MXPA00008124A - Pharmaceutical formulation of a didemnin compound - Google Patents

Abstract

A stable pharmaceutical composition of a didemnin compound, comprises firstly a lyophilised didemnin preparation including water-soluble material and secondly a reconstitution solution of mixed solvents.

Description

PHARMACEUTICAL FORMULATION OF A COMPOUND OF DI DEMNI NA The present invention relates to a pharmaceutical formulation, and more particularly, a pharmaceutical formulation of a didemmna compound THE BACKGROUND U.S. Patent 5,294,603 to Rmehart, claims a pharmaceutical composition comprising a didemnin, in combination with a pharmaceutically acceptable carrier, diluent or excipient. In that patent, extensive results are provided for biological activity tests, notably results of assays for cytotoxicity and activity. antiviral THE PROBLEM In practice, there are some difficulties in preparing pharmaceutical compositions of didemnin compounds suitable for administration to patients, and especially there is a need for a stable parenteral pharmaceutical dosage form. More specifically, didemmna compounds, such as, dehydrodidemnin B, also known as aplidine, require mixing with bulk agents, such as, mamthol, for a stable, optimal preparation of pharmaceutical dosage forms, in particular, lyophilized preparations.

For this purpose, certain bulking agents, such as mannitol, require water for solubilization, while other medicaments such as aplidma are poorly soluble in water. However, the delivery of medicament to patients requires the resuspension of the lyophilized materials before use THE INVENTION The present invention solves the problem for providing a pharmaceutical composition of a didemnin compound, comprising first a lyophilized didemnin preparation, including water-soluble materials, and secondly, a reconstitution solution of mixed solvents. The mixed solvents comprise a aqueous solvent, the water being used to dissolve the water-soluble material and the other solvent serves to dissolve the didemnin compound PREFERRED MODALITIES The pharmaceutical formulation of this invention is usually a stable parental pharmaceutical dosage form, suitable for reconstitution, for administration to patients as an anti-tumor treatment. The invention solves the problem for drugs, such as, aplidine, which should be presented as freeze-dried mixtures of two or more substances soluble in incompatible solvents Preferably, provides, packaged separately or otherwise contained, a mixture of pre-mixed three component solvents, surfactant / alkanol / water In order to allow proper resuspension of such pharmaceutical dosage forms, the separately packed solvent mixture is provided to be added to the dry-prepared preparations containing the medicament and water-soluble substances, such as mannitol, before administration for treatment of the disease. Preferred didemnins for the pharmaceutical compositions of this invention include didemnins and didemnin derivatives, such as, dehydrodidemnins, nordidemnins, didemnane congeners and didemnin analogs. The present invention is particularly directed to didammins with limited water solubility, including, for example, dehydrodidemnin B, also known as aplidine The antidumor agent aplidine (dehydrodidemmna B) is a cyclic depsipeptide that occurs naturally, isolated from the Mediterranean runleaf Aplidium albicans. Aplidine has been characterized using several chromatographic and spectrometry techniques. The solubility tests showed that aplidine exhibits poor aqueous solubility. , the long-term stability of aplidine in solution is currently unknown. The lyophilized didemnin preparation is preferably prepared by freezing a mixture of didemmna / alkanol / water, especially using t-butanol such as alkanol. The alkaline mixture / water contains, suitably, 25 to 60% v / v alkanol. A bulk agent, such as mannitol, may also be included, although other water soluble additives may be included. conventional, known to be useful in the preparation of such lyophilized dosage forms The reconstitution solution preferably comprises a mixture of surfactant / alkanol / water, especially using a non-ionic surfactant and ethanol, such as alkanol. The surfactant is suitably 1 0 a % v / v of the mixture, the alkanol is suitably 1 0 to 25% v / v of the mixture, and the water is suitably 50 to 80% v / v of the mixture EXAMPLES Freeze drying was performed from a solution of aplidine of 10 mg / ml in 40% v / v of t-butanol in water for injection ("WFI"), containing 25 mg / ml of mamtol as the agent of volume Differential scanning calorimetry studies were conducted to determine the parameters of the freeze-drying cycle. The prototype, containing 1.0 mg of aplidine and 25 mg of mamtol per bottle, was found to be the optimal formulation in terms of solubility, length of the freeze-drying cycle and dosage requirements It was found that a solution composed of 1 5/1 5/70% (v / v / v) of Cremophor EL / absolute ethanol / WFI was the optimal reconstitution solution, being Cremophor EL a glycerol-polyethylene glycol pcinoleate available from BASF in Germany Dilutions of reconstituted product with normal saline of up to 1 200 showed to be stable for at least 24 hours after the preparation. of the formulation dried by freezing showed that the manufacturing process does not change the integrity of aplidine The shelf life data, available so far, show that the formulation is stable for at least 6 months when stored at + 4 ° C in the dark 5 of this Thus, the preferred aplidine product of this invention is a dual pack containing a vial containing aplidine 1 mg / bottle of lyophilized product, and an injection bottle containing 2 ml of 1 5/1 5/70% (v / v / v) of Cremophor EL / ethanol / water as reconstitution solution 10 The use of 15/1 5/70% (v / v / v) of Cremophor EL / ethanol / water as a reconstitution solution for a lyophilized product is unprecedented. Now, the combination of Cremophor EL / ethanol in commercially available products has been used exclusively as a solution vehicle (eg, taxol or ciclospopna) 15 The Cremophor EL / ethanol / water vehicle development provides a powerful co-solvent system /his It can be applied as a reconstitution solution in future drug formulations, and allows the addition of a water-soluble volume agent, such as, in addition, by decreasing the relative amount of Cremophor EL, a less toxic vehicle is created The process for making the lyophilized product also has a special feature Normally, the freeze-drying of a drug is carried out from a solution of medicine in water In the case of aplidine, preferably a mixture of 40% (v / v) t-butanol / water as a freeze-drying medium Although previously described (eg rhizoxin), freeze-drying a mixture of 40% t-butanol / water is not a common practice. In conclusion, the combination of lyophilization of a drug from a mixture of t- butanol / water and the subsequent reconstitution of the lyophilized product with 15/15/70% (v / v / v) of Cremophor EL / ethanol / water, is unique

