# US 2021/0330588 A1 · Compositions and methods for administering anesthetics

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- Number: US 2021/0330588 A1
- Document ID: US20210330588A1
- Status: Published application
- Kind: A1
- Application number: 17/284,171
- Filed: 2019-10-10
- Published: 2021-10-28
- Earliest claimed: 2018-10-12
- Assignees: Children's Medical Center Corporation
- Applicants: Children's Medical Center Corporation
- Inventors: Daniel S. Kohane; Tianjiao Ji; Christopher B. Weldon
- Web page: https://patentgrep.com/patent/US20210330588A1

## CPC

- A61K 9/1271: Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911})
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)}
- A61K 9/143: {with inorganic compounds}
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- 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)

## Abstract

Compositions and methods of use related to formulations comprising anesthetics are generally described. Some embodiments are directed to compositions comprising a plurality of micelles and/or particles, and an anesthetic contained internally. These can be used to control and/or prolong the duration of IVRA while reducing the risk of systemic toxicity commonly due to administering anesthetics. The control and/or prolonged duration of IVRA may be due, at least in part, to the attachment of the sufficiently small micelles and/or particles to a biointerface (e.g., blood vessel surface) where the composition has been administered. Conventional IVRA methods commonly do not utilize potent and long-acting anesthetics (e.g., bupivacaine) due to the risks of cardiac toxicity. The compositions and methods described herein, however, provide a pathway for increased safety and efficiency of the use of such anesthetics, in certain embodiments. Resultantly, the performance (e.g., anesthetic distribution) of the micelles and/or particles internally containing an anesthetic may be comparatively better than the performance of free anesthetic, e.g., with respect to nerve blood and systematic drug distribution.

## Claims

### Claim 1

A composition, comprising:
a plurality of micelles and/or particles comprising PEGylated lipids and/or polymers; and
an anesthetic contained internally of the micelles and/or particles,
wherein the micelles and/or particles have an average cross-sectional diameter of less than or equal to 30 nm.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the plurality of micelles comprises PEGylated lipids and/or polymers.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the plurality of particles comprises PEGylated lipids and/or polymers.

### Claim 4

The composition of any one of the preceding claims, wherein the PEGylated lipids and/or polymers comprise DSPE-PEG, DPPE-PEG, DMPE-PEG, PEG-PLGA, and/or PEG-PLA.

### Claim 5

The composition of any one of the preceding claims, wherein the PEGylated lipids and/or polymers have a molecular weight in the range of 200 Daltons to 5,000 Daltons.

### Claim 6

The composition of any one of the preceding claims, wherein the PEGylated lipids and/or polymers comprise DSPE-PEG(2000).

### Claim 7

The composition of any one of the preceding claims, wherein the micelles and/or particles have an average cross-sectional diameter of less than or equal to 20 nm.

### Claim 8

The composition of any one of the preceding claims, wherein the micelles and/or particles have an average cross-sectional diameter of less than or equal to 15 nm.

### Claim 9

The composition of any one of the preceding claims, wherein the anesthetic is a local anesthetic.

### Claim 10

The composition of any one of the preceding claims, wherein the anesthetic is an amide-containing anesthetic.

### Claim 11

The composition of any one of the preceding claims, wherein the anesthetic is an amino-amide anesthetic.

### Claim 12

The composition of any of the preceding claims, wherein the anesthetic comprises articaine, bupivacaine, cinchocaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, and/or trimecaine.

### Claim 13

The composition of any one of the preceding claims, wherein the anesthetic is bupivacaine.

### Claim 14

The composition of any one of the preceding claims, wherein the anesthetic is lidocaine.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The composition of any one of claims 1-9, wherein the anesthetic is an amino-ester anesthetic.

### Claim 16 (depends on 15)

The composition of claim 15, wherein the anesthetic comprises comprise, benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine, piperocaine, propoxycaine, procaine, and/or tetracaine.

### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The composition of any one of claims 1-9, wherein the anesthetic comprises saxitoxin, neosaxitoxin, tetrodotoxin, menthol, eugenol, spilanthol, iontocaine, epinephrine, adrenaline, a vasoconstrictor, an adjuvant compound, a capsinoid, and/or a sodium channel blocker.

