WO2011000811A2

WO2011000811A2 - Organic compounds

Info

Publication number: WO2011000811A2
Application number: PCT/EP2010/059164
Authority: WO
Inventors: Markus Ahlheim
Original assignee: Novartis Ag
Priority date: 2009-06-30
Filing date: 2010-06-29
Publication date: 2011-01-06
Also published as: WO2011000811A3; WO2011000811A4

Abstract

A pharmaceutical composition for infusion comprising (a) N-benzoyl-staurosporine, (b) an organic solvent selected from the group of ethanol, propylene glycol and polyethylene glycol having an average molecular weight of 200 to 600 g/mol, and (c) a surfactant.

Description

ORGANIC COMPOUNDS

The present invention relates to a pharmaceutical solution for infusion for the administration of the poorly soluble N-benzoyl-staurosporine, to a process for the preparation of said solution and to the use thereof in therapy.

The starting material for numerous derivatives, staurosporine, was isolated in 1977 from cultures of Streptomyces staurosporeus AWAYA, TAKAHASHI, OMURA SP. NOV. AM 2282, see S. Omura et al., J. Ant. 30, 275-281 (1977). Initially the relative configuration of the skeletal structure and later the absolute configuration was determined, see N. Fumato et al., Tetrahedron Letters 35: 8, 1251-1254 (1994).

Staurosporine and its derivatives, such as N-benzoylstaurosporine, effect a strong inhibition of protein kinase C, but they also inhibit other types of protein kinases. Staurosporine derivatives are further useful as an inhibitor of FLT3 receptors. They are therapeutically applicable for various indications, especially as tumor inhibitors, e.g. leukemias, e.g. acute myeloblasts leukemia, e.g. myeloplastic syndromes, e.g. mastocytosis, as antiinflammatory agents, as antibiotics, and in the treatment of arteriosclerosis and of various diseases of the cardiovascular system and the central nervous system. A characteristic but undesirable property of staurosporine and most derivatives thereof is their extremely low water solubility, which has hitherto rendered their use for intravenous dosage forms very difficult.

Although peroral dosage forms, such as tablets or capsules, are gaining increasing importance, intravenous dosage forms continue to be relevant in spite of certain

disadvantages. The disadvantages, which include administration only by a physician or specially authorized paramedical personnel and the special skills required of the person administering the drug, the "psychological" problems of the patient and his sensitivity to pain, and the complicated and expensive manufacture of those dosage forms, are offset by clear advantages. In the case of direct intravenous administration of a therapeutic agent, the metabolism in the gastrointestinal tract to which orally administered therapeutic agents are always subjected, can be substantially avoided. In particular, the so-called "first-pass effect" as a result of passage through the liver is minimized. Some therapeutic agents, which would be insufficiently capable of oral absorption, can only be administered by the intravenous route. Other therapeutic agents can be administered intravenously in a less efficacious dose than is required for oral administration. Generally, in the case of life- threatening diseases, such as tumor diseases, intravenous administration is preferred, as the problem of absorption through the gastrointestinal tract in conjunction with undesired metabolism is not acceptable.

A suitable intravenous dosage form has not yet been available for N-benzoyl-staurosporine

Numerous publications propose various means of converting poorly soluble therapeutic agents into a more soluble form that is suitable for intravenous formulations. Such a conversion can be carried out, for example, with the aid of so-called solubilisers, such as 1 ,2-propylene glycol or polyethylene glycol. However this general known approach cannot always successfully applied for all sparingly soluble drugs, including of N-benzoyl- staurosporine. Therefore many efforts have been undertaken to implement a route based on emulsion technology. The emulsion technology enables to provide finely dispersed systems based on lipid mixtures. In such systems, the poorly soluble therapeutic agent is encapsulated in lipid particles of a particle size of less than 1 μm and, together with the aqueous carrier liquid, forms a colloidally-dispersed or preferably finely dispersed system which is an adequate intravenous dosage form.

Even though such an emulsion suspension is acceptable for intravenous administration a solution system is nevertheless more desirable. Further emulsion systems are quite often instable so that such systems can only be stored over a longer time period under controlled conditions. Additionally many emulsion systems cannot be terminal sterilized, which is however a mandatory requirement.

It is therefore an object of the present invention to provide a suitable infusion dosage form in which N-benzoyl-staurosporine is solved and said dosage form is long time stable, can be administered without risk of precipitation and is terminal sterilisable.

