WO2015107534A1 - Lyophilized formulation of treosulfan - Google Patents
Lyophilized formulation of treosulfan Download PDFInfo
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- WO2015107534A1 WO2015107534A1 PCT/IN2014/000692 IN2014000692W WO2015107534A1 WO 2015107534 A1 WO2015107534 A1 WO 2015107534A1 IN 2014000692 W IN2014000692 W IN 2014000692W WO 2015107534 A1 WO2015107534 A1 WO 2015107534A1
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- treosulfan
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- lyophilized formulation
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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
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
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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
Definitions
- the present invention relates to -a stable, lyophilized formulation of an alkylating agent like Treosulfan and a process for its preparation.
- the present invention also relates to new polymorphic forms of treosulfan that can further the development of treosulfan formulations and process for preperation of the same.
- Treosulfan genetically known as (2S,3S)-2,3-Dihydroxy-4-methylsulfonyloxybutyl] methanesulfonate is a prodrug of a bifunctional alkylating agent, widely used as a antineoplastic agent.
- the active ingredient is indicated for all types of ovarian cancer either supplementary to surgery or palliatively.
- preclinical and clinical activities have been demonstrated against some other solid tumours, and haematological malignancies. It has also been used for bone-marrow ablation before stem-cell transplantation and to treat malignant melanoma and breast cancer. Due to lack of cross-resistance reported between treosulfan and other cytotoxic agents, treosulfan is reported to be useful in any neoplasm refractive to conventional therapy.
- Treosulfan first disclosed in US 3,155,702 by Werner et al in 1964, is one of those novel compounds, which possess anticancer activity due to in vivo formation of an epoxide metabolite.
- treosulfan Over the past five decades, considerable amount of literature concerning treosulfan has accumulated. Most of these references, deal mainly with clinical applications of this agent as an antineoplastic drug. Since 1992, treosulfan has been commercially available in Europe for the treatment of ovarian cancer. It is marketed by Medac Pharmaceuticals and is available in vials for parenteral administration by intravenous, intraperitoneal route and as capsule formulation for oral use. In the USA, treosulfan is still under clinical development and is listed in the FDA's orphan drug database.
- treosulfan consists of sterile packaged dry powder of treosulfan.
- the dry powder is dissolved in water prior to administration. It is intended that the sterile powder formulation, once brought into solution, should be used immediately.
- a common practice used for constitution of sterile dry powders and also mentioned in Summary of Product Characteristics of treosulfan injection, is to warm the aqueous vehicle to expedite the dissolution process.
- the document explicitly mentions that the temperature of water for injection should not be higher than 30°C.
- treosulfan powder needs to be carefully removed from the inner surface of the infusion bottle by shaking. This procedure is very important, because moistening of powder that sticks to the surface results in caking.
- the bottle has to be shaken long and vigorously.
- use of double sided cannula is recommended.
- One side of the double sided cannula is put into the rubber stopper of the water bottle.
- the treosulfan bottle is then put on the other end of the cannula with the bottom on top. The whole construction is converted and the water is allowed to run into the lower bottle while the bottle is shaken gently.
- solubility, stability, flowability, fractability, and compressibility of the compound, as well as the safety and efficacy of drug products comprising it are dependent on polymorphic forms of a compound.
- Many compounds can exist in different crystal forms, or polymorphs, which exhibit different physical, chemical, and spectroscopic properties.
- certain polymorphs of a compound may be more readily soluble in particular solvents, may flow more readily, or may compress more easily than others.
- certain solid forms may be more bioavailable than others, while others may be more stable under certain manufacturing, storage, and biological conditions. This is particularly important from a regulatory standpoint, since drugs are approved by agencies such as the U.S.
- the present invention relates to pharmaceutical composition
- treosulfan and a pharmaceutically acceptable excipient or carrier.
- the pharmaceutically composition of the present invention is a lyophilized powder.
- the present invention relates to a process for prepration of lyophilized pharmaceutical compositions of treosulfan.
- the present invention also relates to novel crystalline polymorphs of (2S,3S)-2,3-Dihydroxy- 4-methylsulfonyloxybutyl] methanesulfonate (treosulfan).
- the present invention also provides methods for preparing pharmaceutical compositions comprising same, and methods of use as anticancer agents.
- the present invention provides a novel crystalline polymorphic form of treosulfan, designated as "Form I".
- Form I exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 1, having characteristic peaks (expressed in °2 ⁇ ( ⁇ 0.2 °2 ⁇ ) at one or more of the following positions: 7.72, 15.48, 19.81, 22.1 1, 23.01, 23.28, 29.02 and 40.60.
- Form I also exhibits a Differential Scanning Calorimetry (DSC) thermogram, which is characterized by a predominant endotherm peak at about 104.58 °C as measured by Differential Scanning Calorimeter at a scan rate of 10 °C per minute.
- DSC Differential Scanning Calorimetry
- the present invention provides a novel crystalline polymorphic form of treosulfan, designated as "Form ⁇ ".
- Form II exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 2, having characteristic peaks (expressed in °2 ⁇ ( ⁇ 0.2 °2 ⁇ ) at one or more of the following positions: 7.79, 15.54 and 23.36.
- Form I also exhibits a Differential Scanning Calorimetry (DSC) thermogram, which is characterized by a predominant endotherm peak at about 105.1 °C as measured by Differential Scanning Calorimeter at a scan rate of 10 °C per minute.
- DSC Differential Scanning Calorimetry
- FIG. 1 shows XRPD patterns of the Form - 1 of the treosulfan.
- FIG. 2 shows XRPD patterns of the Form - II of the treosulfan. DETAIL DESCRIPTION OF THE INVENTION
- the present invention is directed towards the pharmaceutical composition of treosulfan.
