[go: up one dir, main page]

WO2024005764A1 - Production method for liquid formulation of aviptadil - Google Patents

Production method for liquid formulation of aviptadil Download PDF

Info

Publication number
WO2024005764A1
WO2024005764A1 PCT/TR2023/050613 TR2023050613W WO2024005764A1 WO 2024005764 A1 WO2024005764 A1 WO 2024005764A1 TR 2023050613 W TR2023050613 W TR 2023050613W WO 2024005764 A1 WO2024005764 A1 WO 2024005764A1
Authority
WO
WIPO (PCT)
Prior art keywords
ppm
water
aviptadil
production
production according
Prior art date
Application number
PCT/TR2023/050613
Other languages
French (fr)
Inventor
Goksu YAG CILINGIROGLU
Tugce CATAK
Adem Sahin
Sena Ozlem GUNDOGDU
Mehmet Numan HAKSAL
Mustafa Ersin ERFA
Guniz CAKAR
Original Assignee
Centurion Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from TR2022/010940 external-priority patent/TR2022010940A2/en
Application filed by Centurion Ilac Sanayi Ve Ticaret Anonim Sirketi filed Critical Centurion Ilac Sanayi Ve Ticaret Anonim Sirketi
Publication of WO2024005764A1 publication Critical patent/WO2024005764A1/en

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2278—Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions

Definitions

  • the present invention relates to an production method for a liquid pharmaceutical formulation of aviptadil.
  • the stability of a pharmaceutical product depends on numerous factors including the chemical activity of an active substance in the product. Some of these include the potential interaction between active and inactive ingredient(s) in formulation, production process, dosage form, container closure system, and environmental conditions encountered during shipment and storage, and the time between production and use of the product.
  • the stability of a pharmaceutical product is defined as both chemical and physical stability. Factors such as heat, light, humidity, oxygen, and the like can induce chemical degradation (Akash MSH, Rehman K. Drug Stability and Chemical Kinetics. Drug Stability and Chemical Kinetics. 2020). In pharmaceutical systems, oxidation is one of the most common causes of drug degradation.
  • Oxidation involves the removal of electrons from (or addition of oxygen to) a molecule, and such reactions can be initiated by light, heat, or some trace metals (Snape T, Astles A, Davies J. Understanding the chemical basis of drug stability and degradation. The Pharmaceutical Journal. 2010 10/09;285; Gabric A, Hodnik Z, Pajk S. Oxidation of Drugs during Drug Product Development: Problems and Solutions. Pharmaceutics. 2022;14(2):325). Oxidation is a common degradation pathway acting on liquid and solid drug products comprising therapeutic proteins and peptides during the production of such products.
  • Aviptadil is the synthetic form of vasoactive intestinal peptide (VIP), which is a human amino acid peptide. Aviptadil is soluble in water and aqueous organic solvents, and due to a methionine residue included therein, oxidation results in a decreased activity for aviptadil. Side chains of methionine, cysteine, histidine, tryptophan, or tyrosine residues are highly susceptible to oxidation.
  • VIP vasoactive intestinal peptide
  • Aviptadil is already approved for the treatment of erectile dysfunction under the brand name Invicorb in the form of a solution for injection containing 25 micrograms aviptadil /2 milligrams phentolamine mesylate.
  • Invicorb in the form of a solution for injection containing 25 micrograms aviptadil /2 milligrams phentolamine mesylate.
  • Ohmori et al. have carried out a study for developing a dry powder inhaler form of aviptadil. This study is focused only on the preparation of a dry powder inhaler, and thus, does not include any information on solution preparation (Ohmori Y, Onoue S, Endo K, et al.
  • EP1855661B1 discloses liquid formulations of aviptadil.
  • the disclosure has not focused on a method for production of aviptadil formulations, rather the conventionally known methods of production were utilized. None of these studies in the state of the art provide a solution for the most important stability problem of aviptadil, i.e. the oxidation impurity (( et(O)17)-Aviptadil), in other words the Met(O) impurity problem.
  • a primary object of the present invention is to provide a new production method for the preparation of a liquid pharmaceutical formulation containing aviptadil, wherein the method eliminates all the above- mentioned problems and brings additional advantages over the prior art.
  • a further object of the present invention is to provide a new method of production in which stable and low-impurity liquid pharmaceutical formulations containing aviptadil are obtained.
  • the present invention provides a production method in which the temperature of the solution and water is maintained at 2-8°C and the amount of dissolved oxygen in the solution and water is maintained in the range of 0.01 ppm to 5 ppm, and preferably of 0.02 ppm to 1 ppm, and more preferably of 0.05 ppm to 0.5 ppm, throughout the production process, in order to prevent oxidation which results in impurities.
  • the present invention also provides a method of production for an liquid pharmaceutical formulation of aviptadil having a Met(O) impurity in the range of 0.01% to 0.2%, wherein the formulation is to be obtained by a method of production according to the present disclosure.
  • a further object of the present invention is to provide a method for production of an liquid pharmaceutical formulation of aviptadil for administration by inhalation.
  • Another object of the present invention is to provide a method for production of a liquid pharmaceutical formulation of aviptadil for use in the treatment of lung diseases, preferably SARS, MERS, CO VID-19, Influenza A, Influenza B, or ZIKA virus diseases, and more preferably COVID-19 virus disease.
  • lung diseases preferably SARS, MERS, CO VID-19, Influenza A, Influenza B, or ZIKA virus diseases, and more preferably COVID-19 virus disease.
  • a method of production for the preparation of a liquid pharmaceutical formulation containing aviptadil is carried out, characterized in that throughout the entire production process in the said method the temperature of the solution and water is maintained at 2-8°C, and the amount of dissolved oxygen in the solution and water is maintained in the range of 0.01 ppm to 5 ppm, preferably of 0.02 ppm to 1 ppm, and more preferably of 0.05 ppm to 0.5 ppm.
  • the method of production for the preparation of the liquid pharmaceutical formulation containing aviptadil comprises the following process steps: a. mixing at least one excipient with water for injection, b. adding aviptadil as an active substance to the resulting solution, and mixing, wherein the temperature of the solution, and of water used during the production process is maintained at 2-8°C and the amount of dissolved oxygen in the solution is maintained in the range of 0.01 ppm to 5 ppm, preferably of 0.02 ppm to 1 ppm, and more preferably of 0.05 ppm to 0.5 ppm.
  • the temperature of the production tank is adjusted to be within this range during the production process, and the temperature of the liquid formulation in the tank is regularly measured by means of a temperature measuring mechanism in the tank; the temperature is monitored by means of a display in the tank.
  • filtered nitrogen gas is passed through the water and/or solution during the production process to maintain the amount of dissolved oxygen in the water and solution within the desired ranges.
  • filtered nitrogen gas is introduced towards the bottom of the water for injection. This removes the dissolved oxygen.
  • filtered nitrogen gas continues to be supplied to the section above the liquid formulation in the tank. This prevents oxygen from entering the liquid formulation.
  • filtered nitrogen gas is also applied into the liquid formulation.
