Classifications

• • 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
  • 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
• • 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

Definitions

• the present invention relates to a storage stable, ready to use, liquid parenteral compositions of pemetrexed and their use in cancer therapy. More particularly, the invention relates to storage stable, concentrated aqueous parenteral compositions comprising pemetrexed disodium and atleast one stability enhancing adjuvant such as cyclodextrin derivative, and method of preparing these compositions.
• Pemetrexed disodium salt is chemically known as N-[4-[2- (2-amino-4,7- dihydro-4-oxo- 1 H-pyrrolo[2,3-d]pyrimidin-5-yl) ethyl]benzoyl]-L-glutamic acid, disodium salt.
• Pemetrexed disodium heptahydrate is marketed by Eli Lilly and Company under the trade name ALIMTA ® , and is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials.
• United States patent number 6,686,365 discloses ready to use (RTU) formulations of pemetrexed, which contain monothioglycerol, L-cysteine or thioglycolic acid as stabilizers to prevent degradation of pemetrexed.
• RTU ready to use
• PCT patent applications No. WO2012/015810 discloses a long term, storage stable liquid pharmaceutical composition, comprising pemetrexed, antioxidants like lipoic acid, dihydrolipoic acid and methionine lactobionic acid, sodium citrate tribasic and pH adjusting/ modifying agents.
• Cyclodextrins are known solubilizing agent and has the ability to complex with lipophilic materials and some proteins to form inclusion complexes and are increasingly used in pharmaceutical formulations.
• United States patent number 5,134,127 discloses use of sulfoalkyl ether cyclodextrins as solubilizing agents for insoluble or poorly soluble drugs.
• United States patent number 4,983,586 and 5,024,998 discuss the use of cyclodextrins (in concentrations of 20-50%) to solubilize (as inclusion complexes) lipophilic drugs for injection.
• PCT patent applications No. WO2008/067027 discloses use of inclusion complexes of disubstituted urea compound capable of inhibiting Chkl and atleast one cyclodextrin;
• U.S. patent applications No. 20120065161 and PCT patent applications No. WO201 1/031865 discloses epothilone polymer conjugates including cyclodextrin-epothilone conjugate for the treatment cancer.
• compositions comprising pemetrexed and a stability enhancing adjuvants like cyclodextrin derivatives, which imparts long term storage stability to pemetrexed in aqueous solution state, without employing stabilizers such as monothioglycerol, L-cysteine, thioglycolic acid, antioxidants like lipoic acid, dihydrolipoic acid, methionine and lactobionic acid or sodium citrate tribasic.
• stabilizers such as monothioglycerol, L-cysteine, thioglycolic acid, antioxidants like lipoic acid, dihydrolipoic acid, methionine and lactobionic acid or sodium citrate tribasic.
• the present invention provides storage stable, ready to use, concentrated aqueous parenteral composition of pemetrexed comprising pemetrexed, a stability enhancing adjuvant, an aqueous vehicle and optional additives like pH modifiers and buffering agents, wherein pemetrexed exhibits long term storage stability in such aqueous solutions.
• a stable, ready to use, concentrated, aqueous parenteral composition of pemetrexed or a pharmaceutically acceptable salt for use in cancer therapy there is provided a stable, ready to use, concentrated, aqueous parenteral composition of pemetrexed or a pharmaceutically acceptable salt for use in cancer therapy.
• Another object of the present invention to provide ready to use, concentrated, aqueous parenteral composition of pemetrexed, comprising pemetrexed disodium and a cyclodextrin derivative, wherein the pemetrexed in aqueous solution at pH 6.0 ⁇ 0.2 to 8.0 ⁇ 0.2 exhibits excellent stability.
• Another object of the present invention is to provide stable, ready to use, concentrated, aqueous parenteral composition of pemetrexed, comprising pemetrexed disodium in an amount form about 1 mg/ml to about 100 mg/ml and hydroxypropyl- ⁇ -cyclodextrin, wherein the composition demonstrates long term storage stability.
• Another object of the present invention is to provide stable, ready to use, concentrated, aqueous parenteral composition of pemetrexed, comprising pemetrexed disodium, hydroxypropyl-p-cyclodextrin, atleast one vehicle and optional additives, wherein the weight ratio of pemetrexed to hydroxypropyl-P-cyclodextrin is in between 1 : 1 to about 1 :5 and wherein said composition on storage exhibits total impurities which are not more than (NMT) 2% weight/weight (wt/wt), preferably NMT 1% wt/wt.
