WO2019069316A1 - Composition stable de bélinostat, procédés pour sa production et ses utilisations - Google Patents

Composition stable de bélinostat, procédés pour sa production et ses utilisations Download PDF

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Publication number
WO2019069316A1
WO2019069316A1 PCT/IN2018/000008 IN2018000008W WO2019069316A1 WO 2019069316 A1 WO2019069316 A1 WO 2019069316A1 IN 2018000008 W IN2018000008 W IN 2018000008W WO 2019069316 A1 WO2019069316 A1 WO 2019069316A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
belinostat
stable
aqueous liquid
pharmaceutically acceptable
Prior art date
Application number
PCT/IN2018/000008
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English (en)
Inventor
Mahendra R. Joshi
Kamalanathan S
V. Phani KUMAR
C. Raghavendra REDDY
Trinath Kumar LMMANNI
Ravindhar Reddy MANDAPATI
Original Assignee
Joshi Mahendra R
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.)
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Application filed by Joshi Mahendra R filed Critical Joshi Mahendra R
Publication of WO2019069316A1 publication Critical patent/WO2019069316A1/fr

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides

Definitions

  • the present invention pertains among others to lyophilized powder and non-aqueous liquid dosage form of Belinostat thereof.
  • the invention concerns a method for the preparation of Belinostat in lyophilized powder form using alkali salts to improve the solubility and Polyols, amino acids (excluding arginine and lysine), monosaccharides, oligo/poly- saccharides, and cyclodextrins to improve dilution and reconstitution stability.
  • the invention also relates to a method for the preparation of Belinostat non-aqueous liquid dosage form using alcohols, glycol, diol, triol, polyoxyehtylene ether, polyethylene glycol ether and their derivatives, pH adjusting agents, suitable stabilizers and/or anti-oxidants.
  • Histones are part of the core proteins of nucleosomes. Acetylation and deacetylation of these proteins play a role in the regulation of gene expressioa
  • HDAC inhibitors include the following: 1) short-chain fatty acids, 2) hydroxamic acids 3) cyclic tetrapeptides 4) cyclic peptides and 5) benzamides. HDAC inhibitors invariably inhibit proliferation of transformed cells in culture, and a subset has been shown to inhibit tumor growth in animal models.
  • Belinostat is a novel histone deacetylase (HDAC) inhibitor that is being developed in various solid tumors and hematologic malignancies. Belinostat has been investigated as a single agent and in groups with further chemotherapies and biological agents, in the management of solid tumors tind lymphoma.
  • HDAC histone deacetylase
  • Belinostat inhibits the activity of histone deacetylase (HDAC) thus prevents the removal of acetyl groups from the lysine residues of histones and some non-histone proteins.
  • HDAC histone deacetylase
  • Belinosiat caused the accumulation of acetylated histones and other proteins increased the expression of tumor-suppressor genes. It ultimately induces cell cycle arrest, inhibition of angiogenesis and/or apoptosis of some transformed cells (Brahma N Singh et al., Future Oncol. 2011 Dec; 7(12): 1415-1428.).
  • Belinostat is under global development with Spectrum Pharmaceuticals, currently approved by the U.S. Food and Drug Administration with indications for relapsed or refractory peripheral T- cell lymphoma on July 2014.
  • Belinostat is a white to off-white powder. It is slightly soluble in distilled water (0.14 mg/mL), polyethylene glycol 400 (about 1.5 mg/mL), and freely soluble in ethanol (> 200 mg/mL). The pKa values are 7.87 and 8.71 by potentiometry and 7.86 and 8.59 by UV.
  • HDAC compounds including Belinostat endure various formulation challenges including low solubility in aqueous solutions, physical and/or chemical instability in aqueous solutions and upon later dilutions.
  • Various studies have done with different researchers to improvise the aqueous solubility and stability of Belinostat with different amino acids (like arginine, lysine, Glycine/NaOH etc.), buffers (phosphate buffer etc.), excipients (like Meglumine, HP-beta-cyclodextrins etc.) and combination thereof as mentioned in US patent 883SS0I .
  • Belinostat was known to have limited long-term chemical stability in solutions at pH above 8.5.
  • the present invention provides a Belinostat ly ' ophilized powder preparation, non-aqueous liquid dosage form of Belinostat and a method for producing the same. Specifically, the present invention is focused to improve the stability of the product after reconstitution of the Belinostat lyophilized powder is improved by an experimental study.
  • a parenteral pharmaceutical dosage form comprising Belinosiat or a pharmaceutically acceptable salt thereof.
  • a lyophilized powder form and non-aqueous liquid dosage form of Belinostat or a pharmaceutically acceptable salt thereof are provided.
  • the dosage form may include solubilizers for example alkali salts and amino acids excluding arginine and lysine.
  • the dosage form may include stabilizers for example Polyols, amino acids (excluding arginine and lysine), monosaccharides, oligo/poly saccharides, and cyclodextrins.
  • stabilizers for example Polyols, amino acids (excluding arginine and lysine), monosaccharides, oligo/poly saccharides, and cyclodextrins.