  • the production method for the liquid pharmaceutical formulation of aviptadil comprises the following process steps: a) taking a portion of the water for injection into the production tank, b) adjusting the temperature of said water for injection to a range of 2-8°C, and the amount of dissolved oxygen to a range of 0.01 ppm to 5 ppm, preferably of 0.02 ppm to 1 ppm, and more preferably of 0.05 ppm to 0.5 ppm, c) adding at least one excipient to the tank, and mixing, d) adding aviptadil as an active substance, and mixing, e) adding the rest of water for injection to the resulting solution, wherein throughout the production process the temperature of the liquid formulation is adjusted to the range of 2-8°C, and the amount of dissolved oxygen is adjusted to the range of 0.01 ppm to 5 ppm, preferably of 0.02 ppm to 1 ppm, and more preferably of 0.05 ppm to 0.5 ppm.
  • the temperature of the liquid formulation is
  • aviptadil in the liquid pharmaceutical formulation may also be a pharmaceutically acceptable derivative of aviptadil, and is preferably aviptadil acetate.
  • the liquid pharmaceutical formulation comprises at least one excipient, and the excipient is selected from the group consisting of a stabilizer, a preservative, an emulsifying agent, an antioxidant, a chelating agent, a buffering agent, a tonicity adjusting agent, an acidifying agent, and an alkalizing agent.
  • the excipient is selected from the group consisting of a stabilizer, a preservative, an emulsifying agent, an antioxidant, a chelating agent, a buffering agent, a tonicity adjusting agent, an acidifying agent, and an alkalizing agent.
  • the emulsifying agent used in the production method according to the present disclosure is selected from the group consisting of polysorbate, lecithin, alginic acid, sodium alginate, potassium alginate, cellulose derivative, carrageenan, guar gum, fatty acid esters, and sorbitan, and is preferably polysorbate.
  • the chelating agent used in the production method according to the present disclosure is selected from the group consisting of ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA) and its pharmaceutically acceptable derivatives, such as disodium, trisodium, tetrasodium, dipotassium, tripotassium, dilithium and diammonium salts, and is preferably disodium EDTA.
  • EDTA ethylenediamine-N,N,N',N'-tetraacetic acid
  • Chelating agents bind free metals in solution, preventing metals from catalyzing a reaction, and thus slowing down degradation reactions and increasing the stability of a product.
  • the buffering agent used in the production method according to the present disclosure is selected from the group consisting of citric acid, trisodium citrate anhydrous, acetic acid, sodium acetate, boric acid, sodium borate, monobasic sodium phosphate, potassium phosphate, lactic acid, tartaric acid, sodium bicarbonate, and a combination thereof, and is preferably a combination of citric acid and trisodium citrate anhydrous.
  • the tonicity adjusting agent used in the production method according to the present disclosure is dextrose or sodium chloride.
  • the method for production of the liquid pharmaceutical formulation of aviptadil comprises the following process steps: a) taking a portion of the water for injection into the production tank, b) adjusting the temperature of said water for injection to a range of 2-8°C, and the amount of dissolved oxygen to a range of 0.01 ppm to 5 ppm, c) adding at least one emulsifying agent, at least one chelating agent and at least one buffering agent to the tank, and mixing, d) adding aviptadil as an active substance, and mixing, e) adjusting the pH of the solution to the appropriate value with at least one buffering agent, and f) adding the rest of water for injection, wherein throughout the production process the temperature of the liquid formulation is adjusted to the range of 2-8°C, and the amount of dissolved oxygen is adjusted to the range of 0.01 ppm to 5 ppm, preferably of 0.02 ppm to 1 ppm, and more preferably of 0.05 ppm to
  • filtered nitrogen gas is applied throughout a method for packaging the liquid pharmaceutical formulation of aviptadil, wherein the packaging method preferably comprises the following steps: a) transferring the liquid pharmaceutical formulation containing aviptadil into vials under nitrogen gas by using a capsule filter, and b) sealing the vials with sterile stoppers, and then capping with aluminum flip off caps.
  • filtered nitrogen gas is passed through both the vials and the liquid pharmaceutical formulation containing aviptadil.
  • the amount of dissolved oxygen is adjusted to the range of 0.01 ppm to 5 ppm, preferably of 0.02 ppm to 1 ppm, and more preferably of 0.05 ppm to 0.5 ppm.
  • the temperature of the liquid formulation is kept within the range of 2-8°C.
  • the inhalation solution obtained by the method according to the present disclosure was developed for use in the treatment of lung diseases.
  • the said lung diseases include SARS, MERS, COVID-19, Influenza A, Influenza B, or ZIKA virus diseases, and preferably COVID-19 virus disease.
  • Preparation Stage for Non-sterile Solution - 75% (7.5 kg) of the total water for injection is taken into the production tank. The temperature of water is adjusted to 2-8°C, and the temperature of the solution is maintained within this range throughout the production process.
  • the temperature of water and the amount of dissolved oxygen are checked and measured in order to ensure that they are within the ranges mentioned above.
  • Disodium EDTA, sodium chloride, trisodium citrate, and polysorbate 80 are weighed and added to the production tank under stirring.
  • the amount of dissolved oxygen is measured. If it is not below 0.5 ppm, filtered nitrogen is passed through the solution until the amount of dissolved oxygen is 0.5 ppm or less than 0.5 ppm.
  • a 0.45 pm + 0.2 pm capsule filter is used to obtain a sterile product.
  • Sterilized vials are filled by constantly checking the fill amount, after which the vials are sealed with sterile stoppers.
  • the capping step is carried out with aluminum flip off caps. - Nitrogen gas is applied to the vials during the filling and capping process.
  • Disodium EDTA, sodium chloride, trisodium citrate, and polysorbate 80, respectively, are weighed and added to the production tank under stirring.
  • the capping step is carried out with aluminum flip off caps.
  • Example 1 Results of initial analysis for Example 1 and Example 2
  • Example - 1 and Example-2 were stored at 2-8°C for 1 month following the production. At the end of 1 month, Assay, Related Compounds 1, and Related Compounds 2 Met(O) tests were performed, and the results are presented in the table below.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pulmonology (AREA)
  • Dispersion Chemistry (AREA)
  • Vascular Medicine (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Endocrinology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a novel production method for obtaining stable, low-impurity liquid pharmaceutical formulations containing aviptadil, preferably including formulations for administration by inhalation. During said production method, the temperature and oxygen content of the solution are kept within a certain range.

