WO2024105521A1 - Composition pharmaceutique peptidique stable - Google Patents

Composition pharmaceutique peptidique stable Download PDF

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Publication number
WO2024105521A1
WO2024105521A1 PCT/IB2023/061375 IB2023061375W WO2024105521A1 WO 2024105521 A1 WO2024105521 A1 WO 2024105521A1 IB 2023061375 W IB2023061375 W IB 2023061375W WO 2024105521 A1 WO2024105521 A1 WO 2024105521A1
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Prior art keywords
composition
room temperature
desmopressin
stored
less
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PCT/IB2023/061375
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English (en)
Inventor
Patel DEEP
Patel MALAY
Dr. Ganeshchandra SONAVANE
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Shilpa Medicare Limited
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Publication of WO2024105521A1 publication Critical patent/WO2024105521A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention is related to the field of pharmaceutical formulation technology. More particularly, the present invention is directed to the aqueous solutions of small and medium size peptides such as vasopressin analogs, for example, desmopressin or its salt for intravenous or subcutaneous administration. It is a well-known fact that peptides are less stable in aqueous solutions and must therefore be kept under refrigerated conditions. So far, no room temperature stable, having extended shelf life aqueous solutions of desmopressin have been made available or explored. In an attempt, therefore, the present invention intends to provide room temperature stable desmopressin compositions having extended shelf life, which are more advantageous over marketed or known compositions having refrigerated storage conditions.
  • vasopressin analogs for example, desmopressin or its salt for intravenous or subcutaneous administration.
  • Desmopressin acetate also known and hereinafter may referred to as DDAVP (1- deamino-8-D-arginine vasopressin) is a synthetic analogue of the natural pituitary hormone 8-arginine vasopressin (ADH), an antidiuretic hormone affecting renal water conservation. Chemically, DDAVP can be described as 1 -(3 -mercaptopropionic acid)- 8-D-arginine vasopressin monoacetate. DDAVP can be administered through various routes of administration, viz. oral, nasal, sublingual, intravenous etc. and so far, approved in the dosage forms, such as, tablet, spray, solution, injectable etc.
  • routes of administration viz. oral, nasal, sublingual, intravenous etc. and so far, approved in the dosage forms, such as, tablet, spray, solution, injectable etc.
  • DDAVP injection 4 mcg/mL, is provided as a sterile, aqueous solution for injection.
  • DDAVP injection contains desmopressin acetate (salt) trihydrate having empirical formula C46He4N14O12S2.C2H4O2.3H2O and molecular weight 1183.34.
  • Desmopressin acetate trihydrate has structural formula as follows:
  • DDAVP Injection provides: 4 mcg desmopressin acetate, 9 mg sodium chloride and hydrochloric acid to adjust pH to 4.0.
  • DDAVP Injection is available in two presentations: in 1 mL ampoule and in 10 mL vial. The 10 mL vial contains 5 mg/mL chlorobutanol as a preservative.
  • One mL (4 mcg) of DDAVP solution has an anti diuretic activity of about 16 IU; 1 mcg of DDAVP is equivalent to 4 IU.
  • DDAVP has been shown to be more potent than arginine vasopressin in increasing plasma levels of factor VIII activity in patients with hemophilia and von Willebrand’s disease Type I.
  • DDAVP Injection 4 mcg/mL is indicated for patients with hemophilia A with factor VIII coagulant activity levels greater than 5%.
  • DDAVP Injection 4 mcg/mL is also indicated for patients with mild to moderate classic von Willebrand’s disease (Type I) with factor VIII levels greater than 5%.
  • DDAVP Injection 4 mcg/mL is indicated as antidiuretic replacement therapy in the management of central (cranial) diabetes insipidus and for the management of the temporary polyuria and polydipsia following head trauma or surgery in the pituitary region.
  • DDAVP is also available as an intranasal preparation.
  • this means of delivery can be compromised by a variety of factors that can make nasal insufflation ineffective or inappropriate. These include poor intranasal absorption, nasal congestion and blockage, nasal discharge, atrophy of nasal mucosa, and severe atrophic rhinitis. Intranasal delivery may be inappropriate where there is an impaired level of consciousness.
  • cranial surgical procedures such as transsphenoidal hypophysectomy, create situations where an alternative route of administration is needed as in cases of nasal packing or recovery from surgery.
  • DDAVP Injection 4 mcg/mL is administered as an intravenous infusion at a dose of 0.3 mcg DDAVP/kg body weight diluted in sterile physiological saline and infused slowly over 15 to 30 minutes. In adults and children weighing more than 10 kg, 50 mL of diluent is recommended; in children weighing 10 kg or less, 10 mL of diluent is recommended. If DDAVP Injection 4 mcg/mL is used preoperatively, it should be administered 30 minutes prior to the scheduled procedure.
  • DDAVP Injection is administered subcutaneously or by direct intravenous injection.
