HK1169960B - Pharmaceutical formulation - Google Patents

Description

This application concerns a pharmaceutical formulation containing as active substance the compound of formula (I): - What? or a salt of this compound with a pharmaceutically acceptable acid.

[Technical issue]

The intravenous administration of an anticancer agent is the preferred route of administration in oncology because it allows rapid diffusion of the agent into the bloodstream. This is sometimes the only form of administration when the agent does not have sufficient bioavailability when administered by another route such as the oral route.

The compound of formula (I) has a low solubility in various media (see Table I). - What?

milieu	solubilité [mg/g]
eau	<0,006
PEG 400	9,5
propylène glycol	1
éthanol	3,8
tert-butanol	1,2

It is necessary to be able to have a stable pharmaceutical formulation which is manipulable and which allows the administration of a sufficient and effective amount of the compound of formula (I) of the order of a few hundred mg. It is also necessary that the pharmaceutical formulation is chemically and physically stable, as is the solution for infusion obtained after dilution in an isotonic medium.

[State of the art]

WO 2007/003765 describes pyrido[2,3-d]pyrimidine derivatives with formula (A): - What? The following information is provided in the package leaflet:

WO 08102075 describes the use of the compound of formula (I) in the treatment of leukaemia. The compound may be administered as a solution. PEG 400 22% / SOLUTOL® HS15 5% / G5 73% for IV treatment of mice with Kasumi1 tumours, G5 being a 5% glucose solution in water; LABRASOL® 21% / SOLUTOL® HS15 5% / HCl 0.001 N 74% for oral treatment of mice with Kasumi1 or KG1 tumours; DMSO 5% / TWEEN® 80 10% / H2O 85% for intra-peritoneal treatment of mice with EOL-1 tumours.

The formulations described are therefore administered as in mice and are not intended to be diluted to form a solution for infusion.

[Brief description of the invention]

The invention relates to a pharmaceutical formulation comprising the compound of formula (I) in the basic form or as a salt of a pharmaceutically acceptable acid soluble in a mixture of ethanol and a surfactant comprising a mixture of the mono- and polyethyl diester of 12-hydroxysthearic acid described below.

The surfactant consists of 35 to 55% mono- and diester and 30 to 40% polyethylene glycol H ((OCH2CH2) n-OH. It consists of 35 to 55% mono- and diester and 30 to 40% polyethylene glycol H ((OCH2CH2) n-OH as major components by weight, as well as other compounds forming the 100% complement. It consists of 10 to 20% monoester, 25 to 35% diester and 30 to 40% polyethylene glycol H ((OCH2CH2) n-OH and other compounds forming the 100% complement by weight.

It may be the surfactant macrogol 15 hydroxysterarate in a surfactant/ethanol weight ratio of 25/75 to 80/20, preferably 73/27 to 77/23.

The surfactant/ethanol ratio ranges from 73/27 to 77/23 and the concentration in formula (I) compound ranges from 5 to 25 mg/ml.

The pharmaceutical formulation is intended to be diluted to form a solution for infusion.

The invention also relates to a process for preparing the pharmaceutical formulation comprising the following steps: The surfactant is heated to liquid; ethanol is added; the surfactant/ethanol mixture is cooled to room temperature; the compound of formula (I) is added to the cooled mixture; the final mixture is sterilised, preferably by filtration.

The invention also relates to a solution for infusion comprising the compound of formula (I) in the form of a base or as a salt of a pharmaceutically acceptable acid obtained by dilution of 1 volume of the pharmaceutical solution in 20 to 500 volumes of an isotonic solution: The compound of formula (I) in a concentration of 0.01 to 1.2 mg/ml, the surfactant in a concentration of 0.48 to 37 mg/ml and ethanol in a concentration of 0.35 to 35 mg/ml are diluted in the isotonic solution.

The invention also relates to the method of preparing the solution for infusion by dilution of 1 volume of the pharmaceutical solution in 20 to 500 volumes of the isotonic solution.

The invention also relates to a vial containing the pharmaceutical solution and an infusion bag containing the solution for infusion.

The invention also relates to the use of a surfactant as defined above for the preparation of a pharmaceutical formulation containing the compound of formula (I) in the form of a base or a salt of a pharmaceutically acceptable acid, which is intended to be diluted to form a solution for infusion.

