted to desired isotonicity by the addition of suitable isotonic agents.
  • the isotonic agent is selected from the group comprising sodium chloride, potassium chloride and sodium bromide or mixtures thereof.
  • the isotonic agent is sodium chloride.
  • the concentration of sodium chloride in the suspension is between 1-10 mg/ml.
  • the concentration of Solution A is 1-30 mg/ml, preferably 5-25 mg/ml, more preferably 10-20 mg/ml.
  • autoclaving of budesonide is carried out at a temperature of 121 °C for about 15 to about 30 minutes, preferably 20 minutes.
  • the inventors have been observed physical and chemical degradations when they applied the various sterilization types specified in the state of the art to this process.
  • One of the most important points of the invention is the use of autoclaving, among the sterilization types mentioned in the state of the art.
  • the inventors have surprisingly been found that the problems of chemical and physical degradation of the product have been solved when they applied autoclaving. Because steam is a kind of vapor that is formed when water is boiled, it effectively is water but in a different state of matter so it is a simple sterilization method without using chemicals etc.
  • the problems of chemical and physical degradation of the product, which occur in other sterilization methods, are solved by autoclaving.
  • the temperature of the mixture in the step numbered a (ii) and b (ii) is 30-60°C, preferably 35-55°C, more preferably 40-50°C.
  • the reason for this specific temperature is to increase the solubility or distribution of the pharmaceutical excipients to be added.
  • the temperature of the mixture in the step numbered b (iii) is 10-40°C, preferably 15-35°C, more preferably 20-30°C.
  • the stability and homogeneity of the colloidal suspension is very important in the production process of the inhaler nebulization suspension.
  • the mixture is homogenized at a minimum speed of 8000 rpm by a high- pressure homogenizer for 2 hours to ensure that the active agent is homogeneously dispersed in the suspension and form a stable colloidal suspension.
  • the said formation of a stable colloidal suspension and homogeneous active ingredient distribution provide a suitable mixing uniformity for the product.
  • the fact that the product has a homogeneous active ingredient distribution and an appropriate mixing uniformity result is advantageous in terms of the appropriate fine particle size and the appropriate total amount of agent delivered.
  • the mixture foams and the active agents attach to the foam and collect at the top of the mixture. If the mixture cannot be homogeneous, a suitable product with desired therapeutic properties cannot be produced.
  • the rotational speed at which the mixing process takes place is also critical. If a low rotational speed is used, mixing uniformity may not be achieved. If the mixture cannot be homogeneous, a suitable product with desired therapeutic properties cannot be produced. On the other hand, at high rotational speed, the mixture foams and the active agents attach to the foam and collect at the top of the mixture. Since the active agent attach to the foam, the problem of loss of active agents and mixing uniformity is observed in the prepared suspension. Thus, the uniformity of mixing will still not be achieved. Therefore, foaming that occurs during mixing at high rotational speed is an important problem. The inventors, surprisingly, have noticed that utilization a peristaltic pump during the transfer of Solution A to the production tank comprising Solution B eliminates the risk of severe foaming.
  • the rotational speed in the step numbered a (v) is 3000-18000 rpm, preferably 3200-15000 rpm, more preferably 3400-12000 rpm.
  • the rotational speed in the step numbered a (iv) and b (iii) is 200-1400 rpm, preferably 500-1000 rpm.
  • duration of the step numbered a (v) and c (ii) is 90-130 minutes, preferably 95-125 minutes, more preferably 100-120 minutes.
  • Particle size distribution of the active agent plays a critical role for the qualification of the composition subjected to the invention.
  • particle size distribution means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (Malvern analysis).
  • Laser diffraction measures particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering. The particle size is reported as a volume equivalent sphere diameter.
  • the active agent particles have a particle size (Dgo value) lower than 10 pm.
  • the below-given formulation can be used process for the preparation of a sterile, homogeneous suspension subjected to the invention.
  • This example is not limiting the scope of the present invention and should be considered under the light of the foregoing detailed disclosure.
  • a sterile, homogeneous suspension subjected to the invention is used to prevent, treat, or alleviate the symptoms of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease.
  • Example 1 Inhalation composition of budesonide for administration by nebulization Sterilization of budesonide
  • Budesonide is weighed into a Schott® bottle and that is sterilized by autoclaving which is carried out at a temperature of 121 °C for about 15 to about 30 minutes, preferably 20 minutes.
