CA1341114C

CA1341114C - Pharmaceutical formulations containing melphalan hydrochloride

Info

Publication number: CA1341114C
Application number: CA000583540A
Authority: CA
Inventors: Stephen William Poole; Timothy Paul Stanley; Geoffrey Divall; Terence William Packham; Joseph Knight
Original assignee: Wellcome Foundation Ltd
Current assignee: Aspen Global Inc
Priority date: 1987-11-19
Filing date: 1988-11-18
Publication date: 2000-10-10
Anticipated expiration: 2017-10-10
Also published as: HU9100335D0; FI924668A0; EP0317281A2; FI885358A0; NZ227004A; FI924668L; HUT48198A; EP0317281A3; SG73894G; FI90204C; GR3007287T3; IE63996B1; IL88419A; KR970002607B1; DE3877151D1; DE3877151T2; FI90204B; HU207286B; ES2052745T3; DK646688D0

Abstract

The present invention relates to a new two-component pharmaceutical formulation of melphalan in which the two components comprise a) freeze-dried mephalan hydrochloride and b) a solvent-diluent comprising a citrate, propylene glycol and ethanol.

Substantially pure melphalan, substantially pure melphalan hydrochloride and methods for preparing them are also described.

Description

~34111~
PHARMi~CEUTICAL FORMULATIONS
CONTAINING MELPHALAN HYDROCHLORIDE
The present invention relates to novel pharmaceutical formulations, in particular to formulations ,containing melphalan as the active ingredient.
Melphalan is a well-~astablished cytotoxic agent which is used to treat a range of neoplastic diseases, including in particular multiple myeloma and ovarian cancer.
.LO Melphalan has i~he chemical name 4-[bis(2-chloroethyl)amino]-L-phenylalanine and the structural formula:
HOOC-CHCH2 1,~ N-(CH2CH2C1)2 This compound is also known variously as L-phenylalanine mustard; L-PAM; L-sarcolysine; NSC-8806 and CB3025.
Melphalan is presently commercially available under the name Alkeran (TM. The Wellcome Foundation Limited) in the 20 form of both tablets .and injectable preparations. Alkeran injection is su.pplie~i as a three component presentation and has to be r~econsi~ituted in two stages, shortly prior to use. Thus, t:he three component system comprises a vial containing melphalan, as a powder, an ampoule containing an acid/alcohol solvent and an ampoule containing a phosphate buffer diluent, together with propylene glycol.
To reconstitute the Alkeran injection, the melphalan powder is first dissolved in the acid/alcohol solvent and when dissolution is complete the solution is then 30 neutralised and adjusted to the required concentration by addition of the diluent. This three-component system and the consequent two-step reconstitution procedure is clearly somewhat: inconvenient and it would therefore be desirable to have available an injectable formulation which is simpler to reconstitute and thus more convenient for the physician to use. A further advantage of the B

presently available injectable formulation is that in some instances the melphalan powder dissolves only slowly or does not completely dissolve.
Th.e present invention provides a novel two-component injectable melphalan preparation which overcomes the disadvantages of the currently available formulation.
In a first aspect the present invention provides an injectable formulation of melphalan comprising as two separate components a) freeze-dried mf:lphalan hydrochloride; and b) a solvent-diluc:nt comprising a citrate, propylene glyCOl, water and ethanol.
Component (a) may ~dvantageousl.y include a non-hydroxylated matrix-forming agent, such as polyvinylpyrrolidone (PVP). A suitable grade of PVP for use in the formulation according to the invention comprises PVP having a molecular weight o'f less than 25,000, for example in the range 2,000 to 2'i,000. A particularly suitable grade of PVP is that designated K12.
The amount of melphalan hydrochloride present in component (a) may vary W:thin wide limits and nay constitute for example 1 to 99% by weight of component (a). Advantageously the melphalan hydrochloride comprises 5 to 80$ by weight of component (a). When a matrix-forming agent is present the amount of matrix-forming agent may also vary within wide limits and may for example constitute between 0.1 and 99% by weight of component (a).
Poe~erably however the amount of matrix forming agent is in the range 20 to 9-'i$ by weight of component (a), In component (b), the citrate may be an alkali metal citrate, e.g.
potassium or preferably sodium citrate. The amount of propylene glycol. in component (b) is generally in the range 40 to 80% by volume. The pi.~oportion of ethanol pvresent in component (b) will generally be in the rFinge 0.1 to 10% by volume. The citrate will generally comprise from 0.05 to 5% w/v e.g. 1.5 to 2..5% w/v of the solvent-diluent.

