PH26521A - Pharmaceutical formulation - Google Patents

Description

Jud 205 i . Pharmaceutical Formulations

The present invention relates to novel pharma~- ceutical formulations, in particular to formu- lations containing melphalan as the active ingredient.

Melphalan is a well-established cytotoxic agent which is used to treat a range of neoplastic diseases, including in particular multiple mye- } loma and ovarian cancer.

Melphalan has the chemical name 4-(bis(2-chloro- ethyl)amino)-L-phenylalanine and the structural formulas mon) N-(CH,CH,C1),

NH,

This compound is also known variously as L-phenyl- alanine mustard; L-PAM; L-sarcolysine; NSC-8806 and CB3025,

“ Jaf 2¢52/ i

Melphalan is presently commercially available under the name BAlkeran (TM. The Wellcome Foun- dation Limited) in the form of both tablets and injectable preparations. Alkeran injection is supplied as a three component presentation and has to be reconstituted in two stages, shortly prior to use. Thus, the 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 dilpent, together with propylene glycol.

To reconstitute the Alkeran injection, the melpha- oo lan powder is first dissolved in the acid/alcohol solvent and when dissolution is complete the solution is then 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 formu- lation which is simpler to feconstitute and thus more convenient for the physiclan to use. A

TA 265721 i } further disadvantage of the presently available injectable formulation is that in some instances the melphalan powder dissolves only slowly or : does not completely dissolve. a The present invention provides a novel two-com- ponent 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 melphalan hydrochloride; * . : “and - b) a slovent-diluent comprising a citrate, propylene glycol and ethanol.

Component (a) may advantageously include a non- * ’ hydroxylated matrix-forming agent, such as poly- vinylpyrrolidone (PVP). A suitable grade of PVP - lo fat. 2652 } for use in the formulation according to the invention comprises PVP having a molecular weight of less than 25,000, for example in the range 2,000 to 25,000. A particularly suitable grade of PVP is that designated K12.

The amount of melphalan hydrochloride present - in component (a) may vary within wide limits and may 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 ’ 15 weight of component (a). Preferably however the amount of matrix forming agent is in the range 20 to 95% 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 glydol in component (b) is generally in the range LO to oo -5-

Jot. 2654 i se 80% by volume. The proportion of ethanol present in component (b) will generally be in the range 0.1 to 10% by volume. The v citrate will generally comprise from 0.05 to “ 5% w/v e.g. 1.5 to 2.5% w/v of the Sbivent- BE oo diluent.

Component (a) may be prepared using freeze- drying procedures well known to those skilled : in the art of pharmaceutical formulation, Thus, . 10 for example the melphalan base and the matrix forming agent may be dissolved in aqueous hydro- .chloric acid, the resulting solution sterilised by aseptic filtration, filled into sterile vials and freeze dried. The melphalan base and hydro- : 15 chloric acid may be used in a stoichmetric (1:1) ratio, but preferably a slight excess of hydrochlo- ric acid is used, Alternatively melphalan hydro- chloride itself may 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

(id 24521 may be added as required. It will be appre- ciated that in the preparation of the freeze dried component aqueous solutions will gene- rally be prepared with Water for Injections to ensure the sterility of the product,

The preparation of component (a), which is obtained as a sterile product, is considerably simpler and more efficient (and hence more eco- nomical) than the preparation of sterile melpha- lan 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 advan- : : 15 tages in manufacturing terms, 2s well as in its use by physicians. i

The solvent-diluent (component (b)) may be prepared . by mixing together an aqueous solution of the cit- rate with the propylene glycol and ethanol, ste- rilizing the solution by aseptic filtration and fut. 2452 ‘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 reconstituted by the single step addition of the solvent-diluent component (b). It will be appreciated that the amount of melphalan hydrochloride in component (a) and volume of solvent-diluent in component (b) can be selected to provide the desired dose and concen- : ’ - 15 tration of melphalan in the reconstituted product. he concentration of melphalan in the final formu- lation suitably lies in the range 0.5 to 10 mg/ml.