Claims (1)

1. REIVI NDICATIONS 1 A pharmaceutical composition of a compound of diameter, comprising first a lyophilized didemmna preparation, including water-soluble material, and secondly, a reconstitution solution of mixed solvents 2 A composition of DNA according to claim 1, intended for reconstitution for administration to patients as an antitumor treatment 3 A composition of diameter according to claim 1 or 2, wherein the diameter is chosen from didemmnas, dehydrodidemmnas, nordidemmnas, congeners of didemnin and didemnma analogues. The composition according to claim 3, wherein the didemnin compound is aplidine. The composition according to claim 1, wherein the reconstitution solution comprises a mixture of alkanol / water. Claim 5, wherein the recon solution stitution includes a non-ionic surfactant A dimer composition according to claim 6, wherein the non-ionic surfactant is 10 to 25% v / v of the solution, the alkanol is ethanol and is 10 to 25% v / v of the solution, and the water is 50 to 80% v / v of the solution 8. A composition of diameter according to any preceding claim, which comprises a lyophilized didemnin preparation bottle including a water soluble volume agent, and a separate bottle of a non-ionic surfactant / ethanol / water premix. for preparing a pharmaceutical composition of a didemnin compound, which comprises freeze drying a mixture of didemnin / water soluble additive / alkanol / water, to provide a first lyophilized component, and separately, to provide a mixture of alkanol / water as reconstitution solution 10 10 A method according to claim 9, wherein the alkanol in the mixture is t-butanol 1 1 A method according to claim 9 or 10, wherein the amount of alkanol in the alkanol / mixture water is 25 to 60% v / v