# US 10,864,158 B2 · Multilayer thin film drug delivery device and methods of making and using the same

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- Number: US 10,864,158 B2
- Document ID: US10864158B2
- Status: Granted
- Kind: B2
- Application number: 14/110,549
- Filed: 2012-04-12
- Published: 2014-06-19
- Granted: 2020-12-15
- Earliest claimed: 2011-04-14
- Assignees: The Regents of the University of California
- Applicants: Tejal A. Desai; Mark Rory Steedman; Robert Bhisitkul; Daniel A. Bernards; Kevin D. Lance
- Inventors: Tejal A. Desai; Mark Rory Steedman; Robert Bhisitkul; Daniel A. Bernards; Kevin D. Lance
- Web page: https://patentgrep.com/patent/US10864158B2

## CPC

- A61K 9/0048: {Eye, e.g. artificial tears}
- A61F 9/0017: {implantable in, or in contact with, the eye, e.g. ocular inserts}
- A61K 9/0051: {Ocular inserts or implants}
- A61K 9/7007: {Drug-containing films, membranes or sheets (A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence)}
- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61K 47/42: Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34)
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- B82Y 30/00: Nanotechnology for materials or surface science, e.g. nanocomposites
- B82Y 40/00: Manufacture or treatment of nanostructures
- C08J 5/18: Manufacture of films or sheets
- A61K 9/2086: {Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat (active cores with a complete drug-free outer coat A61K9/28)}
- C08J 2300/16: Biodegradable polymers
- C08J 2367/04: Polyesters derived from hydroxy carboxylic acids, e.g. lactones (C08J2367/06 takes precedence)
- C08J 2489/06: derived from leather or skin
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61F: FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS (dental prosthetics A61C)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- C08J: WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H (working, e.g. shaping, of plastics B29)

## Abstract

Multilayer thin film devices that include a bioactive agent for elution to the surrounding tissue upon administration to a subject are provided. The multilayer thin film devices are useful as medical devices, such as ocular devices. Also provided are methods and kits for localized delivery of a bioactive agent to a tissue of a subject, and methods of preparing the subject devices. The multilayer thin film medical device includes a first layer, a bioactive agent and a second layer. The first and the second layers may be porous or non-porous. The devices have a furled structure, suitable for administration to a subject.

## Claims

### Claim 1

A multilayer thin film medical device, comprising:
a first layer comprising a polymer, wherein the polymer is selected from the group consisting of poly(ε-caprolactone) (PCL), polylactide (PLA), polyglycolide (PGA), poly(DL-lactide-co-glycolide) (PLGA), and poly(DL-lactide-co-ϑ-caprolactone) (DLPLCL), wherein the first layer does not include a water soluble polymer, wherein the first layer comprises a first surface and a second surface opposite the first surface;
a layer of lyophilized bioactive agent in absence of a polymer; and
a second layer comprising a polymer, wherein the polymer is selected from the group consisting of poly(ε-caprolactone) (PCL), polylactide (PLA), polyglycolide (PGA), poly(DL-lactide-co-glycolide) (PLGA), and poly(DL-lactide-co-ϑ-caprolactone) (DLPLCL), wherein the second layer does not include a water soluble polymer, wherein the second layer comprises a first surface and a second surface opposite the first surface;
wherein the bioactive agent is positioned only between the second surface of the first layer and the first surface of the second layer,
wherein the second surface of the first layer is in contact with the first surface of the second layer at the periphery of the multilayer thin film medical device and wherein the contact extends from the periphery of the device to a periphery of the location at which the bioactive agent is positioned thereby sealing the bioactive agent inside the multilayer thin film medical device, wherein the contact does not extend to regions in interior of the device,
wherein the bioactive agent is not positioned between the first and the second layers at the periphery of the multilayer thin film medical device,
wherein the device has an area between 1 mm2 and 36 mm2,
wherein the device has a thickness between 10 μm and 500 μm, and
wherein the device provides a zero order release of the bioactive agent over at least 10 days following administration.

### Claim 2 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the first layer has a % porosity between about 20% and about 0.01%.

### Claim 3 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the first layer has an average pore size of 30 μm or less.

### Claim 4 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the device is circular and has a diameter between 2 mm and 50 mm.

### Claim 5 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the second layer is biodegradable.

### Claim 6 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the second layer comprises PCL.

### Claim 7 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the bioactive agent is disposed in a plurality of reservoirs located across one surface of the second layer.

### Claim 8 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the second layer comprises a plurality of reservoirs located across one surface of the second layer, wherein a first reservoir of the plurality of reservoirs comprises the bioactive agent and a second reservoir of the plurality of reservoirs comprises another bioactive agent.

### Claim 9 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the bioactive agent is a protein therapeutic, a small molecule drug, a large molecule drug or an aptamer.

### Claim 10 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the bioactive agent is a protein therapeutic selected from ranibizumab, bevacizumab, trastuzumab, rituximab, gentuzumab ozogamicin and cetuximab.

### Claim 11 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the bioactive agent is a small molecule therapeutic selected from steroids, rapamycin, or prostaglandin.

