Claims for Patent: 9,452,138

Summary for Patent: 9,452,138

Title:	Delivery of biologic therapeutics
Abstract:	Formulations and methods are disclosed which provide controlled, sustained release of a biologic therapeutic to a space within the body. More specifically, formulations comprising a plurality of hydrophilic polymer strands, and methods of forming and administering such formulations, are disclosed. In some embodiments, the formulations exhibit a burst release, an initial release, a triphasic release, and release over thirty to ninety days of the biologic therapeutic. In some embodiments, the formulations exhibit reversible precipitation of the biologic therapeutic into precipitates having a diameter of about 50 nm to about 10 .mu.m.
Inventor(s):	Trollsas; Mikael (San Jose, CA), Stankus; John (Campbell, CA), Su; James (San Bruno, CA), Hossainy; Syed (hayward, CA), Smith; Joshua Takeshi (Campbell, CA), Askar; Shadid (Round Rock, TX)
Assignee:	Abbott Cardiovascular Systems Inc. (Santa Clara, CA)
Application Number:	14/142,651
Patent Claims:	1. A formulation comprising: (a) a biologic therapeutic; and (b) a plurality of hydrophilic polymer strands comprising a functional group capable of inter-polymer cross-linking; wherein the plurality of hydrophilic polymer strands comprises PEG-acrylate and PEG-thiol; wherein the weight ratio of the biologic therapeutic to the plurality of hydrophilic polymer strands is between 1:1 and 1:125; wherein said formulation, when cross-linked, forms a hydrogel that exhibits reversible precipitation of the biologic therapeutic into precipitates having a size of about 50 nm to about 10 .mu.m in diameter, and exhibits a triphasic release profile of the biologic therapeutic. 2. The formulation of claim 1, wherein the biologic therapeutic is a protein. 3. The formulation of claim 2, wherein the protein is an antibody. 4. The formulation of claim 2, wherein the protein is a dual variable domain antibody. 5. The formulation of claim 2, wherein the protein is selected from the group consisting of: trastuzumab, bevacizumab, adalimumab, ranibizumab, aflibercept, etanercept, rituximab, pegfilgrastim, interferon beta-1a, and infliximab. 6. The formulation of claim 5, wherein the protein is adalimumab. 7. The formulation of claim 1, wherein each hydrophilic polymer strand of said plurality of hydrophilic polymer strands has a structure selected from the group consisting of linear, branched, star, and comb. 8. The formulation of claim 7, wherein the hydrophilic polymer strand structure is branched, star, or comb and has 2 to 16 arms. 9. The formulation of claim 8, wherein the molecular weight of each of the hydrophilic polymer strands is between about 2 and 30 kDa. 10. The formulation of claim 1, wherein PEG-acrylate has 4 or 8 or 16 arms and PEG-thiol has 4 or 8 or 16 arms. 11. The formulation of claim 1, wherein each arm of the hydrophilic polymer strands comprises a functional group. 12. The formulation of claim 10, wherein the ratio of PEG-acrylate and PEG-thiol is between 9:10 to about 10:9. 13. The formulation of claim 1, wherein PEG-acrylate has 8 arms and PEG-thiol has 8 arms. 14. The formulation of claim 1, wherein PEG-acrylate has 16 arms and PEG-thiol has 16 arms. 15. The formulation of claim 1, wherein the formulation is provided in lyophilized form. 16. The formulation of claim 15, further comprising a buffer solution. 17. The formulation of claim 16, wherein said buffer solution has a pH of about 3.5 to about 6. 18. The formulation of claim 17, wherein the weight to volume ratio of PEG-acrylate and PEG-thiol to buffer is between about 5% and about 30%. 19. The formulation of claim 1, wherein the weight ratio of biologic therapeutic to the plurality of hydrophilic polymer strands is between about 1:3.75 and 1:25. 20. A kit comprising: (a) a formulation comprising a biologic therapeutic and a plurality of hydrophilic polymer strands; wherein the plurality of hydrophilic polymer strands comprises PEG-acrylate and PEG-thiol; wherein the weight ratio of the biologic therapeutic to the plurality of hydrophilic polymer strands is between 1:1 and 1:125; and (b) an activation buffer to induce cross-linking; wherein said formulation, when cross-linked, forms a hydrogel that exhibits: (i) a burst effect of <5% of cumulative biologic therapeutic release at 24 hours post administration to a space within the body of a patient; (ii) an initial release of <10% of cumulative biologic therapeutic release at 7 days post administration to the space within the body of the patient; (iii) a triphasic release profile where the rate of release post administration to a space within the body of the patient is approximately constant for a first phase of about 0-30 days, for a second phase of about 0-30 days, and for a third phase of about 0-30 days; and (iv) a release duration of 1-3 months post administration to the space within the body of the patient for complete release of the biologic therapeutic. 21. The kit of claim 20, further comprising a delivery device for delivery of the formulation mixed with the activation buffer, wherein the delivery device is selected from a single-bore syringe, a dual-bore syringe or a multichannel delivery device comprising a mixing head. 22. A kit comprising: (a) a formulation comprising a biologic therapeutic and a plurality of hydrophilic polymer strands; wherein the plurality of hydrophilic polymer strands comprises PEG-acrylate and PEG-thiol; wherein the weight ratio of the biologic therapeutic to the plurality of hydrophilic polymer strands is between 1:1 and 1:125; and (b) an activation buffer to induce cross-linking; wherein said formulation, when cross-linked, forms a hydrogel that exhibits reversible precipitation of the biologic therapeutic into precipitates having a size of about 50 nm to about 10 .mu.m in diameter, and exhibits a triphasic release profile of the biologic therapeutic. 23. The kit of claim 22, further comprising a delivery device for delivery of the formulation mixed with the activation buffer, wherein the delivery device is selected from a single-bore syringe, a dual-bore syringe or a multichannel delivery device comprising a mixing head. 24. The formulation of claim 1, wherein the biologic therapeutic is released for 30 to 90 days. 25. The formulation of claim 1, wherein the triphasic release profile comprises a first rate of release for a first period of between about 0 to 30 days, a second rate of release for a second period of about 0 to 30 days, and a third rate of release for a third period of about 0 to 30 days.

Details for Patent 9,452,138

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Biogen Inc.	AVONEX	interferon beta-1a	For Injection	103628	05/17/1996		2039-02-26
Biogen Inc.	AVONEX	interferon beta-1a	Injection	103628	05/28/2003		2039-02-26
Biogen Inc.	AVONEX	interferon beta-1a	Injection	103628	02/27/2012		2039-02-26
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2039-02-26
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2039-02-26
Janssen Biotech, Inc.	REMICADE	infliximab	For Injection	103772	08/24/1998		2039-02-26