  • the usual dosage range in adults is 0.5 mL (2.0 mcg) to 1 mL (4.0 mcg) daily, administered intravenously or subcutaneously, usually in two divided doses.
  • the morning and evening doses should be separately adjusted for an adequate diurnal rhythm of water turnover.
  • the comparable anti diuretic dose of the injection is about one-tenth the intranasal dose.
  • DDAVP Injection 4 mcg/mL is available as a sterile solution in cartons of ten 1 mL single-dose ampules and in 10 mL multiple-dose vials, each containing 4 mcg DDAVP per mL.
  • DDAVP Injection must be stored refrigerated 2°C to 8°C.
  • aqueous compositions that is, sterile aqueous solutions containing a known amount of peptide.
  • the biological activity of the peptides to be administered is often extremely high. Thus, only very small amounts of peptide are needed for a single does.
  • dilute aqueous peptide solutions in general are not stable at room temperature for longer periods, even if kept in sealed containers. Desmospressin or its salt is such a peptide. Its aqueous solution has to be stored at a temperature not exceeding 8°C.
  • chlorobutanol 1,1,1 -tri chi oro-2-methylpropan-2-ol
  • chlorobutanol effectively protects desmopressin against microbial attack (United States Patent No. 5,482,931 (Ferring AB), incorporated herein by reference in its entirety, at column 1, lines 25-38).
  • United States Patent No. 5,482,931 provides an aqueous composition, which contains a buffer, a quaternary amine preservative or disinfectant and an osmotic pressure-controlling agent.
  • the quaternary amine preservative or disinfectant selectively used have, in addition to their namesake functions, the unexpected ability to prevent adsorption of small and medium size peptide components from adhering to container walls, particularly walls of containers made of polymeric materials.
  • the buffer it is preferred for the buffer to be capable of maintaining a pH of between 4.0 and 6.0. Especially preferred is a pH of about 5.0.
  • the buffer used is acetic acid/sodium acetate.
  • Preferred buffer systems according to the ‘931 patent are citric acid/disodium hydrogen phosphate, sodium dihydrogen phosphate/di sodium hydrogen phosphate, and citric acid/sodium citrate.
  • a buffer comprising: citrate-phosphate-sodium ions in a molar ratio of from about 1 :3:3 to about 1 : 1 :2.
  • the composition according to the ‘931 patent preferably contains the quaternary amine preservative or disinfectant in a concentration from about 0.05 to about 0.2 mg per ml. Particularly preferred is a concentration of about 0.1 mg per ml.
  • the osmotic pressure-controlling agent it is preferred for the osmotic pressure-controlling agent to be sodium chloride.
  • the buffer components also contribute substantially to osmotic pressure control.
  • the ‘931 patent prepared five test compositions containing desmopressin acetate for nasal spray or drop compositions containing 0.1 mg benzalkonium chloride, 10 mg benzyl alcohol, 0.8 mg methyl paraben, 0.2 mg propyl paraben and 5 mg chlorobutanol and tested them for their stability by detecting peptide degradation.
  • the composition containing chlorobutanol was the least stable amongst others and compositions containing benzalkonium chloride demonstrated the ability to be stored and used for extensive periods without refrigeration.
  • the ‘931 patent does not teach preparation of room temperature stable desmopressin aqueous compositions for intravenous or subcutaneous administration. Nor does the ‘931 patent suggest whether the nasal compositions prepared therein can be used for intravenous or subcutaneous administration.
  • the term “preservatives” embraces both, degradation inhibitors (like antioxidants or antimicrobial additives) as well as adsorption inhibitors (preventing adsorption of the active principle onto container walls).
  • the compositions of the ‘509 patent are nasal compositions and are meant for nasal administration.
  • the ‘509 patent also, does not teach preparation of room temperature stable desmopressin aqueous compositions for intravenous or subcutaneous administration.
  • the ‘509 patent suggest whether the compositions prepared therein can be used for intravenous or subcutaneous administration.
  • United States Patent Application Publication No. 2003/0216302 (Sun Pharmaceutical Industries Limited) teaches a stable aqueous composition comprising desmopressin or its other pharmaceutically acceptable salts in a pharmaceutically acceptable carrier, wherein the carrier comprises a buffering agent, a parahydroxybenzoate preservative, and a cosolvent.
  • the carrier comprises a buffering agent, a parahydroxybenzoate preservative, and a cosolvent.
  • preservative efficacy of desmopressin aqueous compositions containing a parahydroxybenzoate preservative is improved with the use of cosolvents.
  • the compositions taught in the ‘302 publication are nasal compositions and the ‘302 publication does not teach preparation of room temperature stable desmopressin aqueous compositions for intravenous or subcutaneous administration.
  • the inventors of the present invention have attempted to prepare room temperature stable aqueous compositions of desmopressin. And to their surprise, they found that desmopressin acetate may be stabilized in aqueous solutions when stored at room temperature for prolonged period of time. Needless to say, room temperature stable formulations are always advantageous from preparation, storage and logistic point of view.