- Treosulfan the therapeutically active component of this invention, is a well known and widely used anticancer agent and is a dihydroxy derivative of the alkylating agent busulfan.
- Treosulfan was thoroughly tested with those excipients compatible with parenteral administration to determine if a suitable lyophilizate cake could be formed by freeze-drying. Following the lyophilization process, the resulting cake was evaluated visually on its physical appearance using as desired criteria: original shape, no shrinkage or melt-back, good coloration, homogeneity, firmness, and crystallinity. The dissolution rate was then tested. It was unexpectedly found that a lyophilized formulation of treosulfan exhibits all the desired characteristics of a lyophilized formulation and thus lyophilization process helps in achieving an improved solid pharmaceutical composition of treosulfan.
- one aspect of the present invention pertains to pharmaceutical compositions which are suitable for administration to a subject, as well as pharmaceutical compositions (e.g., lyophilates/lyophilisates, concentrates, etc.) from which such formulations may be prepared.
- pharmaceutical compositions e.g., lyophilates/lyophilisates, concentrates, etc.
- the administration is parenteral administration.
- the administration is administration by injection, including, for example, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal injection.
- the administration is intravenous administration.
- the administration is administration by intravenous injection.
- the administration is administration by infusion.
- the administration is administration by intravenous infusion.
- the present pharmaceutical composition comprises treosulfan and a pharmaceutically acceptable excipient or carrier.
- composition describes a material that is in a form (e.g., a liquid) that is ready for administration, as well as describes a material (e.g., lyophilate/lyophilisate, concentrate, etc.) from which a formulation may be prepared (e.g., by re-hydration, dilution, etc.) ,
- the pharmaceutically acceptable excipient or carrier is selected from water-for-injectipn, aqueous saline solution, aqueous glucose solution, saline for injection/infusion, glucose for injection/infusion, Ringer's solution, or lactated Ringer's solution.
- lyophilization refers to a process by which the material to be dried is first frozen and then the ice or frozen solvent is removed by sublimation in a vacuum environment.
- lyophilized powder or "lyophilized preparation” refers to any solid material obtained by lyophilization, i.e., freeze-drying of an aqueous solution.
- the aqueous solution may contain a non-aqueous solvent, i.e. a solution composed of aqueous and one or more non-aqueous solvent(s).
- a lyophilized preparation is one in which the solid material is obtained by freeze-drying a solution composed of water as pharmaceutically acceptable carrier.
- the present invention relates to polymorphic forms of treosulfan.
- such polymorphs comprise stable or substantially stable polymorphs of treosulfan.
- the present invention provides at least polymorphic forms I and II (as designated herein) of treosulfan, each having distinguishing characteristics disclosed herein.
- the present invention provides Polymorph Form I of treosulfan.
- the present invention provides Polymorph Form II of treosulfan.
- the present invention provides solid formulations containing at least polymorphic forms I and II (as designated herein) of treosulfan.
- the form -I of treosulfan is prepared by a process comprising reaction of dimethyl 2,3-0- isopropylidene-L-tartrate with sodium-bis(2-methoxyethoxy) aluminum hydride to give the protected diol, 2,3-O-isopropylidene-L-threitol, which on further treatment with methanesulfonyl chloride, followed by reaction of the resultant ester, 2,3-O-isopropyliden-L- threitol 1 ,4 bismethanesulfonate with formic acid, yields Treosulfan having desired purity and with impurity levels conforming to ICH guidelines.
- the product is recrystallised form organic solvents or mixtures thereof.
- the preffered organic solvents are ethyl acetate, methyl isobutyl ketone, ethanol, n-propanol, t-butanol, isopropyl acetate, methanol, propylene glycol, acetone, acetone : Cyclohexane.
- the present invention provides a lyophilized formulation containing polymorphic form I of treosulfan.
- the solid formulation of the present invention contains treosulfan in therapeutically effective amount which means the amounts that will relieve to some extent one or more of the symptoms of the disorder being treated.
- a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth, and/or, (4) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with cancer.
- Therapeutically effective amount can also mean preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment). Further, therapeutically effective amount can also be the amount that increases the life expectancy of a patient afflicted with a terminal disorder.
- Typical therapeutically effective dose for treosulfan ranges from about 3 g/m 2 to about 8 g/m 2 administered intravenously every 1-3 weeks depending on blood count and concurrent chemotherapy. Single injections of up to 8 g/m 2 have also been reported as therapeutically effective and with no serious adverse effects. Intraperitoneally treosulfan is administered in doses of up to 1.5 g/m 2 .
- the pharmaceutical compositions of the present invention therefore, contain treosulfan in the amount ranging from 500 mg to lOg.
- the solid pharmaceutical compositions of the present invention contain treosulfan in the amount ranging from lg to 5 g.
- the composition contains treosulfan and optionally other excipients commonly used in lyophilized formulation.
- excipient means the substances used to formulate active pharmaceutical ingredients (API) into pharmaceutical formulations and does not lower or interfere with the primary therapeutic effect of the drug substance.
- an excipient is therapeutically inert.
- excipient means the substances which improve or helps in improving the functional properties and/or stability of the lyophilized product.
- excipient encompasses solubilizers, stabilizers, bulking agents, buffering agents, pH adjusting agents, tonicifying agents, antimicrobial agents and collapse! temperature modifying agents.
- Excipients can also be those substances present in a pharmaceutical formulation as an indirect or unintended result of the manufacturing process.
- excipients are approved for or considered to be safe for human and animal administration. Typical examples of the excipients used in the lyophilized formulation are summarized below.