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

(ad 2652] 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 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 respectively.

The melphalan starting material which is used for 10 the preparation of component (a) of the present formulation may itself be prepared by any method known in the art for preparing melphalan. A pre- ; ferred for of melphalan for use in the preparation : of component (a) is melphalan hydrochloride, most . - 15 preferably substantially pure melphalan hydrochloride (i.e. having a purity of 95% or above, preferably 97% or above, measured by high pressure liquid chro- matography (HPLC)). Melphalan hydrochloride may be prepared in highly pure form by crystallisation, for example from a Con alkanol. This may conveniently be achieved by forming a suspension or slurry of

(it. 452 i : melphalan in a mixture of a Coy alkanol, pre- ferably ethanol, 2nd hydrogen chloride, heating the mixture conveniently to reflux temperature and then cooling to about 0°, whereupon melpha- lan hydrochloride crystallizes out. In order to minimize the level of impurities, it is preferred that the duration of heating should be kept to a oo minimum, e.g. less than 5 minutes, preferably 1 to 3 minutes. In order to achieve this, a con- tinuous 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’ : } - 15 may be prepared from substantially pure melphalan, ‘which may itself be prepared by reacting ethyl

N-phthaloyl-p-amino-L-phenylalanine or an acid addition salt thereof with ethylene oxide, such that the reaction temperature does not exceed 35°C, and preferably is in the range 20 to 30°C, : followed by the steps of chlorination and hydro-

Pik. 752] lysis, which may be carried out in conventional manner, to produce melphalan, which can then be converted into the hydrochloride salt in known manner. We hdve found the temperature during the reaction with ethylene oxide is critical : to the purity of the final product and hence must be carefully controlled. As the reaction with ethylene oxide is exothermic the temperature can, if not controlled, rise considerably, for example up to 80°C,

Controlling the temperature in the range 20 to 309% also has the advantage of permitting a reduc~- tion in the amount ethylene oxide employed and thus results in an environmentally favourable . 15% process.

The formulations according to the present invention : may be used to treat a variety of neoplastic condi- tions in analogous manner to the currently available injectable melphalan preparations. Thus for example the formulations may be used in the treatment of fof. 24621 localised malignant melanoma and localised soft tissues 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 con- | ditions to be treated. In general the dosage schedules to be followed may be similar to those : currently used for intravenous melphalan formula- tions. A variety of dosages schedules have been — described in the literature. Thus, for example : 15 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. 148-200 me,/m?) administered intravenously, may be used with or without auto- logous bone marrow transplantation, in the treat- ment of relapsed acute myeloid leukaemia, ovarian

Ful. 265% i carcinoma, malignant melahoma and multiple myeloma. Low intravenous doses of melphalan (e.g. 16 mg/m?) every 2 weeks for four doses and monthly thereafter may also be used.

The formulations according to the present invention will now be illustrated by the fol- : lowing non-limiting examples: - .

Example 1

Component (a)

Ingredient content per vial

Melphalan BP 50.0 mg © Hydrochloric Acid, BP/Ph Eur 34.5 ul

Povidone BP* 20.0 mg

Water for Injections ,BP/Ph Eur 2.0 g * polyvinylpyrrolidone ’

Method :

Prepare a suitable dilution of the Hydrochloric

Acid in Water for Injections.

fof. 2652]

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 Water gor Injections.

Sterilise the solution by aseptic filtration.

Fill into sterile vials.

Freeze dry.

Close and seal the vials.

Component (b)

Ingredients content per vial : Sodium Citrate BP/Ph Eur 0.2 g

Propylene Gylcol BP/Ph Eur 6.0 ml ’ oo Ethanol (96%) BP 0.52 ml

So 15 Water for Injections BP/Ph Eur to 10,0 ml ° {

Method : ’ -

Dissolve the Sodium Citrate in part of the Water for Injections,

Add a mixture of the Propylene Glycol and Ethanol.

Make up to volume with Water for Injections. . - 1h -

(uf. 265 2 ..

Sterilize the solution by aseptic filtration.

Fill into sterile ampoules or vials.