### Claim 18

The composition of any one of the preceding claims, wherein the composition comprises an additive.

### Claim 19 (depends on 18)

The composition of claim 18, wherein the additive comprises a salt, an organic acid, a peptide, a protein, a steroid, and/or a hyperpolarization-activated cation channel blocker.

### Claim 20

The composition of any one of the preceding claims, wherein the composition comprises the anesthetic in an amount of greater than or equal to 10 wt. %.

### Claim 21

The composition of any one of the preceding claims, wherein the composition comprises bupivacaine in an amount of greater than or equal to 10 wt. %.

### Claim 22

The composition of any one of the preceding claims, wherein the composition has a surface area-to-volume ratio of greater than about 0.10 and less than about 0.70.

### Claim 23

The composition of any one of the preceding claims, wherein the composition is formulated via film dispersion.

### Claim 24 (depends on 1)

A method, comprising treating a subject in need of an anesthetic with the composition of claim 1.

### Claim 25

A composition, comprising:
a plurality of micelles and/or particles having an average cross-sectional diameter of less than or equal to 30 nm; and
an anesthetic contained internally within the plurality of micelles and/or particles.

### Claim 26 (depends on 25)

The composition of claim 25, wherein the plurality of micelles and/or particles comprise lipids and/or polymers.

### Claim 27 (depends on 25)

The composition of claim 25, wherein the plurality of micelles and/or particles comprise PEGylated lipids and/or polymers.

### Claim 28 (depends on 25)

The composition of claim 25, wherein the plurality of micelles and/or particles comprise silica based micelles and/or particles.

### Claim 29 (depends on 25)

The composition of claim 25, wherein the plurality of micelles and/or particles comprise dendritic lipids and/or polymers.

### Claim 30

A method of delivering an anesthetic to a subject, comprising:
decreasing blood circulation in an extremity of a subject by at least 50%;
intravenously administering a composition comprising a plurality of micelles and/or particles to the extremity, the micelles and/or particles internally containing an anesthetic, wherein at least 50 mass % of the micelles and/or particles attach to a blood vessel surface within the extremity; and
restoring blood circulation in the extremity of the subject.

### Claim 31 (depends on 30)

The method of claim 30, comprising decreasing blood circulation in the extremity of the subject by 100%.

### Claim 32 (depends on 30)

The method of claim 30, wherein the PEGylated lipids and/or polymers comprise DSPE-PEG, DPPE-PEG, DMPE-PEG, PEG-PLGA, and/or PEG-PLA.

### Claim 33 (depends on 30, 31, 32)

The method of any one of claims 30-32, wherein the PEGylated lipids and/or polymers have a molecular weight in the range of 200 Daltons to 5,000 Daltons.

### Claim 34 (depends on 30, 31, 32, 33)

The method of any one of claims 30-33, wherein the PEGylated lipids and/or polymers comprise DSPE-PEG(2000).

### Claim 35 (depends on 30, 31, 32, 33, 34)

The method of any one of claims 30-34, wherein the micelles and/or particles have an average cross-sectional diameter of less than or equal to 30 nm.

### Claim 36 (depends on 30, 31, 32, 33, 34, 35)

The method of any one of claims 30-35, wherein the micelles and/or particles have an average cross-sectional diameter of less than or equal to 20 nm.

### Claim 37 (depends on 30, 31, 32, 33, 34, 35, 36)

The method of any one of claims 30-36, wherein the micelles and/or particles have an average cross-sectional diameter of less than or equal to 15 nm.

### Claim 38 (depends on 30, 31, 32, 33, 34, 35, 36, 37)

The method of any one of claims 30-37, wherein the subject is a human.

### Claim 39 (depends on 30, 31, 32, 33, 34, 35, 36, 37)

The method of any one of claims 30-37, wherein the subject is an animal.

### Claim 40 (depends on 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)

The method of any one of claims 30-39, wherein the blood vessel surface is a blood vein surface.

### Claim 41 (depends on 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)

The method of any one of claims 30-40, wherein the extremity is an arm.