[Details of the report]

The invention relates to a pharmaceutical formulation containing the compound of formula (I): - What? in the form of a base or a salt of a pharmaceutically acceptable acid, soluble in a mixture of ethanol and the surfactant macrogol 15 hydroxysterarate in a surfactant/ethanol weight ratio of 25/75 to 80/20, preferably 73/27 to 77/23.

The pharmaceutical formulation includes the compound of formula (I) soluble in a mixture: of ethanol and a surfactant consisting of a mixture of the polyethylated mono- and di-ester of 12-hydroxysteroic acid with the formulae: - What? n being an integer from 15 to 16, in a surfactant/ethanol weight ratio of 25/75 to 80/20, preferably 73/27 to 77/23.

The compound of formula (I): - What? is an anticancer agent for use in the treatment of leukaemias described in EP 1902054 B1. It may be in the form of a base (see formula (I)) or as a salt of a pharmaceutically acceptable acid; see on this subject, Remington's pharmaceutical sciences , 17th ed., Mack Publishing Company, Easton, PA, 1985 and Berge et al., Pharmaceutical salts J.Pharm.Sci. 1977, 66, 1-19.

The non-ionic hydrophilic surfactant used is obtained by reacting 12-hydroxysteroic acid and ethylene oxide at 110-165°C in the presence of a basic catalyst such as K2CO3 according to the instructions of Synthetic Detergents from Animal Fats. VIII. The Ethenoxylation of Fatty Acids and Alcohols A.N.Wrigley J.Am.Oil.Chem.Soc. 1957, 34, 39-43 or of J.V.Karabinos J.Am.Oil.Chem.Soc. 1954, 31, 20-23.

The surfactant contains predominantly a monoester of formula: and a diester with formula: - What?

In addition, the surfactant may also contain free polyethylene glycol (C3 ; H ((OCH2CH2) 15-16-OH) and may thus contain 30 to 40% by weight of polyethylene glycol and 60 to 70% of mono- and diester.

The surfactant may also include other compounds from the ethoxylation reaction, including those of the formulae: - What?

For example, the compositions of two surfactants are given in Table II. The surfactant therefore contains 35-55% by weight of mono- and diesters of 12-hydroxysthearic acid and 30-40% of polyethylene glycol H(OCH2CH2)n-OH, as well as other compounds that form the 100% complement. - What?

	19	12	10-20
	30	34	25-35
	35	35	30-40
	9	6	complément à 100%*
	3	6
	3	2
	1	5

* pour l'ensemble des composés C4-C6 + autres composés

The European Pharmacopoeia (PhPh 6.0) describes it as macrogol 15 hydroxystarate; it is described as a mixture of monoester and diester of 12-microxystaric acid and macrogol obtained by esthoxylation of 12-hydroxystaric acid with water. The number of moles of ethylene oxide with the equivalent of:: 30%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, and 25%, The name is macrogol. It is a free-flowing hydrophilic acid that is present in the form of a free-flowing solution at approximately 12°C (approximately 30°C).

According to one form of the invention, the pharmaceutical formulation may include at least one other additive commonly used in liquid pharmaceutical formulations, such as an antioxidant, preservative, buffer, etc. According to another form of the invention, the pharmaceutical formulation may include only the surfactant, ethanol and the compound of formula (I).

The pharmaceutical formulation can be prepared as follows: the surfactant is heated to become liquid;

The temperature at which the surfactant becomes liquid varies according to the surfactant and the proportions of mono- and diester and, where appropriate, free polyethylene glycol.

The amount added is such that the surfactant/ethanol ratio is as given above. The final mixture is sterilised. Sterilisation by filtration can be used to an advantage: see, for example, Pharmaceutical process validation , R.A.Nash, 3rd edition, Marcel Dekker Inc, isbn=0824708385, page 119 or Validation of pharmaceutical processes , J.P.Agalloco, 3rd edition, 2007, is=9780849370557, pages 151-152. Sterilisation by filtration does not degrade the formula (I) compound which is sensitive to the heat of sterilisation e.g. in the case of the formulation with a filter of 75 μm, a temperature of 0.22/225 μm can be used.

The drug formulation described above is a concentrate intended to be diluted to form a solution for infusion. It may be contained in a glass vial. The solution for infusion is prepared extemporaneously by diluting the concentrate in an isotonic solution suitable for infusion (e.g. glucose or salt). The solution for infusion is usually prepared as an infusion bag by hospital staff some time before administration.