• Another object of the present invention is to provide stable, ready to use, concentrated, aqueous parenteral composition of pemetrexed, comprising pemetrexed disodium, hydroxypropyl- -cyclodextrin, water for injection, sodium hydroxide and hydrochloric acid, wherein the weight ratio of pemetrexed to hydroxypropyl- ⁇ - cyclodextrin is in between 1 :1 to about 1 :5.
• Another object of the present invention is to provide process for preparing a storage stable, ready to use, concentrated, aqueous parenteral composition of pemetrexed prepared by a process comprising - dissolving hydroxypropyl- ⁇ - cyclodextrin in water for injection, to this solution pemetrexed disodium is added and stirred to yield complex of pemetrexed-hydroxypropyl-P-cyclodextriii, final volume and pH is then adjusted, the solution is subsequently subjected to aseptic filtration and packed in appropriate container and closure system.
• the present invention is directed to a liquid, parenteral composition comprising pemetrexed or a pharmaceutically acceptable salt, and a stability enhancing adjuvants like cyclodextrin derivatives. Further aspects of the invention include methods of treatment using pemetrexed-containing compositions and kits comprising the same.
• Aqueous parenteral compositions according to the invention comprises solution stable complex of pemetrexed with a cyclodextrin derivative, wherein the amount of pemetrexed is from about 1 mg/ml to about 100 mg/ml, wherein the weight ratio of pemetrexed to hydroxypropyl-P-cyclodextrin is in between 1 : 1 to about 1 :5.
• the composition according to the invention demonstrates long term storage stability and prevents degradation of pemetrexed during the shelf life, wherein the total impurities are not more than (NMT) 2% weight/weight (wt/wt), preferably NMT 1% wt/wt.
• a long term storage stable, concentrated, aqueous parenteral composition of pemetrexed comprising:
• aqueous parenteral composition of the present invention is that the stability of pemetrexed is substantially improved in aqueous solutions.
• the inventive aqueous pemetrexed compositions are substantially free of impurities when storage at a temperature from about 2°C to about 8°C.
• aqueous parenteral compositions of the invention do not require use of i) monothioglycerol, L-cysteine or thioglycolic acid ; ii) lipoic acid, dihydrolipoic acid or methionine; and iii) lactobionic acid or sodium citrate tribasic as taught in the prior art to prevent degradation of pemetrexed in solution state.
• the compositions according to the invention are cost effective as they do not require use of techniques such as freeze drying whose operational cost is high.
• the inventive composition can advantageously be single dose or multi dose ready to use/ ready for further dilution before administration.
• the present invention relates to a storage stable, ready to use, aqueous parenteral compositions of pemetrexed or a pharmaceutically acceptable salt, for use in cancer therapy. More particularly, the invention relates to a storage stable, concentrated aqueous parenteral composition comprising pemetrexed disodium and atleast one stability enhancing adjuvant such as cyclodextrin derivative in the form of pemetrexed-adjuvant complex.
• aqueous parenteral compositions of pemetrexed were not successful as pemetrexed in solution state tends to degrade very rapidly resulting into product having sub-therapeutic amount of pemetrexed in a very short period of time. It has been determined that pharmaceutically acceptable aqueous formulations of pemetrexed, or its pharmaceutically acceptable salts, in particular the sodium salt, can be prepared by combining pemetrexed, a atleast one stability enhancing adjuvant in aqueous medium to form pemetrexed-adjuvant complex according to the invention showing enhanced stability even in aqueous solution.
• aqueous parenteral compositions according to the invention demonstrate long term storage stability.
• the inventive complex of pemetrexed and cyclodextrin derivative in aqueous solution is stable and is substantially free of impurities when stored at a temperature of from about 2°C to about 8°C.
• the total impurity generated in said composition during storage will not be not more than (NMT) 2% weight/weight (wt/wt), preferably NMT 1% wt/wt.
• aqueous parenteral compositions of the invention do not require use of i) monothioglycerol, L-cysteine or thioglycolic acid ; ii) lipoic acid, dihydrolipoic acid or methionine; and iii) lactobionic acid or sodium citrate tribasic as taught in the prior art to prevent degradation of pemetrexed in solution state.