- Bulking agents are typically used to provide product elegance (i.e., satisfactory appearance) as well as sufficient cake mechanical strength to avoid product blow-out. Mannitol is by far the most commonly used bulking agent.
- Buffers are required in pharmaceutical formulations to stabilize pH.
- a good approach is to use low concentrations of a buffer that undergoes minimal pH change during freezing.
- the preferred buffers are selected from group consisting of citrate and phosphates buffers.
- Tonicity modifiers are occasionally formulated in products for human use to make the reconstituted product isotonic (e.g., for subcutaneous or intramuscular injections).
- Excipients are selected from mannitol, sucrose, glycine, glycerol, and sodium chloride are good tonicity adjuster.
- the pharmaceutical formulations of the present invention may also optionally include a parenterally acceptable surfactant wherein the surfactant is selected from the group comprising of polysorbate 20, polysorbate 80, a bile acid, lecithin, an ethoxylated vegetable oil, vitamin E tocopherol propylene glycol succinate, or polyoxyethylene-polyoxypropylene block copolymers.
- a lyophilized formulation of treosulfan is achieved following removal of solvents from the solution. Typically, water is used as solvent, however other organic solvents could also be used individually or in combination.
- the employed solvents must form stable solutions with treosulfan and must not appreciably degrade or deactivate the drug substance. Additionally, the solvent should be capable of being removed easily from an aqueous dispersion or solution of the drug product, e.g., through lyophihzation or vacuum drying.
- Lyophihzation can be carried out using standard equipment as used for lyophihzation or vacuum drying.
- the cycle may be varied depending upon the equipment and facilities used for the fill/finish.
- an aqueous pre- lyophilization solution or dispersion is first formulated in a pharmaceutically acceptable compounding vessel.
- the solution is aseptically filtered into a sterile container, filled into an appropriate sized vial, partially stoppered and loaded into the lyophilizer.
- lyophilization techniques described herein the solution is lyophilized until desirable moisture content is achieved.
- the resulting lyophilization powder can be readily reconstituted with Sterile Water for Injection, or other suitable carrier, to provide liquid formulations of treosulfan, suitable for administration.
- the pre-lyophilization solution or dispersion normally is first formulated in a pharmaceutically acceptable container by:
- the present inventors have also found that by immersing the bulk solution of treosulfan in liquid nitrogen leads to formation of irregular shaped ice crystals with very large ice surface area. This large surface area increases the rate of sublimation during the primary drying and desorption during the secondary drying.
- the pre-lyophilization solution or dispersion can be sterilized prior to lyophilization, sterilization is generally performed by aseptic filtration, e.g., through a 0.22 micron or less filter. Multiple sterilization filters can be used. Sterilization of the solution or dispersion can be achieved by other methods known in the art, e.g., radiation.
- the solution or dispersion is ready for lyophilization.
- the filtered solution will be introduced into a sterile receiving vessel, and then transferred to any suitable container or containers in which the formulation may be effectively lyophilized.
- the formulation is effectively and efficiently lyophilized in the containers in which the product is to be marketed, such as, without limitation, a vial, as described herein and as known in the art.
- the product is placed in a lyophilization chamber under a range of temperatures and then subjected to temperatures well below the product's freezing point, generally for several hours.
- the temperature will be at or below about -45°C for at least 10 hours.
- the chamb r and the condenser are evacuated through vacuum pumps, the condenser surface having been previously chilled by circulating refrigerant. Additionally, evacuation of the chamber should continue until a pressure of about 10 to about 1000 microns,is obtained.
- the freezing rate impacts the quality of lyophilized product. Therefore, freezing is carried out at a rate not less than 5°C/min.
- the product composition is then warmed under vacuum in the chamber and with condenser.
- the product temperature should initially be increased from about -55°C to about - 25°C and maintained for about 2-6 hours.
- complete removal of solvent should be done during the initial drying phase. Complete drying can be confirmed by stabilization of vacuum, condenser temperature and product shelf temperature. After the initial drying, the product temperature should be increased to about 5°C and maintained for about 10-50 hours.
- the pressure in the chamber can be slowly released to atmospheric pressure (or slightly below) with sterile, dry-nitrogen gas (or equivalent gas). If the product composition has been lyophilized in containers such as vials, the vials can be stoppered, removed and sealed. Several representative samples can be removed for purposes of performing various physical, chemical, and microbiological tests to analyze the quality of the product
- the lyophilized formulation is typically marketed in pharmaceutical dosage form.
- the pharmaceutical dosage form ' of the present invention although typically in the form of a vial, may be any suitable container, such as ampoules, syringes, co-vials, which are capable of maintaining a sterile environment.
- Such containers can be glass or plastic, provided that the material does not interact with the treosulfan formulation.
- the closure is typically a stopper, most typically a sterile rubber stopper, preferably a bromobutyl rubber stopper, which affords a hermetic seal.
- a vial will contain a lyophilized powder including about 0.5 to about 10 g/vial, preferably about 1 to 5 g g/vial, treosulfan.
- the lyophilized formulations of the present invention may be reconstituted with water, preferably Sterile Water for Injection, or other sterile fluid such as co-solvents, to provide an appropriate solution of treosulfan for administration, as through parenteral injection following further dilution into an appropriate intravenous admixture container, for example, normal saline.
- Example - 1 Lyophilized Formulation:
- Example - 2 Lyophilized Formulation using quench technique:
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Abstract
The present invention relates to an improved solid formulation of (2S,3S)-2,3-Dihydroxy-4- methylsulfonyloxybutyl] methanesulfonate. The improved formulations are lyophilized pharmaceutical solid composition containing treosulfan for reconstitution with water to provide a solution for parenteral administration. The present invention also relates to Polymorphic Form I and II of treosulfan.