The surfactant is used to solubilize the formula (I) compound in the formulation and to stabilize the solution for infusion (mycellation). The solubility of the formula (I) compound therefore increases with the surfactant/ethanol ratio. However, beyond the 80/20 ratio, the viscosity of the formulation increases to the point where it makes syringe sampling more difficult or impossible.

Ethanol cannot be replaced by PEG 300 or 400 because the surfactant and PEG 300/400 are not miscible at surfactant/PEG ratios of 25/75 to 50/50 or the surfactant/PEG 300/400 mixture is solid at room temperature at ratios of 60/40 to 75/25. Similarly, dilution of the formula compound (IEG) in the compound alone does not allow a solubility of more than 7 mg/L or less than 30 mg/L (HRH) in the solution. Studies have shown that the relative stability of the chemical formulation is not less than 30 mg/L (< 60/L) and less than 30 mg/L (< 80/L) in the solution, depending on the physical conditions.

The formulation according to the invention therefore offers the following advantages: It is a homogeneous solution; it allows sufficient solubility in formula (I) to be achieved to allow a patient to receive a quantity of the order of a few hundred mg; it is manipulable and allows for, inter alia, syringe sampling; the formula (I) does not degrade as much as other surfactants (see Table IV); the solution for infusion obtained from the formulation is physically stable for at least 24 h at room temperature, i.e. it has no visible precipitation criteria; the formulation can be sterilised on a filter.

The concentration of the compound of formula (I) in the pharmaceutical formulation may vary from 5 to 25 mg/ml. The solubility is in fact dependent on the surfactant/ethanol ratio. Examples of pharmaceutical formulations according to the invention are: (A) surfactant to ethanol ratio between 73/27 and 77/23, e.g. 75/25; compound of formula (I) : 5-25 mg/ml; (B) surfactant to ethanol ratio: 50/50; compound of formula (I) : 5-10 mg/ml; (C) surfactant to ethanol ratio: 25/75; compound of formula (I): 5 mg/ml

The solution for infusion consists of formula (I) compound in a concentration of 0,01 to 1,2 mg/ml, surfactant in a concentration of 0,48 to 37 mg/ml and ethanol in a concentration of 0,35 to 35 mg/ml, diluted in isotonic solution. Preferably it consists of formula (I) compound in a concentration of 0,01 to 1,2 mg/ml, surfactant in a concentration of 1,4 to 35 mg/ml and ethanol in a concentration of 0,4 to 13 mg/ml, diluted in isotonic solution.

[Figures]

Fig.1: time evolution of impurity concentration for the formulation SOLUTOL® HS15/ethanol;Fig.2: time evolution of impurity concentration for the formulation PS80/ethanol;Fig.3: time evolution of impurity concentration for the formulation PS80.

[Examples] Preparation of a formulation according to the invention

In a glass reactor, SOLUTOL® HS15 is melted at 40°C for about 3 hours, then the heating is stopped and the tank inerted. The tank temperature is lowered to 20°C, and without waiting for the tank to return to 20°C, ethanol is added to SOLUTOL® HS15 and then homogenised for 30 minutes. The compound of formula (I) (base form) is added and dissolved in the SOLUTOL® HS15/ethanol mixture and left to agitate for 3 hours at room temperature. The solution is then filtered on a PVDF filter of 0.22 μm and stored for 24 hours. The solution is then subjected to sterilizing filtration on a PVDF filter of 0.22 μm.

Other formulations

Several formulations of the compound of formula (I) are compared to determine which achieves the 20 mg/g solubility target (Table III). - What?

PEG 400	9,5	< cible
propylène glycol	1	< cible
éthanol	3,8	< cible
tert-butanol	1,2	< cible
micelles mixtes (Lécithine/Taurocholate Na 1/1) 0,1 M	0,004	< cible
albumine 4%	0,013	< cible
endolipid 20% (émulsion)	0,26	< cible
medialipid 20% (émulsion)	0,13	< cible
HydroxyPropylBetaCyclodextrine 40%	0,087	< cible
	29
	32
	27,5
	30,3
	21,2
	26,9
	30,7
	33,8
	14,4	< cible

A chemical stability study by high performance liquid chromatography (HPLC) measurement of impurity content was performed on formulations to achieve the target solubility by measuring the impurities present in the following three formulations over time: The following shall be added to the list of active substances:

The results are summarised in Table IV.