  • the room temperature stable product does not require be storing and shipping at a controlled temperature (i.e. 2-8°C). It also does not require cold chain transport. It requires less care to be taken as compared to refrigerated formulations.
  • the room temperature stable desmopressin compositions for intravenous or subcutaneous administration of the present invention comprise desmopressin or its salt as an active ingredient and one or more additives/excipients selected from the group of antioxidants, pH adjusting agents, osmolality agents/osmotic pressure-controlling agents and preservatives.
  • an antioxidant helps in preventing and/or slowing down the degradation of the active ingredient in the formulation as diluted aqueous solution and thus helps achieve room temperature stable composition for a prolonged time.
  • the compositions of the present invention may optionally comprise one or more additives/excipients selected from buffering agents, cosolvents and chelating agents.
  • the scope of the present invention is not limited to stable desmopressin compositions and the present invention also intends to provide compositions of other peptides as well which may be stabilized in aqueous solutions using the technology disclosed herein.
  • aqueous compositions of peptides especially small and medium size peptides, particularly of aqueous compositions containing desmopressin or its salt.
  • Another object of the present invention is to provide a stabilized aqueous composition comprising desmopressin for intravenous or subcutaneous administration, which can be conveniently stored at room temperature for extended periods of time, for instance, at least one year or more, without risking partial or total degradation and/or microbial contamination of the peptide contained therein.
  • a further object of the present invention is to protect the peptide, desmopressin or its salt, in the solution from adhering to the walls of the container without using extraneous additives specifically designed for that purpose.
  • a yet another object of the present invention is to provide an aqueous composition for intravenous or subcutaneous administration for the management of diseases and abnormal conditions, which are mitigated by administration of desmopressin or its salt.
  • a yet another object of the present invention is also to provide processes for the preparation of stable desmopressin compositions of the present invention.
  • a further object of the present invention is to provide ready-to-use and/or ready-to- dilute solutions of desmopressin.
  • small and medium size peptides preferably small or medium size cyclic peptides, more preferably those containing one or more sulfur atoms within the cyclus, and most preferably those containing at least two sulfur atoms within the cyclus, such as, for example, analogues and derivatives of oxytocin and vasopressin, such as desmopressin (termed 1-deamino- 8-D-arginin-vasopressin or l-(3-mercaptopropanoic acid)-8-D-argininevasopressin), a powerful antidiuretic, useful in the treatment of urinary disorders associated to, for example, insipidus diabetes and nocturnal enuresis.
  • desmopressin termed 1-deamino- 8-D-arginin-vasopressin or l-(3-mercaptopropanoic acid)-8-D-argininevasopressin
  • the present invention is an aqueous composition for intravenous or subcutaneous administration of peptides, especially small and medium-size peptides, particularly desmopressin or its salt, which can maintain stability over time at room temperature.
  • the solution contains an antioxidant, a preservative or disinfectant and an osmotic pressure-controlling agent/osmolality agent with the optional presence of a pH adjusting agent and/or a buffering agent.
  • the solution may further comprise one or more additives selected from chelating agents and cosolvents.
  • Some of the preservatives or disinfectants, for example, the quaternary amine, used in the present invention may have, in addition to their namesake functions, the ability to prevent adsorption of desmopressin components from adhering to container walls, particularly walls of containers made of polymeric or glass materials.
  • peptide for use in the composition according to the present invention is a peptide having pharmacological effects.
  • specific examples can include calcitonin, insulin, proinsulins, epidermal growth factors, growth hormones, somatomedin C, somatostatin, granulocyte macrophage colonystimulating factor, colony-stimulating factors, erythropoietin, interferons, interleukins, atrial natriuretic peptides, parathyroid hormones, superoxide dismutases, tissue plasminogen activators, antithrombins, blood coagulation-factor, blood coagulationfactor, protein C, hirudine, hepatitis vaccine, endorphins, ACTH-releasing hormone, neurotensin, angiotensin, transferrin, endothelin, vasopressin, desmopressin, terlipressin, atosiban, carbetocin,
  • the peptide or peptide analog prefferably be oxytocin or vasopressin, or their analogs and derivatives, such as desmopressin (1 -(3 -mercaptopropanic acid)-8-D-arginine-vasopressin), terlipressin (N-alpha-triglycyl-8-lysine)-vasopressin), atosiban ((Mpa 1 , D-Tyr(Et) 2 , Thr 4 , Orn 8 )- oxytocin), carbetocin ((1 -desamino- l-monocarba-2(0-methyl)-tyrosine)-oxytocin), and the like.
  • desmopressin (1 -(3 -mercaptopropanic acid)-8-D-arginine-vasopressin
  • terlipressin N-alpha-triglycyl-8-lysine)-vasopressin
  • atosiban
  • the most preferred peptide is desmopressin or its other pharmaceutically acceptable salts, which are used in the management of various medical conditions like irregular urination or diurea, particularly those, associated with diabetes insipidus and nocturnal enuresis.