Description
LYOPHILIZED FORMULATION OF TREOSULFAN
FIELD OF THE INVENTION
The present invention relates to -a stable, lyophilized formulation of an alkylating agent like Treosulfan and a process for its preparation. In another aspect the present invention also relates to new polymorphic forms of treosulfan that can further the development of treosulfan formulations and process for preperation of the same.
BACKGROUND OF THE INVENTION Treosulfan, genetically known as (2S,3S)-2,3-Dihydroxy-4-methylsulfonyloxybutyl] methanesulfonate is a prodrug of a bifunctional alkylating agent, widely used as a antineoplastic agent. The active ingredient is indicated for all types of ovarian cancer either supplementary to surgery or palliatively. In addition, preclinical and clinical activities have been demonstrated against some other solid tumours, and haematological malignancies. It has also been used for bone-marrow ablation before stem-cell transplantation and to treat malignant melanoma and breast cancer. Due to lack of cross-resistance reported between treosulfan and other cytotoxic agents, treosulfan is reported to be useful in any neoplasm refractive to conventional therapy.
Treosulfan, first disclosed in US 3,155,702 by Werner et al in 1964, is one of those novel compounds, which possess anticancer activity due to in vivo formation of an epoxide metabolite.
Over the past five decades, considerable amount of literature concerning treosulfan has accumulated. Most of these references, deal mainly with clinical applications of this agent as an antineoplastic drug. Since 1992, treosulfan has been commercially available in Europe for the treatment of ovarian cancer. It is marketed by Medac Pharmaceuticals and is available in vials for parenteral administration by intravenous, intraperitoneal route and as capsule formulation for oral use. In the USA, treosulfan is still under clinical development and is listed in the FDA's orphan drug database.
l
Currently, the marketed parenteral dosage formulation of treosulfan consists of sterile packaged dry powder of treosulfan. The dry powder is dissolved in water prior to administration. It is intended that the sterile powder formulation, once brought into solution, should be used immediately. A common practice used for constitution of sterile dry powders and also mentioned in Summary of Product Characteristics of treosulfan injection, is to warm the aqueous vehicle to expedite the dissolution process. However, the document explicitly mentions that the temperature of water for injection should not be higher than 30°C. Further, treosulfan powder needs to be carefully removed from the inner surface of the infusion bottle by shaking. This procedure is very important, because moistening of powder that sticks to the surface results in caking. In case caking occurs the bottle has to be shaken long and vigorously. To aid the dissolution of the dry powder formulation, use of double sided cannula is recommended. One side of the double sided cannula is put into the rubber stopper of the water bottle. The treosulfan bottle is then put on the other end of the cannula with the bottom on top. The whole construction is converted and the water is allowed to run into the lower bottle while the bottle is shaken gently.
It is well known in the pharmaceutical art that the solubility, stability, flowability, fractability, and compressibility of the compound, as well as the safety and efficacy of drug products comprising it are dependent on polymorphic forms of a compound. Many compounds can exist in different crystal forms, or polymorphs, which exhibit different physical, chemical, and spectroscopic properties. For example, certain polymorphs of a compound may be more readily soluble in particular solvents, may flow more readily, or may compress more easily than others. In the case of drugs, certain solid forms may be more bioavailable than others, while others may be more stable under certain manufacturing, storage, and biological conditions. This is particularly important from a regulatory standpoint, since drugs are approved by agencies such as the U.S. Food and Drug Administration only if they meet exacting purity and characterization standards. Indeed, the regulatory approval of one polymorph of a compound, which exhibits certain solubility and physico-chemical (including spectroscopic) properties, typically does not imply the ready approval of other polymorphs of that same compound. Therefore, the discovery of new polymoiphs of a drug can provide a variety of advantages. New polymorphic forms of treosulfan can further the development of formulations for the
treatment of these chronic illnesses, and may yield numerous formulation, manufacturing and therapeutic benefits.
SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical composition comprising treosulfan and a pharmaceutically acceptable excipient or carrier. Typically, the pharmaceutically composition of the present invention is a lyophilized powder.
In another embodiment, the present invention relates to a process for prepration of lyophilized pharmaceutical compositions of treosulfan.
The present invention also relates to novel crystalline polymorphs of (2S,3S)-2,3-Dihydroxy- 4-methylsulfonyloxybutyl] methanesulfonate (treosulfan). The present invention also provides methods for preparing pharmaceutical compositions comprising same, and methods of use as anticancer agents.
In one embodiment, the present invention provides a novel crystalline polymorphic form of treosulfan, designated as "Form I". Form I exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 1, having characteristic peaks (expressed in °2Θ (± 0.2 °2Θ) at one or more of the following positions: 7.72, 15.48, 19.81, 22.1 1, 23.01, 23.28, 29.02 and 40.60. Form I also exhibits a Differential Scanning Calorimetry (DSC) thermogram, which is characterized by a predominant endotherm peak at about 104.58 °C as measured by Differential Scanning Calorimeter at a scan rate of 10 °C per minute. In another embodiment, the present invention provides a novel crystalline polymorphic form of treosulfan, designated as "Form Π". Form II exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 2, having characteristic peaks (expressed in °2Θ (± 0.2 °2Θ) at one or more of the following positions: 7.79, 15.54 and 23.36. Form I also exhibits a Differential Scanning Calorimetry (DSC) thermogram, which is characterized by a predominant endotherm peak at about 105.1 °C as measured by Differential Scanning Calorimeter at a scan rate of 10 °C per minute.