  • the non-aqueous liquid dosage form comprise solvents & co- solvents, for example alcohol such as ethyl alcohol, isopropanol, n-butanol and a glycol such as propylene glycol (PG), polyethylene glycol (PEG), polypropylene glycol (PPG), a diol such as straight chain, branched, or cyclic aliphatic diol, a triol, such as a straight chain, branched, or cyclic aliphatic triol, a polyoxyehtylene ether and a polyethylene glycol ether and their derivatives and pH adjusting agents, suitable stabilizers and/or anti-oxidants.
  • alcohol such as ethyl alcohol
  • isopropanol n-butanol
  • a glycol such as propylene glycol (PG), polyethylene glycol (PEG), polypropylene glycol (PPG), a diol such as straight chain, branched, or cyclic alipha
  • the dosage form comprises Belinostat or a pharmaceutically acceptable salt thereof at a concentration of about 10 mg/mL to about 100 mg/mL.
  • the present invention provides improved pharmaceutical formulations of Belinostat indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).
  • PTCL peripheral T-cell lymphoma
  • the present invention discloses novel formulations of Belinostat that increase its stability and maintain solubility for extended periods of time in solution.
  • Belinostat is slightly soluble in aqueous solutions such as normal saline and undergoes degradation once dissolved.
  • the instability and limited solubility of Belinostat in aqueous solution creates serious inconvenience in both manufacturing and clinical use of Belinostat drug product.
  • the present invention provides innovative solutions to the above problems associated with Belinosiat.
  • the pharmaceutical formulations as developed by the Inventors of the present invention are provided as Lyophilized Powder and concentrated non-aqueous liquid form that is stable, and suitable for parenteral administration.
  • pharmaceutically acceptable refers to an ingredient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes those acceptable for human pharmaceutical use.
  • stable and suitable pharmaceutical composition is referred to any pharmaceutical composition having sufficient physical and chemical stability to have utility as a pharmaceutical product.
  • a stable pharmaceutical composition has sufficient stability to allow storage at a convenient temperature for a reasonable period of time subsequent to reconstitution with a suitable diluting fluid.
  • stable pharmaceutical composition includes reference to pharmaceutical compositions with specific ranges of impurities as described herein.
  • a stable pharmaceutical composition is one which has minimal degradation of the active ingredient, e.g., it retains at least about 80% of un-degraded active, preferably at least about 90%, and more preferably at least about 95%, after storage at 15-30°C for a defined period of time.
  • a stable pharmaceutical composition is one which has impurity B level (degradation product of the active ingredient), e.g., it retains at least about ⁇ 1.0% of impurity B, preferably at least about ⁇ 0.5% and more preferably at least about 0.2% after storage at 15-30°C for a defined period of time.
  • impurity B level degradation product of the active ingredient
  • a stable pharmaceutical composition is one which has impurity E level (degradation product of the active ingredient), e.g., it retains at least about ⁇ 1.0% of degraded active, preferably at least about ⁇ 0.5% and more preferably at least about 0.2% after storage at 15.30°C for a defined period of time.
  • impurity E level degradation product of the active ingredient
  • pH of contemplated formulations may vary widely between I and 14, it is preferred that the pH is suitable for parenteral administration, and especially suitable for injection. Therefore, preferred pH values will be in the range of 8-11, preferably between 9 and 11.
  • the non-aqueous solution of Belinostat or its pharmaceutically acceptable salt, according lo the present invention have a pH, in the range of about 3.0 to 7.0.
  • pH of the non-aqueous solution of the present invention was adjusted in the range of about 3.5 to 6.5, preferably about 4.0 to 6.0, and the solution exhibited satisfactory chemical and physical stability. Tn one specific embodiment, the pH of the solution was adjusted to about 5.0.
  • concentrated non-aqueous solution form and/or lyophilized form of Be!inostat formulations can be prepared in an entirely solubilized and stable form suitable for injection.
  • Envisaged non-aqueous solutions can be prepared as concentrates that are diluted with suitable diluents prior to use, for example, within 48 hours of use.
  • Belinostat solutions can be prepared in which Belinosiat is not only soluble at pharmaceutically useful concentration, but also stable (i.e., remains physically/chemically unchanged) over substantial periods of time. Suitable Methods and solvents were described in the present invention.
  • Present invention provides methods in which the solubility of Belinostat in an aqueous solution can be significantly increased over heretofore known formulations by preparing an aqueous single phase solvent system that includes Belinostat, alkali salts and water.
  • the Belinostat-containing compositions include an amount of an alkali salts required for solubility.
  • "Solubilizing amount” shall be understood to include those amounts which increase or enhance the solubility of the Belinostat in the compositions described herein * .
  • suitable alkali salts concentrations in the compositions can range from about 0.5 mg/mL to about 50.0 mg/mL, and preferably from about 5.0mg/mL to about 3S.0 mg/mL or from about 5.0 mg/mL to about 20.0 mg/mL.
