BHAVESH PATEL (IN)
ASHISH SEHGAL (IN)
JAYANTA KUMAR MANDAL (IN)
MUKESH BOTHRA (IN)
BHAVESH PATEL (IN)
ASHISH SEHGAL (IN)
JAYANTA KUMAR MANDAL (IN)
| WO2003099007A1 | 2003-12-04 |
| US7153840B2 | 2006-12-26 | |||
| US5081110A | 1992-01-14 |
Claims:
1) A stable ready-to-use injectable composition of fludarabine phosphate comprising a solution of fludarabine phosphate in water, wherein the pH of the composition is adjusted between 5.5 and 7.1 without the addition of a base.
2) The composition according to claim 1 , which comprises pharmaceutically acceptable buffer and optionally contain tonicity agents.
3) A stable ready-to-use injectable composition of fludarabine phosphate comprising of: a. fludarabine phosphate in the range of 0.5 to 50 mg/ml; b. quantity sufficient amount of pharmaceutically acceptable buffer to adjust the pH of the composition between 5.5 and 7.1; c. optionally tonicity agent in the range between 5 to 100 mg/ml; and d. quantity sufficient amount of water.
4) The composition according to claim 2 or claim 3, wherein the pharmaceutically acceptable buffer comprises of buffer selected from a group comprising of neutralized phthalate buffers, phosphate buffers, acetate buffers, Tris buffers, carbonate buffers or mixtures thereof.
5) The composition according to claim 4, wherein the preferable pharmaceutically acceptable buffer used is phosphate buffers comprising of Na 3 PO 4 , Na2HPO 4 , NaH 2 PO 4 , K 3 PO 4 , K 2 HPO 4 , and KH 2 PO 4 .
6) The composition according to claim 2 or claim 3, wherein the tonicity agent comprises of sugars selected from a group comprising of mannitol, lactose, sucrose, maltose and mixtures thereof.
7) A process for the preparation of a stable ready-to-use composition of fludarabine phosphate, wherein the pH of the composition is adjusted between 5.5 and 7.1 without the addition of a base; comprises of the following steps: a) dispersing fludarabine phosphate in water with constant stirring; b) adding pharmaceutically acceptable buffers to the dispersion obtained in step a) to adjust the pH of the dispersion between 5.5 and 7.1 ; c) constant stirring the product of step b) to obtain a solution of fludarabine phosphate; and d) making up the desired volume with water.
8) A process for the preparation of a stable ready-to-use composition of fludarabine phosphate, wherein the pH of the composition is adjusted between 5.5 and 7.1 without the addition of a base; comprises of the following steps: a) dissolving tonicity agent in water to obtain a solution; b) dispersing fludarabine phosphate in the solution obtained in step a) with constant stirring; c) adding pharmaceutically acceptable buffers to adjust the pH of the dispersion between 5.5 and 7.1; d) constant stirring of the product of step c) to obtain a solution of fludarabine phosphate; and e) making up the desired volume with water.
9) A stable ready-to-use injectable composition of fludarabine phosphate comprising a solution of fludarabine phosphate in water as herein described with foregoing description and examples. |
Field of the invention:
The invention relates to ready-to-use aqueous fludarabine phosphate composition for parenteral use and methods for the preparation of the same.
Background of the invention:
Fludarabine is chemically known as 9-beta-D-arabinofuranosyl-2-fluoroadenine. Fludarabine is commercially available as its phosphate salt; the structure of the phosphate salt of fludarabine is shown below.
Fludarabine phosphate
Fludarabine phosphate is chemically 9-beta-D- arabinofuranosyl-2-fluoroadenine-5'- phosphate. Fludarabine phosphate is a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-beta-D-arabinofuranosyladenine. Fludarabine phosphate is an antineoplastic agent belonging to a class of synthetic purine nucleosides. Fludarabine phosphate has arabinose as sugar moiety whereas physiologic nucleosides (adenosine and deoxy-adenosine) have ribose and deoxy-ribose as sugar moiety respectively.
Commercially available fludarabine phosphate powder for injection is a white, lyophilized solid cake containing fludarabine (50 mg/vial) and mannitol (50 mg/vial). This commercially available product is lyophilized and needs to be reconstituted before use. Following reconstitution of the drug with sterile water for injection to a concentration of 25 mg/ml, the solution has pH of approximately 7.7 (range 7.2 - 8.2). After reconstitution, the product is usually combined with 100 ml of a pharmaceutically
acceptable intravenous solution, such as aqueous 0.9 -percent Sodium chloride or 5 percent dextrose.
Fludarabine phosphate compositions are prone to degradation at higher temperatures than the ambient temperatures. During transport or storage of fludarabine phosphate compositions, exposure to higher temperatures than the ambient temperature, cause the conversion of fludarabine phosphate to fludarabine phosphate, 2-hydroxy analogue (FA-
2HA).
