WO2010133629A1

WO2010133629A1 - Stable pharmaceutical composition of fludarabine phosphate

Info

Publication number: WO2010133629A1
Application number: PCT/EP2010/056878
Authority: WO
Inventors: Iveta Dance
Original assignee: Grindeks, A Joint Stock Company
Priority date: 2009-05-19
Filing date: 2010-05-19
Publication date: 2010-11-25
Also published as: EP2432457A1; EA201190243A1

Abstract

Stable pharmaceutical composition containing Fludarabine phosphate as active ingredient.

Description

Stable pharmaceutical composition of Fludarabine phosphate

Technical Field

The present invention relates to a new and stable Fludarabine phosphate pharmaceutical composition.

Background Art

In order to manufacture solid pharmaceutical compositions, it is necessary to mix the active ingredient with inactive ingredients which may serve as binders, fillers, disintegrating agents, lubricants, and colorants or have other purposes. Inactive ingredients are also known as "excipients". The following general criteria are essential for excipients:

- physiological inertness;

- physical and chemical stability; - conformance to regulatory agency requirements;

- no interference with drug bioavailability;

- absence of pathogenic microbial organisms, and

All of the inactive ingredients together (i.e., the totality of ingredients other than the active ingredient) are known as the "carrier". After the active ingredient is mixed with the carrier, the mix filled into gelatin capsules or compressed in tablets. The processes of preparing the mix and filling capsules, as well tabletting are well known to those skilled in the art of pharmaceutical formulation.

One of the requirements for an acceptable pharmaceutical composition is that it must be stable, so as not to exhibit substantial decomposition of the active ingredient during the time between manufacture of the composition and use by the patient.

In reality, no single excipient would satisfy all the criteria and therefore a compromise of the different requirements has to be made. Impurities in pharmaceuticals are the unwanted chemicals that remain with the active pharmaceutical ingredients (APIs), or develop during formulation, or upon aging of both API and formulated APIs to medicines. The presence of these unwanted chemicals even in small amounts may influence the efficacy and safety of the pharmaceutical products. Impurity profiling (i.e., the identity as well as the quantity of impurity in the pharmaceuticals), is now gaining critical attention from regulatory authorities. Fludarabine (marketed as fludarabine phosphate under the trade name Fludara) is a chemotherapy drug used in the treatment of hematological malignancies. The oral bioavailability of Fludarabine has been studied in dogs by administrating as gelantin capsules to dogs described in MALSPEIS, L., et al. Oral biovailability of 2-F-ara-A from fludarabine phosphate capsules in dogs. Proc Am Assoc Cancer Res. 1989, vol.30, p.534. Nevertheless bioavailability was investigated, but no further pharmaceutical composition of capsules was disclosed. Patent EP 1455760 B (SCHERING AG) 2005.09.07, disclosed fast releasing tablet formulation, which compromises ultra pure Fludarabine phosphate as active ingredient, and lactose monohydrate, colloidal silicon dioxide, microcrystalline cellulose, crosscaramellose-Na and magnesium stearate as excipients.

Disclosure of Invention

Although pharmaceutical compositions of Fludarabine phosphate solid forms are known, there still exists a necessity for another stable Fludarabine phosphate final dosage forms. New solid formulation should enhance the stability and should be characterised with minimized formation of impurities.

It was surprisingly and unexpectedly discovered that the use of mannitol as diluent in a new Fludarabine phosphate composition reduces the formation of impurity, such as 6-amino-9-(5-O-phosphono-β-D-arabinofuranosyl)-9H-purin-2-ol, which formed during storage time. As it was stated above even small amount of impurity, such as 6-amino-9-(5-O-phosphono-β-D-arabinofuranosyl)-9H-purin-2-ol, in Fludarabine phosphate final dosage form can induce activity of Fludarabine phosphate and physical properties of final dosage forms of Fludarabine phosphate. The composition according to the present invention may be prepared in the oral formulation with the conventional pharmaceutical excipients, for example, a disintegrant, such as pregelatinised corn starch, microcrystalline cellulose, croscarmellose sodium, and sodium starch glycolate, a binder, such as colloidal silicon dioxide, a diluent, such as mannitol, a lubricant, such as magnesium stearate or stearic acid, etc. Such oral formulation includes capsule, tablet and granule.

A composition is provided in which the Fludarabine is mixed into a carrier that omits ingredients which could cause instability. The carrier of pharmaceutical composition presented by invention is pregelatinised corn starch and sodium starch glycolate as disintegrant, mannitol as diluent and stearic acid as lubricant.