Description

PRODUCTION METHOD FOR LIQUID FORMULATION OF
AVIPTADIL
Technical Field
The present invention relates to an production method for a liquid pharmaceutical formulation of aviptadil.
Background Art
The stability of a pharmaceutical product depends on numerous factors including the chemical activity of an active substance in the product. Some of these include the potential interaction between active and inactive ingredient(s) in formulation, production process, dosage form, container closure system, and environmental conditions encountered during shipment and storage, and the time between production and use of the product. The stability of a pharmaceutical product is defined as both chemical and physical stability. Factors such as heat, light, humidity, oxygen, and the like can induce chemical degradation (Akash MSH, Rehman K. Drug Stability and Chemical Kinetics. Drug Stability and Chemical Kinetics. 2020). In pharmaceutical systems, oxidation is one of the most common causes of drug degradation. Oxidation involves the removal of electrons from (or addition of oxygen to) a molecule, and such reactions can be initiated by light, heat, or some trace metals (Snape T, Astles A, Davies J. Understanding the chemical basis of drug stability and degradation. The Pharmaceutical Journal. 2010 10/09;285; Gabric A, Hodnik Z, Pajk S. Oxidation of Drugs during Drug Product Development: Problems and Solutions. Pharmaceutics. 2022;14(2):325). Oxidation is a common degradation pathway acting on liquid and solid drug products comprising therapeutic proteins and peptides during the production of such products. It can occur during purification, formulation, transportation, storage, and processing of the product (Torosantucci R, Schbneich C, Jiskoot W. Oxidation of therapeutic proteins and peptides: structural and biological consequences. Pharmaceutical research. 2014 Mar;31(3):541-53). Small peptides are generally unstable, and dosage forms of such molecules prepared as aqueous solutions are susceptible to degradation.
Aviptadil is the synthetic form of vasoactive intestinal peptide (VIP), which is a human amino acid peptide. Aviptadil is soluble in water and aqueous organic solvents, and due to a methionine residue included therein, oxidation results in a decreased activity for aviptadil. Side chains of methionine, cysteine, histidine, tryptophan, or tyrosine residues are highly susceptible to oxidation.
Aviptadil is already approved for the treatment of erectile dysfunction under the brand name Invicorb in the form of a solution for injection containing 25 micrograms aviptadil /2 milligrams phentolamine mesylate. Although new clinical researches have been conducted in the following years, there are no information on industrial production of an inhalable solution for aviptadil. In literature, Ohmori et al. have carried out a study for developing a dry powder inhaler form of aviptadil. This study is focused only on the preparation of a dry powder inhaler, and thus, does not include any information on solution preparation (Ohmori Y, Onoue S, Endo K, et al. Development of dry powder inhalation system of novel vasoactive intestinal peptide (VIP) analogue for pulmonary administration. Life sciences. 2006 Jun 6 ;79(2): 138-43). The dry powder inhaler formulation developed by the same group was tested in an asthma model in another study (Onoue S, Aoki Y, Matsui T, et al. Formulation design and in vivo evaluation of dry powder inhalation system of new vasoactive intestinal peptide derivative ([R(15, 20, 21), L(17), A(24,25), des-N(28)]-VIP-GRR) in experimental asthma/COPD model rats. Int J Pharm. 2011 May 30;410(l-2):54-60).
Refai et al. conducted a study focusing on the preparation of VIP-loaded liposomes (Refai E, Jonsson C, Andersson M, et al. Biodistribution of liposomal 13 II- VIP in rat using gamma camera. Nuclear Medicine and Biology. 1999 1999/11/01/;26(8):931-936). VIP-loaded PLGA nanoparticles have also been developed as a treatment option for asthma (Athari SS, Mortaz E, Pourpak Z, et al. VIP-loaded PLGA as an antiasthma nanodrug candidate. Comparative Clinical Pathology. 2016 2016/07/01;25(4):791-796).
EP1855661B1 discloses liquid formulations of aviptadil. However, the disclosure has not focused on a method for production of aviptadil formulations, rather the conventionally known methods of production were utilized. None of these studies in the state of the art provide a solution for the most important stability problem of aviptadil, i.e. the oxidation impurity (( et(O)17)-Aviptadil), in other words the Met(O) impurity problem. In the state of the art, there are no information about a stable formulation or an industrial production method in which impurities are kept to a minimum, and there is a need in the art for uncomplicated industrial methods for production of stable, low-impurity liquid formulations, particularly including formulations for inhalation.
Objectives and Summary of the Invention
A primary object of the present invention is to provide a new production method for the preparation of a liquid pharmaceutical formulation containing aviptadil, wherein the method eliminates all the above- mentioned problems and brings additional advantages over the prior art.
A further object of the present invention is to provide a new method of production in which stable and low-impurity liquid pharmaceutical formulations containing aviptadil are obtained.
The present invention provides a production method in which the temperature of the solution and water is maintained at 2-8°C and the amount of dissolved oxygen in the solution and water is maintained in the range of 0.01 ppm to 5 ppm, and preferably of 0.02 ppm to 1 ppm, and more preferably of 0.05 ppm to 0.5 ppm, throughout the production process, in order to prevent oxidation which results in impurities. The present invention also provides a method of production for an liquid pharmaceutical formulation of aviptadil having a Met(O) impurity in the range of 0.01% to 0.2%, wherein the formulation is to be obtained by a method of production according to the present disclosure.