  • the concentration of the alkali salts in the Belinostat-containing composition is about 15mg/mL.
  • alkali salts are included in which they are pharmaceutically acceptable for use in human formulations although not limited to those currently regarded as safe by any regulatory authority.
  • alkali salts include but not limited to Sodium hydroxide, Potassium hydroxide, Calcium hydroxide and Magnesium hydroxide.
  • the composition according to ' the invention comprises Sodium hydroxide.
  • the alkali salts including Sodium hydroxide, Potassium hydroxide, Calcium hydroxide and Magnesium hydroxide, nevertheless preferably sodium hydroxide provide a medium for solubilization of Belinostat, i.e., the sodium hydroxide solubilizes Belinostat in a quantity that is higher than the solubilization of Belinostat in other solubilizers.
  • Present invention provides methods in which the stability of Belinostat in an aqueous solution can be significantly increased over heretofore known formulations by preparing an aqueous single phase solvent system that includes Belinostat and stabilizers wherein stabilizer is selected from the group of Polyols, amino acids (excluding arginine and lysine), monosaccharides, oligo/poly saccharides, and cyclodextrins.
  • stabilizer is selected from the group of Polyols, amino acids (excluding arginine and lysine), monosaccharides, oligo/poly saccharides, and cyclodextrins.
  • Suitable Polyols include those which are pharmaceutically acceptable for use in human formulations although not limited to those currently regarded as safe by any regulatory authority.
  • Polyols include but not limited to Sorbitol, Mannitol, Maltitol, Lactitol, Xylitol, Isomalt and Erythritol.
  • the composition according to the invention comprises Mannitol.
  • Suitable Polyols concentrations in the compositions can range from about 10.0 mg/mL to about 250.0mg/mL, and preferably from about 10.0mg/mL to about 200.0 mg/mL or from about 10.0mg/mL to about 150.0 mg/mL.
  • the concentration of the polyols in the Belinostat-containing composition is from about 20 mg/mL to about 120.0 mg/mL '
  • amino acids include but not limited to Alanine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine excluding arginine and lysine.
  • Suitable amino acids concentrations in the compositions can range from about 10.0 mg/mL to about 250-Omg/mL, and preferably from about 20.0mg/mL to about 200.0 mg/mL or from about 20.0 mg/mL to about 150.0 mg/mL. In some other embodiments, the concentration of the aminoacids Belinosiat containing composition is from about 125mg/mL
  • monosaccharides include but not limited to Glucose or dextrose, Fructose, Galactose, Mannose and Ribose and deoxyribose.
  • the composition according to the invention comprises Mannose.
  • Suitable monosaccharides concentrations in the compositions can range from about 10.0 mg/mL to about 250.0mg/mL, and preferably from about 10.0mg/mL to about 200.0 mg/mL or from about 10.0mg/mL to about 200.0 mg/mL.
  • the concentration of the Polyols in the Belinostat containing composition is from about 20mg/mL to about 150.0 mg/mL
  • oligo/polysaccharides include but not limited to Maltose and Sucrose.
  • Suitable Polysaccharides concentrations in the compositions can range from about 10.0 mg/mL to about 250.0mg/mL, and preferably from about 10.0 mg/mL to about 200.0 mg/mL or from about 10.0 mg/mL to about 150.0 mg/mL. In some other embodiments, the concentration of the polysaccharides in the Belinostat-containing composition is from about 20mg/mL to about 120.0 mg/mL.
  • compositions including lyophilized form and non-aqueous form of the present invention have low moisture content.
  • the stable formulations of the present invention can have a moisture content that is less than, 5%, by weight or volume of the formulation.
  • Suitable formulations of the present invention for parenteral administration include cyclodextrin.
  • One or more modified or unmodified cyclodextrins can be employed to stabilize and increase the water solubility of Belinostat formulation of the present invention.
  • Useful cyclodextrins for this purpose include beta-cyclodextrins preferably hydroxy propyl beta cyclodextrin.
  • beta- cyclodextrin refers to cyclic alpha- 1, 4-1 inked oligosaccharides of a D- glucopyranose containing a relatively hydrophobic central cavity and hydrophilic outer surface.
  • hydroxy propyl beta cyclodextrin herein referred to as "HP ⁇ CD”.
  • HP ⁇ CD hydroxy propyl beta cyclodextrin
  • Particular efficacy has been observed in the present invention utilizing hydroxypropyl-beia- cyclodextrin; however, other substituted and unsubstituted beta-cyclodextrins can also be used in the practice of the invention.
  • the w/w ratios of HPPCD to the active can range from about 1 :10 to about 2:10, particularly from about 0.5:5.0 to about 1.0:5.
  • compositions of the present invention can be administered by any route, preferably in the form of a pharmaceutical composition adapted to such a route, as illustrated below and are dependent on the condition being treated.
  • the formulations can be, for example, administered parenterally particularly intravenously.
  • solubilizers used in the non-aqueous liquid dosage form present invention include, but are not limited to, ethanol, isopropanol, n-butanol, glycol, diol. triol, poly oxyehtylene ether and a poly ethylene glycol ether and their derivatives and pH adjusting agents, suitable stabilizers and/or antioxidants.