### Claim 42 (depends on 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)

The method of any one of claims 30-40, wherein the extremity is a leg.

### Claim 43 (depends on 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)

The method of any one of claims 30-40, wherein the extremity is a tail.

### Claim 44 (depends on 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43)

The method of any one of claims 30-43, wherein the method is intravenous regional anesthesia.

### Claim 45 (depends on 44)

The method of claim 44, wherein the intravenous regional anesthesia lasts for at least 4 hours.

### Claim 46 (depends on 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45)

The method of any one of claims 30-45, wherein the micelles and/or particles release 90% of the local anesthetic into the extremity.

### Claim 47 (depends on 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46)

The method of any one of claims 30-46, wherein decreasing blood circulation in the extremity of the subject comprises applying a tourniquet to the extremity of the subject.

### Claim 48 (depends on 47)

The method of claim 47, wherein restoring blood circulation in the extremity of the subject comprises removing the tourniquet from the extremity of the subject.

### Claim 49 (depends on 48)

The method of claim 48, wherein removing the tourniquet from the extremity takes place at least fifteen minutes after applying the tourniquet to the extremity.

### Claim 50 (depends on 48, 49)

The method of any one of claims 48-49, wherein upon removing the tourniquet from the extremity, the concentration of anesthetic in blood of the extremity is less than or equal to 2 mg/mL.

### Claim 51 (depends on 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50)

The method of any one of claims 30-50, wherein the anesthetic comprises bupivacaine.

### Claim 52 (depends on 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51)

The method of any one of claims 30-51, wherein the anesthetic comprises lidocaine.

### Claim 53 (depends on 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52)

The method of any one of claims 30-52, wherein the composition has a surface area-to-volume ratio of greater than about 0.10 and less than about 0.70.

### Claim 54 (depends on 53)

The method of claim 53, wherein the at least 50 mass % of the micelles and/or particles attach to the blood vessel surface due at least in part to the surface area-to-volume ratio.

### Claim 55 (depends on 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54)

The method of claim 30-54, wherein the at least 50 mass % of the micelles and/or particles attach to the blood vessel surface due at least in part to electrostatic interactions and/or hydrogen-bonding between the micelles and/or particles and the blood vessel surface.

### Claim 56 (depends on 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55)

The method of any one of claims 30-55, wherein the at least 50 mass % of the micelles and/or particles attach to the blood vessel surface due at least in part to the average cross-sectional diameter of less than or equal to 30 nm.

### Claim 57 (depends on 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56)

The method of any one of claims 30-56, wherein the micelles and/or particles release the anesthetic upon attaching to the blood vessel surface.

### Claim 58

A method of delivering an anesthetic to a subject, comprising:
applying a tourniquet to an extremity of the subject;
administering a composition to the extremity, the composition comprising a plurality of micelles and/or particles having an average cross-sectional diameter of less than or equal to 30 nm, and internally containing an anesthetic; and
removing the tourniquet from the extremity.

### Claim 59

A method of delivering a drug to a subject, comprising:
applying a tourniquet to an extremity of the subject;
administering a composition to the extremity, the composition comprising a plurality of micelles and/or particles having an average cross-sectional diameter of less than or equal to 30 nm, and internally containing a drug; and
removing the tourniquet from the extremity.

### Claim 60 (depends on 59)

The method of claim 59, wherein the drug comprises an anesthetic.

### Claim 61 (depends on 59)

The method of claim 59, wherein the subject is in need of anesthesia.

### Claim 62 (depends on 59)

The method of claim 59, wherein the drug comprises an anti-cancer drug.

### Claim 63 (depends on 59)

The method of claim 59, wherein the subject has cancer.

### Claim 64

A method of delivering a drug to a subject, comprising:
decreasing blood circulation in an extremity of a subject by at least 50%;
intravenously administering a composition comprising a plurality of micelles and/or particles to the extremity, the micelles and/or particles internally containing a drug, wherein at least 50 mass % of the micelles and/or particles attach to a blood vessel surface within the extremity; and
restoring blood circulation in the extremity of the subject.