Another commercially available ready-to-use Fludarabine phosphate intravenous composition (marketed by Sicor) contains Fludarabine phosphate, mannitol, water and sodium hydroxide to adjust the pH to 6.8. The final pH of the product is in the range of 6.0 to 7.1.
Ready-to-use aqueous fludarabine phosphate composition for parenteral administration is desirable as compared to the lyophilized fludarabine phosphate composition, which needs to be reconstituted before use. Drawback of ready-to-use aqueous fludarabine phosphate composition for parenteral administration is the stability of the composition. Ready-to- use aqueous fludarabine phosphate composition for parenteral administration needs to be stored and transported at refrigerated temperatures (2° C to 8° C). However, during storage and transport of ready-to-use composition of fludarabine phosphate, chances of exposure to elevated temperatures at or above ambient temperature, cannot be undermined. Unacceptable levels of degradation products may be obtained in the ready- to-use aqueous fludarabine phosphate composition upon exposure to elevated temperatures at or above ambient temperatures.
According to US patent US7153840, stability of a ready-to-use aqueous fludarabine phosphate composition at elevated, temperature is dependent on the pH of the product. Stable injectable aqueous fludarabine phosphate at elevated temperatures can be attained by controlling the pH range of the product. US7153840 further mentions about a ready- to-use aqueous fludarabine phosphate composition comprising fludarabine phosphate, a
base and water and maintaining pH of the composition in between 5.5 to 7.1. Another independent claim mentions about a ready-to-use aqueous fludarabine phosphate composition comprising fludarabine phosphate, a base, a buffer and water and maintaining the pH of the composition in between 5.5 to 7.1. US7153840 mentions the advantage for the use of a base for controlling the pH of a ready-to-use aqueous fludarabine phosphate composition, wherein storage of the composition for 1 month at 40° C results in a fludarabine phosphate impurity concentration of not more than about 0.34 percent and/or storage of the composition for 7 months at 27.5° C results in a fludarabine phosphate impurity of less than 0.94 percent. Preferred bases ^ mentioned in US7153840 are NaOH, KOH, and NH40H, moreover pharmaceutically acceptable buffers can be optionally used in the aqueous fludarabine phosphate composition.
According to another US patent US5081110, fludarabine is poorly water soluble, whereas fludarabine phosphate (mono-phosphorylated metabolite of fludarabine) is water soluble. Hence, commercially available parenteral fludarabine products contain fludarabine phosphate as a source for fludarabine.
According to the ongoing studies, dissolving fludarabine phosphate in quantity sufficient water for injection yields a pH in between 2.0 to 3.0. According to the US7153840, fludarabine phosphate formulation shows enhanced stability at elevated temperatures by maintaining the pH of the product in between 5.5 to 7.1. In order to maintain the pH of the product, US7153840 teaches to adjust the pH of the product in between 5.5 to 7.1 using a base.
The present invention discloses a stable injectable ready-to-use aqueous fludarabine phosphate composition at elevated temperatures by maintaining the pH of the composition in between 5.5 to 7.1 by eliminating the use of a base in the composition.
Object of the invention
An object of the invention is to provide a stable injectable ready-to-use aqueous fludarabine phosphate composition at elevated temperatures by adjusting the pH of the
composition between 5.5 and 7.1 without the use of base in the aqueous fludarabine phosphate composition.
Another object of the invention is to provide a method for preparing a stable injectable ready-to-use aqueous fludarabine phosphate composition at elevated temperatures by adjusting the pH of the composition between 5.5 and 7.1 without the use of a base in the aqueous fludarabine phosphate composition.
Summary of the invention:
The present inventors have discovered that it is possible to prepare a stable injectable ready-to-use aqueous fludarabine phosphate composition which remains stable upon transient exposure to elevated temperatures by controlling the pH of the fludarabine phosphate composition without the use of a base in the composition.
The present invention of a stable injectable ready-to-use aqueous fludarabine phosphate composition at higher temperatures than the ambient temperature comprises of fludarabine phosphate, pharmaceutically acceptable buffer and water for injection; wherein the final pH of the product is in the range of 5.5 and 7.1. The pH of the product is adjusted using buffer which would avoid the use of base in the composition.
In another embodiment, a method is disclosed for preparing a stable injectable ready-to- use aqueous fludarabine phosphate composition according to the present invention.
The method of preparing the composition of the present invention comprises the steps of preparing an aqueous solution of fludarabine phosphate in water for injection and adding the pharmaceutically acceptable buffer until pH is adjusted between 5.5 and 7.1.
Detailed description of the invention:
The present invention is based on the discovery that an injectable ready-to-use aqueous fludarabine phosphate composition which is stable at higher temperatures than the ambient temperatures can be achieved by adjusting the pH of the composition between
5.5 and 7.1 using pharmaceutically acceptable buffer. According to the available prior- art, a base with or without a buffer is used in the ready-to-use aqueous fludarabine phosphate composition to adjust the pH of the composition between 5.5 and 7.1. Control of pH of the fludarabine phosphate composition is necessary for enhanced stability of the composition at higher temperature than the ambient temperature.