  • the glycol is preferably selected from the group consisting of propylene glycol (FG). polyethylene glycol (PEG), polypropylene glycol (PPG), tetra glycol and suitable mixtures thereof.
  • Suitable glycol concentrations in the compositions can range from about 10% V/V to about 100% V/V, and preferably from about 50% V/V to about 95%V/V or from about 80%V/V to about 95%V/V.
  • the concentration of the glycol in the Belinostat- containing composition is from about 80%V/V to about 90%V/V.
  • the diol is preferably selected from the group .consisting straight chain, branched, or cyclic aliphatic diol and suitable mixtures thereof. Suitable diol concentrations in the compositions can range from about 0.1% V/V to about 20% V/V, and preferably from about 0.1% V/V to about 15% V/V or from about 0.5%V/V to about 10% V/V. In some other embodiments, the concentration of the diol in the Belinostat-containing composition is from about 1%V/V to about 10%WV.
  • the triol is preferably selected from the group consisting a straight chain, branched, or cyclic aliphatic triol and suitable mixtures thereof.
  • Suitable triol concentrations in the compositions can range from about 0.1%V/V to about 30%V/V, and preferably from about 0.1%V/V to about 20%V/V or from about 0.5%V/V to about 20%V/V.
  • the concentration of the diol in the Belinostat-containing composition is from about 1%V/V to about 10% WV.
  • the glycol is preferably selected from the group consisting of polyethylene glycols, propylene glycol, tetra glycol and mixtures thereof.
  • Polyethylene glycol e.g. PEG 300 and PEG 400
  • the polyethylene glycol has a molecular weight in the range from 200 to 600. More preferably, the polyethylene glycol has a molecular weight of about 300-400 (PEG 300 or PEG 400).
  • PEG 300 or PEG 400 a polyethylene glycol having a molecular weight above 600 is likely to be solid and cannot be used in non-aqueous systems.
  • compositions of the present invention can be in powder form, or preferably lyophilized powder form, for reconstitution in the appropriate pharmaceutically acceptable carrier at the time of delivery.
  • the lyophilized Belinostat formulations of the presently disclosed subject matter display rapid reconstitution times in a pharmaceutically acceptable diluent.
  • the lyophilized Belinostat formulations are reconstituted in a pharmaceutically acceptable diluent in less than about 180seconds.
  • the lyophilized Belinostat formulations are reconstituted in a pharmaceutically acceptable diluent in less than about 25seconds.
  • the lyophilized Belinostat formulations are reconstituted in a pharmaceutically acceptable diluent in less than about 20 seconds.
  • the lyophilized Belinostat formulations are reconstituted in a pharmaceutically acceptable diluent in less than about ISseconds.
  • the lyophilized Belinostat formulations are reconstituted in a pharmaceutically acceptable diluent in less than about 10 seconds.
  • the lyophilized Belinostat formulations of the presently disclosed subject matter can be reconstituted by adding the pharmaceutically acceptable diluent(s) to the lyophilized Belinostat formulation to provide the desired concentration for direct administration or further dilution for administration by infusion.
  • compositions of the presently disclosed subject matter include, but are not limited to, sterile water for injection, 0.9% sodium chloride solution for injection, solution.
  • the lyophilized Belinostat formulations are reconstituted in 0.9% sterile sodium chloride solution for injection.
  • the lyophilized Belinostat formulations are reconstituted in sterile water for injection.
  • the volume of the pharmaceutically acceptable diluent(s) added to the lyophilized Belinostat formulation is from about SmL to about 50mL.
  • the volume of the pharmaceutically acceptable diluent(s) added to the lyophilized Belinostat formulation is from about 5 mL to about 50 mL. In one embodiment, the volume of the pharmaceutically acceptable diluent(s) added to the lyophilized Be!inostat formulation is about 10 mL.
  • lyophilized Belinostat formulations of the presently disclosed subject matter can be reconstituted by any suitable methods known to one of ordinary skill in the art.
  • the Belinostat formulations of the presently disclosed subject matter include Belinostat at a concentration of from about 10mg/mL to about 100mg/mL, e.g., from about 20mg/mL to about 80mg/mL, or from about 40mg/mL to about 60mg/mL, or about 50mg/mL.
  • the present invention provides a method for preparing a lyophilized form of Belinostat formulation.
  • the lyophilized Belinostat formulation is stable and is ready to be diluted once and administered to a patient.
  • the typical method comprises the steps of: i) . Dissolve sodium hydroxide in 80% water, and mixed to get clear solution
  • the vials were stoppered and sealed.
  • the sealed vials were tested for description, drug content and impurities and tabulated in the below table 4.
  • the inventors of the present invention can able to achieve desired aqueous solubility of Belinostat only with use of sodium hydroxide, and it is observed that, the drug product stability is significantly improved when formulated in combination with mannitol or Fructose or HP-beta-cyclodextrin.
  • the inventive formulations may be stored for a long time before being administered to the patient.