Component (a) may be pr~=pared using freeze-drying procedures well known to those skilled in the art of pharmaceutical formulation. Thus, for example the melphalan base and t_he matrix forming agent may be dissolved in aqueous hydrochloric acid, the resulting solution sterilised by aseptic filtration, filled into sterile vials arid freeze dried. The melphalan base and hydrochloric acid may be: used in a stoichmetric (l: l) ratio, but preferably a slight excess of hydrochloric acid is used. Alternatively melphalan hydrochloride itself ma5~ advantageously be used to prepare the freeze dried component. In this case the hydrochloride may simply be dissolved in Water for Injection together with the matrix forming agent. If necessary further hydrochloric acid may be added as required. It will be appreciated that in the the preparation of the freeze dried component aqueous solutions will generally be prepared with Water for Injections to ensure the sterility of the product:.
The preparation of~comp~~nent (a), which is obtained as a sterile product, is considerably simpler and more efficient (and hence more economical) than the preparation of,sterile meap~halan powder and the subsequent procedure of aseptically filling the powder into vials, which is required in the case of the currently available injectable melphalan formulation. The formulation according to the present invention thus has advantages in manufacturing terms, as well as in its use by physicians.
The solvent-diluent (component (b)) may be prepared by mixing together an aqueous solution of the' citrate with the propylene glycol and ethanol, sterilising the solution by aaeptic filtration and filling into sterile ampoules or vials. The solvent-diluent may also be presented in pre-filled syringes. Again aqueous solutions are preferably prepared using Water for Injections, and the preparation is carried out under aseptic conditions.
'The freeze-dried melphalan hydrochloride in component (a) of the formulation according to the present invention can readily be reconstituted by the single step addition of the solvent-diluent component (b). It will he appreciated that the amount of melphalan hydrochloride in component (a) .and volume of solvent-diluent in component (b) can be selected to provide .JB/DR/4th November 1988 the desired dose and concentration of melphalan in the reconstituted product. The concentration of melphalan in the final formulation suitably lies in the range 0.5 t~o 10 mg,/rnl. A suitable unit dose may contain from 1 to 100 mg of melphalan. Preferred unit doses of melphalan contain 10 to 50 mg of the active ingredient in component (a). The volume of solvent diluent in component (b) may for example be from 1 to 50 ml, e.g. 5 to 25 ml, preferably 10 ml. :Particularly preferred formulations according to the present invention are those in which component (a) contains 10 or 50 mg of melphalan and component: (b) comprises 10 ml of the solvent/diluent, such that the final reconstituted formulations have concentrations of 1 mg/ml and 5 mg/ml respectivel;~r.
The melphalan starting material which is used for the preparation of component (a) of the present formulation may itself be prepared by any method known in the a:rt for preparing melphalan. A preferred form of melphalan for use in the preparation of component (a) is melphalan hydrochloride, most preferably substantially pure melphalan hydrochloride (i.e. having a purity oi= 95~ or above, preferably 97~ or above, measured by high pressure liquid criromato~;raphy (HPLC)). Melphalan hydrochloride may be prepared in highly pure forrn by crystallisation, for example from a C2-4 alkanol. This may conveniently be achieved by forming a suspension or slurry of melphalan in a mixture of a C2-4 alkanol, preferably ethanol, and hydrogen chloride, heating the mixture conveniently to reflux temperature and then cooling to about. 0°, whereupon melphalan hydrochloride crystallises out. In order t:o minimise the level of impurities, it is preferred that the duration of: heating should be kept to a minimum, e.g.
less than 5 minutes, preferably 1 to 3 minutes. In order to achieve this, a continuous crystallisation process may be operated in which the suspension is formed at a temperature of 10-20°C, is then passed through a heated vessel e.g. a heated coil, and finally collected and cooled.
Alternatively the substantially pure hydrochloride may be prepared from substantially pure melF~halan, which may itself be prepared by reacting ethyl N-phthaloyl-p-amino-L-phe:nylalanine or an acid addition salt thereof with ethylene oxide, such that the reaction temperature does not exceed JB/DR/4th November 1988 ~~4111d~

