# US 9,517,200 B2 · Methods of delivering pharmaceutical agents

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- Number: US 9,517,200 B2
- Document ID: US9517200B2
- Status: Granted
- Kind: B2
- Application number: 15/069,647
- Filed: 2016-03-14
- Published: 2016-07-07
- Granted: 2016-12-13
- Earliest claimed: 2011-07-29
- Assignees: Massachusetts Eye and Ear Infirmary
- Applicants: Massachusetts Eye and Ear Infirmary
- Inventors: Benjamin S. Bleier
- Web page: https://patentgrep.com/patent/US9517200B2

## CPC

- A61K 9/0085: {Brain, e.g. brain implants; Spinal cord}
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/473: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 38/18: Growth factors; Growth regulators
- A61K 38/185: {Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3}
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K 47/38: Cellulose; Derivatives thereof
- A61M 31/00: Devices for introducing or retaining media, e.g. remedies, in cavities of the body (A61M25/00 takes precedence {; introducing or retaining ophthalmic products into the ocular cavities A61F9/0008})
- A61P 25/00: Drugs for disorders of the nervous system
- 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)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided are methods of delivering at least one pharmaceutical agent to the central nervous system (CNS) of a subject, methods of treating a neurological disorder or pain in a subject that include administering at least one pharmaceutical agent onto a SEM graft in the skull base of the subject. Also provided are methods of treating a neurological disorder or pain in a subject that include forming a SEM graft in the skull base of the subject and administering at least one pharmaceutical agent onto the SEM graft in the skull base of the subject. Also provided are methods of forming a SEM graft in the skull base of a subject, compositions for administration onto a SEM graft in the skull base or into an endonasal reservoir or endonasal reservoir device in a subject, and devices for administering such compositions onto a SEM graft in the skull base of a subject.

## Claims

### Claim 1

A method of delivering at least one pharmaceutical agent to the central nervous system of a subject diagnosed with stroke, the method comprising directly administering at least one pharmaceutical agent onto a semipermeable epithelial membrane (SEM) graft in the skull base of the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein the at least one pharmaceutical agent is administered into an endonasal reservoir.

### Claim 3 (depends on 1)

The method of claim 1, wherein the at least one pharmaceutical agent is placed into an endonasal reservoir device in an endogenous sinus tissue of the subject, wherein the device comprises at least one opening or permeable surface proximal to the SEM graft in the skull base and the at least one pharmaceutical agent in the endonasal reservoir device is administered onto the SEM graft in the skull base.

### Claim 4 (depends on 1)

The method of claim 1, further comprising forming a semipermeable epithelial membrane (SEM) graft in the skull base of the subject.

### Claim 5 (depends on 4)

The method of claim 4, further comprising forming a SEM graft over an endogenous sinus tissue or in a position proximal to the SEM graft in the skull base, where the SEM graft over the endogenous sinus tissue or in the position proximal to the SEM graft in the skull base forms an endonasal reservoir.

### Claim 6 (depends on 4)

The method of claim 4, further comprising:
introducing an endonasal reservoir device comprising at least one opening or permeable surface into an endogenous sinus tissue of the subject; and
placing the at least one pharmaceutical agent into the endonasal reservoir device; wherein the at least one opening or permeable surface is proximal to the SEM graft in the skull base and the at least one pharmaceutical agent in the endonasal reservoir device is administered onto the SEM graft in the skull base.

### Claim 7 (depends on 1)

The method of claim 1, wherein the forming, introducing, placing, or administering is performed by an endoscopic or interfacial procedure.

### Claim 8 (depends on 1)

The method of claim 1, wherein the SEM graft in the skull base is formed from sinonasal mucosa.

### Claim 9 (depends on 1)

The method of claim 1, wherein the SEM graft in the skull base is formed in the posterior frontal table, cribriform plate/ethmoid roof, planum sphenoidale, tuberculum, sella, clival recess, clivus, or cervical spine.

### Claim 10 (depends on 1)

The method of claim 1, wherein the at least one pharmaceutical agent is formulated as a component of a biodegradable biocompatible polymer.

### Claim 11 (depends on 10)

The method of claim 10, wherein the biodegradable biocompatible polymer is cationic.

### Claim 12 (depends on 10)

The method of claim 10, wherein the biodegradable biocompatible polymer is a gel.

### Claim 13 (depends on 12)

The method of claim 12, wherein the gel is an alginate gel, a cellulose-based gel, or a chitosan-based gel.

### Claim 14 (depends on 13)

The method of claim 13, wherein the alginate gel is sodium alginate.

### Claim 15 (depends on 13)

The method of claim 13, wherein the cellulose-based gel is carboxymethyl cellulose or carboxyethyl cellulose.

### Claim 16 (depends on 13)

The method of claim 13, wherein the chitosan-based gel is chitosan glycerophosphate.

### Claim 17 (depends on 1)

The method of claim 1, wherein the at least one pharmaceutical agent is formulated as a liquid.

### Claim 18 (depends on 17)

The method of claim 17, wherein the liquid is a thermosetting liquid.

### Claim 19 (depends on 1)

The method of claim 1, wherein the at least one pharmaceutical agent is administered in a sustained-release formulation.

### Claim 20 (depends on 1)

The method of claim 1, wherein the at least one pharmaceutical agent has a molecular size of greater than 500 Daltons, has a net negative or positive charge, or is a polar molecule.

### Claim 21 (depends on 1)

The method of claim 1, wherein the at least one pharmaceutical agent is selected from the group of: an analgesic, an anti-depressant agent, gene therapy vectors, antisense oligonucleotides, nanoparticles, fusion proteins, and small interfering RNAs (siRNAs).

### Claim 22 (depends on 21)

The method of claim 21, wherein the anti-depressant agent is a selective serotonin reuptake inhibitor.