### Claim 12 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the first and second layers are formed from a single film folded over the bioactive agent and sealed at the periphery.

### Claim 13 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the polymer has a molecular weight of 80 KDa and does not start to degrade until after 1 year after in vivo placement.

### Claim 14 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the polymer has a molecular weight of 15 kDa-20 kDa and does not start to degrade until after 4 months after in vivo placement.

### Claim 15 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the first layer is a non-porous layer and the second layer is a nanoporous layer comprising pores 7 nm-50 nm in diameter, and wherein the device has a diameter of 1 mm-2 mm.

### Claim 16 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the first layer is a non-porous layer and the second layer is a non-porous layer and wherein the bioactive agent is a small molecule therapeutic.

### Claim 17 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the device comprises a furled structure or an unfurled structure.

### Claim 18 (depends on 17)

The multilayer thin film medical device of claim 17, wherein the furled structure is substantially cylindrical or frusto-conical.

### Claim 19 (depends on 17)

The multilayer thin film medical device of claim 17, wherein the unfurled structure comprises a substantially circular peripheral edge.

### Claim 20 (depends on 1)

The multilayer thin film medical device of claim 1, further comprising a third nanostructured porous layer positioned between the first layer and the bioactive agent.

### Claim 21 (depends on 20)

The multilayer thin film medical device of claim 20, wherein the second layer comprises a plurality of reservoirs located across one surface of the second layer, wherein a first reservoir of the plurality of reservoirs comprises the bioactive agent and a second reservoir of the plurality of reservoirs comprises another bioactive agent.

### Claim 22 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the first layer and/or the second layer comprises engineered pores.

### Claim 23 (depends on 22)

The multilayer thin film medical device of claim 22, wherein the engineered pores are nanopores.

### Claim 24 (depends on 22)

The multilayer thin film medical device of claim 22, wherein the engineered pores are micropores.

### Claim 25 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the first layer further comprises a high molecular weight polymer having a molecular weight of at least 80 kDa and a low molecular weight polymer having a molecular weight of 20 kDa or less.

### Claim 26 (depends on 25)

The multilayer thin film medical device of claim 25, wherein ratio by mass of the low molecular weight polymer to the high molecular weight polymer is 3:2.

### Claim 27 (depends on 25)

The multilayer thin film medical device of claim 25, wherein the ratio by mass of the low molecular weight polymer to the high molecular weight polymer is 2:3.

### Claim 28 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the first layer is a non-porous layer and the second layer is a microporous layer comprising pores 1-10 μm in diameter, and wherein the device has a diameter of 1 mm-2 mm.

### Claim 29 (depends on 28)

The multilayer thin film medical device of claim 28, wherein the first layer comprises nanopores, wherein the device comprises a third polymer layer comprising micropores wherein the third layer is in contact with the first surface of the first layer and serves as a structural support for the first layer.

### Claim 30 (depends on 29)

The multilayer thin film medical device of claim 29, wherein the second layer is a nonporous layer and wherein the nanopores are 7 nm-50 nm in diameter and the micropores are 1 μm-10 μm in diameter.

### Claim 31 (depends on 1)

The multilayer thin film medical device of claim 1, wherein the first layer comprises nanopores, wherein the device comprises a third polymer layer comprising micropores wherein the third layer is in contact with the first surface of the first layer and serves as a structural support for the first layer.

### Claim 32 (depends on 31)

The multilayer thin film medical device of claim 31, wherein the second layer is a nonporous layer and wherein the nanopores are 7 nm-50 nm in diameter and the micropores are 1-10 μm in diameter.

### Claim 33

A multilayer thin film medical device, comprising:
a first layer consisting of a polymer, wherein the polymer is selected from the group consisting of poly(ε-caprolactone) (PCL), polylactide (PLA), polyglycolide (PGA), poly(DL-lactide-co-glycolide) (PLGA), and poly(DL-lactide-co-ε-caprolactone) (DLPLCL), wherein the first layer comprises a first surface and a second surface opposite the first surface;
a layer of bioactive agent in a lyophilized form, wherein the layer does not include a gel matrix; and
a second layer consisting of a polymer, wherein the polymer is selected from the group consisting of PCL, PLA, PGA, PLGA, and DLPLCL, wherein the second layer comprises a first surface and a second surface opposite the first surface;
wherein the bioactive agent is positioned only between the second surface of the first layer and the first surface of the second layer,
wherein the second surface of the first layer is in contact with the first surface of the second layer at the periphery of the multilayer thin film medical device and wherein the contact extends from the periphery of the device to a periphery of the layer of the bioactive agent thereby sealing the bioactive agent inside the multilayer thin film medical device, wherein the contact does not extend to regions in interior of the device,
wherein the bioactive agent is not positioned between the first and the second layers at the periphery of the multilayer thin film medical device,
wherein the device has an area between 1 mm2 and 100 mm2,
wherein the device has a thickness between 10 μm and 500 μm, and
wherein the device provides a zero order release of the bioactive agent over at least 10 days following administration.