HK1036012B - Stable mitoxantron solutions - Google Patents

Description

Stable mitoxantrone solutions

Technical Field

The invention relates to mitoxantrone solutions which contain, in addition to the active compound mitoxantrone (1, 4-dihydroxy-5, 8-bis [ [2- [ (2-hydroxyethyl) amino ] ethyl ] amino ] anthraquinone hydrochloride), a stabilizer and do not contain sulfite compounds, and to the use of these solutions as injection solutions and as infusion concentrates.

Prior Art

The compound mitoxantrone is an anthraquinone derivative with the chemical name 1, 4-dihydroxy-5, 8-bis [ [2- [ (2-hydroxyethyl) amino ] ethyl ] amino ] anthraquinone hydrochloride and has the following structural formula:

experimental formula (II): c₂₂H₂₈N₄O₆·2HCl

Mitoxantrone has anti-tumor, anti-viral, anti-protozoal, and immunomodulatory properties. The compound is a strong cytostatic agent, and can be used for treating breast cancer, malignant lymphoma, acute leukemia, primary hepatocellular carcinoma and ovarian cancer.

As a pharmaceutical formulation, an aqueous solution of mitoxantrone was approved for use. However, mitoxantrone has limited stability in aqueous solutions. It is known that mitoxantrone is susceptible to oxidative decomposition if no measures are taken to reduce or, preferably, prevent its degradation. In particular, metal ions accelerate mitoxantrone degradation even at very low concentrations.

It has been shown that the oxidative decomposition of mitoxantrone can be counteracted by the use of an antioxidant.

EP-B-0236822 describes a formulation in which the formulation is stabilised by the addition of the antioxidant sodium metabisulphite, which has a fixed pH, and the chelating agents disodium edetate and glycine.

Although the formulation is stable, the formulation is unsatisfactory in view of side effects of the additives. The disadvantage of this formulation is the use of sodium metabisulphite, which is usually a very effective stabiliser.

The mitoxantrone-containing solution to which the sulfite is added is claimed to be a commercially available product. It has been reported that when a preparation containing sulfite at a conventional concentration is used, allergic reactions occur in the human body, and serious side effects are also produced in some cases. For asthma with sulphite sensitivity, for example, life threatening complications have been mentioned.

Furthermore, the use of a metal ion binding combination of at least two chelating agents supplements the formulation with other components.

A strongly acidic pH range below 3 also has an adverse effect on the tolerability and stability in use (WANG, Da-Peng; LIANG, Gow-Zaw; TU, Yu-Hsing; the stability of mitoxantrone hydrochloride in solution, Drug Development and Industrial Pharmacy, 20(11), 1895-1903 (1994)).

It is an object of the present invention to avoid these side effects and to provide aqueous formulations which are free of sulphite compounds and which remain stable for a considerable period of time under normal storage conditions and at elevated temperatures of 30 ℃.

Description of the invention

In contrast to the cited patent EP-B-0236822, we have surprisingly found that sodium edetate alone is in fact sufficient to stabilize mitoxantrone in aqueous solution.

According to the present invention, the object of the present invention is achieved by providing an aqueous preparation consisting of mitoxantrone hydrochloride in a solution of 1 to 5mg/ml, sodium edetate 0.001 to 0.15%, sodium chloride, sodium acetate and acetic acid. The pH achieved by the formulation of the invention is 3.0-4.5.

The amount of sodium edetate is preferably 0.04%.

The pharmaceutical preparation of the present invention can be used as an injection solution or an infusion concentrate for chemotherapy of the above-mentioned cancers. The pharmaceutical formulation of the present invention avoids the above-mentioned side effects and exhibits the stability required for pharmaceutical formulations.

Method for carrying out the invention

To prepare the solution of the invention, sodium chloride and sodium acetate, acetic acid and sodium edetate are added to hypoxic water and dissolved. Mitoxantrone hydrochloride was added to a portion of the solution and dissolved. The active compound solution is added to the solution with the adjuvants and adjusted to the final volume with hypoxic water.