• the aqueous parenteral composition according to the invention utilizes cost effective sterilizing techniques such as aseptic filtration, which is easy to perform, efficient and cost effective in comparison to techniques such as freeze drying.
• the inventive composition can advantageously be single or multi dose ready to use or ready for further dilution before administration.
• pemetrexed refers to the free acid form of pemetrexed or its pharmaceutically acceptable salts and polymorphs thereof.
• Pharmaceutically acceptable salts of alkali metal, alkaline earth metal, non-toxic metal, ammonium, and substituted ammonium salts such as for example, the sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium, monoethanolammonium, triethanol ammonium, pyridinium, substituted pyridinium, and the like, preferably the disodium salt.
• Pemetrexed disodium is present in an amount from about 1 mg/ml to about 100 mg/ml, preferably from about 10 mg/ml to about 50 mg/ml. More preferably, pemetrexed disodium concentration in the aqueous parenteral compositions according to the invention is from about 20 mg/ml to about 25 mg/ml. It will be understood that aqueous compositions containing any useful concentration within the ranges, i.e. 1, 10, 15, 20, 25, 30, 35, 40, 50, 75, 100 are contemplated.
• Hydroxypropyl-P-cyclodextrin is present in an amount from about 1 mg/ml to about 500 mg/ml, preferably from about 10 mg/ml to about 250 mg/ml. More preferably, the concentration of hydroxypropyl-P-cyclodextrin in the aqueous parenteral compositions according to the invention is from about 20 mg ml to about 60 mg/ml.
• the preferred weight ratio of pemetrexed disodium to hydroxypropyl- ⁇ - cyclodextrin is 1 :3.
• a pharmaceutically acceptable vehicle is a fluid capable of being included in sterile parenteral formulations/ solutions during manufacturing or during administration, and includes but not limited to water for injection, bacteriostatic water for injection, bacteriostatic sodium chloride, saline, 5% dextrose in water, propylene glycol (PG), etc., preferably 0.9% sodium chloride.
• the pharmaceutically acceptable vehicle is water for injection and/ or 0.9% sodium chloride, a mixture of propylene glycol (PG) and water for injection or a mixture of propylene glycol (PG) and 0.9% sodium chloride.
• Other vehicles that can be included are polyethylene glycols, alcohols, nonaqueous ester solvents, vegetable oil, etc.
• the pharmaceutically acceptable alcohol may consist of one alcohol or a mixture of two or more alcohols, preferably a mixture of two alcohols.
• Preferred pharmaceutically-acceptable alcohols for parenteral administration are ethanol, benzyl alcohol or a mixture of both ethanol and benzyl alcohol.
• the pharmaceutically acceptable non-aqueous ester solvent may consist of one or a mixture of two or more pharmaceutically acceptable non-aqueous ester solvents, preferably just one.
• a preferred pharmaceutically acceptable non-aqueous ester solvent for parenteral administration is selected from benzyl benzoate, ethyl oleate, isopropyl myristate, isopropyl palmitate or a mixture of any thereof
• the pharmaceutically acceptable vegetable oil may consist of one or a mixture of two or more vegetable oil, Preferred pharmaceutically acceptable vegetable oil for parenteral administration are castor oil, arachis oil and sesame oil.
• the aqueous parenteral compositions according to the invention may optionally contains additives such as chelating agents, buffers, pH/ tonicity modifiers, preservative, etc., which are commonly found as part of parenteral ⁇
• the compositiOon according to the invention may optionally include one or more chelating agents like ethylenediaminetetraacetic acid (EDTA).
• EDTA ethylenediaminetetraacetic acid
• the buffer systems for sterile products consist of either a weak acid or the salt of weak acid and either weak base or salt of weak base.
• Buffer systems commonly used for sterile products are amino acids, acetates (1-2%), citrate (1-5%) and phosphates (0.8-2%).
• the pH of the aqueous parenteral compositions according to the invention should be in between 6.0 ⁇ 0.2 to about 8.0 ⁇ 0.2.
• the pH of the solution can be adjusted using IN sodium hydroxide/ IN hydrochloric acid solution.