  • the pH adjusting agent(s) and/or buffer(s) of the present invention it is preferred for the pH adjusting agent(s) and/or buffer(s) of the present invention to be capable of maintaining a pH of between about 3.5 and about 6.5. Especially, preferred is a pH between about 4.0 and about 6.5.
  • Antioxidants can be compounds that can reduce a drug that has been oxidized, or compounds that are more readily oxidized than the agents they are to protect (oxygen scavengers). Mixtures of chelating agents and antioxidants are often used because there appears to be a synergistic effect. This occurs because many of the agents act at differing steps in the oxidative process.
  • the antioxidants when used in the compositions of the present invention include, but are not limited to, amino acids, butylated hydroxytoluene, butylated hydroxyanisole, tert-butyl-hydroquinone, 4-hydroxymethyl- 2, 6-di-tert-butylphenol, 2, 4, 5- trihydroxybutyrophenone, alkylgallates, propyl gallate, octyl gallate, dodecyl gallate, ethoxyquin, gallic acid, nordihydroguaiaretic acid, glycine, ascorbic acid, fatty acid esters of ascorbic acid such as ascorbyl palmitate and ascorbyl stearate, and salts of ascorbic acid such as sodium, calcium, or potassium ascorbate; erythorbic acid, L-carnitine, monothioglycerol, acetyl L-carnitine, thioglycolic acid, N-acetyl cysteine, cysteine, glut
  • the buffering agent if used in the stable compositions of the present invention may be any pharmaceutically acceptable agent, known to a person skilled in the art.
  • the buffering agent may be selected from a group consisting of organic acids and its salts, mineral acids, alkali metal phosphates, carbonates, borates, hydroxides, base and the like and mixtures thereof.
  • the buffer components may also contribute substantially to osmotic pressure control.
  • Microbiological contamination presents a significant health hazard in liquid formulations. Therefore, the use of preservatives or disinfectants become inevitable to prevent the growth of microorganisms during the product’s manufacture and shelf life, although it may be most desirable to develop a “preservative-free” formulation to address the increasing concerns about the biological activity of these compounds. Most formulations require some kind of preservative to ensure no microbial growth.
  • Nonlimiting examples of preservatives when used in the formulations of the present invention include alcohol, ethanol, chlorobutanol, phenoxyethanol, potassium benzoate, benzyl alcohol, benzoic acid, potassium sorbate, sorbic acid, quaternary amine, benzethonium chloride, cetrimonium bromide, cetylpyridinium chloride, bronopol, chlorbutol, chlorocresol, cresol, parahydroxybenzoates, phenol, thymol, phenyl ethanol, sodium benzoate, antimicrobial solvents like propylene glycol, glycerin, chloroform and the like.
  • the composition according to the invention contains the quaternary amine preservative or disinfectant preferably in a concentration from about 0.05 to about 0.2 mg per ml. Particularly, preferred is a concentration of about 0.1 mg per ml.
  • Chlorobutanol may also be the choice as preservative or disinfectant to be used in the compositions of the present invention. Chlorobutanol, if used in the present compositions, may be used in an amount ranging from 0.1 mg/mL to 5.0 mg/mL.
  • the parahydroxybenzoate preservative(s) if incorporated in the present compositions is/are selected from the group comprising methyl p-hydroxybenzoate (methyl paraben), ethyl p-hydroxybenzoate (ethyl paraben), propyl p-hydroxybenzoate (propyl paraben), butyl p-hydroxybenzoate (butyl paraben), isobutyl p-hydroxybenzoate (isobutyl paraben), isopropyl p-hydroxybenzoate (isopropyl paraben), benzyl p-hydroxybenzoate (benzyl paraben) and the like and mixtures thereof.
  • tonicity adjusting agents or osmotic pressure-controlling agents or osmolality agents are used to adjust the osmolality of the pharmaceutical compositions to bring it closer to the osmotic pressure of body fluids, such as blood or plasma.
  • the tonicity of the formulation can be modified by adjusting the concentration of buffer and/or other components present in the formulation.
  • the compositions are physiologically compatible, the compositions do not require any particular osmolality.
  • the compositions can be hypotonic, isotonic or hypertonic.
  • the pharmaceutical compositions have a tonicity between about 250 to about 350 mOsm/kg.
  • the formulations of the present invention are isotonic, i.e., in the range of 270-328 mOsm/kg.
  • the formulations may have a tonicity in the range of 250-350 mOsm/kg. Therefore, the formulations may be either slightly hypotonic, 250-269 mOsm/kg, or slightly hypertonic, 329-350 mOsm/kg.
  • Suitable tonicity adjusting agents for use in the pharmaceutical compositions include, but are not limited to, anhydrous or hydrous forms of sodium chloride, dextrose, sucrose, xylitol, fructose, glycerol, sorbitol, mannitol, potassium chloride, mannose, calcium chloride, magnesium chloride and other inorganic salts.