The present invention is directed to a stable injectable ready-to-use aqueous composition of fludarabine phosphate, which comprises of fludarabine phosphate, pharmaceutically acceptable buffer and water; and has a pH in the range of 5.5 to 7.1 ; wherein, only the buffer is used for adjusting the pH of the present invention.
As used herein in the present disclosure, the term "elevated temperatures" refers to temperatures at or above ambient temperatures.
The term "ambient temperature" refers to temperatures ranging from about 22° C to about 28° C.
According to the present invention, the concentration of fludarabine phosphate in the composition may be between 0.5 mg/mL and 50 mg/mL. The concentration of buffer used in the present invention is that amount necessary to provide a solution having a pH within the desired range as per the present invention. The pH of the composition is between about 5.5 and 7.1.
In the present invention, the concentration of fludarabine phosphate in the present composition is in the range of 0.5 mg/ml to 50 mg/ml. Preferably, the concentration of fludarabine phosphate, according to the present invention may be between 20 mg/ml and 30 mg/ml. More preferably, the concentration of fludarabine phosphate, according to the present invention is between 24 mg/ml and 26 mg/ml. Most preferably, concentration of fludarabine phosphate is about 25 mg/ml for the present invention.
According to the present invention, ready-to-use aqueous fludarabine phosphate composition is to be used for parenteral administration. Preferably, ready-to-use aqueous fludarabine phosphate composition according to the present invention is used for intravenous (i.v.) administration.
According to the present invention, ready-to-use aqueous fludarabine phosphate composition is used for the treatment of neoplastic diseases including chronic lymphocytic leukemia. The aqueous fludarabine phosphate composition of the present invention may also be useful for treating acute myeloid leukemia and acute lymphocytic leukemia. Also, these compositions may be used to treat prolymphocytoid chronic lymphocytic leukemia.
The compositions of this invention may also comprise of other pharmaceutically acceptable excipients. Other pharmaceutically accepted excipients which can be used in the present invention can include tonicity agents. Examples of tonicity agents that may be used in the composition of this present invention include sugars, such as, for example, mannitol, lactose, sucrose, maltose and mixtures there-off. These sugars may be present in an amount ranging from about 5 mg/ml to 100 mg/ml. Preferably, the concentration of sugars that may be included in the concentration of the present invention as tonicity agents is about 25 mg/ml.
Pharmaceutically acceptable buffer which may be used in the compositions of the present invention include neutralized phthalate buffer, phosphate buffer, acetate buffer, Tris buffer or Carbonate buffer. Preferable pharmaceutically acceptable phosphate buffer includes Na 3 PO 4 , Na 2 HPO 4 , NaH 2 PO 4 , K 3 PO 4 , K 2 HPO 4 , and KH 2 PO 4 . Most preferable buffer is Na 2 HPO 4 . 2H 2 O.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires
otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
Example
The present invention has been described by way of example only, and it is to be recognized that modifications thereto falling within the scope and spirit of the appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention. The above said invention can be illustrated by but not limited to following example(s):
Composition: Example 1
An aqueous solution containing fludarabine phosphate concentration of 25 mg/ml
Ingredients Quantity
Fludarabine phosphate 25 mg
Disodium phosphate dihydrate q.s.
Water for injection q.s
Method for the preparation of aqueous solution containing fludarabine phosphate of the concentration of 25 mg/ml comprises the steps of:
Dispersing fludarabine phosphate in sufficient quantity of water for injection and adjusting the pH of the composition between 5.5 and 7.1 using quantity sufficient pharmaceutically acceptable buffer where by fludarabine phosphate is completely dissolved. Further, sufficient quantity of water for injection was added to make the required volume of the composition.
Composition: Example 2
An aqueous solution containing fludarabine phosphate concentration of 25 mg/ml
Ingredients Quantity
Fludarabine phosphate 25 mg
Mannitol 25 mg
Disodium phosphate dihydrate q.s.
Water for injection q.s
Method for the preparation of aqueous solution containing fludarabine phosphate concentration of 25 mg/ml comprises the steps of:
Dissolve mannitol in water for injection with constant stirring. To the obtained solution, disperse fludarabine phosphate with stirring. The pH of the resultant solution was adjusted between 5.5 and 7.1 using quantity sufficient buffer where by fludarabine phosphate is completely dissolved. Required quantity of water for injection was added to the obtained solution to make up the desired volume.
From the stability studies carried out for ready-to-use fludarabine phosphate injectable composition prepared according to example 2, it is observed the fludarabine phosphate composition is stable at storage conditions of temperature 25° ± 2 0 C (Relative humidity of 60 % ± 5 %) and temperature 2 - 8 0 C.
Stability data (Example 2):
NMT - Not more than
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