IP Library › Granted Patent US 12,496,218
Granted Patent B1
US 12,496,218 · App. 17/096,348 · Granted Dec 16, 2025

Fractionated topical ocular drug delivery methods and devices for use in the same

Inventors: Mark S. Blumenkranz (Portola Valley, CA); Yehuda Ivri (Newport Coast, CA); Reynaldo Quintana (Menlo Park, CA); Daniel V. Palanker (Sunnyvale, CA)
Assignee: Bausch + Lomb Ireland Limited
A61F9/0008G16H20/13G16H40/67
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Quick Facts
Patent No.
US 12,496,218
App. No.
17/096,348
Granted
Dec 16, 2025
Kind
B1
Abstract

The efficacy of a dosing regimen can be altered, and preferably improved, by fractionating the doses. Here fractionating the doses can be regarded as taking a single conventional dose and splitting that dose into two or more dose-fractions delivered at relatively short time intervals, where the dose-fractions add up to the same total dose as the conventional dose. In cases where dose fractionation increases the therapeutic effect, this can result in a greater therapeutic effect from a smaller total dose when the doses are fractionated. This effect has been demonstrated in an ophthalmic application, but is expected to be more generally applicable.

Claims (36)

1 . A method of delivering a microdose of a therapeutic biological or chemical agent to an ocular surface of an eye of a patient, the method comprising:

determining a total microdose volume of the therapeutic biological or chemical agent to be delivered by a programmable handheld dispenser to the ocular surface of the eye of the patient, wherein the handheld dispenser is programmed to deliver the determined microdose;

ejecting, from the programmable handheld dispenser, a fraction of the total dose volume, each microdose-fraction having a volume between about 1 μl and about 20 μl;

determining a time interval to eject one or more subsequent microdose fractions wherein the time interval is less than the time interval at which the ocular surface returns to equilibrium; and delivering, via the programmable handheld dispenser, the total microdose volume by ejecting the microdose fractions as a stream of micro-droplets at the determined time interval, wherein a therapeutic effect is increased by delivering the therapeutic biological or chemical agent in the microdose fractions compared to delivering the total dose volume in a single microdose and wherein a concentration of the therapeutic biological or chemical agent in each microdose-fraction is 50% or less of a concentration of the therapeutic biological or chemical agent delivered in a single microdose.

2 . The method of claim 1 , wherein the time interval is within 10 seconds and 30 minutes.

3 . The method of claim 2 , wherein the time interval is between 1 minute and 10 minutes.

4 . The method of claim 1 , wherein the therapeutic biological or chemical agent is a liquid ophthalmic agent.

5 . The method of claim 4 , wherein the programmable handheld dispenser includes:

a container configured to hold the liquid ophthalmic agent and having an aperture, wherein the programmable handheld dispenser is configured to emit each microdose-fraction from the container through the aperture when one or more pulses is exerted onto the liquid in the container.

6 . The method of claim 1 , further comprising,

fractionating a second total microdose volume into two or more microdose-fractions, each microdose-fraction having a volume between about 1 μl and 20 μl, and

delivering the second total dose as microdose-fractions an hour or more after the total dose volume.

7 . The method of claim 1 , wherein the programmable handheld dispenser is configured to provide a dose-fraction signal when a next microdose-fraction is due to be delivered.

8 . The method of claim 1 , wherein the programmable handheld dispenser is configured to provide a total-dose signal when a next total-dose is due to be delivered.

9 . The method of claim 1 , wherein the programmable handheld dispenser is in wireless communication with one or more remote devices to provide one or more functions selected from the group consisting of: remote dose monitoring, remote modification of microdose-fraction reminder timing, remote modification of fractionated-microdose reminder timing, remote modification of dose-fraction mass delivery, and remote modification of fractionated-microdose mass delivery, and

wherein the method further comprises providing at least one of the one or more functions via the one or more remote devices.

10 . The method of claim 1 , wherein the total microdose volume is fractionated into more than two microdose fractions.