  • the quantity of the tonicity adjusting agent in the formulation can be expressed in mg/ml or in g/L. In typical embodiments, the tonicity adjusting agent(s) is present from about 1 mg/ml to about 90 mg/ml.
  • the pharmaceutical compositions can comprise one or more tonicity adjusting agents at about 1-5 mg/ml, at about 5-10 mg/ml, at about 10-15 mg/ml, at about 15-25 mg/ml, at about 25-50 mg/ml, at about 50-60 mg/ml, at about 60-70 mg/ml, at about 70-80 mg/ml, and at about 80 to 90 mg/ml, as well as combinations of the above ranges.
  • the tonicity adjusting agent concentration is measured in weight/volume percent.
  • the tonicity adjusting agent(s) is present from about 0.1% to about 10%.
  • suitable tonicity adjusting agent concentrations include, but are not limited to, from about 0.1% to about 0.2%, from about 0.2% to about 0.3%, from about 0.3% to about 0.4%, from about 0.4% to about 0.5%, from about 0.5% to about 0.6%, from about 0.6% to about 0.7%, from about 0.7% to about 0.8%, from about 0.8% to about 0.9%, from about 0.9% to about 1%, from about 1% to about 2%, from about 2% to about 3%, from about 3% to about 4%, from about 4% to about 5%, from about 5% to about 6%, from about 6% to about 7%, from about 7% to about 8%, from about 8% to about 9%, and from about 9% to about 10%, as well as combinations of the above ranges.
  • the osmotic pressure-controlling agent is sodium chloride.
  • concentration of sodium chloride suitable for use in the pharmaceutical compositions is between about 0.1% (w/v) to about 1.8%.
  • suitable sodium chloride concentrations include, but are not limited to, from about 0.1% to about 0.2%, from about 0.2% to about 0.3%, from about 0.3% to about 0.4%, from about 0.4% to about 0.5%, from about 0.5% to about 0.6%, from about 0.6% to about 0.7%, from about 0.7% to about 0.8% (which is equivalent to 8 mg/ml), from out 0.8% to about 0.9% (which is equivalent to 9 mg/ml), from about 0.9% to about 1.0%, from about 1% to about 1.2%, from 1.2% (which is equivalent to 12 mg/ml) to about 1.4%, from about 1.4% to about 1.6%, and from about 1.6% to about 1.8%.
  • the pharmaceutical compositions comprise two, three, four, or more tonicity adjusting agents.
  • the concentration of each tonicity adjusting agent is typically less than the concentration that is used when only a single agent is present in the formulation.
  • the pH adjusting agent(s) may also be required in the formulations of the present invention to adjust the desired pH of the formulation.
  • Suitable pH adjusting agents typically include at least an acid or a salt thereof, and/or a base or a salt thereof. Acids and bases can be added on an as needed basis in order to achieve the desired pH. For example, if the pH is greater than the desired pH, an acid can be used to lower the pH to the desired pH. Acids suitable for use in formulations include, but are not limited to, hydrochloric acid, phosphoric acid, ascorbic acid, acetic acid, sulphuric acid, carbonic acid, nitric acid and the like.
  • a base can be used to adjust the pH to the desired pH.
  • Bases suitable for use in formulations include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium acetate, magnesium hydroxide and the like.
  • a “buffering agent” or a “pH adjusting agent” as used herein is a system, which is used for the purposes and is capable of maintaining the desired/required pH of the formulations throughout desired/required time period, e.g. stability studies and/or shelf life of the drug product.
  • the desired pH of the formulations according to the present invention is between about 3.5 and about 6.5.
  • both buffering agent and pH adjusting agent may be used. In some of the embodiments of the invention, only a buffering agent is used. In some of the embodiments of the invention, only a pH adjusting agent is used.
  • hydrochloric acid and/or sodium hydroxide is used on an as needed basis as a pH adjusting agent(s) which adjusts and/or maintains the desired/required pH (e.g. about 3.5 to about 6.5).
  • composition according to the present invention contains from about 0.001 mg to less than about 0.02 mg desmopressin or its salt, an antioxidant in a quantity sufficient to prevent and/or slow down the degradation of desmopressin or its salt, a preservative or disinfectant in a quantity sufficient to prevent the microbial contamination or microbial growth (the amount of the preservative depends on the preservative used), an osmotic pressure-controlling agent in a quantity sufficient to provide the overall solution with an osmotic pressure comparable to that of human plasma and a pH adjusting agent in a quantity sufficient to adjust/maintain the pH of the solution to about 3.5 to about 6.5.
  • a buffering agent in a quantity sufficient to maintain the pH of the solution to about 3.5 to about 6.5 may optionally be included in the present composition.
  • one or more additives/excipients from chelating agents and cosolvents may optionally be included in the present composition.
  • composition according to the invention contains from about 0.001 mg to less than about 0.02 mg of desmopressin acetate, from about 1.35 to about 1.85 mg of citric acid, from about 0.05 to about 0.20 mg benzalkonium chloride or about 0.5 mg to about 5.0 mg chlorobutanol, and sodium chloride in an amount sufficient to provide the overall solution with an osmotic pressure comparable to that of human plasma.
  • Hydrochloric acid and/or sodium hydroxide is used on an as needed basis as a pH adjusting agent(s) which adjusts and/or maintains the desired/required pH between about 3.5 and about 6.5.
  • a buffering agent in a quantity sufficient to maintain the pH of the solution to about 3.5 to about 6.5 may be included in the present composition.
  • the composition of the present invention contains from about 0.004 to less than about 0.02 mg of desmopressin acetate, preferably about 0.004 mg, from about 1 to about 2.5 mg of citric acid monohydrate, preferably about 1.7 mg, 1 ml of water and an amount of sodium chloride such that the osmolality is kept at the physiological values of the human plasma.
  • Hydrochloric acid and/or sodium hydroxide is used on an as needed basis as a pH adjusting agent(s) which adjusts and/or maintains the desired/required pH between about 3.5 and about 6.5.
  • compositions may optionally be prepared in the presence of a buffer.
  • a buffer for example, from about 2 to about 5 mg of disodium hydrogen phosphate dihydrate, preferably about 3 mg may be included in the composition.
  • the present invention provides a composition comprising from about 0.001 mg to less than about 0.02 mg desmopressin or its salt and from about 1.0 mg to about 2.5 mg of citric acid.
  • Said composition is stable at room temperature wherein the total impurities remain at less than 1% w/w for at least one month, preferably for at least three months and more preferably for at least six months when stored at room temperature.
  • the present invention provides a composition comprising about 0.004 mg desmopressin or its salt and about 1.7 mg of citric acid.
  • Said composition is stable at room temperature wherein the total impurities remain at less than 1% w/w for at least one month, preferably for at least three months and more preferably for at least six months when stored at room temperature.
  • the present invention provides a composition
  • a composition comprising: from about 0.001 mg to less than about 0.02 mg of desmopressin acetate; from about 1.0 to about 2.5 mg of citric acid; from about 0.5 mg to about 5.0 mg chlorobutanol; from about 6.5 mg to about 9.0 mg sodium chloride; water; and a pH adjusting agent selected from hydrochloric acid, sodium hydroxide or combination thereof, wherein the pH of the composition is between about 3.5 and about 6.5, and wherein said composition is stable at room temperature wherein the total impurities remain at less than 1% w/w for at least one month, preferably for at least three months and more preferably for at least six months when stored at room temperature.
  • the present invention provides a composition
  • a composition comprising: about 0.004 mg desmopressin acetate; about 1.7 mg citric acid; about 5.0 mg chlorobutanol; about 7.5 mg sodium chloride; water; and a pH adjusting agent selected from hydrochloric acid, sodium hydroxide or combination thereof, wherein the pH of the composition is between about 3.5 and about 6.5, and wherein said composition is stable at room temperature wherein the total impurities remain at less than 1% w/w for at least one month, preferably at least three months and more preferably at least six months when stored at room temperature.
  • compositions of the present invention may optionally comprise one or more additives selected from chelating agents and cosolvents.
  • Chelating agents if used in the compositions of the present invention may include, but are not limited to, ethylene diaminetetraacetic acid (EDTA), deferoxannine, desferrioxannine B, dithiocarb sodium, penicillamine, pentetate calcium, a sodium salt of pentetic acid, succimer, trientine, nitrilotriacetic acid, diethylenetriaminepentaacetic acid, trans-diaminocyclohexanetetraacetic acid (DCTA), dihydroethylglycine, bis(anninoethyl)glycolether-N,N,N',N'-tetraacetic acid, iminodiacetic acid, poly(aspartic acid), tartaric acid, fumaric acid, succinic acid, glycolic acid, lactic acid, oxalic acid, malic acid, lecithin or any salt thereof, and the like or a combination thereof may be employed.
  • EDTA
  • Cosolvents if used in the formulations of the present invention without limitation include dichloromethane, acetonitrile, ethyl acetate, acetone, propylene carbonate, water, glycerin, coconut fatty acid di ethanol ami de, medium and/or long chain fatty acids or glycerides, monoglycerides, diglycerides, triglycerides, structured triglycerides, soyabean oil, peanut oil, com oil, com oil monoglycerides, com oil diglycerides, com oil triglycerides, polyethylene glycol, caprylocaproylmacroglycerides, caproyl 90, propylene glycol, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene castor oil derivatives, castor oil, cottonseed oil, olive oil, safflower oil, peppermint oil, coconut oil, palm seed oil, beeswax, oleic acid, methanol, ethanol, iso
  • compositions of the present invention are concerned, in some embodiments, the compositions are ready-to-use aqueous compositions. In alternative embodiments, the compositions are ready-to-dilute aqueous compositions.
  • compositions of the present invention may be indicated and used for the therapeutic indications those identified & provided for DDAVP Injection under the heading “Indications and usage” in the patient information leaflet
  • the composition of the present invention is for intravenous or subcutaneous administration.
  • the present invention provides use of the composition as disclosed herein for the management of diseases and abnormal conditions, which are mitigated by administration of desmopressin or its salt.
  • stable or stabilized composition refers to an aqueous solution for therapeutic use, containing at least one small or medium-size biologically active peptide, particularly desmopressin or its salt. Such stabilization should allow the composition to be stored at room temperature for extended periods without loss in biological activity.
  • the term “about” is synonymous with “approximately” and is used to provide flexibility to a numerical value or range endpoint by providing that a given value may be “a little above” or “a little below” the value stated. “About” can mean, for example, within 3 or more than 3 standard deviations. “About” can mean within a percentage range of a given value. For example, the range can be ⁇ 1 %, ⁇ 5%, ⁇ 10%, ⁇ 20%, ⁇ 30%, ⁇ 40% or ⁇ 50% of a given value. “About” can mean with an order of magnitude of a given value, for example, within 2-fold, 3-fold, 4-fold or 5-fold of a value. However, it is to be understood that even when a numerical value is accompanied by the term “about” in this specification, that express support shall be provided at least for the exact numerical value as well as though the term “about” were not present.
  • an optionally substituted group means that the group is un-substituted or is substituted.
  • room temperature as used herein includes storage conditions 25°C ⁇ 5°C and 60% ⁇ 5% relative humidity.
  • degradant as used herein includes storage conditions 25°C ⁇ 5°C and 60% ⁇ 5% relative humidity.
  • degradant as used herein includes storage conditions 25°C ⁇ 5°C and 60% ⁇ 5% relative humidity.
  • degradant as used herein includes storage conditions 25°C ⁇ 5°C and 60% ⁇ 5% relative humidity.
  • degradant as used herein includes storage conditions 25°C ⁇ 5°C and 60% ⁇ 5% relative humidity.
  • impurity impurity
  • degradation impurity as used herein represents the same meaning and can be used interchangeably.
  • the compositions of the present invention are stable for prolonged time when stored under storage conditions.
  • storage conditions include storage conditions such as 25°C.
  • Prolonged time indicates that the formulations of the present invention are stable for at least 1 month or more, at least 3 months or more, at least 6 months or more or at least 12 months or more when stored under storage conditions.
  • Ready-to-use compositions according to the present invention are meant to be administered directly to the patients in required doses without any prior preparation e.g. reconstitution or dilution with suitable diluent such as saline solution or water.
  • suitable diluent such as saline solution or water.
  • compositions of the present invention with respect to a given parameter are well-known to those of skill in the art.
  • individual impurities and total impurities can be assessed by high-performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • HPLC high-performance liquid chromatography
  • TLC thin layer chromatography
  • a percentage amount of any individual impurities (known/unknown), or total impurities reported herein in the formulations are determined by a peak area percent method using HPLC.
  • treatment refers to ameliorating or reducing symptoms associated with a disease or condition. Treatment means any manner in which the symptoms of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Hence treatment encompasses prophylaxis, therapy and/or cure. Treatment also encompasses any pharmaceutical use of the compositions herein.
  • treating means that a composition or other product provided or described herein is administered to the subject to thereby effect treatment thereof.
  • amelioration of the symptoms of a particular disease or disorder by a treatment refers to any lessening, whether permanent or temporary, lasting or transient, of the symptoms that can be attributed to or associated with administration of the composition or therapeutic.
  • prevention refers to methods in which the risk of developing disease or condition is reduced. Prophylaxis includes reduction in the risk of developing a disease or condition and/or a prevention of worsening of symptoms or progression of a disease, or reduction in the risk of worsening of symptoms or progression of a disease.
  • an “effective amount” of a compound or composition for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce symptoms to achieve the desired physiological effect. Such amount can be administered as a single dosage or can be administered according to a regimen, whereby it is effective. The effective amount is readily determined by one of skill in the art following routine procedures.
  • disease or “disorder” or “condition” refers to a pathological condition in an organism resulting from cause or condition including, but not limited to, infections, acquired conditions, genetic conditions, and characterized by identifiable symptoms.
  • patient or “subject” to be treated includes humans and or non-human animals, including mammals.
  • Mammals include primates, such as humans, chimpanzees, gorillas and monkeys; domesticated animals, such as dogs, horses, cats, pigs, goats, cows; and rodents such as mice, rats, hamsters and gerbils.
  • the present invention also provides a container comprising a composition comprising desmopressin or its salt.
  • the container is a vial, an ampoule, a bag, a bottle, a cartridge, or a syringe.
  • the container, the composition, or both the container and the composition are sterile.
  • the container is sealed by way of a closure, such as a stopper, plunger, and/or tip-cap.
  • the container and closure can be made of glass, plastic, and/or rubber.
  • One or more surfaces of the container and/or closure can be treated with a compound to limit reactivity with one or more components of the formulation.
  • the container and/or closure are treated with silicon.
  • the container is treated with ammonium sulfate ((NT ⁇ SC ).
  • the container can be clear or opaque, and can be any color. In some embodiments, the container is flint colored. In other embodiments, the container is amber colored.
  • the invention provides a pre-filled syringe containing a composition of the invention described herein.
  • a syringe according to the invention is a component of an auto-injector.
  • Example-1 Preparation of desmopressin aqueous solutions with and without antioxidant
  • citric acid monohydrate and sodium chloride were dissolved in the sufficient amount of water to achieve the concentration of citric acid and sodium chloride 1.7 mg/mL & 7.5 mg/mL respectively.
  • Required quantities of chlorobutanol 5 and desmopressin acetate were dissolved in the above solution to achieve the concentration of chlorobutanol and desmopressin acetate 5 mg/mL & 0.004 mg/mL respectively.
  • Required quantities of water was added to make up the final volume to the batch size (bulk solution).
  • the batch preparation was started with sufficient quantity of water. Nitrogen was purged in the water to obtain dissolved oxygen level below 2 ppm (parts per million) and it was maintained until the end of the batch manufacturing. Required quantities of an antioxidant selected from citric acid anhydrous or L-cysteine hydrochloride and sodium chloride were added and dissolved under stirring. pH of the above solution was adjusted between about 4.0 and about 6.5 (preferably to about 4.0) using IN sodium hydroxide solution and/or 0.1 N hydrochloric acid solution (as the requirement may be). Required quantity of chlorobutanol (preferably anhydrous) was added and stirred until complete solubilization. Above solution was cooled down to refrigerated temperature (2-8°C).
  • API desmopressin acetate
  • Bulk solution was filtered using 0.22 pm PVDF filter and filled into 5 mL USP type-I clear glass vials with headspace oxygen (HSO) below 5% v/v.
  • HSU headspace oxygen
  • DESP1027B, DESP1031, DESP1032 and DESP1034 were prepared by using different amounts of citric acid, i.e. 1.70mg/mL (100% of the label claim), 1.28mg/mL (75% of the label claim), 0.85mg/mL (50% of the label claim) and 3.40mg/mL (200% of the label claim) respectively to optimize the concentration of citric acid.
  • These batches were stored under refrigerated conditions (2-8°C) and at room temperature (25°C) and tested at 0 (initial), 3 and 6 months’ time points. The results (not included here) show that DESP1027B & DESP1031 showed all test parameters (e.g.
  • the concentration of citric acid to be used in the formulation was finalized to be 1.70mg/mL.
  • room temperature stable diluted aqueous solution comprising 0.004 mg/mL desmopressin or its salt neither are taught nor are suggested. Further, it was also not taught in the prior art that such diluted solutions can be stabilized at room temperature with the help of antioxidant such as citric acid. The inventors of the present invention through their research have proved that the room temperature stable diluted aqueous solution of desmopressin can be prepared with the help of antioxidant such as citric acid.
  • a room temperature stable desmopressin aqueous solution may be prepared which may have shelflife of at least 12 months or more.
  • compositions of the present invention as described herein are suitable for use in the industry.

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Abstract

Aucun des produits d'injection de desmopressine approuvés et commercialisés n'est stable à température ambiante. Il est conseillé de conserver tous les produits d'injection de desmopressine au réfrigérateur entre 2°C et 8°C pour éviter la dégradation du principe actif. Cela fait plus de 35 ans ; cependant, une injection de desmopressine stable à température ambiante n'est toujours pas disponible. Par conséquent, pour tenter de répondre au besoin ressenti depuis longtemps, la présente invention propose des compositions aqueuses stables à température ambiante de desmopressine pour une administration intraveineuse ou sous-cutanée. Les compositions stables à température ambiante de la présente invention sont avantageuses par rapport aux produits stockés dans des conditions de réfrigération du point de vue de la fabrication, du stockage et de la logistique. Le produit stable à température ambiante ne nécessite pas d'être stocké et expédié à une température régulée (c'est-à-dire 2-8 °C). Il ne nécessite également pas de transport à chaîne froide. Il nécessite moins de soins que les formulations réfrigérées.
PCT/IB2023/061375 2022-11-17 2023-11-10 Composition pharmaceutique peptidique stable WO2024105521A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0708657B1 (fr) * 1993-06-29 2001-07-25 Ferring B.V. Compositions permettant l'administration par voie nasale de desmopressine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0708657B1 (fr) * 1993-06-29 2001-07-25 Ferring B.V. Compositions permettant l'administration par voie nasale de desmopressine

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