The finding of the present invention is that the pharmaceutical solution of N-benzoyl- staurosporine must be based on an organic one phase system. Accordingly in a first aspect the present invention is directed to a pharmaceutical solution for infusion comprising

(a) N-benzoyl-staurosporine ,

(b) at least one organic solvent selected from the group of ethanol, propylene glycol and polyethylene glycol having an average molecular weight of 200 to 600 g/mol, and

(c) at least one surfactant,

Preferably the pharmaceutical solution is free of phospholipid and/or water.

In a second aspect the present invention is directed to pharmaceutical solution for infusion comprising

(a) N-benzoyl-staurosporine,

(c) at least one surfactant,

wherein said solution is free of phospholipid and/or water.

It has been surprisingly found out that the pharmaceutical solutions according to the first and second aspect of the present invention are long time stable and stable during terminal sterilization. Further the inventive pharmaceutical solution can be parenteral administered after dilution in a physiological solution without precipitation.

The present invention is now defined in more detail.

As stated above the invention is directed to a pharmaceutical solution, i.e. to a solution which can be used for the cure, the mitigation, the treatment, or the prevention of disease, in particular to the the cure, the mitigation, the treatment, or the prevention of tumor, inflammation, arteriosclerosis and various diseases of the cardiovascular system and the central nervous system. In particular the present pharmaceutical solution is directed to the treatment of tumor.

The term "for infusion" throughout the present invention shall preferably indicate that the pharmaceutical solution is not suitable for any possible administration but only intravenous, arterial, rectal, intramuscular or subcutaneous administration. Especially the pharmaceutical solution of the present invention shall be suitable for intravenous administration.

The term "solution" according to this invention is preferably understood as a homogeneous mixture composed of two or more substances. In such a mixture, the organic components (solvent(s)) dissolve N-benzoyl-staurosporine. Accordingly in a preferred embodiment the pharmaceutical solution according to this invention is an one phase system, or in other words a single phase system, i.e. the solution is isotropic. Thus the pharmaceutical solution according to this invention is not an emulsion or microemulsion, which are systems being heterogeneous and comprising at least two immiscible (unblendable) liquids.

A suitable parameter to determine whether a composition constitutes a solution or an emulsion is its transparency. A high transparency indicates that the solution is rather a single phase system than an emulsion. Accordingly the pharmaceutical solution according to this invention is fully transparent, checked visually.

A pharmaceutical solution according to this invention is preferably free of phospholipid and/or water, which facilitates to obtain a fully miscible solution being hard to disturb.

The solution according to the present invention shows good storage stability and sufficient stability to withstand a terminal heat treatment, e.g. terminal sterilization.

The pharmaceutical solution of the present invention is preferably based on at least one organic solvent, i.e. based on one, two or three different organic solvent(s). Preferably the pharmaceutical solution according to this invention comprises two different organic solvents. Organic solvents according to this invention are any organic solvents suitable in the pharmaceutical sector, i.e. permitted by the national pharmacopeias. Accordingly the organic solvents are preferably selected from the group consisting of ethanol, propylene glycol and polyethylene glycol having an average molecular weight of 200 to 600 g/mol. Preferred polyethylene glycols are PEG 300 and PEG 400. It is in particular preferred that the pharmaceutical composition comprises ethanol together with either PEG 300 or PEG 400. Even more preferred the amount of polyethylene glycol is higher than the amount of ethanol and/or propylene glycol. Thus it is appreciated that the weight ratio between polyethylene glycol and ethanol (or propylene glycol) is 2.0 : 1.0 to 5.0 : 1.0, more preferably 3.0 : 1.0 to 4.0 : 1.0. In a especially preferred embodiment is the weight ratio of the PEG 300 to ethanol in the pharmaceutical solution 3.1 : 1.0 to 3.5 : 1.0.

Further the pharmaceutical solution of this invention must comprise at least one surfactant, preferably one, two or three different surfactant(s). Especially preferred the pharmaceutical solution comprises only one surfactant. A surfactant according to this invention prevents the active ingredient from precipitation after dilution with physiological (aqueous) media.

Accordingly the surfactant(s) is(are) selected from the group consisting of polysorbate, polyethylene glycol ether and polyethylene glycol ester of fatty acid.