A further object of the present invention is to provide a method for production of an liquid pharmaceutical formulation of aviptadil for administration by inhalation.
Another object of the present invention is to provide a method for production of a liquid pharmaceutical formulation of aviptadil for use in the treatment of lung diseases, preferably SARS, MERS, CO VID-19, Influenza A, Influenza B, or ZIKA virus diseases, and more preferably COVID-19 virus disease.
Detailed Description of the Invention
In one embodiment of the invention, a method of production for the preparation of a liquid pharmaceutical formulation containing aviptadil is carried out, characterized in that throughout the entire production process in the said method the temperature of the solution and water is maintained at 2-8°C, and the amount of dissolved oxygen in the solution and water is maintained in the range of 0.01 ppm to 5 ppm, preferably of 0.02 ppm to 1 ppm, and more preferably of 0.05 ppm to 0.5 ppm. This results in liquid pharmaceutical solutions with a negligible amount of impurity of Met(O) arising from the degradation of aviptadil. In a preferred embodiment of the invention, the method of production for the preparation of the liquid pharmaceutical formulation containing aviptadil comprises the following process steps: a. mixing at least one excipient with water for injection, b. adding aviptadil as an active substance to the resulting solution, and mixing, wherein the temperature of the solution, and of water used during the production process is maintained at 2-8°C and the amount of dissolved oxygen in the solution is maintained in the range of 0.01 ppm to 5 ppm, preferably of 0.02 ppm to 1 ppm, and more preferably of 0.05 ppm to 0.5 ppm.
According to the present invention, in order to maintain the temperature of the water and the solution in the range of 2-8°C, the temperature of the production tank is adjusted to be within this range during the production process, and the temperature of the liquid formulation in the tank is regularly measured by means of a temperature measuring mechanism in the tank; the temperature is monitored by means of a display in the tank.
According to the present invention, filtered nitrogen gas is passed through the water and/or solution during the production process to maintain the amount of dissolved oxygen in the water and solution within the desired ranges. According to a preferred embodiment of the invention, after the water for injection is added to the production tank, filtered nitrogen gas is introduced towards the bottom of the water for injection. This removes the dissolved oxygen. During production process, filtered nitrogen gas continues to be supplied to the section above the liquid formulation in the tank. This prevents oxygen from entering the liquid formulation. In addition, if needed, filtered nitrogen gas is also applied into the liquid formulation.
According to the present invention, the production method for the liquid pharmaceutical formulation of aviptadil comprises the following process steps: a) taking a portion of the water for injection into the production tank, b) adjusting the temperature of said water for injection to a range of 2-8°C, and the amount of dissolved oxygen to a range of 0.01 ppm to 5 ppm, preferably of 0.02 ppm to 1 ppm, and more preferably of 0.05 ppm to 0.5 ppm, c) adding at least one excipient to the tank, and mixing, d) adding aviptadil as an active substance, and mixing, e) adding the rest of water for injection to the resulting solution, wherein throughout the production process the temperature of the liquid formulation is adjusted to the range of 2-8°C, and the amount of dissolved oxygen is adjusted to the range of 0.01 ppm to 5 ppm, preferably of 0.02 ppm to 1 ppm, and more preferably of 0.05 ppm to 0.5 ppm. According to the present invention, the concentration of aviptadil in the liquid pharmaceutical formulation ranges from 50 to 150 pg/ml, and is preferably 100 pg/ml.
According to the present invention, aviptadil in the liquid pharmaceutical formulation may also be a pharmaceutically acceptable derivative of aviptadil, and is preferably aviptadil acetate.
According to the present invention, the liquid pharmaceutical formulation comprises at least one excipient, and the excipient is selected from the group consisting of a stabilizer, a preservative, an emulsifying agent, an antioxidant, a chelating agent, a buffering agent, a tonicity adjusting agent, an acidifying agent, and an alkalizing agent.
The emulsifying agent used in the production method according to the present disclosure is selected from the group consisting of polysorbate, lecithin, alginic acid, sodium alginate, potassium alginate, cellulose derivative, carrageenan, guar gum, fatty acid esters, and sorbitan, and is preferably polysorbate.
The chelating agent used in the production method according to the present disclosure is selected from the group consisting of ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA) and its pharmaceutically acceptable derivatives, such as disodium, trisodium, tetrasodium, dipotassium, tripotassium, dilithium and diammonium salts, and is preferably disodium EDTA. Chelating agents bind free metals in solution, preventing metals from catalyzing a reaction, and thus slowing down degradation reactions and increasing the stability of a product.
The buffering agent used in the production method according to the present disclosure is selected from the group consisting of citric acid, trisodium citrate anhydrous, acetic acid, sodium acetate, boric acid, sodium borate, monobasic sodium phosphate, potassium phosphate, lactic acid, tartaric acid, sodium bicarbonate, and a combination thereof, and is preferably a combination of citric acid and trisodium citrate anhydrous.
The tonicity adjusting agent used in the production method according to the present disclosure is dextrose or sodium chloride.