	0	0,13	0,13	0,15
	1,5	0,14	0,15	0,19
	2,5	0,26	0,29	0,25
	0	0,13	0,13	0,15
	1,5	2	2	2,3
	2,5	3,5	3,8	4,6
	0	0,13	0,13	0,15
	1,5	4	4,7	5,1
	2,5	6,7	8	9,7

The combination formulation of SOLUTOL® HS15 and ethanol is found to be the most stable of the three.

Physical and chemical stability of the dilution in the infusion bag

SOLUTOL® HS15/ethanol 75/25 concentrate (weight/ weight) is dilute extemporaneously in the infusion bag. The physical and chemical stability of the dilution in the infusion bag has been studied. The dilution: 0.04 mg/mL and 1 mg/mL the dilution medium (NaCl 0.9% or Glucose 5%) the storage temperature (5°C and 30°C) the storage time

Regardless of the test conditions, the pockets have been shown to be chemically and physically stable for at least 72 hours.

The following shall be added:

Claims (16)

1. Pharmaceutical formulation comprising the compound of the formula (I): in the form of the base or in the form of a salt of a pharmaceutically acceptable acid, solubilized in a mixture:

   • of ethanol and

   • of a surfactant comprising a mixture of the polyethoxylated mono- and diester of 12-hydroxystearic acid having the respective formulae:

   n being an integer in the range of from 15 to 16, in a surfactant/ethanol weight ratio in the range of from 25/75 to 80/20.
2. Pharmaceutical formulation according to claim 1, characterized in that the surfactant is the surfactant macrogol 15-hydroxystearate.
3. Pharmaceutical formulation according to claim 1 or 2, characterized in that the surfactant/ethanol weight ratio is in the range of from 73/27 to 77/23.
4. Formulation according to claim 2, in which the surfactant comprises from 35 to 55 % by weight of mono- and diester and from 30 to 40 % by weight of polyethylene glycol H (OCH₂CH₂) _n-OH.
5. Formulation according to claim 4, in which the surfactant comprises as the main components from 35 to 55 % by weight of mono- and diester and from 30 to 40 % by weight of polyethylene glycol H(OCH₂CH₂)_n-OH, as well as other compounds to make up to 100 %.
6. Formulation according to claim 1 or 2, in which the surfactant comprises from 10 to 20 % by weight of monoester, from 25 to 35 % by weight of diester and from 30 to 40 % by weight of polyethylene glycol H(OCH₂CH₂)_n-OH, as well as other compounds to make up to 100 %.
7. Pharmaceutical formulation according to claim 1 to 6, in which the surfactant/ethanol ratio is in the range of from 73/27 to 77/23 and the concentration of compound of the formula (I) is in the range of from 5 to 25 mg/ml.
8. Pharmaceutical formulation according to one of claims 1 to 7 intended for dilution to form a perfusion solution.
9. Process for the preparation of a pharmaceutical formulation according to any one of claims 1 to 8, comprising the following steps:

   - the surfactant is heated until it becomes liquid;

   - the ethanol is added;

   - the surfactant/ethanol mixture is cooled to ambient temperature;

   - the compound of the formula (I) is added to the cooled mixture;

   - the final mixture is sterilized.
10. Process according to claim 9, in which the mixture is sterilized by filtration.
11. Perfusion solution comprising the compound of the formula (I): in the form of the base or in the form of a salt of a pharmaceutically acceptable acid, obtained by dilution of 1 volume of the pharmaceutical solution according to claim 1 to 8 in 20 to 500 volumes of an isotonic solution.
12. Perfusion solution comprising the compound of the formula (I) : in the form of the base or in the form of a salt of a pharmaceutically acceptable acid, in a concentration in the range of from 0.01 to 1.2 mg/ml, the surfactant as defined in one of claims 1 to 7 in a concentration in the range of from 0.48 to 37 mg/ml and ethanol in a concentration in the range of from 0.35 to 35 mg/ml, diluted in an isotonic solution.
13. Perfusion solution according to claim 11 or 12 for administration to a human being.
14. Process for the preparation of a perfusion solution, consisting of dilution of 1 volume of the pharmaceutical solution according to claim 1 to 8 in 20 to 500 volumes of an isotonic solution.
15. Bottle containing the pharmaceutical solution as described in one of claims 1 to 8.
16. Drip bag containing the perfusion solution of claim 11 to 13.