WO2019097413A1 - Stable non-aqueous pharmaceutical compositions - Google Patents

Stable non-aqueous pharmaceutical compositions Download PDF

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Publication number
WO2019097413A1
WO2019097413A1 PCT/IB2018/058942 IB2018058942W WO2019097413A1 WO 2019097413 A1 WO2019097413 A1 WO 2019097413A1 IB 2018058942 W IB2018058942 W IB 2018058942W WO 2019097413 A1 WO2019097413 A1 WO 2019097413A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
stable non
aqueous pharmaceutical
cyclodextrin
hydrophobic drug
Prior art date
Application number
PCT/IB2018/058942
Other languages
French (fr)
Inventor
Kamal Kumar Upadhyay
Alex George
Kirti MAHESHWARI
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Intas Pharmaceuticals Ltd.
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Publication date
Application filed by Intas Pharmaceuticals Ltd. filed Critical Intas Pharmaceuticals Ltd.
Publication of WO2019097413A1 publication Critical patent/WO2019097413A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/69—Boron compounds
    • 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
    • A61K38/05—Dipeptides
    • 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
    • A61K38/07—Tetrapeptides
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives 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
    • 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
    • A61K9/08—Solutions

Definitions

  • the present invention relates to a stable non-aqueous pharmaceutical composition for a hydrophobic drug, or its pharmaceutically acceptable salt or a co-crystal thereof; wherein the said pharmaceutical composition comprises of cyclodextrin and propylene glycol (PG).
  • the pharmaceutical composition according to the present invention can be used to provide an alternate means of formulating a ready-to-use or a ready-to-dilute pharmaceutical composition of a hydrophobic drug, or its pharmaceutically acceptable salt or a co-crystal thereof, without the need for lyophilization.
  • the present invention relates to process for the preparation of the said pharmaceutical composition and the use of the said pharmaceutical composition in pharmaceutical industry.
  • Parenteral formulations are suitable for delivery of pharmaceutical drugs which have narrow therapeutic index and poor bioavailability.
  • Parenteral formulations are sterile, pyrogen-free liquids or lyophilized powders which are packaged in single dose or multiple dose containers.
  • Development of parenteral formulation depends on the physical and chemical properties (including the solubility and stability) of the drug which is to be dispensed through the parenteral route. Based on the hydrophilic or hydrophobic nature of the drug, the type of parenteral formulation can be designed. For most of the drugs which does not undergo hydrolytic degradation, an aqueous medium is used as a vehicle for the preparation of the parenteral composition. However, for drugs undergoing hydrolytic degradation, parenteral formulation are designed as lyophilized or freeze-dried formulation.
  • lyophilized formulation is reconstituted with water for injection (WFI) prior to administration.
  • WFI water for injection
  • the lyophilized composition comprises of a bulking agent, a pH adjusting agent, optional stabilizers, to provide a stable lyophilized composition.
  • Cyclodextrins have been also used for preparing parenteral formulations. Cyclodextrins form an inclusion complex with hydrophobic drug which is soluble in aqueous medium and hence improves the aqueous solubility of hydrophobic drugs. These cyclodextrin-hydrophobic drug inclusion complex are lyophilized. Illustrations of these marketed lyophilized inclusion complexes include VTEND ® (Voriconazole for injection), Kyprolis ® (Carfilzomib for injection), etc. Before administration, these lyophilized powders are reconstituted with water. However, there exists uncertainty and irregular solubility of a stable pharmaceutical composition formulated by dissolving cyclodextrin into non-aqueous solvents.
  • the inventors of present invention have developed a stable non-aqueous pharmaceutical composition for a hydrophobic drug, or its pharmaceutically acceptable salt or a co-crystal thereof; which provides an alternate means of formulating a ready-to-use or a ready-to-dilute pharmaceutical composition for hydrophobic drug, or its pharmaceutically acceptable alt or a co-crystal thereof, without the need for lyophilization.
  • the present invention relates to a stable non-aqueous pharmaceutical composition for a hydrophobic drug, or its pharmaceutically acceptable salt or a co-crystal thereof; wherein the said pharmaceutical composition comprises of cyclodextrin and PG.
  • the cyclodextrin consists of sulfobutyl ether beta-cyclodextrin (SBE-BCD).
  • SBE-BCD sulfobutyl ether beta-cyclodextrin
  • the pharmaceutical composition according to the present invention can be used to provide a ready-to-use or a ready-to-dilute pharmaceutical composition for hydrophobic drug, or its pharmaceutically acceptable salt or a co-crystal thereof. Further, the present invention also discloses the process for the preparation of said pharmaceutical composition and its use in pharmaceutical applications.
  • the main object of the present invention is to provide a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising cyclodextrin and PG.
  • Another object of the present invention is to provide a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising SBE-BCD and PG.
  • Another object of the present invention is to provide a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising SBE-BCD, PG and an optional anti-oxidant.
  • another object of the present invention is to provide a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising SBE-BCD and PG; wherein the amount of SBE-BCD solubilized in PG is in the amount ranging from 0 to 200 mg/ml in the said stable non-aqueous pharmaceutical composition.
  • Another object of the present invention is to provide a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising SBE-BCD and PG; wherein the concentration of hydrophobic drug in the said stable non-aqueous pharmaceutical composition would range from about 0.1 mg/ml to about 250 mg/ml.
  • Another object of the present invention is to provide a method for the preparation of a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising SBE-BCD and PG.
  • Another object of the present invention is to provide a method for the preparation of a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising SBE-BCD and PG; wherein the method comprises the steps of:
  • step b) Optionally dissolving a stabilizer/antioxidant to the solution obtained in step a), c) Solubilizing the hydrophobic drug, or its pharmaceutically acceptable salt or co crystal thereof in the solution obtained in step a) or b),
  • step c) Optionally adjusting the pH of the solution obtained in step c) to obtain desired pH
  • step d) Filtering the obtained solution in step d) through a sterile grade filter, and aseptically filling the solution in a suitable container (vial).
  • Another object of the present invention is to provide a stable non-aqueous pharmaceutical composition for a pharmaceutical drug or a pharmaceutically acceptable salt or a co-crystal thereof, which undergoes hydrolytic degradation, wherein the said pharmaceutical composition comprises SBE-BCD and PG.
  • Another object of the present invention is to provide a stable non-aqueous pharmaceutical composition for a pharmaceutical drug or a pharmaceutically acceptable salt or a co-crystal thereof, which undergoes hydrolytic degradation, wherein the said pharmaceutical composition comprises SBE-BCD, PG and optionally an anti-oxidant.
  • hydrophobic drug relates to a pharmaceutical drug in its free base form, which are not soluble or are sparingly soluble in water.
  • hydrophobic drug according to the present invention is a drug having an aqueous solubility of less than 0.1 mg/ml at room temperature.
  • examples of hydrophobic drug include but not limited to Bendamustine, Carmustine, Carfilzomib, Bortezomib, Erlotinib, etc.
  • the effective amount of the hydrophobic drug for the present invention can be selected based on the approved strength or doses used for treatment that is routinely known to a person of ordinary skill in the art.
  • pharmaceutically acceptable salt refers to salt(s) of the said pharmaceutical drug.
  • the salts of the said pharmaceutical drug are prepared by treating the pharmaceutical drug with a base or an acid.
  • pharmaceutically acceptable acid addition salts include but not limited to hydrochloric acid, hydrobromic acid, fumaric acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid phthalic acid, benzenesulfonic acid, nitric acid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, maleic acid, benzoic acid, succinic acid, and the likes thereof.
  • the term“Co-crystals” refer to crystalline materials composed of two or more molecules within the same crystal lattice, typically a pharmaceutical drug and co crystal formers (“co-formers”), in the same crystal lattice.
  • Cyclodextrins refers to cyclic oligosaccharides consisting of six a- cyclodextrin, seven b-cyclodextrin, eight -g-cyclodextrin or more glucopyranose units linked by a-(l,4) bonds. Cyclodextrins interact with hydrophobic drug molecules to form inclusion complexes to improve the aqueous solubility of the drug molecule.
  • b-cyclodextrin which itself has a relatively low aqueous solubility because of strong intermolecular hydrogen bonding, substitution of any of the hydrogen bond-forming hydroxyl groups, even by lipophilic functions, results in a dramatic improvement in the aqueous solubility of the derivative.
  • b- cyclodextrin comprises of Sulfobutylether b-cyclodextrin and Hydroxypropyl-b- cyclodextrin.
  • SBE-BCD refers to a highly water soluble derivative of b-cyclodextrin.
  • SBE-BCD is a polyanionic b-cyclodextrin derivative with a sodium sulfonate salt separated from the lipophilic cavity by a butyl ether spacer group, or sulfobutylether.
  • SBE-BCD are commercially available as Captisol ® , Dexolve ® , etc.
  • PG propane- l,2-diol
  • PG is a viscous colorless liquid and is used as a non-aqueous medium for the preparation of stable non-aqueous pharmaceutical composition according to the present invention.
  • stable non-aqueous pharmaceutical composition refers to a pharmaceutical composition comprising SBE-BCD and PG; wherein no water is added during preparation of the composition, and wherein the composition has sufficient stability to allow storage at convenient temperature, about 2-8 °C.
  • the stable non-aqueous pharmaceutical composition according to the present invention can also be used to prepare stable pharmaceutical composition of drugs other than the said hydrophobic drugs.
  • the stable non-aqueous pharmaceutical composition according to the present invention can also be used to prepare the stable pharmaceutical compositions for peptide, protein or small molecules which are prone to hydrolytic degradation when formulated using aqueous medium for preparing liquid pharmaceutical composition or lyophilized pharmaceutical composition.
  • the pharmaceutical composition of a hydrophobic drug prepared using the said stable non-aqueous pharmaceutical composition is a ready-to-use or ready-to-dilute pharmaceutical composition of the said drug, which is storage-stable for a reasonable period of time, e.g., the shelf-life of the product which can be as short as one month but is typically six months or longer, preferably at least 18 months or more preferably at least 2 years.
  • the pharmaceutical composition of a hydrophobic drug prepared using the said stable non-aqueous pharmaceutical composition has a minimal degradation of the active ingredient, e.g., it retains at least about 80% of active ingredient, preferably at least about 90%, and more preferably at least about 95%, after storage at typical commercial conditions.
  • antioxidant refers to the ingredients that act as a stabilizer by enhancing the stability of the hydrophobic drug or its pharmaceutically acceptable salt and co crystal thereof, by inhibiting the oxidation of these drug.
  • Antioxidant for the present invention includes but are not limited to propyl gallate, methionine, Cysteine HC1, metabisulfites, Tocopherols, monothioglycerol, Butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT) and mixtures thereof.
  • BHA Butylated hydroxyanisole
  • BHT Butylated hydroxytoluene
  • the antioxidant is Cysteine HC1.
  • the concentration of antioxidant can range from about 0.1 mg/ml to about 20 mg/ml, and preferably from about 0.5 mg/ml to about 5 mg/ml.
  • the stable non-aqueous pharmaceutical composition according to the present invention may also comprise pharmaceutically acceptable ingredients known in the art which include, for example, surfactants (e.g., Polysorbates), organic acids (e.g., citric acid), chelating agents (e.g., EDTA), preservatives (e.g., benzyl alcohol), stabilizer such as chloride salts (sodium chloride, calcium chloride), pH adjusting agents (e.g., sodium hydroxide, triethylamine), etc.
  • surfactants e.g., Polysorbates
  • organic acids e.g., citric acid
  • chelating agents e.g., EDTA
  • preservatives e.g., benzyl alcohol
  • stabilizer such as chloride salts (sodium chloride, calcium chloride), pH adjusting agents (e.g., sodium hydroxide, triethylamine), etc.
  • the stable non-aqueous pharmaceutical composition according to the present invention comprises PG as a non-aqueous medium.
  • SBE- BCD is solubilized in PG in an amount ranging from 0 to 125 mg/ml in the said stable non-aqueous pharmaceutical composition.
  • the amount of SBE- BCD solubilized in PG is 0 to 100 mg/ml in the said stable non-aqueous pharmaceutical composition.
  • more amount of SBE-BCD can be added such that the amount of SBE-BCD is within the allowable limit for parenteral use, and it achieves the desired solubility and stability of the composition.
  • the amount of SBE-BCD is added as 200 mg/ml in the bendamustine composition comprising 25 mg/ml.
  • One aspect of the invention is to provide a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co crystal thereof, comprising SBE-BCD, PG and an optional anti-oxidant.
  • Another aspect of the invention is to provide a method for the preparation of a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising SBE-BCD and PG; wherein the method comprises the steps of:
  • step b) Optionally dissolving stabilizer/antioxidant to the solution obtained in step a), c) Solubilizing the hydrophobic drug, or its pharmaceutically acceptable salt or co- crystal thereof in the solution obtained in step a) or b),
  • the concentration of hydrophobic drug in the said stable non-aqueous pharmaceutical composition would range from about 0.1 mg/ml to about 250 mg/ml.
  • the concentration of hydrophobic drug would range from 0.1 mg/ml to 100 mg/ml; more preferably, the concentration of the hydrophobic drug would range from 0.1 mg/ml to 50 mg/ml.
  • the stable non-aqueous pharmaceutical composition according to the present invention can be used for the development of pharmaceutical composition of hydrophobic drugs and shall have high industrial applicability.
  • various hydrophobic drugs that can be formulated using the pharmaceutical composition according to the present invention are Bendamustine, Carmustine, Carfilzomib, Erlotinib, and Bortezomib.
  • non-limiting examples of hydrophobic drugs shall include Docetaxel, Paclitaxel, Cabazitaxel, Teniposide, and the likes thereof.
  • the stable non-aqueous pharmaceutical composition can be used for preparing pharmaceutical compositions of pharmaceutical drugs which undergo hydrolytic degradation.
  • the non-limiting examples include Bortezomib, methylphenidate, spironolactone, cephalosporins, penicillins, etc.
  • Example 1 Stable non-aqueous pharmaceutical composition
  • step c) Optionally adjusting pH of the solution obtained in step c) to obtain desired pH
  • step d) Filtering the obtained solution in step d) through a sterile grade filter, and 6) Aseptically filling the solution in a suitable container (vial).
  • Example 2 Stable non-aqueous pharmaceutical composition for Bendamustine
  • Example 3 Stable non-aqueous pharmaceutical composition for Carmustine
  • Example 4 Stable non-aqueous pharmaceutical composition comprising Carfilzomib
  • Example 5 Stable non-aqueous pharmaceutical composition comprising
  • Example 6 Stable non-aqueous pharmaceutical composition comprising
  • compositions disclosed in the examples given herewith have been found to be clear, colorless to pale yellow concentrated solution and no precipitation occurred, such that it provides sufficient stability to allow storage at convenient temperature of about 2-8 °C.
  • compositions disclosed in these examples can be further diluted using 0.9% NaCl, dextrose solution or water for injection prior to administration.
  • Example 7 Stable non-aqueous pharmaceutical composition comprising Bendamustine HC1 (25 mg/ml) with the results of the stability study.
  • the pharmaceutical composition was prepared according to the steps mentioned in Example 1.
  • the stable non-aqueous composition can be further diluted using 0.9% NaCl, dextrose solution or water for injection prior to administration.
  • Impurity A (Mono-hydroxy Bendamustine): 4-(5-((2-chloroethyl)(2- hydroxyethyl) amino)- 1 -methyl- 1H benzo[d]imidazol-2-yl)butanoic acid
  • Impurity B (Bendamustine Dimer): 4-(5-((2-((4-(5-(bis(2-hydroxy ethyl) amino)-
  • H-BMHRC01 lH-Benzimidazole-l-methyl-5-N, N-di(2-chloroethyl)-2-butanoic acid ethyl ester
  • H-BMHRC02 4-(7,8-dihydro-6-(2-chloroethylamino)-3-methyl-l,4-thiazino[3,2- g]benzimidazoyl(2))butyric acid
  • Example 8 Stable non-aqueous pharmaceutical composition comprising Bendamustine HC1 (90 mg/ml) with the results of the stability study.
  • the pharmaceutical composition was prepared according to the steps mentioned in Example 1.
  • the stable non-aqueous composition can be further diluted using 0.9% NaCl, dextrose solution or water for injection prior to administration.
  • the stability results of the non-aqueous pharmaceutical composition comprising Bendamustine HC1 as described in the Example 8.
  • Example 9 Stable non-aqueous pharmaceutical composition comprising Bendamustine HC1 (25 mg/ml) with the results of the stability study.
  • the pharmaceutical composition was prepared according to the steps mentioned in Example 1.
  • the stable non-aqueous composition can be further diluted using 0.9% NaCl, dextrose solution or water for injection prior to administration.
  • the stability results of the non-aqueous pharmaceutical composition comprising Bendamustine HC1 as described in the Example 9.
  • the stability study of the inventive composition shows that the bendamustine composition (25 mg/ml) remains stable for at least 6 months when stored at 2-8 °C, and the total impurities remained below 3%.
  • Example 10 Stable non-aqueous pharmaceutical composition comprising
  • the pharmaceutical composition was prepared according to the steps mentioned in Example 1.
  • the stable non-aqueous composition can be further diluted using 0.9% NaCl, dextrose solution or water for injection prior to administration.
  • the stability results of the non-aqueous pharmaceutical composition comprising Bendamustine HC1 as described in the Example 10.
  • the stability study of the inventive composition shows that the bendamustine composition (25 mg/ml) remains stable for at least 9 months when stored at 2-8 °C, and the total impurities remained below 3%.
  • Example 11 Dilution study of non-aqueous pharmaceutical composition comprising Bendamustine HC1 (25 mg/ml) at 20-25°C and 2-8°C.
  • the non-aqueous pharmaceutical composition described in the Example 10 was used for dilution study, wherein the composition was diluted with 0.9% Sodium chloride.

Abstract

The present invention relates to a stable non-aqueous pharmaceutical composition comprising a hydrophobic drug or a pharmaceutically acceptable salt thereof, involving cyclodextrin and propylene glycol. The present invention can be used as a ready-to-use composition or a ready-to-dilute composition without the need for lyophilization. Further it relates to a process for the preparation of the said composition and uses thereof.

Description

STABLE NON-AQUEOUS PHARMACEUTICAL COMPOSITIONS
RELATED APPLICATIONS
This application is related to Indian Provisional Application 201721040840 filed l 5th November, 2017 and is incorporated herein in its entirety.
FIELD OF THE INVENTION
The present invention relates to a stable non-aqueous pharmaceutical composition for a hydrophobic drug, or its pharmaceutically acceptable salt or a co-crystal thereof; wherein the said pharmaceutical composition comprises of cyclodextrin and propylene glycol (PG). The pharmaceutical composition according to the present invention can be used to provide an alternate means of formulating a ready-to-use or a ready-to-dilute pharmaceutical composition of a hydrophobic drug, or its pharmaceutically acceptable salt or a co-crystal thereof, without the need for lyophilization. Further, the present invention relates to process for the preparation of the said pharmaceutical composition and the use of the said pharmaceutical composition in pharmaceutical industry. BACKGROUND OF THE INVENTION
Parenteral formulations are suitable for delivery of pharmaceutical drugs which have narrow therapeutic index and poor bioavailability. Parenteral formulations are sterile, pyrogen-free liquids or lyophilized powders which are packaged in single dose or multiple dose containers. Development of parenteral formulation depends on the physical and chemical properties (including the solubility and stability) of the drug which is to be dispensed through the parenteral route. Based on the hydrophilic or hydrophobic nature of the drug, the type of parenteral formulation can be designed. For most of the drugs which does not undergo hydrolytic degradation, an aqueous medium is used as a vehicle for the preparation of the parenteral composition. However, for drugs undergoing hydrolytic degradation, parenteral formulation are designed as lyophilized or freeze-dried formulation.
There are many illustrations in the art which exemplifies the use of lyophilization for providing vials comprising lyophilized powder as parenteral formulation. Some of the examples of drugs dispensed as lyophilized products include Velcade® (Bortezomib for injection), Tygacil® (Tigecycline for injection), Cubicin® (Daptomycin for injection), Treanda® (Bendamustine for injection), Candidas® (Caspofungin for injection) etc. The lyophilized formulation is reconstituted with water for injection (WFI) prior to administration. Generally speaking, the lyophilized composition comprises of a bulking agent, a pH adjusting agent, optional stabilizers, to provide a stable lyophilized composition.
As a formulator, it is a challenge to develop a parenteral formulation for hydrophobic drugs and / or drugs which undergo hydrolytic degradation. An option for the development of parenteral formulation for such drugs is to provide a non- aqueous pharmaceutical composition. Currently, non-aqueous pharmaceutical compositions are available in the art, however it has been very challenging to produce a stable non-aqueous pharmaceutical composition for hydrophobic drugs.
Cyclodextrins have been also used for preparing parenteral formulations. Cyclodextrins form an inclusion complex with hydrophobic drug which is soluble in aqueous medium and hence improves the aqueous solubility of hydrophobic drugs. These cyclodextrin-hydrophobic drug inclusion complex are lyophilized. Illustrations of these marketed lyophilized inclusion complexes include VTEND® (Voriconazole for injection), Kyprolis® (Carfilzomib for injection), etc. Before administration, these lyophilized powders are reconstituted with water. However, there exists uncertainty and irregular solubility of a stable pharmaceutical composition formulated by dissolving cyclodextrin into non-aqueous solvents. Several attempts have been made in the prior art to develop stable non-aqueous pharmaceutical compositions for hydrophobic drugs. In particular, the PCT publications such as W02010036702 and WO2011094565 disclose liquid compositions for bendamustine with non-aqueous solvents. Further, the PCT publications such as WO2010097700 and WO2012127277 discloses composition comprising bendamustine, a charged cyclopolysaccharide, and a stabilizing agent. However, there exists a need for the development of a stable non-aqueous composition that would inhibit the degradation and also increase the solubility and stability of hydrophobic drugs. The inventors of present invention have developed a stable non-aqueous pharmaceutical composition for a hydrophobic drug, or its pharmaceutically acceptable salt or a co-crystal thereof; which provides an alternate means of formulating a ready-to-use or a ready-to-dilute pharmaceutical composition for hydrophobic drug, or its pharmaceutically acceptable alt or a co-crystal thereof, without the need for lyophilization.
SUMMARY OF THE INVENTION
The present invention relates to a stable non-aqueous pharmaceutical composition for a hydrophobic drug, or its pharmaceutically acceptable salt or a co-crystal thereof; wherein the said pharmaceutical composition comprises of cyclodextrin and PG. Specifically, the cyclodextrin consists of sulfobutyl ether beta-cyclodextrin (SBE-BCD). The pharmaceutical composition according to the present invention can be used to provide a ready-to-use or a ready-to-dilute pharmaceutical composition for hydrophobic drug, or its pharmaceutically acceptable salt or a co-crystal thereof. Further, the present invention also discloses the process for the preparation of said pharmaceutical composition and its use in pharmaceutical applications.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising cyclodextrin and PG.
Another object of the present invention is to provide a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising SBE-BCD and PG.
Another object of the present invention is to provide a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising SBE-BCD, PG and an optional anti-oxidant.
Further, another object of the present invention is to provide a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising SBE-BCD and PG; wherein the amount of SBE-BCD solubilized in PG is in the amount ranging from 0 to 200 mg/ml in the said stable non-aqueous pharmaceutical composition.
Another object of the present invention is to provide a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising SBE-BCD and PG; wherein the concentration of hydrophobic drug in the said stable non-aqueous pharmaceutical composition would range from about 0.1 mg/ml to about 250 mg/ml. Another object of the present invention is to provide a method for the preparation of a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising SBE-BCD and PG. Another object of the present invention is to provide a method for the preparation of a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising SBE-BCD and PG; wherein the method comprises the steps of:
a) Solubilizing SBE-BCD in PG,
b) Optionally dissolving a stabilizer/antioxidant to the solution obtained in step a), c) Solubilizing the hydrophobic drug, or its pharmaceutically acceptable salt or co crystal thereof in the solution obtained in step a) or b),
d) Optionally adjusting the pH of the solution obtained in step c) to obtain desired pH,
e) Filtering the obtained solution in step d) through a sterile grade filter, and aseptically filling the solution in a suitable container (vial).
Another object of the present invention is to provide a stable non-aqueous pharmaceutical composition for a pharmaceutical drug or a pharmaceutically acceptable salt or a co-crystal thereof, which undergoes hydrolytic degradation, wherein the said pharmaceutical composition comprises SBE-BCD and PG. Another object of the present invention is to provide a stable non-aqueous pharmaceutical composition for a pharmaceutical drug or a pharmaceutically acceptable salt or a co-crystal thereof, which undergoes hydrolytic degradation, wherein the said pharmaceutical composition comprises SBE-BCD, PG and optionally an anti-oxidant.
DETAILED DESCRIPTION
The detailed description and the examples provided herein are exemplary and any modification or variation within the scope of the invention will be apparent to a person skilled in the art. Further, unless otherwise defined, all the technical and scientific terms used herein shall bear the meaning as understood by a person who is ordinarily skilled in the art. The term“hydrophobic drug” relates to a pharmaceutical drug in its free base form, which are not soluble or are sparingly soluble in water. Specifically, hydrophobic drug according to the present invention is a drug having an aqueous solubility of less than 0.1 mg/ml at room temperature. Examples of hydrophobic drug include but not limited to Bendamustine, Carmustine, Carfilzomib, Bortezomib, Erlotinib, etc. The effective amount of the hydrophobic drug for the present invention can be selected based on the approved strength or doses used for treatment that is routinely known to a person of ordinary skill in the art.
The term “pharmaceutically acceptable salt” refers to salt(s) of the said pharmaceutical drug. The salts of the said pharmaceutical drug are prepared by treating the pharmaceutical drug with a base or an acid. Examples of pharmaceutically acceptable acid addition salts include but not limited to hydrochloric acid, hydrobromic acid, fumaric acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid phthalic acid, benzenesulfonic acid, nitric acid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, maleic acid, benzoic acid, succinic acid, and the likes thereof. The term“Co-crystals” refer to crystalline materials composed of two or more molecules within the same crystal lattice, typically a pharmaceutical drug and co crystal formers (“co-formers”), in the same crystal lattice.
The term“Cyclodextrins” refers to cyclic oligosaccharides consisting of six a- cyclodextrin, seven b-cyclodextrin, eight -g-cyclodextrin or more glucopyranose units linked by a-(l,4) bonds. Cyclodextrins interact with hydrophobic drug molecules to form inclusion complexes to improve the aqueous solubility of the drug molecule. For b-cyclodextrin, which itself has a relatively low aqueous solubility because of strong intermolecular hydrogen bonding, substitution of any of the hydrogen bond-forming hydroxyl groups, even by lipophilic functions, results in a dramatic improvement in the aqueous solubility of the derivative. Specifically, b- cyclodextrin comprises of Sulfobutylether b-cyclodextrin and Hydroxypropyl-b- cyclodextrin. The term“Sulfobutylether b-cyclodextrin” (SBE-BCD) refers to a highly water soluble derivative of b-cyclodextrin. SBE-BCD is a polyanionic b-cyclodextrin derivative with a sodium sulfonate salt separated from the lipophilic cavity by a butyl ether spacer group, or sulfobutylether. SBE-BCD are commercially available as Captisol®, Dexolve®, etc.
The term“propylene glycol” (PG) used herein is also called propane- l,2-diol, which is a synthetic organic compound with chemical formula C3H8O2. PG is a viscous colorless liquid and is used as a non-aqueous medium for the preparation of stable non-aqueous pharmaceutical composition according to the present invention.
The term "stable non-aqueous pharmaceutical composition" refers to a pharmaceutical composition comprising SBE-BCD and PG; wherein no water is added during preparation of the composition, and wherein the composition has sufficient stability to allow storage at convenient temperature, about 2-8 °C. The stable non-aqueous pharmaceutical composition according to the present invention can also be used to prepare stable pharmaceutical composition of drugs other than the said hydrophobic drugs.
Apart from the hydrophobic drug, the stable non-aqueous pharmaceutical composition according to the present invention can also be used to prepare the stable pharmaceutical compositions for peptide, protein or small molecules which are prone to hydrolytic degradation when formulated using aqueous medium for preparing liquid pharmaceutical composition or lyophilized pharmaceutical composition.
The pharmaceutical composition of a hydrophobic drug prepared using the said stable non-aqueous pharmaceutical composition is a ready-to-use or ready-to-dilute pharmaceutical composition of the said drug, which is storage-stable for a reasonable period of time, e.g., the shelf-life of the product which can be as short as one month but is typically six months or longer, preferably at least 18 months or more preferably at least 2 years. Further, the pharmaceutical composition of a hydrophobic drug prepared using the said stable non-aqueous pharmaceutical composition has a minimal degradation of the active ingredient, e.g., it retains at least about 80% of active ingredient, preferably at least about 90%, and more preferably at least about 95%, after storage at typical commercial conditions.
The term "antioxidant" refers to the ingredients that act as a stabilizer by enhancing the stability of the hydrophobic drug or its pharmaceutically acceptable salt and co crystal thereof, by inhibiting the oxidation of these drug. Antioxidant for the present invention includes but are not limited to propyl gallate, methionine, Cysteine HC1, metabisulfites, Tocopherols, monothioglycerol, Butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT) and mixtures thereof. Preferably the antioxidant is Cysteine HC1. The concentration of antioxidant can range from about 0.1 mg/ml to about 20 mg/ml, and preferably from about 0.5 mg/ml to about 5 mg/ml.
In addition to the above-mentioned ingredients, the stable non-aqueous pharmaceutical composition according to the present invention may also comprise pharmaceutically acceptable ingredients known in the art which include, for example, surfactants (e.g., Polysorbates), organic acids (e.g., citric acid), chelating agents (e.g., EDTA), preservatives (e.g., benzyl alcohol), stabilizer such as chloride salts (sodium chloride, calcium chloride), pH adjusting agents (e.g., sodium hydroxide, triethylamine), etc.
In one aspect of the invention, the stable non-aqueous pharmaceutical composition according to the present invention comprises PG as a non-aqueous medium. SBE- BCD is solubilized in PG in an amount ranging from 0 to 125 mg/ml in the said stable non-aqueous pharmaceutical composition. Preferably, the amount of SBE- BCD solubilized in PG is 0 to 100 mg/ml in the said stable non-aqueous pharmaceutical composition. Further, depending upon the concentration of the hydrophobic drug, more amount of SBE-BCD can be added such that the amount of SBE-BCD is within the allowable limit for parenteral use, and it achieves the desired solubility and stability of the composition. For example, the amount of SBE-BCD is added as 200 mg/ml in the bendamustine composition comprising 25 mg/ml.
One aspect of the invention is to provide a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co crystal thereof, comprising SBE-BCD, PG and an optional anti-oxidant.
Another aspect of the invention is to provide a method for the preparation of a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal thereof, comprising SBE-BCD and PG; wherein the method comprises the steps of:
a) Solubilizing SBE-BCD in PG,
b) Optionally dissolving stabilizer/antioxidant to the solution obtained in step a), c) Solubilizing the hydrophobic drug, or its pharmaceutically acceptable salt or co- crystal thereof in the solution obtained in step a) or b),
d) Optionally adjusting pH of the solution obtained in step c) to obtain desired pH, e) Filtering the obtained solution in step d) through a sterile grade filter, and aseptically filling the solution in a suitable container (vial). In another aspect of the invention, the concentration of hydrophobic drug in the said stable non-aqueous pharmaceutical composition would range from about 0.1 mg/ml to about 250 mg/ml. Preferably, the concentration of hydrophobic drug would range from 0.1 mg/ml to 100 mg/ml; more preferably, the concentration of the hydrophobic drug would range from 0.1 mg/ml to 50 mg/ml.
The stable non-aqueous pharmaceutical composition according to the present invention can be used for the development of pharmaceutical composition of hydrophobic drugs and shall have high industrial applicability. Not limiting the use, various hydrophobic drugs that can be formulated using the pharmaceutical composition according to the present invention are Bendamustine, Carmustine, Carfilzomib, Erlotinib, and Bortezomib. Further, non-limiting examples of hydrophobic drugs shall include Docetaxel, Paclitaxel, Cabazitaxel, Teniposide, and the likes thereof.
Further, the stable non-aqueous pharmaceutical composition can be used for preparing pharmaceutical compositions of pharmaceutical drugs which undergo hydrolytic degradation. The non-limiting examples include Bortezomib, methylphenidate, spironolactone, cephalosporins, penicillins, etc.
In order to further illustrate the present invention, the following examples are provided for the purpose of clarity of understanding. However, it is not intended in any way to limit the scope of present invention and it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the scope of the invention.
Example 1: Stable non-aqueous pharmaceutical composition
Figure imgf000012_0001
Manufacturing process:
1) Solubilize the defined amount of SBE-BCD in PG,
2) Optionally dissolving an antioxidant/stabilizer to the solution obtained in step a), 3) Solubilize the hydrophobic drug, or its pharmaceutically acceptable salt or co crystal thereof in the solution obtained in step a) or b),
4) Optionally adjusting pH of the solution obtained in step c) to obtain desired pH,
5) Filtering the obtained solution in step d) through a sterile grade filter, and 6) Aseptically filling the solution in a suitable container (vial).
Example 2: Stable non-aqueous pharmaceutical composition for Bendamustine
Hydrochloride
Figure imgf000013_0001
Example 3: Stable non-aqueous pharmaceutical composition for Carmustine
Figure imgf000013_0002
Example 4: Stable non-aqueous pharmaceutical composition comprising Carfilzomib
Figure imgf000013_0003
Example 5: Stable non-aqueous pharmaceutical composition comprising
Bortezomib
Figure imgf000014_0001
Example 6: Stable non-aqueous pharmaceutical composition comprising
Erlotinib
Figure imgf000014_0002
Manufacturing process: The pharmaceutical compositions were prepared according to the steps mentioned in Example 1.
The pharmaceutical compositions disclosed in the examples given herewith have been found to be clear, colorless to pale yellow concentrated solution and no precipitation occurred, such that it provides sufficient stability to allow storage at convenient temperature of about 2-8 °C.
The compositions disclosed in these examples can be further diluted using 0.9% NaCl, dextrose solution or water for injection prior to administration. Example 7: Stable non-aqueous pharmaceutical composition comprising Bendamustine HC1 (25 mg/ml) with the results of the stability study.
Figure imgf000015_0001
The pharmaceutical composition was prepared according to the steps mentioned in Example 1. The stable non-aqueous composition can be further diluted using 0.9% NaCl, dextrose solution or water for injection prior to administration.
The stability results of the non-aqueous pharmaceutical composition comprising Bendamustine HC1 as described in the Example 7.
Figure imgf000015_0002
The impurities detected in the stability study are described as follows:
Impurity A (Mono-hydroxy Bendamustine): 4-(5-((2-chloroethyl)(2- hydroxyethyl) amino)- 1 -methyl- 1H benzo[d]imidazol-2-yl)butanoic acid Impurity B (Bendamustine Dimer): 4-(5-((2-((4-(5-(bis(2-hydroxy ethyl) amino)-
1 -methyl- lHbenzo[d]imidazol-2-l) butanoyl) oxy)ethyl)(2-hydroxyethyl) amino)-l- methyl-lH-benzo [d]imidazol-2-yl) butanoic acid
H-BMHRC01: lH-Benzimidazole-l-methyl-5-N, N-di(2-chloroethyl)-2-butanoic acid ethyl ester
H-BMHRC02: 4-(7,8-dihydro-6-(2-chloroethylamino)-3-methyl-l,4-thiazino[3,2- g]benzimidazoyl(2))butyric acid
Bendamustine Deschloroethyl: 4-[5-(2-chloroethylamino)-l -methylbenzimidazol-
2-yl]butanoic acid
The stability study of the inventive composition shows that bendamustine composition (25 mg/ml) remains stable for at least 3 months when stored at 2-8 °C, and the total impurities remained below 3%. Example 8: Stable non-aqueous pharmaceutical composition comprising Bendamustine HC1 (90 mg/ml) with the results of the stability study.
Figure imgf000016_0001
The pharmaceutical composition was prepared according to the steps mentioned in Example 1. The stable non-aqueous composition can be further diluted using 0.9% NaCl, dextrose solution or water for injection prior to administration. The stability results of the non-aqueous pharmaceutical composition comprising Bendamustine HC1 as described in the Example 8.
Figure imgf000017_0001
*Not detected The stability study of the inventive composition shows that the bendamustine composition (90 mg/ml) remains stable for at least 6 months when stored at 2-8 °C, and the total impurities remained below 3%.
Example 9: Stable non-aqueous pharmaceutical composition comprising Bendamustine HC1 (25 mg/ml) with the results of the stability study.
Figure imgf000017_0002
The pharmaceutical composition was prepared according to the steps mentioned in Example 1. The stable non-aqueous composition can be further diluted using 0.9% NaCl, dextrose solution or water for injection prior to administration. The stability results of the non-aqueous pharmaceutical composition comprising Bendamustine HC1 as described in the Example 9.
Figure imgf000018_0001
The stability study of the inventive composition shows that the bendamustine composition (25 mg/ml) remains stable for at least 6 months when stored at 2-8 °C, and the total impurities remained below 3%.
Example 10: Stable non-aqueous pharmaceutical composition comprising
Bendamustine HC1 (25 mg/ml) with the results of the stability study.
Figure imgf000018_0002
The pharmaceutical composition was prepared according to the steps mentioned in Example 1. The stable non-aqueous composition can be further diluted using 0.9% NaCl, dextrose solution or water for injection prior to administration. The stability results of the non-aqueous pharmaceutical composition comprising Bendamustine HC1 as described in the Example 10.
Figure imgf000019_0001
The stability study of the inventive composition shows that the bendamustine composition (25 mg/ml) remains stable for at least 9 months when stored at 2-8 °C, and the total impurities remained below 3%.
Example 11: Dilution study of non-aqueous pharmaceutical composition comprising Bendamustine HC1 (25 mg/ml) at 20-25°C and 2-8°C.
The non-aqueous pharmaceutical composition described in the Example 10 was used for dilution study, wherein the composition was diluted with 0.9% Sodium chloride.
The stability results of the composition at 20-25°C:
Figure imgf000020_0001
The stability results of the composition at 2-8°C:
Figure imgf000020_0002
The dilution study of the inventive composition shows that the bendamustine composition (25 mg/ml) remains stable after reconstitution, and the total impurities remained below 3%. All of the compositions and methods disclosed in this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the spirit and scope of the invention.

Claims

We claim:
1. A stable non-aqueous pharmaceutical composition comprising a hydrophobic drug or a pharmaceutically acceptable salt or a co-crystal, wherein the composition comprises of cyclodextrin and propylene glycol.
2. The stable non-aqueous pharmaceutical composition according to any of the preceding claims, wherein the hydrophobic drug comprises of Bendamustine, Carmustine, Carfilzomib, Bortezomib or Erlotinib.
3. The stable non-aqueous pharmaceutical composition according to any of the preceding claims, wherein the concentration of hydrophobic drug in the said composition would range from about 0.1 mg/ml to about 250 mg/ml.
4. The stable non-aqueous pharmaceutical composition according to any of the preceding claims, wherein the cyclodextrin consists of sulfobutylether beta- cyclodextrin.
6. The stable non-aqueous pharmaceutical composition according to any of the preceding claims, wherein the composition further comprises antioxidant.
7. The stable non-aqueous pharmaceutical composition according to any of the preceding claims, wherein the concentration of antioxidant in the said composition can range from about 0.1 mg/ml to about 20 mg/ml.
8. A stable non-aqueous pharmaceutical composition comprising Bendamustine or its pharmaceutically acceptable salt, sulfobutylether beta-cyclodextrin, propylene glycol, and optionally antioxidant, stabilizer and a pH adjusting agent.
1
9. The stable non-aqueous pharmaceutical composition according to any of the preceding claims, wherein the stabilizer is a chloride salt; the antioxidant is selected from propyl gallate, methionine, Cysteine HC1, metabisulfites, Tocopherols, monothioglycerol, Butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT) and mixtures thereof; and the pH adjusting agent is selected from sodium hydroxide and triethylamine.
10. A method for the preparation of a stable non-aqueous pharmaceutical composition for a hydrophobic drug or a pharmaceutically acceptable salt or a co crystal thereof, comprising sulfobutylether beta-cyclodextrin and propylene glycol; wherein the method comprises the steps of:
a. Solubilizing sulfobutylether beta-cyclodextrin in propylene glycol,
b. Optionally dissolving a stabilizer / antioxidant to the solution obtained in step a), c. Solubilizing the hydrophobic drug, or its pharmaceutically acceptable salt or co crystal thereof in the solution obtained in step a) or b),
d. Optionally adjusting the pH of the solution obtained in step c) to obtain desired pH,
e. Filtering the obtained solution in step d) through a sterile grade filter, and aseptically filling the solution in a suitable container.
2
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WO2010036702A1 (en) * 2008-09-25 2010-04-01 Cephalon, Inc. Liquid formulations of bendamustine
WO2011116286A2 (en) * 2010-03-18 2011-09-22 Innopharma, Llc Stable bortezomib formulations
WO2016059587A1 (en) * 2014-10-16 2016-04-21 Piramal Enterprises Limited Stable injectable composition of pharmaceutically active agents and process for its preparation
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WO2010036702A1 (en) * 2008-09-25 2010-04-01 Cephalon, Inc. Liquid formulations of bendamustine
WO2011116286A2 (en) * 2010-03-18 2011-09-22 Innopharma, Llc Stable bortezomib formulations
WO2016059587A1 (en) * 2014-10-16 2016-04-21 Piramal Enterprises Limited Stable injectable composition of pharmaceutically active agents and process for its preparation
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