WO2011061761A2 - Composition pharmaceutique à usage parentéral - Google Patents

Composition pharmaceutique à usage parentéral Download PDF

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Publication number
WO2011061761A2
WO2011061761A2 PCT/IN2010/000745 IN2010000745W WO2011061761A2 WO 2011061761 A2 WO2011061761 A2 WO 2011061761A2 IN 2010000745 W IN2010000745 W IN 2010000745W WO 2011061761 A2 WO2011061761 A2 WO 2011061761A2
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WO
WIPO (PCT)
Prior art keywords
mycophenolate mofetil
solution
acid
minutes
vials
Prior art date
Application number
PCT/IN2010/000745
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English (en)
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WO2011061761A3 (fr
Inventor
Vj. Pakalapati Ramani
Nagaraj Amminabavi
Subhash Gore
Manoj Pananchukunnath
Rajesh Gupta
Indu Bhushan
Original Assignee
Matrix Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Publication of WO2011061761A2 publication Critical patent/WO2011061761A2/fr
Publication of WO2011061761A3 publication Critical patent/WO2011061761A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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 invention relates to pharmaceutical compositions comprising an immunosuppressant, for parenteral administration.
  • compositions for parenteral administration which comprises mycophenolate mofetil or its pharmaceutically acceptable salt thereof.
  • Mycophenolate mofetil is an immunosuppressant and a prodrug of mycophenolic acid, used extensively as an immunosuppressant for the treatment or prevention of organ or tissue transplant rejection. Chemically, it is 2- morpholinoethyl 2-(4-morpholino) ethyl-E-6-(l, 3-dihydro-4-hydroxy-6-mettioxy- 7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate and disclosed in U.S. Patent No. 4,753,935. As compared to mycophenolic acid, these ester derivatives show advantageous pharmacokinetic properties which enhance the systemic introduction of mycophenolic acid, for example, solubility in the delivery environment (e.g., stomach), maximum plasma concentration and improved activity.
  • solubility in the delivery environment e.g., stomach
  • Mycophenolate mofetil is marketed under the trade name Cellcept ® in the form of tablet, capsule and intravenous injection in the US.
  • Mycophenolate mofetil and its use in treating various disorder such as autoimmune disorders, psoriasis, inflammatory diseases (including in particular, rheumatoid arthritis), tumors and viruses, and for immunosuppression, particularly for treatment of allograft rejection, especially including cardiac allograft rejection, pancreatic allograft rejection and renal allograft rejection, and for treating autoimmune diseases, including diabetes etc. were disclosed in various prior art reference such as US Patent Nos. 4,808,592, 4,952,579, 4,786,637, 4,948,793, 4,992,467.
  • the compositions of mycophenolate mofetil can be used in various prior art reference such as US Patent Nos. 4,808,592, 4,952,579, 4,786,637, 4,948,793, 4,992,467.
  • the compositions of mycophenolate mofetil can be used in various prior art reference such as US Patent Nos. 4,808,592, 4,952,579, 4,786,637, 4,948,793, 4,99
  • compositions suitable for parenteral administration e.g. suitable for intravenous, subcutaneous or intramuscular administration, is desired.
  • Cellcept ® is available as a sterile white to off- white lyophilized powder filled in vials containing mycophenolate mofetil hydrochloride for administration by intravenous infusion only.
  • Each vial of Cellcept ® contains the equivalent of 500 mg mycophenolate mofetil as hydrochloride salt.
  • the inactive ingredients are polysorbate 80 and citric acid.
  • Sodium hydroxide may have been used in the manufacture of Cellcept ® intravenous infusion to adjust the pH. Reconstitution and dilution with 5% Dextrose Injection USP yields a slightly yellow solution of mycophenolate mofetil hydrochloride.
  • parenteral preparations are used widely in comparison to oral administration due to its quick and easy delivery in targeted area of the body and suitability in patients with physical and mental state. Moreover, it also doesn't cause any irritation in digestive system. Irrespective of all the advantages, it is very necessary to maintain a proper solubility and stability of the drug during the shelf-life of such parenteral preparation which makes the parenteral preparations more costly. So various efforts have been taken for making the process simple and cost-effective.
  • US 3,705,946 disclose a method of reducing a uric acid level in human which comprises administering mycophenolic acid or an alkali metal salt thereof via parenteral route but without using lyophilization method.
  • US 5,543,408 and US 5,545,637 discloses pharmaceutical compositions suitable for preparing an aqueous intravenous formulation of mycophenolate mofetil, which composition includes a crystalline anhydrous salt of mycophenolate mofetil and pharmaceutically acceptable excipients.
  • This patent further disclose a process for manufacturing the pharmaceutical composition of crystalline anhydrous salt of mycophenolate mofetil with pharmaceutically acceptable excipients to form a bulking solution having a pH of about 3.2 to 3.6, loading the bulking solution into a container, and lyophilizing the loaded container.
  • compositions in the form of a powder or a lyophilized composition for parenteral administration comprising mycophenolic acid, a salt or a prodrug thereof.
  • This publication further discloses the composition comprising a cationic salt of mycophenolic acid.
  • the inventors of the present invention surprisingly found an improved composition of mycophenolate mofetil, which form a single and stable cake on lyophilization and is easy to reconstitute during formulation.
  • the improved stability of mycophenolate mofetil or its pharmaceutically acceptable salt thereof is the result of their amorphous nature, being obtained as a result of their lyophilization.
  • the invention relates to a pharmaceutical composition for parenteral administration comprising mycophenolate mofetil or its pharmaceutically acceptable salt thereof, wherein the mycophenolate mofetil is in amorphous form.
  • the invention also relates to a process for preparing a pharmaceutical composition for parenteral administration comprising mycophenolate mofetil or its pharmaceutically acceptable salt thereof, wherein the mycophenolate mofetil is in amorphous form. More particularly, the invention relates to a lyophilized pharmaceutical composition for parenteral administration comprising mycophenolate mofetil or its pharmaceutically acceptable salt thereof, wherein the mycophenolate mofetil is in amorphous form.
  • Fig. 1 X-ray diffraction pattern (XRD) of crystalline mycophenolate mofetil.
  • Fig. 2 Differential Scanning Calorimetry (DSC) thermogram of crystalline mycophenolate mofetil.
  • Fig. 3 X-ray diffraction pattern (XRD) of crystalline anhydrous mycophenolate mofetil hydrochloride [Cellcept ® ] after lyophilization.
  • XRD X-ray diffraction pattern
  • Fig. 4 X-ray diffraction pattern (XRD) of amorphous mycophenolate mofetil after lyophilization (Example 1).
  • Fig.5 X-ray diffraction pattern (XRD) of amorphous mycophenolate mofetil after lyophilization (Example 3).
  • Fig 6 X-ray diffraction pattern (XRD) of wet sample of crystalline mycophenolate mofetil (Example 7).
  • Fig 7 X-ray diffraction pattern (XRD) of crystalline mycophenolate mofetil dried at 25 °C for 24 hours under vacuum (Example 7).
  • Fig 8 X-ray diffraction pattern (XRD) of crystalline mycophenolate mofetil dried at 50°C for 24 hours under vacuum (Example 7).
  • Fig 9 Differential scanning calorimetry (DSC) of crystalline mycophenolate mofetil dried at 25°C for 24 hours under vacuum (Example 7).
  • Fig 10 Differential scanning calorimetry (DSC) of crystalline mycophenolate mofetil dried at 50°C for 24 hours under vacuum (Example 7).
  • Fig. 11 Polymorphic study of stability of the sample at 20 weeks as compared to initial sample (Example 2).
  • the invention relates to a pharmaceutical composition for parenteral administration comprising mycophenolate mofetil or its pharmaceutically acceptable salt, wherein the mycophenolate mofetil is in amorphous form.
  • the invention relates to a lyophilized pharmaceutical composition for parenteral administration comprising mycophenolate mofetil or its pharmaceutically acceptable salt thereof, wherein the mycophenolate mofetil is in amorphous form.
  • the invention also relates to a process for preparing a pharmaceutical composition for parenteral administration comprising mycophenolate mofetil or its pharmaceutically acceptable salt thereof, wherein the mycophenolate mofetil is in amorphous form.
  • a “pharmaceutically acceptable salt” means that mycophenolate mofetil is complexed with pharmaceutically acceptable anion of various acids either ionically or covalently.
  • the salt may be derived from an inorganic or organic acid. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfate salts), nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, lactic acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. More preferably, the pharmaceutically acceptable salt refers to either citrate or lactate
  • parenteral preparation of the invention wherein the drug is in amorphous form results in a single and stable cake on lyophilization, which is easy to reconstitute, by virtue of improved solubility and stability of mycophenolate mofetil or its pharmaceutically acceptable excipient after lyophilization.
  • composition may further contain various pharmaceutically acceptable excipients such as bulking agents, solubilizing agents, stabilizing agents, buffering agents, preservatives and the like.
  • the bulking agent according to the invention is selected from a group comprising dextrose, glucose, maltose, lactose, sucrose, mannitol, sorbitol and the like or combinations thereof.
  • the solubilizing agent according to the invention is selected from a group comprising polyoxyl cetostearyl ether (CremophoreTM), propylene glycol, polyethylene glycol, polysorbate, sodium deoxycholate, povidone and the like or combinations thereof.
  • the stabilizing agent according to invention is selected from a group comprising sodium metabisulfite, calcium gluconate, acetic acid, ascorbic acid, aspartic acid and the like or combinations thereof.
  • the buffering agent according to invention is selected from buffers belonging to a group comprising phosphate, acetate, succinate, tartarate, ascorbate, benzoate, citrate, lactate and the like or combinations thereof.
  • the preservative according to invention is selected from a group comprising benzoic acid, benzethonium chloride, benzyl alcohol, benzylkonium chloride and the like or combinations thereof.
  • the molar ratio of mycophenolate mofetil to buffer is from about 1: 0.5 to about 1 :2.0 and more preferably in a molar ratio of about 1 :1.
  • the invention relates to a pharmaceutical composition for parenteral administration comprising mycophenolate mofetil or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients prepared by lyophilization, wherein the mycophenolate mofetil is in amorphous form.
  • the invention also relates to pharmaceutical compositions for parenteral administration, comprising mycophenolate mofetil citrate.
  • Mycophenolate mofetil citrate prepared according to the invention can exist in an amorphous or in different crystalline form. More particularly, mycophenolate mofetil citrate prepared is in crystalline form.
  • the crystalline mycophenolate mofetil citrate present may be in the form of an anhydrous or hydrous state.
  • the amorphous or crystalline mycophenolate mofetil citrate salt prepared according to the invention has improved solubility as compared to mycophenolate mofetil and provides cake with requisite bulkiness on lyophilization.
  • the invention also provides a process for preparing pharmaceutical compositions for parenteral administration, comprising mycophenolate mofetil or its pharmaceutically acceptable salt, wherein the mycophenolate mofetil is in amorphous form.
  • One set of non-limiting, demonstrative process involves the following steps:
  • step (b) Making up the volume of solution of step (b) with water;
  • step (c) 4. Filtering the solution of step (c) and placing it into suitable vials;
  • the invention also provides a process for preparing mycophenolate mofetil citrate, wherein the mycophenolate mofetil is in crystalline form, involving the steps of:
  • step 2 Heating the solution of step 1 to about 30°-60°C followed by cooling to about 2°C-15°C.
  • step 2 Crystallizing the solution of step 2 for about 2-20 hrs to get the desired crystallized solid.
  • step 4 Drying the solid of step 3, at atmospheric or reduced pressure to get the desired crystalline mycophenolate mofetil citrate.
  • the parenteral composition is compounded or formulated before lyophilization by using either purified water or by using suitable solvent.
  • the parenteral composition of mycophenolate mofetil started with crystalline mycophenolate mofetil which after lyophilization, changes its phase from crystalline to amorphous and is demonstrated by XRD as shown in Fig. 4 and Fig. 5.
  • composition which can be distributed to the dispensing person, e.g., in a pharmacy or a hospital, in the form of a vial containing the composition, or in the form of a kit comprising a vial or vials containing the composition and an appropriate amount of a liquid medium.
  • step 2 To the solution of step 1, mycophenolate mofetil was added under stirring.
  • Step 2 solution was made up to volume by addition of water followed by stirred for 5 minutes, wherein the pH was found to be 3.5.
  • Step 4 solution was filtered using 0.22 ⁇ PVDF filters and filled in vials (5ml in each vial).
  • the temperature was measured from the shelf where the loaded vials were placed and the thermocouples were fitted to various vials to measure their temperature. 7. The shelf temperature was decreased from 25°C to -40°C over 30 minutes.
  • the shelf temperature was maintained at -40°C for 180 minutes.
  • the Lyophilization chamber pressure was reduced to 250 mTorr.
  • the temperature was increased from -40°C to 0°C over 1200 minutes with chamber pressure at 150 mTorr.
  • the temperature was maintained at 0°C for 600 minutes.
  • the temperature was increased from 0°C to 15°C over 300 minutes along with decrease in the chamber pressure to 100 mTorr.
  • the temperature was increased from 15°C to 25°C over 300 minutes along with decrease in the chamber pressure to 50 mTorr
  • the temperature was maintained at 25°C for 450 minutes with chamber pressure at 50 mTorr.
  • Polysorbate 80 was mixed with water for injection and stirred till clear solution was formed.
  • step 1 The solution of step 1 was transferred to a jacketed steel container and maintained at 40-45°C.
  • step 2 citric acid was added under continuous stirring and stirring was continued for further 5 minutes.
  • step 4 Mycophenolate mofetil was added to step 3 solution under continuous stirring and stirred for 20 minutes with temperature at 40°— 45 °C till visibly clear solution with no particulate matter was formed.
  • Step 4 solution was made up to volume using water for injection and kept for stirring for about 5minutes.
  • Step 5 solution was filtered using 1.0 micron glass fiber filter followed by 0.22 micron PVDF filter under pressure using nitrogen gas.
  • Step 6 solution was filled in vials (20ml in each vial) and the vials were half stoppered.
  • the temperature was measured from the shelf where the vials were placed, and thermocouples were fitted to various vials to measure their temperature.
  • the shelf temperature was reduced from 25 °C to -40°C over 60 minutes.
  • the shelf temperature was maintained at -40°C for 300 minutes.
  • the shelf temperature was increased from -40°C to -25 °C over 60 minutes with chamber pressure reduced to 300mTorr.
  • the shelf temperature was increased from -25°C to -15°C over 1200 minutes with chamber pressure at 300mTorr.
  • the shelf temperature was maintained at -15°C for 1000 minutes with chamber pressure at 300mTorr.
  • the shelf temperature was increased from -15°C to 25°C over 60 minutes with chamber pressure decreased to 50 mTorr.
  • the shelf temperature was maintained at 25°C for 60 minutes with chamber pressure at 50 mTorr.
  • Citric acid was dissolved in water for injection at about 40°-45°C to get a solution.
  • step 2 To the solution of step 1, required quantity of mycophenolate mofetil was added under continuous stirring to get clear solution.
  • step 1 The solution of step 1 was maintained at 40°-45°C for about 5-25 mins under continuous stirring.
  • Step 3 solution was filled in vials and the vials were half stoppered.
  • thermocouples were fitted to various vials to measure their temperature.
  • the shelf temperature was reduced from 25°C to -35°C at the ramp rate of lC/min and the freezed solution was maintained at 35°C for 5 Hours.
  • the shelf temperature was increased from -35°C to -15°C over a period of 15hrs and held at - 15 °C for 5 Hours.
  • the shelf temperature was further increased from -15°C to 25°C over a period of 5hrs and held at 25 °C for 20 Hours.
  • step 2 To the solution of step 1, mycophenolate mofetil was added under stirring.
  • step 2 solution was adjusted to 2.5 to 3.6 using hydrochloric acid.
  • Step 3 solution was made up to volume by addition of water followed by stirring for 5 minutes.
  • Step 4 solution was filtered using 0.22 ⁇ PVDF filters and filled in vials (5ml in each vial).
  • the shelf temperature was decreased from 25°C to 10°C over 30 minutes.
  • the shelf temperature was decreased from 10°C to 0°C over 60 minutes.
  • the shelf temperature was decreased from 0°C to -15°C over 60 minutes.
  • the shelf temperature was decreased from -15°C to -40°C over 60 minutes.
  • the shelf temperature was maintained at -40°C for 120 minutes.
  • the lyophilization chamber pressure was reduced to 250 mTorr.
  • the temperature was increased from -40°C to 0°C over 1200 minutes with chamber pressure at 150 mTorr.
  • the temperature was maintained at 0°C for 600 minutes.
  • the temperature was increased from 0°C to 15°C over 300 minutes along with decrease in the chamber pressure to 100 mTorr.
  • the temperature was increased from 15°C to 25°C over 300 minutes along with decrease in the chamber pressure to 50 mTorr
  • the temperature was maintained at 25°C for 450 minutes with chamber pressure at 50 mTorr.
  • Step 4 solution was made up to volume by adding water and stirred well for 2-3 minutes.
  • Step 5 solution was filtered using 0.22 ⁇ PVDF filter and filled in vials (5 ml in each vial).
  • the temperature was measured from the shelf where the loaded vials were placed, and the thermocouples were fitted to various vials to measure their temperature.
  • the shelf temperature was decreased from 25°C to 0°C over 30 minutes.
  • the shelf temperature was decreased from 0°C to -10°C over 30 minutes.
  • the shelf temperature was decreased from -10°C to -35°C over 30 minutes.
  • the shelf temperature was maintained at -35°C for 120 minutes.
  • the lyophilization chamber pressure was reduced to 400 mTorr.
  • the temperature was increased from -35°C to 0 °C over 1000 minutes with chamber pressure at 150 mTorr.
  • the temperature was maintained at 0°C for 300 minutes along with decrease in the chamber pressure to 100 mTorr.
  • the temperature was increased from 0°C to 15°C over 300 minutes along with decrease in the chamber pressure to 100 mTorr.
  • the temperature was increased from 15°C to 25°C over 300 minutes along with decrease in the chamber pressure to 50 mTorr
  • the temperature was maintained at 30°C for 10 minutes with chamber pressure at 50 mTorr.
  • Polysorbate 80 was taken in a beaker; water was added to it and stirred well to prepare a clear solution.
  • step 2 Mycophenolate mofetil was added to step 1 under stirring and the stirring was continued till a uniform dispersion was formed.
  • Step 4 solution was made up to volume using water by stirred for 5 mins, wherein the pH was found to be 3.57.
  • Step 6 was filtered using 0.45 ⁇ PVDF filter and filled in vials.
  • the chamber at 20°C was cooled to -5°C over period of 60 minutes.
  • the chamber at 20°C was cooled to -35°C over period of 60 minutes.
  • the chamber at -35°C was maintained at same temperature for 120 minutes.
  • the chamber pressure was reduced to 250 mTorr.
  • the pressure of the chamber at -35°C was further reduced to 200 mTorr over period of 60 minutes.
  • the chamber at -35°C was heated to 0°C over period of 1300 minutes.
  • the chamber at 0°C was maintained at same temperature for 600 minutes. 17. The chamber at 0°C was heated to 15°C over 60 minutes.
  • step 2 The solution of step 1 was heated at about 30°C to 50°C followed by cooling at about 2°C to 15°C for about 2 to 20 hours to get a solid mass.
  • step 2 was further dried at atmospheric or reduced pressure at about 40°C to 80°C and characterized by various analytical procedures such as XRD, DSC and TGA.
  • the amorphous mycophenolate mofetil composition prepared according to Example 2 was subjected to temperature 2-8°C; as well as at accelerated conditions [25°C/60% RH and 30°C/75% RH] for 20 weeks.
  • the related substances were analyzed and the results obtained are given in Table 1.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention concerne des compositions pharmaceutiques comprenant un immunosuppresseur et destinées à l'administration parentérale. Plus particulièrement, l'invention concerne des compositions pharmaceutiques destinées à l'administration parentérale et comprenant le mycophénolate mofétil ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/IN2010/000745 2009-11-17 2010-11-16 Composition pharmaceutique à usage parentéral WO2011061761A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2821/CHE/2009 2009-11-17
IN2821CH2009 2009-11-17

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WO2011061761A2 true WO2011061761A2 (fr) 2011-05-26
WO2011061761A3 WO2011061761A3 (fr) 2013-04-25

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106943359A (zh) * 2016-01-06 2017-07-14 山东新时代药业有限公司 一种稳定的注射用吗替麦考酚酯及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087174A1 (fr) * 2003-04-01 2004-10-14 Novartis Ag Formulation parenterale

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087174A1 (fr) * 2003-04-01 2004-10-14 Novartis Ag Formulation parenterale

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RxList The Internet Drug Index: "CellCept", , 29 June 2012 (2012-06-29), XP002692430, Retrieved from the Internet: URL:http://www.rxlist.com/script/main/rxlist.asp?articlekey=66621&pf=3&page=1 [retrieved on 2013-02-19] *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106943359A (zh) * 2016-01-06 2017-07-14 山东新时代药业有限公司 一种稳定的注射用吗替麦考酚酯及其制备方法
CN106943359B (zh) * 2016-01-06 2020-05-01 山东新时代药业有限公司 一种稳定的注射用吗替麦考酚酯及其制备方法

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