In a preferred embodiment of the present invention, the method for production of the liquid pharmaceutical formulation of aviptadil comprises the following process steps: a) taking a portion of the water for injection into the production tank, b) adjusting the temperature of said water for injection to a range of 2-8°C, and the amount of dissolved oxygen to a range of 0.01 ppm to 5 ppm, c) adding at least one emulsifying agent, at least one chelating agent and at least one buffering agent to the tank, and mixing, d) adding aviptadil as an active substance, and mixing, e) adjusting the pH of the solution to the appropriate value with at least one buffering agent, and f) adding the rest of water for injection, wherein throughout the production process the temperature of the liquid formulation is adjusted to the range of 2-8°C, and the amount of dissolved oxygen is adjusted to the range of 0.01 ppm to 5 ppm, preferably of 0.02 ppm to 1 ppm, and more preferably of 0.05 ppm to 0.5 ppm.
According to another embodiment of the present invention, filtered nitrogen gas is applied throughout a method for packaging the liquid pharmaceutical formulation of aviptadil, wherein the packaging method preferably comprises the following steps: a) transferring the liquid pharmaceutical formulation containing aviptadil into vials under nitrogen gas by using a capsule filter, and b) sealing the vials with sterile stoppers, and then capping with aluminum flip off caps.
Throughout the packaging method, filtered nitrogen gas is passed through both the vials and the liquid pharmaceutical formulation containing aviptadil. Thus, the amount of dissolved oxygen is adjusted to the range of 0.01 ppm to 5 ppm, preferably of 0.02 ppm to 1 ppm, and more preferably of 0.05 ppm to 0.5 ppm. Furthermore, the temperature of the liquid formulation is kept within the range of 2-8°C.
According to a preferred embodiment of the present invention, during the transfer of the aviptadil inhalation solution into the vials, and filling and capping of the vials, nitrogen gas is applied to the vials. The inhalation solution obtained by the method according to the present disclosure was developed for use in the treatment of lung diseases. The said lung diseases include SARS, MERS, COVID-19, Influenza A, Influenza B, or ZIKA virus diseases, and preferably COVID-19 virus disease.
EXAMPLES
The following examples are given to illustrate the production method of the present disclosure, and the subject matter of the present invention is not limited to these examples.
Example 1
Unit Formula and Batch Quantity of Aviptadil Vials containing Aviptadil 100 gg/m Solution for Inhalation
Figure imgf000012_0001
Production Method
Preparation Stage for Non-sterile Solution: - 75% (7.5 kg) of the total water for injection is taken into the production tank. The temperature of water is adjusted to 2-8°C, and the temperature of the solution is maintained within this range throughout the production process.
- During the solution preparation process, filtered nitrogen gas is passed through the solution. It is ensured that the content of dissolved oxygen is below 0.5 ppm.
- Before adding the active substance and the excipients, the temperature of water and the amount of dissolved oxygen are checked and measured in order to ensure that they are within the ranges mentioned above.
- Disodium EDTA, sodium chloride, trisodium citrate, and polysorbate 80, respectively, are weighed and added to the production tank under stirring.
- pH is adjusted to 5.7 with 0.1 M Citric Acid.
- Aviptadil acetate is weighed and added to the tank. Aviptadil is added to the tank under continuous stirring.
- If necessary, pH is adjusted to 5.7 with 0.1 M Citric Acid.
- An amount of water for injection is added up to a total weight of 10.1 kg, and the solution is stirred.
- The amount of dissolved oxygen is measured. If it is not below 0.5 ppm, filtered nitrogen is passed through the solution until the amount of dissolved oxygen is 0.5 ppm or less than 0.5 ppm.
Aseptic Filtration, Filling, and Sealing Stage:
- Bulk solution is transferred under nitrogen gas.
- A 0.45 pm + 0.2 pm capsule filter is used to obtain a sterile product. - Sterilized vials are filled by constantly checking the fill amount, after which the vials are sealed with sterile stoppers.
- Following the sealing step, the capping step is carried out with aluminum flip off caps. - Nitrogen gas is applied to the vials during the filling and capping process.
Example 2:
Unit Formula and Batch Quantity of Aviptadil Vials containing Aviptadil 100 gg/m Solution for Inhalation
Figure imgf000014_0001
- No filtered nitrogen gas is used in the production process.
- 75% (7.5 kg) of the total water for injection is taken into the production tank. The temperature of water is adjusted to 2-8°C, and maintained within this range throughout the production process. - The temperature of water is measured before adding the active substance and the excipients.
Disodium EDTA, sodium chloride, trisodium citrate, and polysorbate 80, respectively, are weighed and added to the production tank under stirring.
- pH is adjusted with 0.1 M Citric Acid.
- Aviptadil acetate is weighed and added to the tank. While being added to the tank, it is continuously stirred. - If needed, pH is adjusted with 0.1 M Citric Acid.
- An amount of WFI is added up to a total weight of 10.1 kg, and the solution is stirred.
Aseptic Filtration, Filling, and Sealing Stage
- A 0.45 pm + 0.2 pm capsule filter is used to obtain a sterile product.
- Sterilized vials are filled by constantly checking the fill amount, after which the vials are sealed with sterile stoppers.
- Following the sealing step, the capping step is carried out with aluminum flip off caps.
The results obtained in Example and Example 2 at the end of the corresponding production processes are presented in the table below: Table 1: Results of initial analysis for Example 1 and Example 2
Figure imgf000016_0001
In this embodiment of the present invention, the products of Example - 1 and Example-2 were stored at 2-8°C for 1 month following the production. At the end of 1 month, Assay, Related Compounds 1, and Related Compounds 2 Met(O) tests were performed, and the results are presented in the table below.
Table 2: 1st month (2-8°C) analysis results obtained for Example 1 and Example 2
Figure imgf000016_0002