• the pH of the final solution according to the invention containing pemetrexed, hydroxypropyl-P-cyclodextrin and water for injection should preferably be 7.0 ⁇ 0.2.
• aqueous, parenteral compositions of pemetrexed according to the invention described herein may be administered by intravenous injection, by intravenous infusion, by intramuscular injection, by subcutaneous injection, by intracutaneous injection, by intrathecal injection or by intracranial injection.
• the preferred method of administration is by intravenous infusion.
• inventive aqueous, parenteral composition can advantageously be multi dose ready to use or ready for further dilution before administration, in such cases more than one dose of pemetrexed is packed and hence the compositions may additionally contains a suitable preservative commonly found as part of parenteral formulations.
• aqueous, parenteral compositions of the present invention can be administered in combination with one or more anti-neoplastic agents where the antineoplastic agent is given prior to, concurrently with, or subsequent to the administration of the composition of the present invention.
• filter with pore size 0.2 ⁇ that effectively remove microorganisms are commonly used.
• Nanofilter with smaller pore size of 20 -50 nm (nanofiltration) can also be employed.
• pre-filters might be used to protect small pore membrane filters.
• the manufacturing procedure for the aqueous parenteral composition according the invention involves dissolving pemetrexed disodium salt and cyclodextrin derivative such as hydroxypropyl-p-cyclodextrin in water, adjusting the final volume and pH if required and filtering the solution using appropriate filter to get sterile, ready to use, storage stable aqueous solution of pemetrexed disodium, which is packaged in a suitable container and closure system.
• aqueous parenteral compositions of pemetrexed disodium according to invention can be packaged in any suitable sterile vial or container fit for the sterile storage for extended periods of time.
• Suitable containers can be glass vials, i.e. Schott treated vials, molded glass vials, and non-glass component vials such as CZ resin vials, polyolefins like polypropylene or polyethylene vials, cyclic olefins polymer (COP) vials and cyclic olefin copolymer (COC) like Schott TopPac vials or other special purpose bags or containers.
• Containers are of a size sufficient to hold one or more doses of pemetrexed. In accordance with current FDA requirements, vials containing the inventive formulations also have particulate matter well below the acceptable limits.
• aqueous, parenteral compositions according to the invention can be packaged in glass vials, such as Schott treated vials, molded glass vials and non-glass component vials, which minimize delamination and pitting of the glass, as pemetrexed being a cytotoxic substance has a tendency to delaminate glass and due to this glass components leach out to the product resulting in particulate contamination of the product.
• glass vials such as Schott treated vials, molded glass vials and non-glass component vials, which minimize delamination and pitting of the glass, as pemetrexed being a cytotoxic substance has a tendency to delaminate glass and due to this glass components leach out to the product resulting in particulate contamination of the product.
• Typical long term storage includes time periods of, for example, about 30 days, about 90 days, about 180 days, about 365 days, and about 730 days (i.e. about 1 month, about 3 months, about 6 months, about 1 year and about 2 year).
• Preferred commercial storage conditions include temperatures of about 2°C to about 8°C, wherein the compositions according to the invention demonstrate long term storage stability.
• the volume of the liquid formulation of the present invention needed for the required dose can be aseptically withdrawn and transferred to an infusion bag of 0.9% Sodium Chloride (or other pharmaceutically acceptable intravenous solution) for injection. After transfer, the contents of the infusion bag are thoroughly mixed. Administration by intravenous infusion is typically provided over a time period of from about 30 to about 60 minutes.
• the present invention provides stable, ready to use, concentrated, aqueous parenteral composition
• pemetrexed disodium and hydroxypropyl-p-cyclodextrin containing 25 mg/ml of pemetrexed (2.5% wt/wt), 75 mg/ml of hydroxypropyl-P-cyclodextrin (7.5% wt/wt), water for injection and optional additives, wherein the composition demonstrate long term storage stability.
• aqueous parenteral composition according to the invention can be prepared in the following manner;
• a stock solution of pemetrexed or pharmaceutically acceptable salt is prepared at the desired concentration in a suitable solvent, such as water.
• a second stock solution of the cyclodextrin in a suitable solvent, such as water is added.
• the resulting solution can be sonicated to ensure complete mixing of the components so that complex of pemetrexed-cyclodextrin derivative is formed.
• Final volume is adjusted using water.
