Patent EA-000970-B1 (EA)
Title: Parenteral paarmaceutical formulation with protracted effect comprising monomeric insulin, insulin analog crystal and process of preparing crystal analog
Inventor: DE FELIPPIS MICHAEL R
IPC: C07K14/62
Filed: 1996-03-28
Abstract: 1. A parenteral pharmaceutical formulation having a protracted effect at a pH of about 6.5 to about 7.8 consisting essentially of a sterile aqueous suspension of insulin analog, sodium chloride, physiologically acceptable buffer, a physiologically acceptable preservative and zinc ions, wherein comprising about 20 U/mL to about 500 U/mL monomeric insulin analog, about 5 mg/mL to about 10 mg/mL sodium chloride, about 0.2 to about 2.0 mg/mL physiologically acceptable buffer, a zinc ion content of about 0.04 mg/mL to about 20.0 mg/mL, such that less than 5% of the analog present in the suspension is in the dissolved state. 2. A parenteral pharmaceutical formulation of claim 1, wherein the monomeric insulin analog is Lys<B28>Pro<B29>-human insulin. 3. A parenteral pharmaceutical formulation of claim 2, wherein analog present in suspension in not dissolved state is substantially crystalline insulin. 4. A parenteral pharmaceutical parenteral pharmaceutical formulation of claim 3 wherein: the monomeric insulin analog concentration is about 40 U/mL insulin analog, sodium chloride concentration is about 7 mg/mL sodium chloride, the buffer is sodium acetate at about 1.6 mg/mL, and the pH is about pH 7.0 to about pH 7.4. 5. A parenteral pharmaceutical parenteral pharmaceutical formulation of claim 3 wherein: the monomeric insulin analog concentration is about 100 U/mL insulin analog, sodium chloride concentration is about 7 mg/mL sodium chloride, the buffer is sodium acetate at about 1.6 mg/mL sodium acetate, and the pH is about pH 7.0 to about pH 7.4. 6. A parenteral pharmaceutical formulation of claim 1, wherein analog present in suspension is not in dissolved state is substantially amorphous insulin. 7. A formulation of claim 1, wherein analog present in suspension is not in dissolved state is about 70% crystalline and about 30% amorphous insulin. 8. A parenteral pharmaceutical formulation of any preceding claim, wherein comprises m-cresol or reserpine or phenol less than 3000 U/mL. 9. An insulin analog crystal prepared by precipitating crystals from a solution consisting essentially of about 200 to about 1200 U/mL insulin analog, about 50 mg/mL to about 100 mg/mL sodium chloride, about 2.0 to about 20.0 mg/mL physiologically acceptable buffer, and a molar excess of zinc ions at a pH of about 5.0 to about 6.0 used to prepare a formation of any claim 1 through 5 and 7, 8. 10. An insulin analog crystal, prepared by combining a first solution comprising about 300 U/mL to about 2000 U/mL insulin analog and a molar excess of zinc ion at a pH from about 2.0 to about 3.0; and a second solution comprising about 130 mg/mL to about 270 mg/mL sodium chloride, about 5.0 to about 55.0 mg/mL physiologically acceptable buffer at a pH from about 10.5 to 12.5; such that the pH of the combined solutions is pH 5.0 to pH 6.0 used to prepare a formation of any claim 1 through 5 and 7, 8. 11. The insulin analog crystal of any one of claims 9 through 10, wherein the insulin analog is Lys<B28>P<B29>ro-human insulin. 12. A process of preparing LysPro-human nsulin crystals, comprising:combining a first solution comprising about 300 U/mL to about 2000 U/mL insulin analog, and a molar excess of zinc ion at a pH from about 2.0 to about 3.0; and a second solution comprising about 130 mg/mL to about 270 mg/mL sodium chloride, about 5.0 to about 55.0 mg/mL physiologically acceptable buffer at a pH from about 10.5 to 12.5; such that the pH of the combined solutions is pH 5.0 to pH 6.0.