Stable Suspension Formulation
AssigneeDouglas Pharmaceuticals Limited
InventorsPeter William Surman, Sharon Ferguson, Wai Bik Mak, Andrew Douglas McLeod, Praneeta Sharma, Sunitha de Costa
Life of this patent
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Abstract
A physicochemically stable aqueous composition including clozapine suspension.
Claims44
A physicochemically stable aqueous composition for oral administration comprising clozapine in suspension and an agent capable of controlling and/or maintaining the pH of the composition, wherein the pH of the composition is maintained within the range of about 5.6 to about 11.
A method for preparing a physicochemically stable aqueous composition including clozapine in suspension, the method comprising the step of controlling the pH of the formulation between about 5.6 and about 11 using a buffer.
A method for preparing a physicochemically stable aqueous composition comprising clozapine in suspension, a wetting agent comprising propylene glycol, a buffer, one or more preservatives and a suspending agent, comprising the following steps:
- (a) stirring the clozapine with about three quarters of the propylene glycol ascribed to the batch;
- (b) addition of the buffer salt (and optionally sweetening agents) dissolved in about half the volume of water ascribed to the batch with constant stirring;
- (c) adjusting the pH value of the batch with the base component of the buffer with mixing;
- (d) addition to the batch of the preservatives dissolved in the remaining propylene glycol;
- (e) slow addition of the suspending agent to the batch with continuous stirring until the mixture thickens;
- and,
- (f) further diluting the suspension with water to the desired end-volume.
A method for producing a physicochemically stable aqueous composition comprising clozapine in suspension, a wetting agent comprising glycerine, a buffer, one or more preservatives and a suspending agent, comprising the following steps:
- (a) stirring the clozapine with about three quarters of the glycerine ascribed to the batch;
- (b) addition of the buffer salt (and optionally sweetening agents) dissolved in about half the volume of water ascribed to the batch with constant stirring;
- (c) adjusting the pH value with the base component of the buffer with mixing;
- (d) addition of the preservatives dissolved in a small volume of water;
- (e) slow addition of the suspending agent wetted with the remaining glycerine with continuous stirring until the mixture thickens;
- and
- (f) further diluting the suspension with water to a desired end-volume.
A method for preparing a physicochemically stable aqueous composition comprising clozapine in suspension, a wetting agent comprising glycerine, a buffer, a suspending agent comprising xanthan gum, sorbitol, and PVP, comprising the following steps:
- (a) wetting Clozapine with glycerine;
- (b) adding PVP solution (0.025% w/v) and additional water;
- (c)adding 0.25 M buffer at pH 6.3 to the mixture;
- (d) adding Semi hydrated xanthan gum/glycerol solution;
- (e) adding Sorbitol and additional water;
- (f) adding PVP solution (0.18% w/v) and additional water;
- (g) adding Paraben/glycerine solution and additional water;
- (h) wherein the pH of the final suspension is between about 6.7 and 7.
A method for producing a physicochemically stable aqueous composition including clozapine in suspension, a wetting agent comprising glycerine, a buffer, a suspending agent comprising xanthan gum, sorbitol, PVP, and one or more preservatives, comprising the following steps:
- (a) wetting Clozapine with glycerine;
- (b) making a PVP solution at 0.025% w/v and adding to the mixture;
- (c) adding additional water so that the concentration of PVP becomes 0.0125% w/v to promote flocculation;
- (d) adding 0.25 M buffer at pH 6.3 to the mixture to enhance flocculation;
- (e) adding Sorbitol 70% crystallizing solution and xanthan gum;
- (f) adding additional PVP as a 0.18% w/v solution;
- (g) adding preservatives;
- wherein the pH of the final suspension is about 6.9, and the final concentration of PVP is 0.01% and the buffer is 50 mM.
A physicochemically stable aqueous composition comprising about:
- (a) 50 mg/ml Clozapine in suspension
- (b) 150 mg/ml Sorbitol 70% crystallizing solution
- (c) 0.1 mg/ml Povidone K90
- (d) 7.8 mg/ml Sodium dihydrogen phosphate dihydrate
- (e) 0.48 to 0.66 mg/ml Sodium hydroxide
- (f) 2 mg/ml Sodium methylparaben
- (g) 0.2 mg/ml Sodium propylparaben
- (h) 182 mg/ml Glycerol
- (i) 2 mg/ml Xanthan gum
- (j) q.s. Water.
A physicochemically stable aqueous composition comprising about:
- (a) 50 mg/ml Clozapine in suspension
- (b) 150 mg/ml Sorbitol 70% crystallizing solution
- (c) 10 mg/ml Povidone K90
- (d) 3.9 mg/ml Sodium dihydrogen phosphate dihydrate
- (e) 2 mg/ml Sodium methylparaben
- (f) 0.2 mg/ml Sodium propylparaben
- (g) 130 mg/ml Glycerol
- (h) 5.5 mg/ml Xanthan gum
- (i) 0 to 4 mg/ml Sodium Hydroxide Solution (1M)
- (j) 0 to 4 mg/ml Hydrochloric acid Solution (1M)
- (k) q.s. Water.
A physicochemically stable aqueous composition for oral administration comprising clozapine in suspension, a wetting agent, a stabilizing agent, and a buffer, wherein the pH of the composition is maintained within the range of about 6 to about 11.
A physicochemically stable aqueous composition consisting of about:
- (a) 50 mg/ml Clozapine in suspension
- (b) 150 mg/ml Sorbitol 70% crystallizing solution
- (c) 0.1 mg/ml Povidone K90
- (d) 7.8 mg/ml Sodium dihydrogen phosphate dihydrate
- (e) 0.48 to 0.66 mg/ml Sodium hydroxide
- (f) 2 mg/ml Sodium methylparaben
- (g) 0.2 mg/ml Sodium propylparaben
- (h) 182 mg/ml Glycerol
- (i) 2 mg/ml Xanthan gum
- (j) q.s. Water .
A physicochemically stable aqueous composition consisting of about:
- (a) 50 mg/ml Clozapine in suspension
- (b) 150 mg/ml Sorbitol 70% crystallizing solution
- (c) 10 mg/ml Povidone K90
- (d) 3.9 mg/ml Sodium dihydrogen phosphate dihydrate
- (e) 2 mg/ml Sodium methylparaben
- (f) 0.2 mg/ml Sodium propylparaben
- (g) 130 mg/ml Glycerol
- (h) 5.5 mg/ml Xanthan gum
- (i) 0 to 4 mg/ml Sodium Hydroxide Solution (1M)
- (j) 0 to 4 mg/ml Hydrochloric acid Solution (1M)
- (k) q.s. Water.
A physicochemically stable aqueous composition consisting essentially of about:
- (a) 50 mg/ml Clozapine in suspension
- (b) 150 mg/ml Sorbitol 70% crystallizing solution
- (c) 0.1 mg/ml Povidone K90
- (d) 7.8 mg/ml Sodium dihydrogen phosphate dihydrate
- (e) 0.48 to 0.66 mg/ml Sodium hydroxide
- (f) 2 mg/ml Sodium methylparaben
- (g) 0.2 mg/ml Sodium propylparaben
- (h) 182 mg/ml Glycerol
- (i) 2 mg/ml Xanthan gum
- (j) q.s. Water.
A physicochemically stable aqueous composition consisting essentially of about:
- (a) 50 mg/ml Clozapine in suspension
- (b) 150 mg/ml Sorbitol 70% crystallizing solution
- (c) 10 mg/ml Povidone K90
- (d) 3.9 mg/ml Sodium dihydrogen phosphate dihydrate
- (e) 2 mg/ml Sodium methylparaben
- (f) 0.2 mg/ml Sodium propylparaben
- (g) 130 mg/ml Glycerol
- (h) 5.5 mg/ml Xanthan gum
- (i) 0 to 4 mg/ml Sodium Hydroxide Solution (1M)
- (j) 0 to 4 mg/ml Hydrochloric acid Solution (1M)
- (k) q.s. Water.
Dependencies are inferred from the claim text.