Stopper with sterile closures and secure with aluminium collars, ' Addition 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.

Example 2

Component (a)

Ingredients content per vial

Melphalan BP 10.0 mg > ~~ Hydrochloric Acid, BP/Ph Eur 25.875 ul : Povidone BP 90.0 mg

Water for Injections, BP/Ph Eur 1.5 g

Method ’

The freeze-dried melphalan hydrochloride is pre- pared as described in Example 1.

Jib 571 i :

Component (b)

The solvent-diluent is prepared as described in

Example 1.

Example 3

Preparation of substantially vure melphalan hydro- chloride .

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 dis- : ~ : charge from the coil. The filtrate was stirred ‘at 0-5°C for 18 hours. The solid which crystal- lised was filtered, washed with diethylether, and dried at 30-40°C in vacuo to yield melphalan hydrodhloride (1586 g, 71%). . #

Purity (HPLC) 97.5%

. ' Co (Jat 26521

Analysis

Calculated for Cy 3H) gOpN C150 C 45.7%; H 5,6%;

N 8.2%; C1 31.1%

Found + C 45.82%; H 5.37%;

N 8.06%; C1 31.08%

An infra-red spectrum was obtained which was con- sistent with the structure of melphalan hydrochlo- : ride.

Substantially pure Melphalan : N-phthaloyl-p-amino-L-phenylalanine ethyl ester hydrochloride (187.25 g, 0.5 mole) was dissolved in a mixture of glacial acetic acid (205 ml) and water (205 ml), with stirring. Ethylene oxide : ’ (83.0 g, 1.9 moles) was added slowly at 20-30°C, with cooling, then the solution stirred overhight at 20-30°C. The excess ethylene oxide was removed :

Fad. 26521 by stirring the solution in vacuo for 1 hour, then benzene (700 ml) and water (950 ml) were added. The acetic acid was neutralized by the addition of sodium bicarbonate (280 g), and the aqueous phase separated and extracted with i benzene (2 x 140 ml). The benzene solutions were combined, washed with water (2 x 140 ml) : | and dried by distillation. Phos phorus oxychloride (600 g, 3.9 moles) was added slowly to the benzene solution, whilst stirring 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-1l-ol (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 hydro- ‘chloride was filtered, stirred as a suspénsion in diethyl ether (625 ml), filtered, washed with diethyl ether (340 ml) and dried at 20°C in vacuo to afford a white solid (167.4 & 67%). The chlo- roethyl compound was added to concentrated hydro-

ok 2652 i . chloric 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 vacua and the residue dissolved in methanol (840 ml). Melphalan was precipitated : by the addition of diethylanmine (ga ©0 ml) at 5-1.0°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 vacuo to afford the title compound as a white solid (6812 g 666%). ’ Purity (HPLC) 97.3% . :

Claims (6)

1. (Gof. 26521 :

   ’ 1. A pharmaceutical formulation of melphalan comprising as two separate components a) freeze-dried melphalan hydrochloride, ° and oo b) a solvent-diluent comprising a citrate, propylene glycol and ethanol in an amount sufficient to dissolve the com- ponent (a).
2. 2. A pharmaceutical formulation according to claim 1 wherein component (a) includes a non- hydroxylated matrix-forming agent.
3. 3. A pharmaceutical formulation according to : ’ claim 2 wherein the non-hydroxylated matrix-
4. 15 . forming agent is polyvinylpyrrolidone. h, A pharmaceutical formulation according to claim 1 wherein the citrate is an alkali metal citrate.
5. 5. Melphalan hydrochloride having a purity of . 95% or above.

   { : .
6. 6, A process for preparing melphalan or melphalan hydrochloride in substantially : pure form which comprises reacting ethyl N-phthaloyl-p-amino-L-phenylalanine or an acid addition salt thereof with ethylene oxide such that the reaction tBmperature does not exceed 35%, followed by the steps So of chlorination and hydrolysis to produce melphalan, and if desired conversion into the hydrochloride salt.

   ON # : : - 21 = Ce B Fi !