35oC, and preferably is in the range 20 to 30oC, followed by the steps of chlorination and hydrolysis, which may be carried out in conventional manner, to produce me:lphalan, which can then be converted into the hydrochloride salt in l~:nown manner. We have found the temperature during the reaction with ethy:Lene oxide is critical to the purity of the final product and hence must. be c;3refully controlled. As the reaction with ethylene oxide is exothermic t:he temperature can, if not controlled, rise considerably, for examp:~e up to 80°C.
Controlling the temperature in the range 20 to 30°C also has the advantage of permitting a reduction in 'the amount ethylene oxide employed and thus results in an environmentally favourable process.
The formulations according to vthe present invention may be used to treat a variety of neoplastic conditians in analogous manner to the currently available injectable melphalan preparations. Thus for example the formulations may be used in the treatment of localised malignant melanoma and localised soft t:~ssue ;sarcoma of the extremities, by regional perfusion. The formulations may also be used in the treatment of relapsed acute myeloid leukaemia, ovarian carcinoma, malignant melanoma, and multiple myeloma.
The dose of melphalan to be administered _via the formulations of the present invention will depend upon the nature and severity of the conditions to be treated. In general the dosage schedules to be followed may be similar to those currently used for intravenous melphalan formulations. A variet=,~ of dosages schedules have been described in the literature. Thus, for example in the treatment of ovarian carcinoma a single intravenous infusion of 1 mg/kg bodyweight over 8 hours may be given every 4 weeks. High doses of melphalan (e. g. 140-200 mg/m2) administered intravenously, may be used with or without sutologous bone marrow transplantation , in the treai~ment of relapsed acute myeloid luekaemia, ~warian carcinoma, malignant melanoma and multiple myeloma. Low :intravenous doses of mel;phalan (e. g. 16 mg/m2) every 2 weeks for four doses and monthly thereafter m,3y also be used.
:fB/DR/4th November 1988 The formulations according to the present invention will now be illustrated by the following non-limiting ~examples:-Example 1 Component (a) Ingedients content per vial Melphalan BP 50.0 mg Hydrochloric Acid, BP/Ph Eur 34.5 dal Povidone BP* 20.0 mg Water for Injections, BP/fh Eur to 2.0 g * polyvinylpyrrolidone Method Prepare a suitable dilution of the Hydrochloric Acid in Water for Inj ections .
Add the Melphalan to part of the Water for Injections.
Add the Hydrochloric Acid solution and stir until solution is complete.
Add and dissolve the Povidone.
Make up to weight with 4~'ater for Inj ections .
Sterilise the solution by aseptic filtration.' Fill into sterile vials.
Freeze dry.
Close and seal the vials.
.JB/DR/4th November 1988 1 341 1 1 ~
_, _ Component (b) Ingredients content per vial Sodium Citrate BP/Ph Eur 0.2 g Propylene Gylcol BP/Ph Eur 6.0 ml Ethanol (96~) 13P 0.52 ml Water for Injections BP/Ph Eur to 10.0 ml Method Dissolve the Sodium Citr~3te in part of the Water for Injections.
E~dd a mixture of the Propylene Glycol and Ethanol.
Make up to volume with Water fo:r Injections.
:>terilise the solution b:y aseptic filtration.
1?ill into sterile ampoul~as or vials.
:>topper with sterile closures and secure with aluminium collars.
~~ddition of component (b) to component (a) rapidly reconstitutes the freeze dried product to yield a solution for injection in the pH range 6 to 7.5.
,1B/DR/4th November 1988 _8_ Example 2 Component (a) Ingredients content.per vial Melphalan BP 7_0.0 mg Hydrochloric .Acid, BP/Ph Eur 25.875 pl Povidone BP 90.0 mg Water for Injections, BP/Ph Eur to 1.5 g Method The freeze-dried melphalan hydrochloride is prepared as described in Example 1.
Component (b) ' The solvent-diluent is prepared as described in Example 1.
Example 3 Preparation of substanti.allv vure melphalan hydrochloride A suspension of melphalan (2.0 kg) was stirred in 0.36 M ethanolic hydrogen chloride solution (18.0 litres) and then passed through a heated coil over a period of ca 2 minutes to give a clear solution, which was continuously filtered on discharge from the coil. The filtrate was stirred at 0-5°C
for 18 hours. The solid which crystallised was filtered, washed with diethylether, and dried at 30-40oC in vacuo to yield melphalan hydrochloride (1586g, 71$).
Purity (HPLC) 97.5$
Analysis JB/DR/4th November 1988 Calculated for C1,3H1902N2C13: C 45.7; H 5,6~; N 8.2~; C1 31;13 Found . C 45.82; H 5.37; N 8.06$; Cl 31.08$
An infra-red spectrum was obtained which was consistent with the structure of melphalan hydrochloride.
Example 4 Substantially pure Melphalan N-phthaloyl-p-amino-L-phenylal<inine ethyl ester hydrochloride (187.25g, 0.5 mole) was dissolved in a mixture of glacial acetic acid (205m1) and water (205m1), with stirring. Ethyle>.ne oxide (83.Og, 1.9 moles) was added slowly at 20-30°C, with cooling, them the solution stirred overnight at 20-30°C.
The excess ethylene oxide was removed by stirring the solution in vacuo for 1 hour, then benzene (7CIOm1) and water (950m1) were added. The acetic acid was neutralised by the addition of sodium bicarbonate (280g),.'and the aqueous phase separated and extracted with benzene (2 x 140m1). The benzene solutions were combined, washed with water (2 x 140m1) and dried by distillation. Phosphorus oxychloride (600g, 3.9 moles) was added slowly to the benzene solution, u~hilst :>tirring under reflux, the reaction mixture stirred under reflux for a further hour, then evaporated to dryness at 60°C
in vacuo. The residue was dissolved in a mixture of butan-1-of (625 ml) and ethanol (155 ml) at 80°C, and the solution was cooled to 10°C until the product crystallised. The N,N-p-di (2-chloroethyl)-amino-N'-phthaloyl-L-phenylalanine ethyl ester hydrochloride was filtered, stirred as a suspension in diethyl et=her (625 ml) , filtered, washed with diethyl ether (340 ml) and dried at 20 °C in vacuo to afford a white solid (167.4g 67~).
'Che chloroethyl compound was added to concentrated hydrochloric acid (840 ml), and the mixture stirred under reflux for 5 hours, cooled to 20°C
and filtered. The aqueous solution was evaporated to dryness in vacuo and the residue dissolved in methanol (840 ml). Melphalan was precipitated by the addition of diethylamine (ca 90m1) at 5-10°C until the final suspension was at pH7. The melphalan was filtered, washed thoroughly with methanol (1000 ml) and dried at 30-40°C in vac:~xo to afford the title compound as a white =solid (68.2g, 66~).
Purity (HPLC) 97.3 JB/DR/4th November 1988

