Therapeutic agent formulations for implanted devices

Patent metadata

Field	Value
Publication number	US-11065151-B2
Application number	US-202017127741-A
Country	US
Kind code	B2
Filing date	Dec 18, 2020
Priority date	Nov 19, 2010
Publication date	Jul 20, 2021
Grant date	Jul 20, 2021

Abstract

An injectable formulation of therapeutic agent may comprise the therapeutic agent and a stabilizer such that a substantial portion of the stabilizer remains in the therapeutic device to stabilize the therapeutic agent when the therapeutic agent is released from the therapeutic device. The injectable formulation may comprise one or more of binding agent particles or erodible material particles, such that the formulation can be injected into the therapeutic device. The binding agent particles can bind reversibly to the therapeutic agent so as to modulate release of the therapeutic agent, and the erodible material particles can generate protons of an acid so as to increase stability of the therapeutic agent and may modulate release of the therapeutic agent. The therapeutic agent can be combined with one or more of the stabilizer, the binding agent particles or the erodible particles to increase stability of the therapeutic agent and may modulate release.

First claim

What is claimed is:

1. A therapeutic device comprising:
(i) a flowable formulation provided within the therapeutic device, the formulation comprising: a therapeutic agent having a molecular weight; and a stabilizer selected based on the stabilizer having a molecular weight that is at least 10% of the molecular weight of the therapeutic agent; wherein the molecular weight of the stabilizer is at least 10% of the molecular weight of the therapeutic agent such that the half-life of the stabilizer when placed in the device comprises at least about 50% of the half-life of the therapeutic agent when placed in the device;
(ii) a retention structure near a proximal end of the therapeutic device having an indentation sized to receive a sclera;
(iii) a refillable, non-permeable chamber coupled to the retention structure and configured to hold the formulation, the chamber having at least one opening to release the therapeutic agent to a vitreous humour when said device is implanted in any eye;
(iv) a penetrable barrier disposed through the retention structure and the indentation into a proximal end of the chamber; and
(v) a rigid porous structure placed in the at least one opening, the rigid porous structure comprising sintered metal, ceramic, glass, or plastic material allowing for molecular diffusion of the therapeutic agent and the stabilizer from the chamber into the vitreous humor for an extended amount of time.

2. The device of claim 1 , wherein the stabilizer comprises one or more of a buffer to maintain a pH of the formulation, hydrophilic functional groups to provide a co-solvent stabilization, a charged functional group to provide charge interaction, or a functional group to form a complex with the therapeutic agent, so as to increase one or more of physical stability or chemical stability of the therapeutic agent and maintain biological activity of the therapeutic agent; and optionally wherein the stabilizer is soluble and comprises one or more of a sugar, an alcohol, a polyol, or a carbohydrate and wherein the functional group comprises a hydroxyl group.

3. The device of claim 1 , wherein the molecular weight of the stabilizer is at least about 3 k Daltons.

4. The device of claim 1 , wherein the molecular weight of the stabilizer is at least about 25% of the molecular weight of the therapeutic agent, and optionally no more than about 500% of the molecular weight of the therapeutic agent when the stabilizer is water soluble.

5. The device of claim 4 , wherein the molecular weight of the therapeutic agent is at least about 40 k Daltons.

6. The device of claim 5 , wherein the therapeutic agent comprises a Fab antibody fragment or a derivative thereof, optionally wherein the therapeutic agent comprises the Fab antibody fragment and deamidized derivatives of the Fab antibody fragment.

7. The device of claim 6 , wherein the therapeutic agent comprises ranibizumab or ranibizumab and degradation products of ranibizumab, wherein the degradation products optionally comprise one or more of deamidized ranibizumab or oxidized ranibizumab.

8. The device of claim 1 , wherein the stabilizer comprises:
(i) one or more of: HA (hyaluronic acid) having the molecular weight of at least 2 k Daltons, histidine polymer buffer having the molecular weight of at least 2 k Daltons, sugar having the molecular weight of at least 2 k Daltons, polysaccharides having the molecular weight of at least 2 k Daltons, carbohydrate having the molecular weight of at least 2 k Daltons, starch having the molecular weight of at least 2 k Daltons, alcohol having the molecular weight of at least 2 k Daltons, polyol having the molecular weight of at least 2 k Daltons, or polyethylene oxide having the molecular weight of at least 2 k Daltons, so as to stabilize the therapeutic agent and decrease release of the therapeutic agent when placed in a therapeutic device; or
(ii) one or more of: a phenol, a protein, or a charged stabilizers, such as a metal comprising one or more of zinc ion, calcium ion, or iron ion, so as to form a reversible complex with the therapeutic agent; or
(iii) a plurality of micelles, wherein the molecular weight of the stabilizer corresponds to a weight of each micelle of the plurality such that diffusion of the plurality of micelles corresponds to the weight of said each micelle.

9. The device of claim 1 , wherein the chamber of the device comprises:
(i) a plurality of particles having a dimension across within a range from about 0.1 um across to about 200 um across, such that the plurality of particles is sized to pass through a lumen of a needle, which dimension across is optionally within a range from about 0.1 um across to about 50 um across such that the plurality of particles is sized to pass through a lumen of a 33 Gauge needle; or
(ii) comprises a plurality of pellets having a dimension across within a range from about 0.1 um to about 500 um, such that the plurality of pellets are sized to pass through a lumen of a 19 Gauge needle, wherein the plurality of pellets optionally comprises one or more of a plurality of stabilizer particles, a plurality of erodible particles to generate protons of an acid, or a plurality of binding agent particles.

10. The device of claim 1 , further comprising a plurality of particles of an erodible material to release protons of an acid, wherein the plurality of particles optionally comprises the stabilizer mixed with the erodible material to provide the stabilizer when the particles erode.

11. The device of claim 10 , wherein the plurality of erodible particles comprises one or more of a suspension or a slurry of the erodible particles for injection into or exchange from the therapeutic device.

12. The device of claim 10 , wherein the formulation comprises a pH of at least about 5.5 and the plurality of particles of formulation is capable of releasing about 1×10 10 moles of protons per uL of device reservoir volume so as to maintain a pH of the formulation below about 7 for an extended time of at least about one month.

13. The device of claim 10 , wherein the plurality of particles of the erodible material comprises an amount corresponding to about 0.01% to about 5% by weight of the formulation, optionally wherein the erodible material is a polymer, the polymer comprising one or more of polylactic acid (PLA), polyglutamic acid (PGA), and PLA/PGA copolymer.

14. The device of claim 10 , further comprising:
(i) an amount of the erodible material to maintain the pH of the chamber of the device at no more than about 6.5 for an extended time of at least about one month when injected into the chamber of the therapeutic device when coupled to the eye with the porous structure; or
(ii) an amount of an erodible material to maintain the pH of the chamber at no more than about 6.0 for an extended time of at least about one month or at least about three months when exposed to physiological phosphate buffer diffused through the porous structure.

Assignees

• Forsight Vision4 Inc

Inventors

• De Juan Jr Eugene
• Alster Yair
• Chamow Steven M
• Farinas Kathleen Cogan
• Macfarlane K Angela
• Reich Cary J
• Campbell Randolph E
• Erickson Signe
• Bueche Blaine

Classifications

• A61K9/0051 Primary

  Ocular inserts or implants · CPC title

• A61K31/573

  substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone · CPC title

• A61K9/1647

  Polyesters, e.g. poly(lactide-co-glycolide) · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61K9/1652

  Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623) · CPC title