BRIEF DESCRIPTION OF THE FIGURES:
FIG. 1 shows XRPD patterns of the Form - 1 of the treosulfan.
FIG. 2 shows XRPD patterns of the Form - II of the treosulfan. DETAIL DESCRIPTION OF THE INVENTION
In the preferred embodiment, the present invention is directed towards the pharmaceutical composition of treosulfan. Treosulfan, the therapeutically active component of this invention, is a well known and widely used anticancer agent and is a dihydroxy derivative of the alkylating agent busulfan. Treosulfan was thoroughly tested with those excipients compatible with parenteral administration to determine if a suitable lyophilizate cake could be formed by freeze-drying. Following the lyophilization process, the resulting cake was evaluated visually on its physical appearance using as desired criteria: original shape, no shrinkage or melt-back, good coloration, homogeneity, firmness, and crystallinity. The dissolution rate was then tested. It was unexpectedly found that a lyophilized formulation of treosulfan exhibits all the desired characteristics of a lyophilized formulation and thus lyophilization process helps in achieving an improved solid pharmaceutical composition of treosulfan.
Thus, one aspect of the present invention pertains to pharmaceutical compositions which are suitable for administration to a subject, as well as pharmaceutical compositions (e.g., lyophilates/lyophilisates, concentrates, etc.) from which such formulations may be prepared.
In one embodiment, the administration is parenteral administration.
In another embodiment, the administration is administration by injection, including, for example, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal injection. In one embodiment, the administration is intravenous administration. In one embodiment, the administration is administration by intravenous injection. In one embodiment, the administration is administration by infusion. In one embodiment, the administration is administration by intravenous infusion.
Thus, the present pharmaceutical composition comprises treosulfan and a pharmaceutically acceptable excipient or carrier. t
As used herein, the term " pharmaceutical composition " describes a material that is in a form (e.g., a liquid) that is ready for administration, as well as describes a material (e.g., lyophilate/lyophilisate, concentrate, etc.) from which a formulation may be prepared (e.g., by re-hydration, dilution, etc.) ,
The pharmaceutically acceptable excipient or carrier is selected from water-for-injectipn, aqueous saline solution, aqueous glucose solution, saline for injection/infusion, glucose for injection/infusion, Ringer's solution, or lactated Ringer's solution. The terms "lyophilization," "lyophilized," and "freeze-dried" refers to a process by which the material to be dried is first frozen and then the ice or frozen solvent is removed by sublimation in a vacuum environment. The term "lyophilized powder" or "lyophilized preparation" refers to any solid material obtained by lyophilization, i.e., freeze-drying of an aqueous solution. The aqueous solution may contain a non-aqueous solvent, i.e. a solution composed of aqueous and one or more non-aqueous solvent(s). Preferably, a lyophilized preparation is one in which the solid material is obtained by freeze-drying a solution composed of water as pharmaceutically acceptable carrier.
In another aspect the present invention relates to polymorphic forms of treosulfan.
In further aspect, such polymorphs comprise stable or substantially stable polymorphs of treosulfan.
In still another aspect, the present invention provides at least polymorphic forms I and II (as designated herein) of treosulfan, each having distinguishing characteristics disclosed herein.
In yet another aspect, the present invention provides Polymorph Form I of treosulfan.
In yet further aspect, the present invention provides Polymorph Form II of treosulfan. In a further aspect, the present invention provides solid formulations containing at least polymorphic forms I and II (as designated herein) of treosulfan.
The form -I of treosulfan is prepared by a process comprising reaction of dimethyl 2,3-0- isopropylidene-L-tartrate with sodium-bis(2-methoxyethoxy) aluminum hydride to give the protected diol, 2,3-O-isopropylidene-L-threitol, which on further treatment with methanesulfonyl chloride, followed by reaction of the resultant ester, 2,3-O-isopropyliden-L- threitol 1 ,4 bismethanesulfonate with formic acid, yields Treosulfan having desired purity and with impurity levels conforming to ICH guidelines. The product is recrystallised form organic solvents or mixtures thereof. The preffered organic solvents are ethyl acetate, methyl isobutyl ketone, ethanol, n-propanol, t-butanol, isopropyl acetate, methanol, propylene glycol, acetone, acetone : Cyclohexane. Typically, the present invention provides a lyophilized formulation containing polymorphic form I of treosulfan.
The solid formulation of the present invention contains treosulfan in therapeutically effective amount which means the amounts that will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of neoplasms, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth, and/or, (4) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with cancer. Therapeutically effective amount can also mean preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment). Further, therapeutically effective amount can also be the amount that increases the life expectancy of a patient afflicted with a terminal disorder. Typical therapeutically effective dose for treosulfan ranges from about 3 g/m2 to about 8 g/m2 administered intravenously every 1-3 weeks depending on blood count and concurrent chemotherapy. Single injections of up to 8 g/m2 have also been reported as therapeutically effective and with no serious adverse effects. Intraperitoneally treosulfan is administered in doses of up to 1.5 g/m2. Typically, the pharmaceutical compositions of the present invention, therefore, contain treosulfan in the amount ranging from 500 mg to lOg. In the preferred embodiment, the solid pharmaceutical compositions of the present invention contain treosulfan in the amount ranging from lg to 5 g.