Claims

CLAIMS A method of production for the preparation of a liquid pharmaceutical formulation containing aviptadil, comprising the following process steps: a. taking an amount of water for injection into a production tank, b. mixing at least one excipient with water for injection, c. adding aviptadil as an active substance to the resulting solution, and mixing, wherein the temperature of the solution, and of water used during the production process is maintained at 2-8°C and the amount of dissolved oxygen is maintained in a range of 0.01 ppm to 5 ppm. A method of production according to claim 1 , wherein the amount of dissolved oxygen in the solution and water is maintained in the range of 0.02 ppm to 1 ppm. A method of production according to claim 2, wherein the amount of dissolved oxygen in the solution and water is maintained in the range of 0.05 ppm to 0.5 ppm. A method of production according to any one of the preceding claims, wherein filtered nitrogen gas is passed through the solution and/or water during the production process. A method of production according to claim 4, wherein after water for injection is taken into the production tank, filtered nitrogen gas is introduced below the water, and during the subsequent process steps, filtered nitrogen gas continues to be introduced into the tank section just above the formulation in addition to the nitrogen gas introduced below the water and/or solution.
6. A method of production according to any one of the preceding claims, wherein the concentration of aviptadil added is in the range of 50 to 150 pg/ml.
7. A method of production according to any one of the preceding claims, wherein the at least one excipient is selected from the group consisting of a stabilizer, a preservative, an emulsifying agent, a chelating agent, an antioxidant, a buffering agent, a tonicity adjusting agent, an acidifying agent, and an alkalizing agent.
8. A method of production according to claim 7, wherein the chelating agent is selected from the group consisting of EDTA and its pharmaceutically acceptable derivatives.
9. A method of production according to claim 8, wherein the chelating agent is disodium EDTA.
10.A method of production according to claim 7, wherein the buffering agent is selected from the group consisting of citric acid, trisodium citrate anhydrous, acetic acid, sodium acetate, boric acid, sodium borate, monobasic sodium phosphate, potassium phosphate, lactic acid, tartaric acid, sodium bicarbonate, and a combination thereof. A method of production according to claim 10, wherein the buffering agent is a combination of citric acid and trisodium citrate. A method of production according to any one of the preceding claims, wherein the liquid pharmaceutical formulation containing aviptadil is an inhalation formulation.
PCT/TR2023/050613 2022-07-01 2023-06-22 Production method for liquid formulation of aviptadil WO2024005764A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2022/010940 TR2022010940A2 (en) 2022-07-01 AVIPTADIL LIQUID FORMULATION PRODUCTION METHOD.
TR2022010940 2022-07-01