• the pH of the mixture is adjusted using known techniques, such as the addition of suitable buffer or pH adjusting/ modifying agents. Sterilizing the solution using filtration and filing said final sterile solution in appropriate container and closure system to get composition according to the invention.
• the aqueous parenteral composition is prepared by a process comprising the step of:
• the present invention provides a kit comprising a separate single dose/ multi dose container containing ready to use aqueous solution comprising 25 mg/ml of pemetrexed disodium and 75mg/ml of hydroxypropyl-P- cyclodextrin, prepared according to the invention and atleast one separate 100 ml pack of 0.9% sodium chloride injection.
• the standard therapy of pemetrexed marketed formulation Alimta ® involves administering pemetrexed as a solution via injection into a vein and is usually given once every 21 days as a 10-minute outpatient infusion.
• a daily low-dose 350 ⁇ g to 1000 ⁇ g of folic acid orally is given as a pre-administration regimen to pemetrexed therapy.
• the method involve at least 5 daily doses must be taken during this 7-day period preceding the first dose of pemetrexed and continuing throughout treatment and for 21 days after the last dose of pemetrexed.
• 1000 ⁇ g of vitamin B12 intramuscularly - every 3 cycles is also administered.
• the method involve mandatory administering one intramuscularly injection during the week preceding the first dose of pemetrexed and every 3 cycles thereafter.
• the present invention provides a pharmaceutical kit comprising single dose or multiple dose container comprising a complex of pemetrexed- hydroxypropyl-P-cyclodextrin (1 :3 ratio), a pack of 100 ml 0.9% sodium chloride injection or dextrose solution, a pack of 1000 g vitamin B12 injection and blister pack containing folic acid tablet each tablet containing 400 ⁇ g folic acid.
• the kit may contain optional materials for storing and/or administering the drug like infusion bag as well as instructions for storage and use.
• the pre-administration of vitamin B12 and folic acid may be achieved by administering vitamin B12 via injection or orally in the form of vitamin B12 tablets/ capsules, folic acid in the form of tablets/ capsules or a combination tablet/ capsule comprising vitamin B12 and folic acid.
• the present invention provides a method of administering compositions according to the invention in combination with about 1000 to about 2000 ⁇ g/d of vitamin B12 administered intramuscularly atleast 1 to about 3 weeks prior to the administration of first dose of pemetrexed, which is repeated every 3 cycles and about 350 to about 1000 ⁇ g/d of folic acid orally atleast 5 to about 7 days prior to the administration of first dose of pemetrexed, which is continued throughout treatment and for 21 days after the last dose of pemetrexed.
• the present invention provides a method of administering composition according to the invention in combination with about 1000 to about 2000 ⁇ g/d of vitamin B12 administered orally atleast 1 to about 3 weeks prior to the administration of first dose of pemetrexed, and about 350 to about 1000 ⁇ g/d of folic acid orally atleast 5 to about 7 days prior to the administration of first dose of pemetrexed, which is continued throughout treatment and for 21 days after the last dose of pemetrexed.
• aqueous parenteral compositions of the present invention are storage stable; ready to be used and do not require cost sensitive sterilization technique such as lyophilization/ freeze drying and are safer to handle and distribute.
• the invention also contemplates reducing the amount of pemetrexed impurities generated, especially in aqueous solution state when stored for extended periods. There is a concomitant reduction in unit cost, as the compositions are sterilized using cost effective aseptic filtration technique.
• step c] The pH of the solution of step c] is adjusted to about 7.0 ⁇ 0.2, by adding suitable buffer or pH modifying agent;
• step d] The solution of step d] is subjected to aseptic filtration;
• step e] The solution of step e] is filled in an appropriate container and closure system to get composition according to the invention.
• Example 1 Three composition of Example 1, 3 and 5 were assayed for initial total impurities, pH and drug content. Then these samples were stored at a temperature for about 2- 8°C for 24 weeks and then again by analytical testing total impurities, pH and drug content was measured. From the data on total impurity data as depicted in table II, it can be inferred that hydroxypropyl- -cyclodextrin improves the pemetrexed disodium stability in solution state.

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Citations (6)

• 2013
  • 2013-05-31 WO PCT/IN2013/000346 patent/WO2013179310A1/fr not_active Ceased

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