In another embodiment of the invention, the composition contains treosulfan and optionally other excipients commonly used in lyophilized formulation. As used herein, the term "excipient" means the substances used to formulate active pharmaceutical ingredients (API) into pharmaceutical formulations and does not lower or interfere with the primary therapeutic effect of the drug substance. Preferably, an excipient is therapeutically inert. Further the term excipient means the substances which improve or helps in improving the functional properties and/or stability of the lyophilized product. The term "excipient" encompasses solubilizers, stabilizers, bulking agents, buffering agents, pH adjusting agents, tonicifying agents, antimicrobial agents and collapse! temperature modifying agents. Excipients can also be those substances present in a pharmaceutical formulation as an indirect or unintended result of the manufacturing process. Preferably, excipients are approved for or considered to be safe for human and animal administration. Typical examples of the excipients used in the lyophilized formulation are summarized below.
Bulking agents are typically used to provide product elegance (i.e., satisfactory appearance) as well as sufficient cake mechanical strength to avoid product blow-out. Mannitol is by far the most commonly used bulking agent.
Buffers are required in pharmaceutical formulations to stabilize pH. A good approach is to use low concentrations of a buffer that undergoes minimal pH change during freezing. The preferred buffers are selected from group consisting of citrate and phosphates buffers. Tonicity modifiers are occasionally formulated in products for human use to make the reconstituted product isotonic (e.g., for subcutaneous or intramuscular injections). Excipients are selected from mannitol, sucrose, glycine, glycerol, and sodium chloride are good tonicity adjuster.
The pharmaceutical formulations of the present invention may also optionally include a parenterally acceptable surfactant wherein the surfactant is selected from the group comprising of polysorbate 20, polysorbate 80, a bile acid, lecithin, an ethoxylated vegetable oil, vitamin E tocopherol propylene glycol succinate, or polyoxyethylene-polyoxypropylene block copolymers.
As described herein, a lyophilized formulation of treosulfan is achieved following removal of solvents from the solution. Typically, water is used as solvent, however other organic solvents could also be used individually or in combination. The employed solvents must form stable solutions with treosulfan and must not appreciably degrade or deactivate the drug substance. Additionally, the solvent should be capable of being removed easily from an aqueous dispersion or solution of the drug product, e.g., through lyophihzation or vacuum drying.
A typical formulation and lyophihzation cycle useful in accordance with the present invention is provided below. Lyophihzation can be carried out using standard equipment as used for lyophihzation or vacuum drying. The cycle may be varied depending upon the equipment and facilities used for the fill/finish.
In accordance with a typical embodiment of the present invention, an aqueous pre- lyophilization solution or dispersion is first formulated in a pharmaceutically acceptable compounding vessel. The solution is aseptically filtered into a sterile container, filled into an appropriate sized vial, partially stoppered and loaded into the lyophilizer. Using lyophilization techniques described herein the solution is lyophilized until desirable moisture content is achieved. The resulting lyophilization powder can be readily reconstituted with Sterile Water for Injection, or other suitable carrier, to provide liquid formulations of treosulfan, suitable for administration.
The pre-lyophilization solution or dispersion normally is first formulated in a pharmaceutically acceptable container by:
1) Taking about 65% of the total volume of water to be used and adding a water soluble excipient, if any (about 0 to about 50 mg/mL) with mixing at ambient temperature, ,
2) Optionally, adding an organic solvent (0.5-99.9% v/v), to the aqueous solution with mixing,
3) adding treosulfan to the desired concentration (about 40 to about 100 mg/mL) with mixing,
4) adding water to achieve the final volume, and
5) Optionally, quench cooling the solution before loading in to lyophilizer
Although the preceding steps are shown in a certain order, it is understood that one skilled in the art can change the order of the steps and quantities based on requirement. Quantities can be added on a weight basis also.
Further, in one aspect, the present inventors have also found that by immersing the bulk solution of treosulfan in liquid nitrogen leads to formation of irregular shaped ice crystals with very large ice surface area. This large surface area increases the rate of sublimation during the primary drying and desorption during the secondary drying.
The pre-lyophilization solution or dispersion can be sterilized prior to lyophilization, sterilization is generally performed by aseptic filtration, e.g., through a 0.22 micron or less filter. Multiple sterilization filters can be used. Sterilization of the solution or dispersion can be achieved by other methods known in the art, e.g., radiation.
In this case, after sterilization, the solution or dispersion is ready for lyophilization. Generally, the filtered solution will be introduced into a sterile receiving vessel, and then transferred to any suitable container or containers in which the formulation may be effectively lyophilized. Usually the formulation is effectively and efficiently lyophilized in the containers in which the product is to be marketed, such as, without limitation, a vial, as described herein and as known in the art.
A typical procedure for use in lyophilizing the pre-lyophilization solutions or dispersions is set forth below. However, a person skilled in the art would understand that modifications to the procedure or process may be made depending on such things as, but not limited to, the pre- lyophilization solution or dispersion and lyophilization equipment.
Initially, the product is placed in a lyophilization chamber under a range of temperatures and then subjected to temperatures well below the product's freezing point, generally for several hours. Preferably, the temperature will be at or below about -45°C for at least 10 hours. After freezing is complete, the chamb r and the condenser are evacuated through vacuum pumps, the condenser surface having been previously chilled by circulating refrigerant. Additionally, evacuation of the chamber should continue until a pressure of about 10 to about 1000 microns,is obtained. In the preferred embodiment, the freezing rate impacts the quality of lyophilized product. Therefore, freezing is carried out at a rate not less than 5°C/min.
The product composition is then warmed under vacuum in the chamber and with condenser. This usually will be carried out by warming the shelves within the lyophilizer on which the product rests during the lyophilization process at a pressure ranging from about 10 to about 600 microns. The warming process will optimally take place very gradually, over the course of several hours. For example, the product temperature should initially be increased from about -55°C to about - 25°C and maintained for about 2-6 hours. To prevent powder ejection of the lyophilisate from vials, complete removal of solvent should be done during the initial drying phase. Complete drying can be confirmed by stabilization of vacuum, condenser temperature and product shelf temperature. After the initial drying, the product temperature should be increased to about 5°C and maintained for about 10-50 hours.