Publications (1)

Publication Number Publication Date
WO2024005764A1 true WO2024005764A1 (en) 2024-01-04

Family

ID=89381021

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2023/050613 WO2024005764A1 (en) 2022-07-01 2023-06-22 Production method for liquid formulation of aviptadil

Country Status (1)

Country Link
WO (1) WO2024005764A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1855661A1 (en) * 2005-03-07 2007-11-21 MondoBIOTECH Licensing Out AG Formulation for aviptadil
EP3583933A1 (en) * 2018-06-20 2019-12-25 Albert-Ludwigs-Universität Freiburg Administration of aviptadil by inhalation to treat chronic beryllium disease

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1855661A1 (en) * 2005-03-07 2007-11-21 MondoBIOTECH Licensing Out AG Formulation for aviptadil
EP3583933A1 (en) * 2018-06-20 2019-12-25 Albert-Ludwigs-Universität Freiburg Administration of aviptadil by inhalation to treat chronic beryllium disease

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MVS ENGINEERING PVT. LTD.: "Use of Nitrogen Gas Generator in Pharmaceuticals Industry", YOUTUBE, XP093126784, Retrieved from the Internet <URL:https://www.youtube.com/watch?v=g_TuBjKgo3k&t=61s> [retrieved on 20240202] *
NIAZI, SARFARAZ K.: "HANDBOOK OF PHARMACEUTICAL MANUFACTURING FORMULATIONS", vol. 2, 2019, article NIAZI, SARFARAZ K.: "Uncompressed Solid Products; The last paragraph of title "V. Compounding"" *

Similar Documents

Publication Publication Date Title
EP2299987B1 (en) Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative
WO2013103801A1 (en) Pharmaceutical spray drying
CN110464846B (en) Meloxicam composition, preparation method and application thereof
HUE034059T2 (en) A method of producing a pharmaceutical composition comprising glatiramer acetate
US11045481B2 (en) Quetiapine oral liquid suspension and use thereof
CN101716149B (en) Precursor medicinal preparation
CN117263848A (en) Inhalation spray of raffinacin
US8420687B2 (en) Pharmaceutical composition
WO2016139635A1 (en) A pharmaceutical composition for the parenteral administration of melatonin, and a process for its preparation
JP7538802B2 (en) Carbetocin drug and its manufacturing process
JP2003510293A (en) Stable calcitriol solution for vial packaging
WO2024005764A1 (en) Production method for liquid formulation of aviptadil
TW202327643A (en) Process for formulating compositions comprising glucagon-like-peptide-2(glp-2) analogues
WO2024179467A1 (en) Solution, freeze-dried formulation, freeze-dried formulation unit package, injection, and injection preparation method
CN102233130B (en) Stable pharmaceutical preparation containing thymosin 1 derivatives
CN118403008A (en) Vitamin B6 injection and preparation method thereof
RU2241488C1 (en) Injection dalargin solution
TR2024021826T2 (en) Aviptadil liquid formulation manufacturing method.
TR2022010940A2 (en) AVIPTADIL LIQUID FORMULATION PRODUCTION METHOD.
CN115487140A (en) Coenzyme Q10 injection and preparation method thereof
JP3668225B2 (en) OCT formulation
JP2001519395A (en) Parenteral preparation containing carbamazepine or its derivative
JPH08508244A (en) Process for producing pharmaceutical composition containing vecuronium bromide
JP3103535B2 (en) Prefilled syringe preparation of calcitonin
WO1996036340A1 (en) STABLE AQUEOUS FORMULATIONS OF 1α,25-DIHYDROXYCHOLECALCIFEROL FOR PARENTERAL ADMINISTRATION

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23832045

Country of ref document: EP

Kind code of ref document: A1

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE