WO2011116286A2 - Stable bortezomib formulations - Google Patents
Stable bortezomib formulations Download PDFInfo
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- WO2011116286A2 WO2011116286A2 PCT/US2011/029003 US2011029003W WO2011116286A2 WO 2011116286 A2 WO2011116286 A2 WO 2011116286A2 US 2011029003 W US2011029003 W US 2011029003W WO 2011116286 A2 WO2011116286 A2 WO 2011116286A2
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- bortezomib
- pharmaceutical composition
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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
- A61K31/69—Boron compounds
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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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
- A61K31/495—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
- A61K31/4965—Non-condensed pyrazines
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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
- A61K38/05—Dipeptides
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- 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
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Definitions
- the field of the invention is bortezomib formulations with improved stability.
- Bortezomib (( -(2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronic acid); sold as VelcadeTM, Millennium Pharmaceuticals) is a 26S proteasome inhibitor that is approved for use in treating various neoplastic diseases, and especially treatment of relapsed multiple myeloma and mantle cell lymphoma. It is believed that the boron atom in bortezomib binds to the catalytic site of the proteasome, ultimately leading to proteasome inhibition and reduced degradation of pro-apoptotic factors, which in turn triggers apoptosis in treated cells.
- 71 19080, 6713446, 6958319, 6747150, and 6297217 disclose formation of diester of boronic acid functional group with mannitol after lyophilization. From the so formed ester, the active boronic acid is obtained upon reconstitution of the drug product in saline solution for injection. Similarly, attempts to form the ester of boronic acid with alpha-hydroxy and beta-carboxylic acids like citric acid along with bulking agents and buffers was disclosed in WO 2009/154737.
- the compound can be lyophilized and reconstituted prior to injection.
- unused reconstituted solution must be injected within hours or days (see e.g., Stability of unused reconstituted bortezomib in original manufacturer vials; J Oncol Pharm Pract. 2010 Oct 6, or Stability of bortezomib 1-mg/mL solution in plastic syringe and glass vial; Ann Pharmacother. 2005 Sep;39(9): 1462-6).
- bortezomib esters of mannitol when reconstituted are suitable only for
- Still further known approaches include isolation of specific polymorphic forms having improved stability as described in WO2008075376A1, and lyophilized forms with tromethamine as described in
- inventive subject matter is drawn to compositions and methods for bortezomib in which bortezomib has significantly increased stability of a prolonged period of time.
- contemplated formulations are substantially non-aqueous liquid formulations and/or formulations in which bortezomib formulated with a hetero-bifunctional Lewis base donor compound to form a Lewis donor-acceptor complex.
- a multi-dosage pharmaceutical composition is manufactured as a container for both single and multiple use that includes a liquid formulation comprising bortezomib, wherein the liquid formulation is a substantially non-aqueous solvent system suitable for injection, and wherein the solvent system comprises as a main component propylene glycol.
- formulations is present at a pharmaceutically effective concentration and in an amount sufficient for at least two independent dosages, and the solvent system is formulated to maintain degradation of the bortezomib at a level of less than 10 wt% (more typically equal or less than 8 wt%, and most typically 2-6 wt% and even lower) when the liquid formulation is stored over at least three months at ambient conditions.
- the substantially non-aqueous solvent system comprises at least 50 vol%, more preferably at least 75 vol%, and most preferably 100 vol% propylene glycol.
- the substantially non-aqueous solvent system further comprises a polar solvent in an amount of equal or less than 50 vol%, more preferably equal or less than 25 vol%, and most preferably equal or less than 15 vol%.
- the polar solvent is most preferably ethanol.
- the substantially non-aqueous solvent system may include the polar solvent in an amount of equal or less than 15 vol%, and more typically equal or less than 10 vol%. In such case, the polar solvent is preferably water.
- a pharmaceutical composition comprises bortezomib and a hetero-bifunctional Lewis base, wherein the bortezomib and the hetero-bifunctional Lewis base together are present in form of a Lewis donor-acceptor complex, and wherein especially preferred hetero-bifunctional Lewis bases have at least two distinct donor groups (most preferably selected from -NH 2 , -SH, COOH, and -OH).