  • Budesonide is easily wetted and sinks to the bottom. For this reason, the sterile Polysorbate 80 solution is slowly transferred to the bottle comprising budesonide, which has been sterilized by autoclaving. The speed of the magnetic stirrer is gradually increased to a minimum of 600 rpm and mixed for a minimum of 2 hours.
  • the final mixture is homogenized with a homogenizer at 8000 rpm for a minimum of 120 minutes. During homogenization, the mixture is also mixed by a magnetic stirrer with a magnetic stirring bar at a minimum speed of 600 rpm.
  • the temperature of the mixture should be at room temperature (25-30°C), so the temperature is controlled before filtration.
  • the rest of the water for injection is taken into the tank which has mixer.
  • the temperature of the water is heated to 40 ⁇ 5 °C.
  • Sodium chloride, disodium edetate, sodium citrate dihydrate and citric acid anhydrous are respectively added at period of 10 minutes while the tank with mixer is mixing at approximately 600 rpm.
  • the final mixture is mixed for 1 hour with the mixer of the tank at a minimum speed of 600 rpm.
  • the solution in the tank is filtered with a 0.45 p + 0.2 p pore size membrane filter and transferred to the production tank.
  • Solution A is slowly transferred onto Solution B by a peristaltic pump to prevent foam formation.
  • Solution A is mixed with a magnetic stirring bar at a minimum speed of 600 rpm by a magnetic stirrer.
  • the production tank will be mixed at a minimum speed of 50 rpm.
  • the Solution A bottle is washed with Solution B divided for washing and transferred to the production tank comprising Solution B.
  • the final mixture is mixed at a minimum speed of 50 rpm for 2 hours.

Abstract

The invention relates to a simple, rapid, cost effective, timesaving and industrially convenient process for the preparation of a sterile, homogeneous suspension of budesonide or a pharmaceutically acceptable salt thereof for inhalation by nebulization to prevent, treat, or alleviate the symptoms of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease. Further, the present invention also relates to a new inhalation composition comprising budesonide, dispersing or suspending agents, buffering agents, isotonic agents and water for injection.

Description

A PROCESS FOR THE PREPARATION OF SUSPENSIONS FOR INHALATION BY NEBULIZATION
Field of Invention
The invention relates to a simple, rapid, cost effective, timesaving and industrially convenient process for the preparation of a sterile, homogeneous suspension of budesonide or a pharmaceutically acceptable salt thereof for inhalation by nebulization to prevent, treat, or alleviate the symptoms of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease. Further, the present invention also relates to a new inhalation composition comprising budesonide, dispersing or suspending agents, buffering agents, isotonic agents and water for injection.
The background of the invention
The respiratory tract comprises mainly the lungs and the entirety of the ducts and sacs from the mouth and nose to the alveoli. The respiratory tract has a direct functional relation with the muscle and skeletal system (primarily the diaphragm muscle) providing mechanical ventilation, as well as the cardiovascular system providing blood circulation within the respiratory tract. There are many factors leading to respiratory tract diseases. The factors causing respiratory tract diseases (e.g. chronic obstructive pulmonary disease, lung cancer, cystic fibrosis, asthma, pneumonia, tuberculosis) include genetic factors, age, gender, race, infections, as well as environmental factors such as smoking or exposure to cigarette smoke, air pollution, seasonal factors, geographical conditions, professional factors, etc.
Drugs such as beta-adrenergic agonists or corticosteroids used in the treatment of respiratory tract diseases are administered through various routes (e.g. inhalation, oral, or parenteral routes). However, the preferred route of administration of these drugs is inhalation, since the drugs are directly delivered to the affected sites (airways) in high doses via this route, have a short onset time, and they lack or have minimal systemic side effects. For this reason, main the inhalation devices, nebulizers, metered dose inhalers, and dry powder inhalers have a widespread use.
Among the most frequently encountered problems in the use of metered dose inhalers (MDIs) are the lack of achieving an adequate "hand-inhalation" synchronization in terms of inhaler users, the decline in cognitive functions due to advanced age and mental disorders, and the inability of the users in recognizing the finished state of the inhaler drug due to the lack of a counter. Dry Powder Inhaler (DPIs) used to deliver active agents requires adequate flow rate. So, DPIs still have the disadvantage of significant upper airway deposition of drug. As compared to other inhalation devices, nebulizers are easier to use. Nebulizers have a relatively simple usage technique compared to metered dose inhaler and dry powder inhaler devices. Nebulizer devices can be selected for patients who cannot use these two devices effectively. The medicine produced in the form of nebules from these devices can be delivered to the lungs by inhaling and exhaling with a mouthpiece or mask.
Corticosteroids (also known as glucocorticosteroids, glucocorticoids or just steroids) are among the most widely used drugs in the world and are effective in many inflammatory and immune diseases. The most common use of corticosteroids is in the treatment of asthma, where inhaled corticosteroids have become first-line therapy and by far the most effective antiinflammatory treatment. (Barnes & Adcock, 2003; Rhen & Cidlowski, 2005) Inhaled corticosteroids are now used as first-line therapy for the treatment of persistent asthma in adults and children in many countries, as they are the most effective treatments for asthma currently available. The predominant effect of corticosteroids is to switch off multiple inflammatory genes (encoding cytokines, chemokines, adhesion molecules, inflammatory enzymes, receptors and proteins) that have been activated during the chronic inflammatory process. (Barnes (2003) Ann Stajyer Med139:359-370)
Budesonide, sold under the brand name Pulmicort®, is a medication of the corticosteroid type. It is available as an inhaler, nebulization solution, pill, nasal spray, and rectal forms. The inhaled form is used in the long-term management of asthma and chronic obstructive pulmonary disease. Interim results from a randomized open-label UK study using the inhaled steroid budesonide reported faster recovery and reduced hospitalization in people with mild COVID-19 at higher risk of progression.
The chemical name of budesonide is 16,17-Butylidenebis(oxy)-11 ,21-dihydroxypregna-1 ,4- diene-3, 20-dione, has the following chemical structure of Formula I.
Figure imgf000004_0001
Formula I
Effective delivery of the inhaler formulations to the lungs is achieved by optimizing the formulation and process steps with the device, active agent and pharmaceutical excipients. In order to ensure effective delivery of budesonide to the lungs, the pharmaceutical excipients included in the drug formulation must be properly selected, quantified, and included in the process in determining steps.
The dispersing or suspending agents, buffering agents, isotonic agents and water for injection used in a certain order in the process steps and their weight ratio are important in terms of increased stability, delivery rate, and total active agent values. Also, the type of all these pharmaceutical excipients has a critical effect on these quality parameters and accordingly, the performance of the suspension product.
The weight ratios of the said pharmaceutical excipients used in the process and the steps of adding them to the process are of great importance in terms of ensuring homogenization and preventing losses in the process.
The patent numbered EP 1 494 647 B1 relates a process for the preparation of aqueous suspensions of sterile micronized drug particles, in particular corticosteroid, to be administered by inhalation, which produces homogenous dispersions of particles characterized by optimal size and size distribution is disclosed. The process is carried out by using a turbo-emulsifier equipped with a high-power turbine and connected to a loading hopper.
In the prior art, there are several processes for producing sterile pharmaceutical formulations for inhalation. However, the stages of adding the pharmaceutical excipients and active agents used in the process and the rotation speed applied are of great importance in terms of ensuring homogenization, completing the process in a short time and preventing losses in the process. For example, the high rotational speed causes the product to foam. Since the active agents adhere to the foam, the problem of loss of active agents occurs and poor blend uniformity is observed in the prepared suspension. On the other hand, mixing the active agents at a very low rotational speed causes the problem of blend uniformity.
Considering the state of art, there is still a need for innovative processes that will solve the homogenization and sterilization problems, and which will provide a standardized method for the fast, robust and reproducible production of sterile, homogeneous suspensions for inhalation.
Therefore, production processes consisting of optimized steps for the preparation of a sterile, homogeneous suspension comprising budesonide as an active agent for inhalation by nebulization will provide a development and improvement in the technical field. For this purpose, the present invention provides a new process for the preparation of a sterile, homogeneous suspension of budesonide or a pharmaceutically acceptable salt thereof for inhalation by nebulization to prevent, treat, or alleviate the symptoms of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease.
Objects and Brief Description of the Invention
The main object of the present invention is to provide a new process for the preparation a sterile, homogeneous suspension of budesonide or a pharmaceutically acceptable salt thereof for inhalation by nebulization which eliminates all aforesaid problems and brings additional advantages to the relevant prior art.
Another object of the present invention is to provide a process for the preparation of a sterile, homogeneous suspension of budesonide or a pharmaceutically acceptable salt thereof for inhalation by nebulization to prevent, treat or alleviate, the symptoms of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease.
Another object of the present invention is to optimize the formulation and processing steps comprising the active agent and pharmaceutical excipients to ensure effective delivery of inhaler formulations to the lung.
Another object of the present invention is to provide a process for the preparation of a sterile, homogeneous suspension of budesonide or a pharmaceutically acceptable salt thereof for inhalation by nebulization with enhanced uniformity and homogeneity. Another object of the present invention is to provide a process for the preparation of suspension to be used in pharmaceutical formulations for inhalation by nebulization with increased stability, enhanced fine particle dose (FPD), fine particle fraction (FPF), delivery rate and total active agent values.
Another object of the present invention is to homogenize the active agent properly and to ensure the formation of a stable colloidal suspension by the production process. Thus, a stable, homogeneous and effective suspension to delivery to the lungs is obtained by the said production process.
Another object of the present invention is to provide a new drug delivery formulation that allows budesonide or a pharmaceutically acceptable salt thereof to reach the target tissue effectively provided by the above-mentioned process.
Another object of the present invention is to provide a process for the preparation of suspension to prevent foam formation by using the peristaltic pump.
Another object of the present invention is to provide a sterile active agent that is sterilized by autoclaving.
Detailed description of the invention
In accordance with the objects outlined above, detailed features of the present invention are given herein.
The present invention relates a process for the preparation of a sterile, homogeneous suspension of budesonide or a pharmaceutically acceptable salt thereof for inhalation by nebulization, which comprises the following steps; a- obtaining Solution A
(i) sterilizing budesonide by autoclaving,
(ii) heating the water for injection,
(iii) adding dispersing or suspending agents to the water for injection and mixing,
(iv) filtering the said mixture through the membrane filter, transferring to the bottle comprising the budesonide and mixing,
(v) homogenizing the mixture by a homogenizer. b- obtaining Solution B
(i) adding the rest of the water for injection into the tank which has mixer, (ii) heating the water for injection,
(iii) adding respectively isotonic agent and at least one buffering agents and mixing,
(iv) filtering the mixture through the membrane filter, c- mixing Solution A and Solution B
(i) transferring Solution A to the production tank comprising Solution B by a peristaltic pump,
(ii) mixing the final mixture.
The invention defines a sterile, homogeneous suspension for inhalation by nebulization obtained by the process subjected to the invention.
According to the preferred embodiment, a sterile, homogeneous suspension for inhalation by nebulization comprising the active agent, dispersing or suspending agents, buffering agents, isotonic agents and water for injection.
According to the preferred embodiment, the active agent is budesonide or pharmaceutically acceptable salt thereof.
According to one embodiment, the concentration of budesonide in the suspension is 0.1-5 mg/ml, preferably 0.1-3 mg/ml, more preferably 0.1-2.5 mg/ml.
An important factor is the preparation of a suitable dispersing medium by including the dispersing or suspending agents in the process before the active agents to help disperse the active agents which are easily wetted and sinks to the bottom such as budesonide.
The main purpose of dispersing a powder in a liquid is to separate primary particles from aggregates and agglomerates and then stabilize them in the liquid medium. This requires an effective dispersing or suspending agent that adsorbs very quickly at the solid/liquid interface. The key criterion for an effective dispersing or suspending agent is strong adsorption or attachment to the particle surface. This requires the dispersing or suspending agents to be attached to the active agent particle surface at multiple points.
In addition, another role of the dispersing or suspending agents in suspension is to reduce the surface energy of the powder. This facilitates the decomposition and homogeneous dispersion stages of the agglomerates of the particles in the following homogenization.
The applied process steps have a direct effect on the blend uniformity, which is one of the first chemical indicators of the product's quality profile. It has been observed that the blend uniformity is increased by adding dispersing or suspending agents to the process. The steps of adding dispersing or suspending agents and their weight ratios of great importance in order to ensure homogenization and prevent losses in the process.
According to the one embodiment, the dispersing or suspending agents are selected from the group comprising polysorbate 80, polysorbate 20, sorbitan monolaurate, sorbitan trioleate (SpanR85), sorbitan mono-oleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, glyceryl mono-oleate, polyethylene glycol 400 and glyceryl monolaurate or mixtures thereof.
According to the preferred embodiment, dispersing or suspending agent is polysorbate 80.
According to one embodiment, the concentration of polysorbate 80 in the suspension is between 0.01-1 mg/ml.
Typically, the pharmaceutical suspension comprises one or more buffering agents. The buffering agents may be any buffering agents suitable for use in a liquid pharmaceutical composition for administration by inhalation.
According to one embodiment, the pharmaceutical composition comprises at least two buffering agents in the present invention.
According to one embodiment, the buffering agents are selected from the group comprising disodium edetate, monosodium phosphate dihydrate, dibasic sodium phosphate anhydrous, citric acid anhydrous, phosphate buffers, acetate buffers, acetic acid, sulfuric acid, fumaric acid, lactic acid, malic acid, tartaric acid, phosphoric acid, sodium carbonate, potassium carbonate, ammonium carbonate, sodium sulfate, sodium hydroxide, potassium hydroxide, sodium citrate dihydrate or mixtures thereof.
According to the preferred embodiment, the buffering agents are disodium edetate, sodium citrate dihydrate and citric acid anhydrous.
According to one embodiment, the concentration of disodium edetate in the suspension is between 0.01-1 mg/ml.
According to one embodiment, the concentration of sodium citrate dihydrate in the suspension is between 0.1-5 mg/ml. According to one embodiment, the concentration of citric acid anhydrous in the suspension is between 0.1-5 mg/ml.
The pharmaceutical suspension typically comprises isotonic agents. Suspensions will desirably be isotonic. The formulations which are used present process may be adjusted to desired isotonicity by the addition of suitable isotonic agents.
According to the preferred embodiment, the isotonic agent is selected from the group comprising sodium chloride, potassium chloride and sodium bromide or mixtures thereof.
According to the preferred embodiment, the isotonic agent is sodium chloride.
According to one embodiment, the concentration of sodium chloride in the suspension is between 1-10 mg/ml.
According to the preferred embodiment, the concentration of Solution A is 1-30 mg/ml, preferably 5-25 mg/ml, more preferably 10-20 mg/ml.
According to one embodiment, autoclaving of budesonide is carried out at a temperature of 121 °C for about 15 to about 30 minutes, preferably 20 minutes.
The inventors have been observed physical and chemical degradations when they applied the various sterilization types specified in the state of the art to this process. One of the most important points of the invention is the use of autoclaving, among the sterilization types mentioned in the state of the art. On the other hand, the inventors have surprisingly been found that the problems of chemical and physical degradation of the product have been solved when they applied autoclaving. Because steam is a kind of vapor that is formed when water is boiled, it effectively is water but in a different state of matter so it is a simple sterilization method without using chemicals etc. The problems of chemical and physical degradation of the product, which occur in other sterilization methods, are solved by autoclaving.
According to the one embodiment, the temperature of the mixture in the step numbered a (ii) and b (ii) is 30-60°C, preferably 35-55°C, more preferably 40-50°C. The reason for this specific temperature is to increase the solubility or distribution of the pharmaceutical excipients to be added.
According to the one embodiment, the temperature of the mixture in the step numbered b (iii) is 10-40°C, preferably 15-35°C, more preferably 20-30°C. The stability and homogeneity of the colloidal suspension is very important in the production process of the inhaler nebulization suspension. In the present invention, after mixing solution A at a minimum speed of 600 rpm by a magnetic stirrer with a magnetic stirring bar for a minimum of 2 hours, the mixture is homogenized at a minimum speed of 8000 rpm by a high- pressure homogenizer for 2 hours to ensure that the active agent is homogeneously dispersed in the suspension and form a stable colloidal suspension. The said formation of a stable colloidal suspension and homogeneous active ingredient distribution provide a suitable mixing uniformity for the product. The fact that the product has a homogeneous active ingredient distribution and an appropriate mixing uniformity result is advantageous in terms of the appropriate fine particle size and the appropriate total amount of agent delivered.
On the other hand, at high rotational speed, the mixture foams and the active agents attach to the foam and collect at the top of the mixture. If the mixture cannot be homogeneous, a suitable product with desired therapeutic properties cannot be produced.
In the present invention, the rotational speed at which the mixing process takes place is also critical. If a low rotational speed is used, mixing uniformity may not be achieved. If the mixture cannot be homogeneous, a suitable product with desired therapeutic properties cannot be produced. On the other hand, at high rotational speed, the mixture foams and the active agents attach to the foam and collect at the top of the mixture. Since the active agent attach to the foam, the problem of loss of active agents and mixing uniformity is observed in the prepared suspension. Thus, the uniformity of mixing will still not be achieved. Therefore, foaming that occurs during mixing at high rotational speed is an important problem. The inventors, surprisingly, have noticed that utilization a peristaltic pump during the transfer of Solution A to the production tank comprising Solution B eliminates the risk of severe foaming.
According to one embodiment, the rotational speed in the step numbered a (v) is 3000-18000 rpm, preferably 3200-15000 rpm, more preferably 3400-12000 rpm.
According to one embodiment, the rotational speed in the step numbered a (iv) and b (iii) is 200-1400 rpm, preferably 500-1000 rpm.
According to one embodiment, duration of the step numbered a (v) and c (ii) is 90-130 minutes, preferably 95-125 minutes, more preferably 100-120 minutes.
Particle size distribution of the active agent plays a critical role for the qualification of the composition subjected to the invention. As used herein, ‘particle size distribution’ means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (Malvern analysis).
Laser diffraction measures particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering. The particle size is reported as a volume equivalent sphere diameter.
In the preferred embodiment of the invention, the active agent particles have a particle size (Dgo value) lower than 10 pm.
As seen above, there are various processes for the preparation of a sterile, homogeneous suspension. The active and pharmaceutical excipients used in the process steps in a certain order in the process steps and using certain mixing speeds in certain steps, the time and temperature of the process steps are important in terms of increased stability, delivery rate and total active agent values.
According to all these embodiments, the below-given formulation can be used process for the preparation of a sterile, homogeneous suspension subjected to the invention. This example is not limiting the scope of the present invention and should be considered under the light of the foregoing detailed disclosure.
According to the preferred embodiment, a sterile, homogeneous suspension subjected to the invention is used to prevent, treat, or alleviate the symptoms of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease.
Example 1 : Inhalation composition of budesonide for administration by nebulization
Figure imgf000011_0001
Sterilization of budesonide
Budesonide is weighed into a Schott® bottle and that is sterilized by autoclaving which is carried out at a temperature of 121 °C for about 15 to about 30 minutes, preferably 20 minutes.
Mixing the water for injection-Polysorbate 80
1400 grams of water for injection is weighed into another Schott® bottle. The temperature of the water is heated to 45±5°C. Approximately 400 ml of the heated water is divided for washing. The weighed Polysorbate 80 is added to the water. The weighing bottle is washed by the water divided for washing. Polysorbate 80 solution is mixed at a minimum speed of 600 rpm by a magnetic stirrer with a magnetic stirring bar for a minimum of 1 hour. Then, the prepared Polysorbate 80 solution is sterilized by filtering through a 0.45 p + 0.2 p pore size membrane filter into Schott® bottle.
Preparation of Solution A
Budesonide is easily wetted and sinks to the bottom. For this reason, the sterile Polysorbate 80 solution is slowly transferred to the bottle comprising budesonide, which has been sterilized by autoclaving. The speed of the magnetic stirrer is gradually increased to a minimum of 600 rpm and mixed for a minimum of 2 hours.
Homogenization
The final mixture is homogenized with a homogenizer at 8000 rpm for a minimum of 120 minutes. During homogenization, the mixture is also mixed by a magnetic stirrer with a magnetic stirring bar at a minimum speed of 600 rpm. The temperature of the mixture should be at room temperature (25-30°C), so the temperature is controlled before filtration.
Preparation of Solution B
The rest of the water for injection is taken into the tank which has mixer. The temperature of the water is heated to 40±5 °C. Sodium chloride, disodium edetate, sodium citrate dihydrate and citric acid anhydrous are respectively added at period of 10 minutes while the tank with mixer is mixing at approximately 600 rpm. The final mixture is mixed for 1 hour with the mixer of the tank at a minimum speed of 600 rpm. The solution in the tank is filtered with a 0.45 p + 0.2 p pore size membrane filter and transferred to the production tank.
Mixing Solution A and Solution B
Approximately 3 L of Solution B is divided for washing. Solution A is slowly transferred onto Solution B by a peristaltic pump to prevent foam formation. During the transfer of Solution A to the production tank comprising Solution B, Solution A is mixed with a magnetic stirring bar at a minimum speed of 600 rpm by a magnetic stirrer. During the transfer of Solution A to the production tank comprising Solution B with a peristaltic pump, the production tank will be mixed at a minimum speed of 50 rpm. The Solution A bottle is washed with Solution B divided for washing and transferred to the production tank comprising Solution B. The final mixture is mixed at a minimum speed of 50 rpm for 2 hours.

