Methods of manufacturing injectable sustained release formulations
The present application provides a method for the manufacture of a viscous liquid suspension or emulsion for controlled release drug delivery, where the composition comprises: a lactate-based polymer having a weight average molecular weight between 5,000 and 50,000 dalton; a biocompatible solvent; and a bioactive substance or a salt thereof. The method involves weighing, mixing, dissolving the raw materials, filtering the product, and degassing the product to produce a uniform formulation that can be accurately filled in a single ready to use syringe.
1 . A method of manufacturing an injectable sustained release formulation, wherein the injectable sustained release formulation comprises a luteinizing hormone releasing hormone (LHRH) agonist or a salt thereof, an N-methylpyrrolidone (NMP), and a biodegradable polymer, and wherein the method comprises:
i. a compounding step that is conducted under a controlled humidity of less than 60% at 15-25° C., wherein the compounding step comprises a) introducing ≥70% of a total amount of the NMP into a compounding vessel; b) dividing the biodegradable polymer into multiple fractions and adding a first fraction of the biodegradable polymer to the compounding vessel, and mixing the first fraction of the biodegradable polymer with the NMP in the compounding vessel until the first fraction of the biodegradable polymer is wetted or dissolved, then separately and sequentially introducing each of the remaining fraction(s) of the biodegradable polymer to the compounding vessel and mixing until the newly added fraction of the biodegradable polymer is wetted or dissolved before introducing a next fraction of the biodegradable polymer; c) after all the fractions of the biodegradable polymer are wetted or dissolved, adding the LHRH agonist in 1 to 20 fractions separately and sequentially into the compounding vessel and mixing the fraction of LHRH agonist with the NMP and biodegradable polymer in the compounding vessel until the LHRH agonist is wetted or dissolved, wherein a subsequent fraction of the LHRH agonist, if any, is added after the LHRH agonist previously added into the compounding vessel is wetted or dissolved, and mixing the LHRH agonist with the NMP and biodegradable polymer in the compounding vessel to form the formulation; and
ii. a degassing step that is performed by four (4) or more vacuum/vent cycles of applying a relative vacuum pressure between −300 mbar and −1000 mbar to the compounding vessel or a degassing vessel containing the formulation prepared in (i) above, maintaining the vacuum for a time period between 5 min and 720 min, and releasing the vacuum to allow venting; wherein the vacuum level maintained at each vacuum/vent cycle is at least as strong as or stronger than that maintained in an immediately previous cycle,
wherein the formulation is a viscous suspension or emulsion of LHRH agonist rich phase having a droplet diameter of Dv50 of less than 50 pm suspended in a biodegradable polymer rich continuous phase and has a viscosity of greater than 10,000 centipoise (cPs).
2 . The method of claim 1 wherein after the last fraction of LHRH agonist is introduced, the formulation is further mixed for at least 15 minutes to obtain LHRH/NMP droplets in the formulation having a droplet size of Dv50≤25 μm with an RSD≤100%.
3 . The method of claim 1 wherein the LHRH agonist is leuprolide mesylate or triptorelin mesylate.
4 . The method of claim 1 wherein the biodegradable polymer is selected from the group consisting of polylactic acid (PLA), and a copolymer poly (lactic acid-co-glycolic acid) (PLGA), and a combination thereof, wherein the ratio of lactic acid:glycolic acid of the copolymer is from 50:50 to 99:1; wherein the PLGA or PLA polymer has a molecular weight from 5,000-50,000 dalton.
5 . The method of claim 1 wherein the compounding step is performed under a controlled humidity of less than or equal to 40% at 15-25° C.
6 . The method of claim 1 wherein 70-90% of the total NMP is introduced to the compounding vessel initially, with remaining 10-30% being introduced after the adding of all the biodegradable polymer and LHRH agonist.
7 . The method of claim 1 wherein the LHRH agonist is added to the compounding vessel all at once and dissolved.
8 . The method of claim 1 where the LHRH agonist is added to the compounding vessel in 2 or more fractions separately and sequentially and dissolved, and the subsequent fraction of the LHRH agonist is added after the LHRH agonist previously added in the compounding vessel is dissolved.
9 . The method of claim 1 further comprises performing a filtration step using a filter having average pore sizes ranging from 20 μm to 100 μm under an inlet pressure of 1 bar to 10 bars and an outlet relative vacuum pressure of −300 mbar to −1000 mbar, wherein the filtration is performed before the degassing step.
10 . The method of claim 9 wherein the filter has an average pore size of 40 μm, and the filtration is performed under an inlet pressure of 1.8 to 2.0 bars and an outlet relative vacuum pressure of −700 mbar to −950 mbar.
11 . The method of claim 1 wherein the suspension or emulsion is substantially air bubble free and homogeneous.
12 . The method of claim 1 wherein the LHRH agonist is triptorelin mesylate and the biodegradable polymer is PLA or PLGA.