- a pharmaceutical composition comprises bortezomib and a hetero-bifunctional Lewis base, wherein the bortezomib and the hetero-bifunctional Lewis base together are present in form of a Lewis donor-acceptor complex, and wherein especially preferred hetero-bifunctional Lewis bases have at least two distinct donor groups (most preferably selected from -NH 2 , -SH, COOH, and -OH).
- Such contemplated formulations will preferably be lyophilized or in solution.
- bortezomib and the hetero- bifunctional Lewis base are present in a ratio of 1 :200, more preferably in a ratio of 5:80, and most preferably in a ratio of 20:40.
- preferred hetero-bifunctional Lewis bases include amino acids (e.g., naturally occurring amino acid or an N-acetylated amino acid), peptides (e.g., naturally or synthetic dipeptides or tripeptides), and substituted polyethylene glycols.
- Particularly preferred substituted polyethylene glycol have a structure according to Formula I
- n is an integer between 2 and 5,000, and wherein each A is independently selected from the group consisting of hydrogen, -NH2, -SH, COOH, and -OH.
- the formulation includes a buffering agent, a lyoprotectant, a cryoprotectant, a preservative, and/or an antioxidant.
- the present invention is generally directed towards to pharmaceutical compositions and methods of preparing liquid and lyophilized formulations containing therapeutically effective concentrations of bortezomib, where the formulation provides significantly improved stability for bortezomib. Where the formulation is lyophilized or concentrated above the concentration suitable for injection, contemplated compositions will be
- compositions administered after reconstitution with one or more pharmaceutically acceptable diluents, optionally further containing pharmaceutically acceptable antioxidants, stabilizers, preservatives and/or co-solvents.
- contemplated formulations will include bortezomib and a hetero-bifunctional Lewis base donor to so form a donor acceptor complex, while in other aspects contemplated formulations are liquid formulations and will include an at least binary non-aqueous solvent system.
- bortezomib and/or bortezomib donor acceptor complexes may also be encapsulated in a pharmaceutically acceptable delivery or carrier system, particularly in liposomes, micelles, nanoparticles, microspheres, emulsions, and/or suspensions.
- contemplated formulations may further include stabilizing agents, buffer components, anti-oxidants, isotonicity adjusting agents and lyoprotective agents.
- contemplated pharmaceutical formulations are stable for months at ambient conditions (i.e., 25 °C, 60 % relative humidity) when stored in an amber vial with nitrogen head space.
- contemplated formulations will be subjected to sterile filtration, and when lyophilized, can be reconstituted with intravenous diluents such as saline, dextrose, or water for injection.
- contemplated pharmaceutical compositions will include a liquid formulation that includes bortezomib in a substantially non-aqueous solvent system suitable for injection, and wherein the solvent system comprises propylene glycol as a main component.
- substantially non-aqueous solvent system refers to a solvent system in which bortezomib is completely soluble without water and that comprises water in a total amount of equal or less than 15 vol%.
- an antioxidant may be included in the formulation.
- contemplated pharmaceutical compositions will include a formulation in which bortezomib and a hetero-bifunctional Lewis base form a Lewis donor-acceptor complex.
- the hetero-bifunctional Lewis base has at least two distinct donor groups (preferably selected from the group of -NH 2 , -SH, COOH, and -OH), and the formulation is lyophilized or in solution.
- donor acceptor complex refers to a non-covalent and non-ionic association with a stability that is intermediate with respect to stability of covalent and ionic bonds.
- bortezomib and the hetero-bifunctional Lewis base are present in a ratio of 1 : 100 to 1 :200, more typically 1 : 10 to 1 : 100, and most typically 1 : 1 to 1 : 10.
- all ranges set forth herein should be interpreted as being inclusive of their endpoints, and open-ended ranges should be interpreted to include commercially practical values.
- all lists of values should be considered as inclusive of intermediate values unless the context indicates the contrary.
- compositions and pharmaceutical formulations comprising bortezomib in a stable liquid dosage form or as a stable lyophilized product.
- the stable in liquid forms provide stability of bortezomib at ambient conditions for at least two, more typically six, and most typically 12 months and even longer.
- contemplated formulations provided significant stability to bortezomib in various solvent systems, and preferred solvent systems were formulated such that degradation of bortezomib was maintained at or below 10 wt%, more typically at or below 8 wt%, even more typically at or below 6 wt%, and most typically at or below 4 wt% and even at or below 2 wt% where the liquid formulation was stored over at least three months at ambient conditions.
- contemplated forms will provide stability of bortezomib at ambient conditions for at least two, more typically 6, and most typically 12 months and even longer.
- bortezomib may be present in contemplated pharmaceutical formulations in any suitable amount, and most preferably in an amount that is suitable for injection after reconstitution.
- bortezomib is present in a therapeutically effective amount to treat a neoplastic (or other) condition in a human or other non-human mammal.
- bortezomib is present in a therapeutically effective amount to treat cancer.
- the Bortezomib is present in an amount of about 0.01% to about 99 % w/w of the total composition.
- the non-aqueous solvent system is a single solvent or a binary solvent system, which may optionally further include a buffer.
- a buffer for use herein, particularly preferred solvents and solvent systems include propylene glycol, one or more short chain alcohols (Ci-Ce), dimethyl acetamide, N-methyl pyrrolidone, dimethyl sulphoxide, and glycerol.
- suitable solvents especially include polar non-protic and protic solvents.
- the solvents are two or more of short chain alcohols (e.g., ethanol, tert-buyl alcohol), aryl alcohols (e.g., benzyl alcohol), glycols (and especially propylene glycol), dimethyl acetamide N-methyl pyrrolidone, and dimethyl sulphoxide.
- short chain alcohols e.g., ethanol, tert-buyl alcohol
- aryl alcohols e.g., benzyl alcohol
- glycols and especially propylene glycol
- dimethyl acetamide N-methyl pyrrolidone e.g., dimethyl sulphoxide.
- bortezomib will not form an ester or di-ester with a (hetero-)bifunctional Lewis base donor molecule. Instead, bortezomib will form in most cases a donor acceptor complex that is intermediate in stability to an ionic bond and a covalent bond. Thus, the boronic acid moiety remains protected in solution or in lyophilized state without ester formation, leading to significantly improved stability.
- suitable hetero-bifunctional Lewis base donors include compounds with two or more -OH, - SH, -COOH, and/or -NH2 groups, which are most typically vicinal groups or separated by no more than 4 atoms in linear dimension.
- suitable hetero-bifunctional Lewis base donors include compounds include compounds in which the two hetero-functional groups are -OH and -SH, -OH and -NH2, -SH and -NH2, -COOH and -NH2, and -COOH and -SH.
- hetero-bifunctional Lewis base donors include numerous amino acids (e.g., proteinogenic, essential, non-essential, chemically modified, synthetic, beta-, gamma-amino acids, etc. acids), all of which may be in D- or L-configuration.
- contemplated amino acids include alanine, asparagine, aspartic acid, arginine, cysteine, glutamine, glycine, glutamic acid, histidine, isoleucine, lysine, leucine, phenylalanine, methionine, serine, proline, tryptophan, threonine, tyrosine and valine.
- the hetero-bifunctional Lewis base donor may also be a synthetic or natural peptide, and especially a dipeptide, a tripeptide, or an oligopeptide.
- peptides include carnosine, anserine, homoanserine, kyotorphin, balenine, aspartame, glorin, barettin, pseudoproline, glycylglycine, isoleucine-proline-proline (ipp), glutathione, thyrotropin-releasing hormone, melanostatin, ophthalmic acid, leupeptin, and eisenin.
- Oligopeptides are also deemed suitable, albeit less preferred.
- hetero-bifunctional Lewis base donors may also be various polymers with pendant and/or terminal Lewis base donor groups.
- suitable polymers include pharmaceutically acceptable polymers, including substituted polyethylene glycols with structure according to Formula I
- n is an integer between 2 and 5,000, and wherein each A is independently selected from the group consisting of hydrogen, -NH 2 , -SH, COOH, and -OH.
- the polymer may also comprise a carbohydrate backbone that is derivatized with two or more distinct Lewis donor groups.
- all polymers are especially that are pharmaceutically acceptable.
- the complex of the hetero-bifunctional Lewis base donor with bortezomib may be formed in numerous manners, and particularly suitable manners include heating in a solvent of choice for an appropriate period of time.
- complexes or esters can also be prepared by evaporation of solvent, salting out, or precipitation (facilitated by seeding).
- a further especially preferred manner is co- lyophilization of bortezomib with a hetero-bifunctional Lewis base donor, typically from an aqueous solution comprising of bortezomib and a molar excess of the hetero-bifunctional Lewis base donor.
- the aqueous solution additionally comprises a (preferably water-miscible) co-solvent.
- suitable co-solvents includes, but not limited to tert-butyl alcohol, methanol, ethanol, and mixtures thereof.
- the molar excess of the hetero-bifunctional Lewis base donor relative to bortezomib can be in a wide range, it is generally preferred that the excess is between 1 : 1 to 1 :200, more typically 1 : 100 to 1 :200, even more typically 1 : 10 to 1 : 100, and most typically 1 : 1 to 1 : 10.
- contemplated compositions may comprise one or more bulking agent, cryoprotectant, or lyoprotectants to facilitate lyophilization.
- the Lewis base donor molecule may also act as a bulking agent, cryoprotectant, lyoprotectants, and/or stabilizer.
- suitable lyoprotectants including amino acids, and polymers.
- amino acids will be selected from lysine, alanine, glycine.
- Suitable polymers include various proteins (e.g., gelatin, albumin, etc.), polyethylene glycol, polyvinyl pyrrolidone, and Dextran-40.
- the lyoprotectant represents less than 50% w/w of the total composition, and all concentrations above 1% w/w of the total composition are deemed effective to enhance the stability of the formulation.
- the lyoprotectant may be present in an amount of at least about 5% w/w, at least about 10% w/w, or at least about 20% w/w of the total composition.
- compositions contemplated herein may further include tonicity agents, and suitable tonicity agents include sodium chloride, glycerol, thioglycerol. Additionally, contemplated formulations may include further pharmaceutically acceptable excipients, and especially buffers, preservatives, and antioxidants, and any reasonable mixture thereof.
- the pH of the formulation may vary. However, it is generally preferred that the pH of the formulations is suitable for injection and will typically be between 4.0 and 9.0, more typically between 5.5 and 8.0. Thus, one or more buffer systems may be employed to stabilize the pH at a desired value or range. Suitable buffers include citric acid buffer, acetic acid buffer, maleic acid buffer, phosphoric acid buffer, succinic acid buffer, and tartaric acid buffer. Most typically, the buffer strength is between 5 mM to 150 mM, however, higher and lower strengths are also deemed suitable for use herein. To still further improve the stability, the formulations may also include one or more anti-oxidants.
- hydrophobic anti-oxidants include butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, and a-tocopherol, DL- tocopherol, a-tocopherol acetate, Tocopherol Polyethylene Glycol Succinate (Vitamin E TPGS), L-cysteine, or hydrophilic anti-oxidants, including sodium EDTA and thioglycerol. Most typically, the concentration of the anti-oxidant will be between 0.005% and 5% w/w of the total composition.
- contemplated formulations may include a preservative (e.g., phenol, thimerosal, chlorobutanol, benzyl alcohol, m-cresol, phenoxyethanol, methylparaben and propylparaben), typically at a concentration of between 0.001% w/w and less than 5% w/w of the total composition, and most typically between 0.003 % and 2.0 % w/w of the total composition.
- a preservative e.g., phenol, thimerosal, chlorobutanol, benzyl alcohol, m-cresol, phenoxyethanol, methylparaben and propylparaben
- contemplated formulations will be sterilized and all known manners of sterilization are deemed suitable for use herein, including filtration through 0.22 micron filters, heat sterilization, radiation (e.g., gamma, electron beam, microwave), and/or ethylene oxide sterilization to render the formulations sterile.
- contemplated formulations are lyophilized, they may be prepared as lyophilized cake, lyophilized powder, etc.
- the solutions or lyophilized forms may be diluted and/or reconstituted with standard intravenous diluents known in the art.
- suitable intravenous diluents for use in the present invention include water, saline, dextrose 5% in water, water for injection or lactated ringer's solution.
- especially preferred that the formulation is packaged in a container suitable for both single and multi use.
- especially preferred containers include an ampoule, a vial, a pre-filled syringe, and intravenous bag.
- Especially preferred multi-use containers will contain bortezomib in an amount suitable to allow at least two distinct uses, more typically at least five, and most typically at least ten distinct uses.
- contemplated formulations will typically allow storage of the bortezomib for at least 1 week after first use, more typically at least 2-4 weeks after first use, and most typically at least 1-3 months (and even longer) after first use without significant degradation (i.e., less than 10% degradation) of the bortezomib under ambient conditions.
- Bortezomib may therefore be formulated for administration to human and various animals, and especially mammals.
- formulations may be in the form of a solution for injection (e.g., injectable multi dose sterile composition), in the form of a sterile powdered composition (e.g., lyophilized cake, powder, lyophilized powder), which may be administered after dilution or reconstitution.
- a solution for injection e.g., injectable multi dose sterile composition
- a sterile powdered composition e.g., lyophilized cake, powder, lyophilized powder
- Non-aqueous Formulations (1) Five non-aqueous formulations were prepared with various ingredients shown in Table 1. More particularly, a stock solution of D/L-Tocopherol was made by dissolving 625 mg of D/L-Tocopherol in 25 ml of ethanol, and a stock solution of butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) were prepared by dissolving 15 mg of each in 100 ml of ethanol, respectively.
- BHT butylated hydroxytoluene
- BHA butylated hydroxyanisole
- Stability results are shown in Tables 2-4, wherein Table 2 lists results for the stability tests of bortezomib at 40°C and 75% relative humidity, Table 3 lists results for the stability tests of bortezomib at 25°C and 60% relative humidity, and Table 4 lists results for the stability tests of bortezomib at 4°C.
- Non-aqueous Formulations (2) Five substantially non-aqueous formulations were prepared with various ingredients as shown in Table 5. The formulations were prepared as follows: Degas the water for injection (WFI) to remove the dissolved oxygen in WFI and Propylene Glycol, refined Polyethylene Glycol 300 and Acetate buffer, weigh required amount of Bortezomib and add to the compounding vessel and dissolve in PG or PEG in the compounding vessel with stirring. After complete dissolution of the drug add remaining amount of vehicle such as propylene glycol, polyethylene glycol, and buffer. In case of the formulation with N-acetyl cysteine, add and dissolve N-acetyl cysteine in buffer under nitrogen and add to the drug solution.
- WFI water for injection
- Propylene Glycol refined Polyethylene Glycol 300 and Acetate buffer
- Stability results are shown in Tables 6-8, wherein Table 6 lists results for the 2-week stability tests of bortezomib at certain storage conditions, Table 7 lists results for the 6-week stability tests of bortezomib at certain storage conditions, and Table 8 lists results for the 2- month stability tests of bortezomib at certain storage conditions.
- Formulation B with PEG was not included in the study due to in solubility of the drug in PEG.
- stability of bortezomib is enhanced in the presence of PG, with % highest impurity of less than 1% when stored at accelerated storage conditions.
- Formulation with 10% of aqueous buffer also showed a comparable stability to that of formulation with PG alone.
- increase in the buffer has revealed an undesirable increase in degradation products.
- a stabilizer/anti- oxidant like N- Acetyl Cysteine resulted in a significant degradation of the bortezomib.
- Non-aqueous Formulations (3) Five substantially non-aqueous formulations were prepared with various ingredients as shown in Table 9. The formulations were prepared as follows: Degas the WFI to remove the dissolved oxygen in WFI and Propylene Glycol, refined Polyethylene Glycol 300 and acetate buffer, weigh required amount of bortezomib and add to the compounding vessel and dissolve in propylene glycol or polyethylene glycol in the compounding vessel with stirring. After complete dissolution of the drug add remaining amount of vehicle such propylene glycol, polyethylene glycol, and buffer. In case of the formulation with N-acetyl cysteine, ascorbic acid and sodium bisulphate, dissolve all these ingredients in acetate buffer under nitrogen and disperse it into the drug solution to make 1 mg/ml solutions.
- batches A, B, D and E will provide the highest stability and that batch C will exhibit moderate degradation under corresponding storage conditions with respect to the results provided in Tables 6-8 above.
- the results indicate that there is no influence of the type of PG used in the formulation.
- the inventors have observed a significant degradation of bortezomib in the presence of super-refined PEG. This indicates that bortezomib can be stabilized in presence of propylene glycol, but can not be stabilized in the presence of a closely related alternative glycolic solvent, PEG.
Abstract
Description
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NZ602392A NZ602392A (en) | 2010-03-18 | 2011-03-18 | Stable bortezomib formulations |
AU2011227083A AU2011227083B2 (en) | 2010-03-18 | 2011-03-18 | Stable bortezomib formulations |
RU2012144316/15A RU2529800C2 (en) | 2010-03-18 | 2011-03-18 | Stable formulations of bortezomib |
JP2013500229A JP5661912B2 (en) | 2010-03-18 | 2011-03-18 | Stable bortezomib formulation |
EP11757060.6A EP2547333B1 (en) | 2010-03-18 | 2011-03-18 | Stable bortezomib formulations |
KR1020127027272A KR101530942B1 (en) | 2010-03-18 | 2011-03-18 | Stable bortezomib formulations |
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US31508010P | 2010-03-18 | 2010-03-18 | |
US61/315,080 | 2010-03-18 |
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WO2011116286A3 WO2011116286A3 (en) | 2012-03-22 |
WO2011116286A4 WO2011116286A4 (en) | 2012-05-10 |
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Cited By (10)
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JP2013203738A (en) * | 2012-03-27 | 2013-10-07 | Innopharma Inc | Stable bortezomib formulation |
WO2013128419A3 (en) * | 2012-03-02 | 2013-11-21 | Dr. Reddy's Laboratories Limited | Pharmaceutical compositions comprising boronic acid compounds |
EP3031811A1 (en) | 2014-12-09 | 2016-06-15 | Teva Pharmaceuticals Ltd. | Malic acid esters of bortezomib |
WO2016110870A1 (en) * | 2015-01-07 | 2016-07-14 | Emcure Pharmaceuticals Limited | Pharmaceutical composition of bortezomid |
EP3120836A1 (en) | 2015-07-22 | 2017-01-25 | Stada Arzneimittel Ag | Ready-to-use solution of bortezomib |
EP3120837A1 (en) | 2015-07-22 | 2017-01-25 | Stada Arzneimittel Ag | Ready-to-use solution of bortezomib |
CN107224569A (en) * | 2016-03-26 | 2017-10-03 | 复旦大学 | Water-soluble Pharmaceutical composition of a kind of bortezomib and its production and use |
US10167311B2 (en) | 2014-02-03 | 2019-01-01 | Ohio State Innovation Foundation | Boronic acid esters and pharmaceutical formulations thereof |
WO2019097413A1 (en) * | 2017-11-15 | 2019-05-23 | Intas Pharmaceuticals Ltd. | Stable non-aqueous pharmaceutical compositions |
TWI660727B (en) * | 2017-03-09 | 2019-06-01 | 韓商Cj醫藥健康股份有限公司 | Stable formulation comprising bortezomib, and its preparation method |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8263578B2 (en) | 2010-03-18 | 2012-09-11 | Innopharma, Inc. | Stable bortezomib formulations |
US9061037B2 (en) | 2010-03-18 | 2015-06-23 | Innopharma, Inc. | Stable bortezomib formulations |
US8962572B2 (en) | 2010-10-05 | 2015-02-24 | Fresenius Kabi Usa, Llc | Bortezomib formulations |
JP6165986B2 (en) * | 2013-08-23 | 2017-07-19 | シントン・ビー.ブイ.Synthon B.V. | Pharmaceutical composition comprising bortezomib |
WO2016059590A1 (en) * | 2014-10-16 | 2016-04-21 | Piramal Enterprises Limited | Stable injectable composition of small molecule drugs and process for its preparation |
US20170239335A1 (en) * | 2014-10-16 | 2017-08-24 | Piramal Enterprises Limited | Stable injectable composition of pharmaceutically active agents and process for its preparation |
WO2016059592A1 (en) * | 2014-10-16 | 2016-04-21 | Piramal Enterprises Limited | Stable injectable composition of peptide drugs and process for its preparation |
US10239897B2 (en) * | 2015-04-29 | 2019-03-26 | Nanosilical Devices S.r.l. | Bortezomib-based delivery system |
JP6706988B2 (en) * | 2016-07-20 | 2020-06-10 | 日本化薬株式会社 | Pharmaceutical composition containing bortezomib |
US10988489B2 (en) * | 2018-11-27 | 2021-04-27 | Clark Atlanta University | Organoboranes useful as electrolytes for lithium batteries |
WO2022094396A1 (en) * | 2020-11-02 | 2022-05-05 | Spes Pharmaceuticals Inc. | Aqueous compositions of bortezomib |
US11805323B2 (en) | 2021-04-01 | 2023-10-31 | Brillnics Singapore Pte. Ltd. | Solid-state imaging device, method for driving solid-state imaging device, and electronic apparatus |
EP4134083A1 (en) | 2021-08-12 | 2023-02-15 | Extrovis AG | Pharmaceutical compositions of bortezomib |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4525309A (en) * | 1983-03-15 | 1985-06-25 | Washington State University Research Foundation, Inc. | Lewis acid catalysis of the homologation of boronic esters with haloalkylmetal reagents |
US6083903A (en) * | 1994-10-28 | 2000-07-04 | Leukosite, Inc. | Boronic ester and acid compounds, synthesis and uses |
US5780545A (en) * | 1996-03-08 | 1998-07-14 | Eastman Kodak Company | Stable release agents |
JP2000336041A (en) * | 1999-03-19 | 2000-12-05 | Wakamoto Pharmaceut Co Ltd | Urinastatin-containing aqueous preparation characterized in containing propylene glycol |
ES2206288T3 (en) | 1999-08-30 | 2004-05-16 | Debiopharm S.A. | STABLE PHARMACEUTICAL PREPARATION OF OXYLIPLATINE FOR PARENTERAL ADMINISTRATION. |
AU2002243646B2 (en) * | 2001-01-25 | 2006-06-22 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Formulation of boronic acid compounds |
KR101169478B1 (en) * | 2003-04-30 | 2012-07-27 | 다이닛본 스미토모 세이야꾸 가부시끼가이샤 | Medicinal Composition in Solution Form |
CN104826116A (en) | 2003-11-20 | 2015-08-12 | 诺沃挪第克公司 | Propylene glycol-containing peptide formulations which are optimal for production and for use in injection devices |
SG10201600029PA (en) * | 2004-03-30 | 2016-02-26 | Millennium Pharm Inc | Synthesis of boronic ester and acid compounds |
US20050256097A1 (en) * | 2004-05-11 | 2005-11-17 | Kosan Biosciences, Inc. | Pharmaceutical solution formulations containing 17-AAG |
US20080038316A1 (en) * | 2004-10-01 | 2008-02-14 | Wong Vernon G | Conveniently implantable sustained release drug compositions |
US20060084691A1 (en) | 2004-10-18 | 2006-04-20 | Bilal Piperdi | Combined treatment with bortezomib and an epidermal growth factor receptor kinase inhibitor |
TW200618820A (en) * | 2004-11-05 | 2006-06-16 | Alza Corp | Liposome formulations of boronic acid compounds |
US8283352B2 (en) * | 2005-06-13 | 2012-10-09 | Dainippon Sumitomo Pharma Co., Ltd. | Solubilization preparation |
WO2007041294A2 (en) * | 2005-09-29 | 2007-04-12 | The Trustees Of Boston University | Methods for sensitizing cancer cells to inhibitors |
BRPI0617751A2 (en) * | 2005-10-25 | 2011-08-02 | Aegera Therapeutics Inc | iap bir domain binding compounds |
WO2007056135A1 (en) * | 2005-11-04 | 2007-05-18 | Merck & Co., Inc. | Method of treating cancers with saha and pemetrexed |
US20090222080A1 (en) * | 2005-11-08 | 2009-09-03 | Picarus Nv Sa | Medical stent provided with inhibitors of tumor necrosis factor-alpha |
US8158152B2 (en) * | 2005-11-18 | 2012-04-17 | Scidose Llc | Lyophilization process and products obtained thereby |
CN101535300B (en) * | 2006-05-16 | 2014-05-28 | 埃格拉医疗公司 | Iap bir domain binding compounds |
WO2008057456A2 (en) | 2006-11-03 | 2008-05-15 | University Of Maryland, Baltimore | Methods of using saha and bortezomib for treating multiple myeloma |
WO2008075376A1 (en) | 2006-12-18 | 2008-06-26 | Natco Pharma Limited | Polymorphic forms of bortezomib and process for their preparation |
EP2190411A2 (en) * | 2007-08-21 | 2010-06-02 | Alza Corporation | Liposome compositions for in vivo administration of boronic acid compounds |