The solution thus obtained was filtered and then filled into injection bottles, sealed and crimped-on caps.

For sterilization, a conventional antibacterial filter, for example, a membrane filter having a pore size of 0.2 μm, is used. The containers used are sterilized by conventional methods prior to use. The water used must be sterile and pyrogen free and comply with the requirements of the european pharmacopoeia 1997. The injection container is conveniently made of type I glass according to the requirements of the european pharmacopoeia 1997.

The amount of solution in each container is 2.5ml to 50ml per container, preferably 5ml to 15ml per container. The amount of mitoxantrone in each container is 5 to 100mg, preferably 10 to 30 mg.

When assembling the injection solution under sterile conditions, the injection bottle is suitably rinsed to remove oxygen, sealed with an injection stopper and crimped over.

The following examples are intended to illustrate the invention in more detail.

Example 1

An injection bottle containing 5ml of a 0.2% mitoxantrone injection.

Composition comprising a metal oxide and a metal oxide

1ml of injection contains:

mitoxantrone hydrochloride 2.328mg

Sodium chloride 8.000mg

Sodium acetate 3H₂O 0.085mg

Disodium edetate 0.040mg

7.680 μ l of 1N acetic acid

Water for injection to 1ml

Preparing the solution

To prepare the injection, sodium chloride, sodium acetate, acetic acid and disodium edetate are added to water and dissolved. The oxygen content of the water is reduced in advance in a suitable manner. The solution was partitioned and mitoxantrone hydrochloride was dissolved in a portion of the solution. The solution containing mitoxantrone was mixed with the remaining solution and adjusted to the final volume with low oxygen water.

The resulting solution was then sterilized by filtration through a membrane filter.

Example 2

An injection bottle containing 12.5ml of a 0.2% mitoxantrone injection.

The composition and preparation of this mitoxantrone solution was identical to example 1.

Stability test results

Preparation	Storage temperature	The total amount of impurities%
							℃	Initial value	After 6 months	After 18 months	After 24 months
Example 2	25	0.60	0.75	0.72	1.39
						The procedure of example 2 was repeated except that sodium ethylenediaminetetraacetate was not contained	25	0.52	0.57	1.73	2.3
Example 2	30	0.60	0.82	1.78	2.00
						The procedure of example 2 was repeated except that sodium ethylenediaminetetraacetate was not contained	30	0.52	0.93	2.74	4.16
Example 2	40	0.60	1.45	-	-
						The procedure of example 2 was repeated except that sodium ethylenediaminetetraacetate was not contained	40	0.52	2.72	-	-

Claims (7)

1. A stabilized mitoxantrone solution comprising 1 to 5mg/ml mitoxantrone hydrochloride in solution, 0.001 to 0.15% sodium edetate and, as further components, sodium chloride, sodium acetate and acetic acid, wherein said solution is free of sulfite compounds as stabilizers.

2. The stable mitoxantrone injection of claim 1 characterized in that the sodium edetate is present in an amount of 0.004 wt%.

3. A process for the preparation of a stable mitoxantrone solution according to claim 1 or 2, characterized in that sodium chloride, sodium acetate, acetic acid and sodium edetate are dissolved in hypoxic water, mitoxantrone hydrochloride is placed in a part of the solution, the solutions are combined and adjusted to a final volume containing 1-5mg mitoxantrone hydrochloride per ml solution and 0.001-0.15% sodium edetate per ml solution.

4. A method according to claim 3, characterized in that 0.004 wt% sodium edetate is added.

5. Use of the stable mitoxantrone solution of claim 1 in the preparation of a medicament for the treatment of cancer.

6. A medicament for the treatment of cancer, characterized in that it contains 1-5mg mitoxantrone hydrochloride per ml solution, 0.001-0.15% sodium edetate, and as further components sodium chloride, sodium acetate and acetic acid, wherein the percentages are based on the mitoxantrone hydrochloride solution, wherein the solution does not contain a sulphite compound as a stabilizer.

7. Medicament according to claim 6, characterized in that it contains 0.004% by weight of sodium edetate.