Once the drying cycle is completed, the pressure in the chamber can be slowly released to atmospheric pressure (or slightly below) with sterile, dry-nitrogen gas (or equivalent gas). If the product composition has been lyophilized in containers such as vials, the vials can be stoppered, removed and sealed. Several representative samples can be removed for purposes of performing various physical, chemical, and microbiological tests to analyze the quality of the product
The lyophilized formulation is typically marketed in pharmaceutical dosage form. The pharmaceutical dosage form'of the present invention, although typically in the form of a vial, may be any suitable container, such as ampoules, syringes, co-vials, which are capable of maintaining a sterile environment. Such containers can be glass or plastic, provided that the material does not interact with the treosulfan formulation. The closure is typically a stopper, most typically a sterile rubber stopper, preferably a bromobutyl rubber stopper, which affords a hermetic seal. Typically, a vial will contain a lyophilized powder including about 0.5 to about 10 g/vial, preferably about 1 to 5 g g/vial, treosulfan. The lyophilized formulations of the present invention may be reconstituted with water, preferably Sterile Water for Injection, or other sterile fluid such as co-solvents, to provide an appropriate solution of treosulfan for administration, as through parenteral injection following further dilution into an appropriate intravenous admixture container, for example, normal saline.
The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
The invention is further explained with the help of following illustrative examples, however, in no way these examples should be construed as limiting the scope of the invention.
EXAMPLES
Example - 1 : Lyophilized Formulation:
Based upon the solubility, stability, ease of reconstitution and manufacturing considerations, the following is the preferred pre-lyophilization formulation of the present invention:
Water for injection was transferred to suitable container. Treosulfan was added with continuous stirring. Remaining quantity of water for injection was then added and stirred to get clear solution. This solution was then filtered through 0.22 μ PVDF filter and filled in glass vials. The vials were stoppered with slotted rubber stopper and loaded in lyophillizer.
Example - 2: Lyophilized Formulation using quench technique:
Based upon the solubility, stability, ease of reconstitution and manufacturing considerations, the following is the preferred pre-lyophilization formulation of the present invention:
Water for injection was transferred to suitable container. Treosulfan was added with continuous stirring. Remaining quantity of water for injection was then added and stirred to get clear solution. This solution was then filtered through 0.22 μ PVDF filter and filled in glass vialsJjThe bulk solution filled vials were quench freeze before loading in to lyophilizer. The vials were half stoppered with slotted rubber stopper and loaded in lyophilizer.
Example - 3: Lyophilized Formulation at cooling rate >5°C/miri;
Based upon the solubility, stability, ease of reconstitution and manufacturing considerations, the following is the preferred pre-lyophilization formulation of the present invention:
Water for injection was transferred to suitable container. Treosulfan was added with continuous stirring. Remaining quantity of water for injection was then added and stirred to get clear solution. This solution was then filtered through 0.22 μ PVDF filter and filled in glass vialsjThe bulk solution filled and half stoppered vials were loaded in to lyophilizer and frozen at rate of not less than 5°C/min.
Example - 4: Lyophilization Cycle Development:
Numerous lyophilization cycles were performed to evaluate the critical stages of lyophilization and achieve the most efficient drying cycle. Experiments were performed to evaluate the effect of the freezing rate, primary drying temperature, time, and pressure on the product. The optimized cycle was as follows:
Example - 5: Stability of the Lyophilized Formulation
The developed formulation was evaluated under accelerated (40±2°C &75±5 % RH) and long term (30±2°C &75±5 % RH) conditions of stability testing and data are presented below:
Table: Accelerated Stability Study Data
Claims
1. A pharmaceutical composition comprising treosulfan and a pharmaceutically acceptable excipient or carrier.
2. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipient or carrier is selected from water-for-injection, aqueous saline solution, aqueous glucose solution, saline for injection/infusion, glucose for injection/infusion, Ringer's solution, or lactated Ringer's solution.
3. The pharmaceutical composition as claimed in claim 1, which is freeze dried to form a lyophilized powder.
4. The lyophilized formulation as claimed in claim 3, comprising a polymorphic form -I of treosulfan.
5. The lyophilized formulation as claimed in claim 3, comprising a polymorphic form -II of treosulfan.
6. The lyophilized formulation as claimed in claim 3, comprising a mixture of polymorphic form -I and polymorphic form -II of treosulfan.
7. A polymorphic form -I of treosulfan characterized by an X-ray powder diffraction pattern comprising characteristic peaks at approximately 7.72, 15.48, 19.81, 22.11, 23.01, 23.28, 29.02 and 40.60 expressed in °2Θ (± 0.2 °2Θ).
8. A polymorphic form -II of treosulfan characterized by an X-ray powder diffraction pattern comprising characteristic peaks at approximately 7.79, 15.54 and 23.36 expressed in °2Θ
(± 0.2 °2Θ).
9. A method of preparing a treosulfan lyophilized formulation comprising: a. dissolving treosulfan in suitable concentration in an aqueous solvent to form a pre- lyophilization solution; and b. lyophilizing the pre-lyophilization solution.
10. The method of preparing a treosulfan lyophilized formulation as claimed in claim 9, wherein the pre-lyophilized solution prepration comprises the step of:
a. Taking about 65% of the total volume of water to be used and adding a water soluble excipient, if any (about 0 to about 50 mg/mL) with mixing at ambient temperature,
b. Optionally, adding an organic solvent (0.5-99.9% v/v), to the aqueous solution with mixing,
c. adding treosulfan to the desired concentration (about 40 to about 100 mg/mL) with mixing,
d. adding water to achieve the final volume, and
e. Optionally, quench cooling the solution before loading in to lyophilizer.