JP2010539183A (en) * | 2007-09-12 | 2010-12-16 | ドクター・レディーズ・ラボラトリーズ・リミテッド | Bortezomib and process for its production |
US7838673B2 (en) * | 2007-10-16 | 2010-11-23 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
US20090202540A1 (en) | 2008-02-11 | 2009-08-13 | Auspex Pharmaceuticals, Inc. | Substituted oxazaphosphorines |
WO2010039762A2 (en) | 2008-10-01 | 2010-04-08 | Dr. Reddy's Laboratories Ltd. | Pharmaceutical compositions comprising boronic acid compounds |
US20100137246A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Anti-inflammatory compositions and methods |
US20100135984A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Anti-inflammatory compositions and methods |
KR20110114562A (en) | 2009-01-09 | 2011-10-19 | 썬 파마 어드밴스트 리서치 컴패니 리미티드 | Pharmaceutical composition |
EP2238973A1 (en) * | 2009-04-07 | 2010-10-13 | Cephalon France | Lyophilized preparations of proteasome inhibitors |
US9061037B2 (en) | 2010-03-18 | 2015-06-23 | Innopharma, Inc. | Stable bortezomib formulations |
US8263578B2 (en) * | 2010-03-18 | 2012-09-11 | Innopharma, Inc. | Stable bortezomib formulations |
-
2011
- 2011-03-18 US US13/051,102 patent/US9061037B2/en not_active Expired - Fee Related
- 2011-03-18 AU AU2011227083A patent/AU2011227083B2/en not_active Ceased
- 2011-03-18 NZ NZ602392A patent/NZ602392A/en not_active IP Right Cessation
- 2011-03-18 EP EP11757060.6A patent/EP2547333B1/en not_active Not-in-force
- 2011-03-18 JP JP2013500229A patent/JP5661912B2/en not_active Expired - Fee Related
- 2011-03-18 RU RU2012144316/15A patent/RU2529800C2/en not_active IP Right Cessation
- 2011-03-18 WO PCT/US2011/029003 patent/WO2011116286A2/en active Application Filing
- 2011-03-18 KR KR1020127027272A patent/KR101530942B1/en not_active IP Right Cessation
Non-Patent Citations (1)
Title |
---|
See references of EP2547333A4 * |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013128419A3 (en) * | 2012-03-02 | 2013-11-21 | Dr. Reddy's Laboratories Limited | Pharmaceutical compositions comprising boronic acid compounds |
JP2013203738A (en) * | 2012-03-27 | 2013-10-07 | Innopharma Inc | Stable bortezomib formulation |
US10167311B2 (en) | 2014-02-03 | 2019-01-01 | Ohio State Innovation Foundation | Boronic acid esters and pharmaceutical formulations thereof |
EP3031811A1 (en) | 2014-12-09 | 2016-06-15 | Teva Pharmaceuticals Ltd. | Malic acid esters of bortezomib |
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DE202016009131U1 (en) | 2015-07-22 | 2022-08-15 | STADA Arzneimittel Aktiengesellschaft | Ready-to-use bortezomib solution |
CN107224569A (en) * | 2016-03-26 | 2017-10-03 | 复旦大学 | Water-soluble Pharmaceutical composition of a kind of bortezomib and its production and use |
TWI660727B (en) * | 2017-03-09 | 2019-06-01 | 韓商Cj醫藥健康股份有限公司 | Stable formulation comprising bortezomib, and its preparation method |
WO2019097413A1 (en) * | 2017-11-15 | 2019-05-23 | Intas Pharmaceuticals Ltd. | Stable non-aqueous pharmaceutical compositions |
Also Published As
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AU2011227083A1 (en) | 2012-10-04 |
KR101530942B1 (en) | 2015-06-23 |
RU2012144316A (en) | 2014-04-27 |
KR20130010902A (en) | 2013-01-29 |
US9061037B2 (en) | 2015-06-23 |
EP2547333A4 (en) | 2014-04-30 |
WO2011116286A3 (en) | 2012-03-22 |
US20110230441A1 (en) | 2011-09-22 |
EP2547333A2 (en) | 2013-01-23 |
JP5661912B2 (en) | 2015-01-28 |
NZ602392A (en) | 2014-03-28 |
EP2547333B1 (en) | 2017-08-23 |
JP2013522320A (en) | 2013-06-13 |
RU2529800C2 (en) | 2014-09-27 |
AU2011227083B2 (en) | 2013-07-18 |
WO2011116286A4 (en) | 2012-05-10 |
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