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Abstract

L'invention concerne une forme posologique comprenant une forme de poudre lyophilisée obtenue à partir d'une solution comprenant un agent de solubilisation, un stabilisant et du bélinostat. La présente invention a identifié des sels alcalins en tant qu'agents de solubilisation appropriés et des polyols, des acides aminés (excepté l'arginine et la lysine), des monosaccharides, des oligosaccharides/polysaccharides et des cyclodextrines en tant que stabilisants appropriés pour une forme posologique en poudre lyophilisée. Parmi d'autres avantages des formulations selon l'invention, le bélinostat est dissous à des concentrations élevées et reste dissous et stable, même sur des durées prolongées. En outre, la présente invention concerne une forme posologique liquide non aqueuse stable de bélinostat comprenant des agents de solubilisation, des agents d'ajustement du pH, des stabilisants et/ou des antioxydants.
PCT/IN2018/000008 2017-10-05 2018-01-29 Composition stable de bélinostat, procédés pour sa production et ses utilisations WO2019069316A1 (fr)

Applications Claiming Priority (2)

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IN201741035295 2017-10-05
IN201741035295 2017-10-05

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115068620A (zh) * 2022-07-20 2022-09-20 天津睿创康泰生物技术有限公司 能够减少芳胺类杂质生成的药物组合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
No relevant documents disclosed *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115068620A (zh) * 2022-07-20 2022-09-20 天津睿创康泰生物技术有限公司 能够减少芳胺类杂质生成的药物组合物

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