US-12622963-B2 - Micromolded or 3-D printed pulsatile release vaccine formulations

Abstract

Emulsion-based and micromolded (“MM”) or three dimensional printed (“3DP”) polymeric formulations for single injection of antigen, preferably releasing at two or more time periods, have been developed. Formulations are preferably formed of biocompatible, biodegradable polymers. Discrete regions encapsulating antigen, alone or in combination with other antigens, adjuvants, stabilizers, and release modifiers, are present in the formulations. Antigen is preferably present in excipient at the time of administration, or on the surface of the formulation, for immediate release, and incorporated within the formulation for release at ten to 45 days after initial release of antigen, optionally at ten to 90 day intervals for release of antigen in one or more additional time periods. Antigen may be stabilized through the use of stabilizing agents such as trehalose glass. In a preferred embodiment for immunization against polio, antigen is released at the time of administration, and two, four and six months thereafter.

Inventors

• Ana Jaklenec
• Kevin McHugh
• William Gates
• Philip A. Welkhoff
• Boris Nikolic
• Lowell L. Wood, JR.
• Robert S. Langer
• Thanh Duc Nguyen
• Stephany Yi Tzeng
• James J. Norman

Assignees

• MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• TOKITAE LLC

Dates

Publication Date

20260512

Application Date

20231229

Claims (9)

1. 1 . A microdevice for delivering a therapeutic or prophylactic agent to a human or animal, the microdevice comprising: a non-spherical biocompatible polymeric shell defining a discrete region including the therapeutic or prophylactic agent; and a biocompatible polymeric cap; wherein the biocompatible polymeric cap and the biocompatible polymeric shell are sealed together, wherein at least one dimension of the microdevice is between about 1 μm to about 1000 μm.
2. 2 . The microdevice of claim 1 wherein at least one of the polymeric shell and the polymeric cap comprises a water insoluble polymer.
3. 3 . The microdevice of claim 1 wherein at least one of the polymeric shell and the polymeric cap comprises polyester or polyanhydride.
4. 4 . The microdevice of claim 1 wherein at least one of the polymeric shell and the polymeric cap comprises poly(lactic acid), poly(glycolic acid), or poly(lactic-co-glycolic acid).
5. 5 . The microdevice of claim 1 , wherein the polymeric shell, the polymeric cap, or both, are formed from micromolding, three-dimensional printing, or nanoimprint lithography.
6. 6 . The microdevice of claim 1 wherein the therapeutic or prophylactic agent comprises an antigen.
7. 7 . A vaccine formulation comprising a plurality of the microdevices of claim 6 , optionally wherein the formulation is configured to provide pulsatile release of the therapeutic or prophylactic agent, wherein the pulsatile release includes releasing the therapeutic or prophylactic agent at two or more time periods.
8. 8 . The microdevice of claim 1 , wherein all dimensions of the microdevice are between about 1 μm to about 1000 μm.
9. 9 . The microdevice of claim 1 , wherein at least one dimension of the microdevice is between about 100 μm to about 1000 μm.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional of U.S. application Ser. No. 17/143,871, filed Jan. 7, 2021, which is a divisional of U.S. application Ser. No. 16/401,476, filed May 2, 2019, now U.S. Pat. No. 10,960,073, issued Mar. 30, 2021, which is a divisional of U.S. application Ser. No. 14/572,631, filed Dec. 16, 2014, now U.S. Pat. No. 10,300,136, issued May 28, 2019, which claims benefit of and priority to U.S. Provisional Application No. 61/916,555, filed Dec. 16, 2013, which are hereby incorporated herein by reference in their entirety. FIELD OF THE INVENTION This invention is generally in the field of injectable vaccine formulations providing multiple releases of vaccine. BACKGROUND OF THE INVENTION Vaccines typically involve an initial dose of antigen, followed by one or more booster doses at defined times after the initial administration, typically ten to 60 days later. The need for administration of a booster dose clearly limits the practicality of vaccines in much of the world, as well as increases costs and difficulties in agricultural applications. Polymeric microspheres have the potential to be effective vaccine delivery vehicles. They have the ability to enhance targeting of antigen presenting cells (APCs) and have the potential for controlled, sustained release of antigen-thereby potentially eliminating the need for multiple vaccination doses. Further, the polymer matrix can act as a shield from a hostile external environment and has the potential to reduce adverse reactions and abrogate problems caused by the vaccine strain in immunocompromised individuals. PLGA microspheres have been developed for single immunization, with and without burst release. Given the biodegradable nature and sustained release properties that PLGA offers, microspheres formulated from PLGA could be useful for the delivery of vaccines. Summarized in Kirby et al., Chapter 13: Formation and Characterisiation of polylactide-co-galactide PLGA microspheres (2013). PLGA based microparticles are traditionally produced by double emulsion-solvent evaporation, nano-precipitation, cross-flow filtration, salting-out techniques, emulsion-diffusion methods, jet milling, and spray drying. Summarized in Kirby et al., Chapter 13: Formation and Characterisiation of polylactide-co-galactide PLGA microspheres (2013). PLGA microspheres can also be formulated to incorporate a range of moieties, including drugs and proteins, that can act as adjuvants. It has been contemplated that PGLA particles produced by these methods can be lyophilized and stored for later use and delivery. Hanes et al., Adv. Drug. Del. Rev., 28:97-119 (1997), report on attempts to make polymeric microspheres to deliver subunit protein and peptide antigens in their native form in a continuous or pulsatile fashion for periods of weeks to months with reliable and reproducible kinetics, to obviate the need for booster immunizations. Microspheres have potential as carriers for oral vaccine delivery due to their protective effects on encapsulated antigens and their ability to be taken up by the Peyer's patches in the intestine. The potency of these optimal depot formulations for antigen may be enhanced by the co-delivery of vaccine adjuvants, including cytokines, that are either entrapped in the polymer matrix or, alternatively, incorporated into the backbone of the polymer itself and released concomitantly with antigen as the polymer degrades. As reported by Cleland et al., J. Controlled Rel. 47(2):135-150 (1997), the administration of a subunit vaccine (e.g., gp120) for acquired immunodeficiency syndrome (AIDS) can be facilitated by a single shot vaccine that mimics repeated immunizations. Poly(lactic-co-glycolic acid) (PLGA) microspheres were made that provide a pulsatile release of gp120. Microspheres were made using a water-in-oil-in-water microencapsulation process with either methylene chloride or ethyl acetate as the polymer solvent. The protein was released under physiological conditions in two discrete phases: an initial burst released over the first day and after several weeks or months, a second burst of protein was released. The second burst of protein was dependent upon the PLGA inherent viscosity and lactide/glycolide ratio (bulk erosion). These studies demonstrate that it is possible to achieve a vaccine response using injectable microparticles. However, no such product has ever been approved for human or animal use. It is difficult to achieve effective loading of antigen, uniformity of encapsulation and release, and extremely low levels of solvent not affecting antigenicity. It is estimated that precluding the need for a “cold chain” for vaccine distribution through the development of thermo-stable formulations could save about $200 million annually. Trouble with implementing these strategies rests on the lack of appropriate cryprotectant methods. A Summarized in Kirby et al., Chapter 13: Formation and Characterisiation of polyl