Claims

1 . A process for the preparation of a sterile, homogeneous suspension of budesonide or a pharmaceutically acceptable salt thereof for inhalation by nebulization, which comprises the following steps; a- obtaining Solution A
(i) sterilizing budesonide by autoclaving,
(ii) heating the water for injection,
(iii) adding dispersing or suspending agents to the water for injection and mixing,
(iv) filtering the said mixture through the membrane filter, transferring to the bottle comprising the budesonide and mixing,
(v) homogenizing the mixture by a homogenizer. b- obtaining Solution B
(i) adding the rest of the water for injection into the tank which has mixer,
(ii) heating the water for injection,
(iii) adding respectively isotonic agent and at least one buffering agents and mixing,
(iv) filtering the mixture through the membrane filter, c- mixing Solution A and Solution B
(1) transferring Solution A to the production tank comprising Solution B by a peristaltic pump,
(ii) mixing the final mixture.
2. The process according to claim 1 , wherein the dispersing or suspending agents are selected from the group comprising polysorbate 80, polysorbate 20, sorbitan monolaurate, sorbitan trioleate (SpanR85), sorbitan mono-oleate, natural lecithin, oleyl polyoxyethylene
(2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, glyceryl mono-oleate, polyethylene glycol 400 and glyceryl monolaurate or mixtures thereof.
3. The process according to claim 2, dispersing or suspending agent is polysorbate 80.
4. The process according to claim 1 , wherein the buffering agents are selected from the group comprising disodium edetate, monosodium phosphate dihydrate, dibasic sodium phosphate anhydrous, citric acid anhydrous, phosphate buffers, acetate buffers, acetic acid, sulfuric acid, fumaric acid, lactic acid, malic acid, tartaric acid, phosphoric acid, sodium carbonate, potassium carbonate, ammonium carbonate, sodium sulfate, sodium hydroxide, potassium hydroxide, sodium citrate dihydrate or mixtures thereof.
5. The process according to claim 4, wherein the buffering agents are disodium edetate, sodium citrate dihydrate and citric acid anhydrous.
6. The process according to claim 1 , wherein the isotonic agent is selected from the group comprising sodium chloride, potassium chloride and sodium bromide or mixtures thereof.
7. The process according to claim 6, the isotonic agent is sodium chloride.
8. The process according to any one of the preceding claims, wherein the autoclaving of budesonide is carried out at a temperature of 121°C for about 15 to about 30 minutes, preferably 20 minutes.
9. The process according to any one of the preceding claims, wherein the temperature of the mixture in the step numbered a (ii) and b (ii) is 30-60°C, preferably 35-55°C, more preferably 40-50°C.
10. The process according to any one of the preceding claims, wherein the temperature of the mixture in the step numbered b (iii) is 10-40°C, preferably 15-35°C, more preferably 20- 30°C.
11. The process according to any one of the preceding claims, wherein the rotational speed in the step numbered a (v) is 3000-18000 rpm, preferably 3200-15000 rpm, more preferably 3400-12000 rpm.
12. The process according to any one of the preceding claims, wherein the rotational speed in the step numbered a (iv) and b (iii) is 200-1400 rpm, preferably 500-1000 rpm.
13. The process according to any one of the preceding claims, wherein duration of the step numbered a (v) and c (ii) is 90-130 minutes, preferably 95-125 minutes, more preferably 100-120 minutes.
14. The process according to any one of the preceding claims, wherein the concentration of Solution A is 1-30 mg/ml, preferably 5-25 mg/ml, more preferably 10-20 mg/ml.
PCT/TR2022/050794 2022-07-28 2022-07-28 A process for the preparation of suspensions for inhalation by nebulization WO2024025486A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140120165A1 (en) * 2010-09-22 2014-05-01 Map Pharmaceuticals, Inc. Corticosteroid particles and method of production

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140120165A1 (en) * 2010-09-22 2014-05-01 Map Pharmaceuticals, Inc. Corticosteroid particles and method of production

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ALI HANY SM, YORK PETER, AMANI AMIR, BLAGDEN NICHOLAS: "Evaluation of a Nanodispersion Formulation Prepared through Microfluidic Reactors for Pulmonary Delivery of Budesonide Using Nebulizers", IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH, vol. 13, no. 3, 1 January 2014 (2014-01-01), IR , pages 785 - 795, XP093136124, ISSN: 1735-0328 *

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