Stabilized pharmaceutical formulations comprising antineoplastic compounds
The present invention relates to stabilized pharmaceutical formulations prepared from solutions comprising an antineoplastic compound having a cyclic or non-cyclic hydrazine, triazine, or tetrazine group, or a pharmaceutically acceptable salt thereof, and a stabilizer, wherein the stabilizer is an antioxidant and/or more susceptible to nucleophilic attack than the antineoplastic compound.
1. A process for preparing a pharmaceutical formulation, comprising the steps of:
(a) dissolving at least one excipient and at least one buffer into an aqueous diluent to form an acidic solution, wherein the temperature of the aqueous diluent is in the range of 16 to 24° C. before addition of the excipient and buffer;
(b) dissolving a stabilizer either into the solution of step (a) or into the aqueous diluent of step (a) before addition of the excipient and buffer;
(c) dissolving an antineoplastic compound having a cyclic or non-cyclic hydrazine, triazine, or tetrazine group, or a pharmaceutically acceptable salt thereof, into the solution of step (b) at a temperature in the range of 16 to 24° C.; and
(d) adding a bulking agent selected from mannitol, lactose, sucrose, sodium chloride, trehalose, dextrose, starch, hydroxyethylstarch (hetastarch), cellulose, cyclodextrins, glycine, and combinations thereof;
wherein the stabilizer is an antioxidant and/or more susceptible to nucleophilic attack than the antineoplastic compound.
2. The process of claim 1 , further the comprising the step of lyophilizing the solution of step (c) to yield a lyophilized powder that contains less than 0.6 wt % of total impurities, based on the total weight of the lyophilized powder, after storage for 3 months at 40° C./75% RH.
3. The process of claim 2 , wherein the lyophilized powder contains less than 0.4 wt % of total impurities after storage for 3 months at 40° C./75% RH.
4. The process of claim 2 , wherein the lyophilized powder contains less than or equal to 10% of the initial amount of stabilizer added in step (b).
5. The process of claim 1 , wherein the stabilizer is added in step (b) in an amount of 0.01 to 1% w/v.
6. The process of claim 1 , further comprising the step of adjusting the pH of the solution of step (c) to about 3 to about 4.
7. The process of claim 1 , wherein the antineoplastic compound is selected from altretamine, dacarbazine, mitozolomide, procarbazine, and temozolomide.
8. The process of claim 7 , wherein the antineoplastic compound is temozolomide.
9. The process of claim 1 , wherein the stabilizer is an antioxidant.
10. The process of claim 1 , wherein the stabilizer is selected from alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, tartaric acid, and combinations thereof.
11. The process of claim 10 , wherein the stabilizer is sodium metabisulfite.
12. The process of claim 1 , wherein the excipient is selected from polysorbate, polyethylene glycol, propylene glycol, polypropylene glycol, and combinations thereof.
13. The process of claim 1 , wherein the buffer is selected from sodium citrate dihydrate, hydrochloric acid, and combinations thereof.
14. The process of claim 1 , wherein the aqueous diluent is selected from water, normal saline, 5% dextrose solution, Lactated Ringer's solution, and combinations thereof.