Brief Description of Drawings

Figure 1 shows changes of impurity content, such as 6-amino-9-(5-O-phosphono- b-D-arabinofuranosyl)-9A/-purin-2-ol in Fludarabine 10mg capsule, containing mannitol as a dilent, Fludarabine 10mg capsule containing lactose as a diluent and Fludara oral 10mg film-coated tablet conatining lactose as diluent samples after their degradation

Best Mode for Carrying Out the Invention

The present invention will be described in detail through the following examples. The examples are presented for illustrating purposes only and should not be construed as limiting the invention. Example 1 Fludarabine phosphate (10 mg), lactose monohydrate (75 mg), colloidal silicon dioxide (0.5 mg), microcrystalline cellulose (60 mg), croscarmellose Na (3.0 mg) and magnesium stearate (1.5 mg) were mixed in a mortar. The blend was sieved through a screen and dried. The dried particles were used to prepare a granulation. The granules were filled into capsules so that each of them would contain 150 mg of the granules.

Components Contents (mg/capsule)

Fludarabine phosphate 10

Lactose monohydrate 75

Colloidal silicon dioxide 0.5

Microcrystalline cellulose 60

Croscarmellose Na 3.0

Magnesium stearate 1.5

Total 150 mg Example 2

Fludarabine phosphate (10 mg), mannitol (112 mg), stearic acid (1.5 mg), pregelantinised corn starch (16.5 mg) and sodium starch glycolate (10.0 mg) were mixed in a mortar. The blend was sieved through a screen and dried. The dried particles were used to prepare a granulation. The granules were filled into capsules so that each of them would contain 150 mg of the granules.

Components Contents (mg/capsule)

Fludarabine phosphate 10

Mannitol 112

Stearic acid 1.5

Pregelantinised corn starch 16.5

Sodium starch glycolate 10.0

Total 150 mg

Example 3 Fludarabine phosphate (10 mg), mannitol (112 mg), stearic acid (1.5 mg), pregelantinised corn starch (16.5 mg) and sodium starch glycolate (10.0 mg) were mixed in a mortar. The blend was sieved through a screen and dried. The dried particles were used to prepare a granulation. The granules were then compresses with a conventional tableting machine, thereafter were coated by conventional coating materials.

Components Contents (mg/tablet)

Fludarabine phosphate 10

Mannitol 112

Stearic acid 1.5

Pregelantinised corn starch 16.5

Sodium starch glycolate 10.0

Total 150 mg

In order to determine the effect of excipients stabilizes Fludarabine phosphate; capsules of Example 1 and Example 2 and Fludara, were degraded under the accelerated test condition, in 0.1 HCI at 80°C and analysed by HPLC for the content of 6-amino-9-(5-O-phosphono-β-D-arabinofuranosyl)-9#-purin-2-ol impurity, after 3 hours and after 6 hours.

As it was showed Figure 1 , Fludarabine 10mg capsule, containing mannitol as a diluent had pronounced effect, because amount of impurity, 6-amino-9-(5-O- phosphono-β-D-arabinofuranosyl)-9#-purin-2-ol, is significantly reduced by comparing with Fludarabine 10mg capsule containing lactose as a diluent or Fludara oral 10mg film-coated tablet conatining lactose as diluent thereby shell life of composition caintaining mannitol was increased.

Claims

1. A stable pharmaceutical composition, which comprises 1 -100 mg of active ingredient Fludarabine phosphate, mannitol, stearic acid, pregelatinised corn starch and sodium starch glycolate.

2. A stable pharmaceutical composition according to claim 1 , which comprises 1- 50 mg of active ingredient Fludarabine phosphate, 100-120 mg mannitol,

1-2 mg stearic acid,

15-17 mg pregelatinised corn starch and 8-12 mg sodium starch glycolate.

3. A stable pharmaceutical composition according to claim 1 , which comprises 10 mg of active ingredient Fludarabine phosphate,

112 mg mannitol, 1.5 mg stearic acid,

16.5 mg pregelatinised corn starch and 10 mg sodium starch glycolate.

4. A stable pharmaceutical composition according to claims 1-3 is oral dosage form.

5. A stable pharmaceutical composition according to claim 4, wherein oral dosage form is capsule.

6. A stable pharmaceutical composition according to claim 4, wherein oral dosage form is tablet.

7. The stable pharmaceutical composition according to claims 1-6 for use as a medicament.