11. The method of preparing a treosulfan lyophilized formulation as claimed in claim 9, wherein the concentration of treosulfan in the pre-lyophilized solution is from about 40 mg/ ml to 100 mg/ml.
12. The method of preparing a treosulfan lyophilized formulation as claimed in claim 9, wherein the pre-lyophilized solution is quench cooled before lyophilization.
13. The method of preparing a treosulfan lyophilized formulation as claimed in claim 9, wherein the lyophlization is carried out by using following parameters:
14. The method of preparing a treosulfan lyophilized formulation as claimed in claim 13, wherein freezing is carried out at a rate not less than 5°C/min.
15. A lyophilized formulation of treosulfan.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020064815A1 (en) | 2018-09-26 | 2020-04-02 | Medac Gesellschaft für klinische Spezialpräparate mbH | Crystalline form of treosulfan |
WO2020064816A1 (en) | 2018-09-26 | 2020-04-02 | Medac Gesellschaft für klinische Spezialpräparate mbH | Solution comprising treosulfan |
WO2020064819A1 (en) | 2018-09-26 | 2020-04-02 | Medac Gesellschaft für klinische Spezialpräparate mbH | Lyophilisate of treosulfan |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3155702A (en) | 1960-02-22 | 1964-11-03 | Lphivens Kemiske Fabrik Ved A | Stereoisomers and the racemate of butane-1, 2, 3, 4-tetrol-1, 4-di |
WO2003078411A1 (en) * | 2002-03-12 | 2003-09-25 | Bristol-Myers Squibb Company | C3-cyano epothilone derivatives |
WO2008135232A1 (en) * | 2007-05-02 | 2008-11-13 | Riccardo Cortese | Use and compositions of purine derivatives for the treatment of proliferative disorders |
DE102009022046A1 (en) * | 2009-05-16 | 2010-11-18 | Evoria Gmbh | Decoloured extracts of the plant Pandanus conoideus |
-
2014
- 2014-10-31 IN IN3491MU2013 patent/IN2013MU03491A/en unknown
- 2014-10-31 WO PCT/IN2014/000692 patent/WO2015107534A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3155702A (en) | 1960-02-22 | 1964-11-03 | Lphivens Kemiske Fabrik Ved A | Stereoisomers and the racemate of butane-1, 2, 3, 4-tetrol-1, 4-di |
WO2003078411A1 (en) * | 2002-03-12 | 2003-09-25 | Bristol-Myers Squibb Company | C3-cyano epothilone derivatives |
WO2008135232A1 (en) * | 2007-05-02 | 2008-11-13 | Riccardo Cortese | Use and compositions of purine derivatives for the treatment of proliferative disorders |
DE102009022046A1 (en) * | 2009-05-16 | 2010-11-18 | Evoria Gmbh | Decoloured extracts of the plant Pandanus conoideus |
Non-Patent Citations (1)
Title |
---|
PAWEL VON J ET AL: "CLINICAL PHASE II TRIAL OF TREOSULFAN IN PATIENTS WITH NON-RESECTABLE NON-SMALL-CELL LUNG CANCER", ONKOLOGIE, KARGER, FREIBURG, DE, vol. 21, no. 4, 1 January 1998 (1998-01-01), pages 316 - 319, XP001020843, ISSN: 0378-584X, DOI: 10.1159/000026853 * |
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WO2020064815A1 (en) | 2018-09-26 | 2020-04-02 | Medac Gesellschaft für klinische Spezialpräparate mbH | Crystalline form of treosulfan |
WO2020064816A1 (en) | 2018-09-26 | 2020-04-02 | Medac Gesellschaft für klinische Spezialpräparate mbH | Solution comprising treosulfan |
WO2020064819A1 (en) | 2018-09-26 | 2020-04-02 | Medac Gesellschaft für klinische Spezialpräparate mbH | Lyophilisate of treosulfan |
CN112739421A (en) * | 2018-09-26 | 2021-04-30 | 默德克学会特殊临床公司 | Crystalline forms of trooshusufen |
CN112752569A (en) * | 2018-09-26 | 2021-05-04 | 默德克学会特殊临床公司 | Freeze-dried substance of trooshusan |
JP2022509904A (en) * | 2018-09-26 | 2022-01-25 | メダック ゲゼルシャフト フィア クリニッシェ スペツィアルプレパラーテ ミット ベシュレンクタ ハフトゥンク | Freeze-dried treosulfan |
JP2022509905A (en) * | 2018-09-26 | 2022-01-25 | メダック ゲゼルシャフト フィア クリニッシェ スペツィアルプレパラーテ ミット ベシュレンクタ ハフトゥンク | Crystal form of treosulfan |
US20220031620A1 (en) * | 2018-09-26 | 2022-02-03 | Medac Gesellschaft für klinische Spezialpräparate mbH | Lyophilisate of treosulfan |
EP4257122A2 (en) | 2018-09-26 | 2023-10-11 | medac Gesellschaft für klinische Spezialpräparate mbH | Lyophilisate of treosulfan |
EP4257122A3 (en) * | 2018-09-26 | 2024-01-10 | medac Gesellschaft für klinische Spezialpräparate mbH | Lyophilisate of treosulfan |
JP7431815B2 (en) | 2018-09-26 | 2024-02-15 | メダック ゲゼルシャフト フィア クリニッシェ スペツィアルプレパラーテ ミット ベシュレンクタ ハフトゥンク | Crystalline form of treosulfan |
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