Claims

1. A injectable formulation of melphalan comprising as two separate components a) freeze-dried melphalan hydrochloride, and b) a solvent-diluent comprising a citrate, propylene glycol, water and ethanol.

2. A formulation according to claim 1, wherein component (a) includes a non-hydroxylated matrix-forming agent.

3. A formulation according to claim 2, wherein the non-hydroxylated matrix-forming agent is polyvinylpyrrolidone.

4. A formulation according to claim 1, wherein the citrate is an alkali metal citrate.

5. A formulation according to claim 2, wherein the citrate is an alkali metal citrate.

6. A formulation according to claim 3, wherein the citrate is an alkali metal citrate.

7. A formulation according to claim 2, 3, 5 or 6, wherein component a) comprises 5 to 80%, by weight, of the freeze-dried melphalan hydrochloride and 20 to 95% of said matrix-forming agent.

8. A formulation according to claim 1, 2, 3, 4, 5 or 6, wherein component b) comprises 40 to 80% by volume of said propylene glycol, 0.1 to 10% by volume of said ethanol and said citrate comprises 1.5 to 2.5%
w/v of said solvent diluent.

9. A formulation according to claim 7, wherein component b) comprises 40 to 80% by volume of said propylene glycol, 0.1 to 10% by volume of said ethanol and said citrate comprises 1.5 to 2.5% w/v of said solvent diluent.

10. A. formulation according to claim 3 or 6, wherein said polyvinylpyrrolidone has a molecular weight in the range 2,000 to 25,000.

11. A method for preparing an injectable formulation of melphalan which comprises formulating as two separate components a) freeze-dried melphalan hydrochloride and b) a solvent-diluent comprising a citrate, propylene glycol, water and ethanol.

12. A method for preparing an injectable formulation of melphalan as claimed in claim 11, wherein the melphalan hydrochloride is produced by a process which comprises heating a mixture of melphalan and hydrogen chloride in a C2-4 alkanol for up to 5 minutes and cooling to effect crystallisation of melphalan hydrochloride.

13. The uses of a formulation of claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, in the treatment of persons suffering from neoplastic diseases.

14. Use of a formulation of claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, in the manufacture of an injectable melphalan medicament for the treatment of neoplastic diseases.