Polysorbates are oily liquids derived from poly(ethylene glycosylated sorbitan (a derivative of sorbitol) esterfied with fatty acids. Especially preferred polysorbates are polysorbate 20 (T ween 20 or polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (Tween 40 or polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (Tween 60 or

polyoxyethylene (20) sorbitan monostearate), polysorbate 80 (Tween 80 or polyoxyethylene (20) sorbitan monooleate), wherein the number 20, 40, 60 and 80 following the

polyoxyethylene part refers to the total number of oxyethylene -(CH₂CH₂O)- groups found in the molecule. The number following the polysorbate is related to the type of fatty acid associated with the polyoxyethylene sorbitan part of the molecule. Monolaurate is indicated by 20, monopalmiate is indicated by 40, monostearate by 60 and monooleate by 80.

Especially preferred are Tween 60 and Tween 80, the latter is most preferred.

Examples of polyethylene glycol ethers are "Cremophor RH" and "Cremphore EL", the latter being preferred. Cremophor EL is the registered trademark of BASF Corp. for its version of polyethoxylated castor oil. It is prepared by reacting 35 moles of ethylene oxide with each mole of castor oil. The resulting product is a mixture (CAS number 61791-12-6): the major component is the material in which the hydroxyl groups of the castor oil triglyceride have ethoxylated with ethylene oxide to form polyethylene glycol ethers. Minor components are the polyethyelene glycol esters of ricinolic acid, polyethyelene glycols and polyethyelene glycol ethers of gylcerol. Cremophor EL is a synthetic, nonionic surfactant.

Examples of polyethylene glycol esters are polyethylene glycol stearates and polyethylene glycol 15 hydroxy stearates, like "Solutol HS 15". Of the surfactants mentioned in the present invention polysorbates, like Tween 80, are especially appreciated.

N-benzoyl-staurosporine is the chemical name of Λ/-[(9S,10/?,1 1 /?,13/?)-2,3,10,1 1 ,12,13- hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1 /-/,9/-/-diindolo[1 ,2,3-gh:3',2',1 '- lm]pyrrolo[3,4-j][1 ,7]benzodiazonin-1 1-yl]-Λ/-methylbenzamide (PKC412) of the formula (I):

or a salt thereof.

N-benzoyl-staurosporine is described in U.S. Pat. No. 5,093,330.

The components of the present pharmaceutical solution are preferably chosen and mixed in a ratio that a stable pharmaceutical solution is obtained, which can be for instance sterilized without any precipitation phenomena.

Therefore the following amounts of components within the pharmaceutical solution are appreciated.

First the amount of the pharmacological substance N-benzoyl-staurosporine shall be rather high. It contains at least 0.80 wt.-%, more preferably of at least 0.90 wt.-%, yet more preferably of at least 0.93 wt.-%, of N-benzoyl-staurosporine. Thus preferably N-benzoyl- staurosporine is present in the pharmaceutical solution from 0.85 wt.-% to 1.05 wt.-%, more preferably from 0.90 to 1.0 wt.-%.

Thus the pharmaceutical solution according to this invention is preferably a concentrate, which can be easily diluted to the desired concentration with any known physiological solutions before administration without precipitation. Suitable physiological solutions according to this invention are a 5 wt.-% glucose solution and/or a saline solution.

Assumed, that organic concentrates for solution for infusion have to be diluted with physiological solutions in a weight ratio of at least 1 :10 as known in the art, thus the pharmaceutical solution for infusion according to the present invention contains preferably 0.1 wt.-%, of N-benzoyl-staurosporine or below.

Therefore it is appreciated that the pharmaceutical solution according this invention comprises

(a) 0.80 wt.-% to 1.2 wt.-%, more preferably 0.90 to 1.1 wt.-%, yet more preferably 0.88 to 0.98 wt. -% of N-benzoyl-staurosporine,

(b) 50.00 to 70.00 wt.-%, more preferably 60.00 to 70.00 wt.-%, yet more preferably 62.00 to 66.00 wt.-%, of organic solvent(s) selected from the group of ethanol, propylene glycol and polyethylene glycol having an average molecular weight of 200 to 600 g/mol, and

(c) 25 to 40. wt.-%, more preferably 30.0 to 40 wt.-%, yet more preferably 33. to 37 wt- %, of surfactant(s),

based on the total pharmaceutical composition, more preferably based on the amount of N- benzoyl-staurosporine, the organic solvent(s) and the surfactant(s) together.

Further it is appreciated that the pharmaceutical solution according to this invention is sterilized.

Additionally the pharmaceutical solution is preferably obtained by the process as defined in detail below.

The pharmaceutical solution according to this invention is stored in closed containers such as vials or ampoules containing e.g. about 50 mg/5ml of N-benzoyl-staurosporine. Further the present invention is additionally directed to a kit comprising the pharmaceutical solution as defined herein and a physiological solution, especially a physiological solution as defined earlier above. A kit according to this invention preferably means that the pharmaceutical solution and the physiological solution are stored in different reservoirs, whereby both components, i.e. the pharmaceutical solution and the physiological solution are not in contact to each other.

Of course the present invention is also directed to the use of the pharmaceutical solution and the use of the kit for the cure, the mitigation, the treatment, or the prevention of disease, in particular the cure, the mitigation, the treatment, or the prevention of tumor, , e.g. leukemias, e.g. acute myeloblasts leukemia, e.g. myeloplastic syndromes, inflammation, arteriosclerosis and of various diseases of the cardiovascular system and the central nervous system. Accordingly the pharmaceutical solution and the kit of the present invention are for surgery and/or therapy on the human or animal body. Especially the pharmaceutical solution or the kit according to this invention is for the treatment of at least one member selected from the group consisting of tumor, inflammation, arteriosclerosis, various diseases of the cardiovascular system and the central nervous system. Especially the pharmaceutical solution or the kit according to this invention is for the treatment of tumor.

In the following the preparation of the pharmaceutical solution is described in detail.

The process for the preparation of a pharmaceutical solution according to the instant invention comprises the steps of

(a) mixing at least one organic solvent and at least one surfactant together and stirring said mixture as long as a clear solution is obtained,

(b) subsequently adding to said clear solution under stirring N-benzoyl-staurosporine,

(c) stirring the mixture of step (b) as long as a clear solution is obtained,

(d) filling up with solvent to the final concentration (final weight) obtaining thereby a one phase clear solution.

Preferably step (a) includes at least two mixing steps, namely (a1 ) mixing at least two different organic solvents and stirring said mixture as long as a clear solution is obtained,

(a2) subsequently adding to said clear solution under stirring at least one surfactant and stirring said mixture as long as a clear solution is obtained.

It is especially preferred that in step (a1 ) two or three different organic solvent(s) are mixed. However it is especially preferred that two different organic solvents are mixed and stirred as long as a clear solution is obtained. The organic solvents are those as mentioned above, preferably however the organic solvents are ethanol and polyethylene glycol having an average molecular weight of 200 to 600 g/mol. Preferred polyethylene glycols are PEG 300 and PEG 400. It is in particular preferred that in step (a1 ) ethanol and either PEG 300 or PEG 400, like ethanol and PEG 300, are mixed together. Even more preferred the amount of polyethylene glycol is higher than the amount of ethanol in step (a1 ). Thus it is appreciated that the weight ratio between polyethylene glycol and ethanol is 2.0 : 1.0 to 5.0 : 1.0, more preferably 3.0 : 1.0 to 4.0 : 1.0. In a especially preferred embodiment is the weight ratio of the PEG 300 to ethanol in the pharmaceutical solution 3.1 : 1.0 to 3.5 : 1.0.

Thereafter the clear (yellowish) solution is preferably protected by inert gassing, like with nitrogen. Thereby the solution is first evacuated to 0.75 to 0.95 bar and afterwards released with inert gas, like nitrogen. During this process step the solution is preferably stirred. Care must be taken during this step that the composition is kept in the desired range as indicated above. If needed evaporated solvent , for instance ethanol has to be added afterwards.

It follows the filtration of the solution. Accordingly after step (d), optionally after the gassing step,

(e) the solution is filtrated through a filter having a pore size of 0.40 to 0.50 μm, like of 0.41 to 0.47 μm,

(f) subsequently the solution is filtered through a filter having a pores size of 0.15 to 0.30 μm, like 0.18 to 0.25 μm.

Thereafter the solution is preferably filled in ampoules with protective gassing by the technique known in the art and closed under inert conditions. Finally the solution is preferably sterilized for 10 to 20 min at a temperature of 1 18 to 125 ⁰C.

In the following the invention is described by way of examples.

E X A M P L E S EXAMPLE 1

The following example is an illustrative example; also fractions or multiples can be produced thereof:

10.3 kg of PEG300, 2.4 kg of abs. Ethanol are introduced in a suitable reactor, protected from direct light and are stirred until a homogeneous solution is achieved. 7.3 kg of Tween 80 are added and stirred until a homogeneous solution is achieved. While stirring, 0.2 kg of PKC412 are added slowly and stirred for at least 45 min. until complete dissolution. The final weight of 20.9 kg is filled up with abs. ethanol. While stirring the reactor (0.8 - 0.9 bar) is evacuated and released with nitrogen afterwards. This procedure is repeated further two times. The final weight is checked and replaced with abs. ethanol in case of loss due to evacuation and nitrogen purging.

The solution is filtered through a 0.45 μm filter into a nitrogen purged vessel. The filter is tested for integrity. The solution is filled into ampoules using online filtration through a 0.2 μm filter with a automatic filling machine. The ampoules are purged with nitrogen prior and after filling and are sealed. The final filter is tested for integrity prior and after filtration. The ampoules are sterilized in an autoclave for 15 min at 121⁰C.

The pharmaceutical concentrate can be diluted with physiological media such as glucose solution 5% without precipitation in a volume ratio of 1 :10 to 1 :300 (Table 1 ). The diluted solution is ready for injection or infusion.

Table 1

EXAMPLE 2

Non isothermal stress test of Formulation PKC412/PEG300/Tween 80/Ethanol:

PKC412 1 1.78 mg/mlg

PEG300 515 mg/ml

Tween 80 365 mg/ml

Ethanol 120 mg/ml

*) data of non isothermal stress test from 25°C to 120⁰C within 8 h:

samples of the formulation are stressed in an oven for a time period of 8h while the temperature is raised in steps from 25°C to 120⁰C. Samples at the start of the stresstest (t=0) and at the end (t=8h) are analyzed and reported

*) sterilization conditions: 15 min, 121⁰C

Claims

C L A I M S

1. A pharmaceutical solution for infusion comprising

(a) N-benzoyl-staurosporine ,

(c) at least one surfactant,

2. A pharmaceutical solution according to claim 1 , wherein said solution is free of

phospholipid and/or water.

3. A pharmaceutical solution according to claim 2, wherein said solution is isotropic.

4. A pharmaceutical solution according to anyone of the preceding claims, wherein said solution is an one phase system.

5. A pharmaceutical solution according to anyone of the preceding claims, wherein said solution is a concentrate comprising at least 0.8 wt.-% of N-benzoyl-staurosporine.

6. A pharmaceutical solution according to anyone of the preceding claims, wherein the surfactant(s) is(are) selected from the group consisting of polysorbate, polyethylene glycol ether and polyethylene glycol ester of fatty acid.

7. A pharmaceutical solution according to anyone of the preceding claims, wherein said solution comprises

(a) 0.88 to 1.0 wt. -% of N-benzoyl-staurosporine ,

(b) 60.00 to 70.00 wt. -% of organic solvent(s) selected from the group of ethanol, propylene glycol and polyethylene glycol having an average molecular weight of 200 to 600 g/mol, and

(c) 30.0. to 40.0 wt.-% of surfactant(s), based on the pharmaceutical composition.

8. A pharmaceutical solution according to anyone of the preceding claims, wherein said solution comprises at least two different organic solvents.

9. A pharmaceutical solution according to claim 7, wherein said solution comprises ethanol and a polyethylene glycol having an average molecular weight of 200 to 600 g/mol.

10. A pharmaceutical solution according to anyone of the preceding claims, wherein said solution is obtainable according to a process according to anyone of the claims 1 1 to 14.

1 1. Process for the preparation of a pharmaceutical solution according to anyone of the preceding claims 1 to 9 comprising the steps of

(b) subsequently adding under stirring to said clear solution N-benzoyl- staurosporine,

(c) stirring the mixture of step (b) as long as a clear solution is obtained,

(d) filling up with solvent to the final concentration obtaining thereby a one phase clear solution.

12. Process according to claim 1 1 , wherein step (a) comprises the steps

(a1 ) mixing at least two different organic solvents and stirring said mixture as long as a clear solution is obtained,

(a2) subsequently adding under stirring to said clear solution at least one

surfactant and stirring said mixture as long as a clear solution is obtained.

13. Process according to claim 1 1 or 12, wherein after step (d)

(e) the solution is filtrated through a filter having a pore size of 0.40 to 0.50 μm

(f) subsequently the solution is filtered through a filter having a pores size of 0.15 to 0.30 μm.

14. Pharmaceutical solution according to anyone of claims 1 to 9 or kit according to claim 19 for the treatment of tumor.