11 . A method of delivering a microdose of a medication to a patient, the method comprising;

determining a total dose volume of the medication to be delivered by a programmable handheld dispenser to the patient, wherein the handheld dispenser is programmed to deliver the determined total dose volume in two or more microdose-fractions;

ejecting, via the programmable handheld dispenser, one of the microdose-fractions, each microdose-fraction having a volume between about 1 μl and about 20 μl;

wherein the ejecting of each of the microdose-fractions is separated by a time interval until the determined total dose volume is delivered by the programmable handheld dispenser, wherein the time interval is less than the time interval at which an ocular surface returns to equilibrium; altering one or more biological effects of the medication in the patient by the ejecting of the total dose volume into the two or more microdose-fractions; wherein a therapeutic effect is increased by delivering the medication in the microdose fractions compared to delivering the total dose volume in a single microdose and wherein a concentration of the medication in each microdose fraction is 50% or less of a concentration of the medication in a single microdose;

wherein the programmable handheld dispenser is in wireless communication with one or more remote devices to provide one or more functions selected from the group consisting of:

remote dose monitoring, remote modification of microdose-fractions reminder timing, remote modification of fractionated-microdose reminder timing, remote modification of microdose-fraction mass delivery, and remote modification of fractionated-microdose mass delivery; and providing at least one of the one or more functions via the one or more remote devices.

12 . The method of claim 11 , wherein a therapeutic effect of the medication in humans is increased by the fractionating the total dose into the two or more microdose-fractions.

13 . The method of claim 11 , wherein the time interval is within 10 seconds and 30 minutes.

14 . The method of claim 13 , wherein the time interval is between 1 minute and 10 minutes.

15 . The method of claim 11 , wherein the medication is a liquid ophthalmic agent for topical application to an eye of the patient.

16 . The method of claim 15 , wherein the programmable handheld dispenser includes:

a container configured to hold the liquid ophthalmic agent and having an aperture, wherein the programmable handheld dispenser is configured to emit the microdose fractions from the container through the aperture when one or more pulses is exerted onto the liquid in the container.

17 . The method of claim 11 , further comprising,

fractionating a second total dose volume into two or more microdose-fractions, each microdose-fraction having a volume between about 1 μl and 20 μl, and

delivering the second total dose volume as microdose-fractions an hour or more after the total dose volume.

18 . The method of claim 11 , wherein the programmable handheld dispenser is configured to provide a dose-fraction signal when a next microdose-fraction is due to be delivered.

19 . The method of claim 11 , wherein the programmable handheld dispenser is configured to provide a total-dose signal when a next total-dose is due to be delivered.

20 . A method of delivering a microdose of a medication to a patient, the method comprising;

ejecting, via a programmable handheld dispenser, a fraction of a determined total dose volume into two or more microdose-fractions, each microdose-fraction having a volume between about 1 μl and 20 μl, wherein the handheld dispenser is programmed to deliver the determined microdose; wherein a therapeutic effect is increased by delivering the medication in the microdose fractions over delivering the total dose volume in a single dose, wherein a concentration of active drug in each microdose-fraction is 50% or less of the concentration of the active drug than if delivered to the patient in a single dose, providing a time window within which a subsequent microdose-fraction is ejected; and ejecting, from the programmable handheld dispenser, a series of subsequent microdose-fractions, whereby a time interval between each subsequent microdose-fraction varies, so long as the time interval is within the provided time window, and wherein the time interval is less than the time interval at which the ocular surface returns to equilibrium.

Assignments (7)
INTELLECTUAL PROPERTY SECURITY AGREEMENT Recorded Dec 23, 2025
From: BAUSCH + LOMB IRELAND LIMITED
To: CITIBANK, N.A., AS NOTES COLLATERAL AGENT
Reel/Frame 074050/0709 →
INTELLECTUAL PROPERTY SECURITY AGREEMENT Recorded Dec 23, 2025
From: BAUSCH + LOMB IRELAND LIMITED
To: CITIBANK, N.A., AS NOTES COLLATERAL AGENT
Reel/Frame 074050/0682 →
INTELLECTUAL PROPERTY SECURITY AGREEMENT Recorded Dec 23, 2025
From: BAUSCH + LOMB IRELAND LIMITED
To: JPMORGAN CHASE BANK, N.A., AS COLLATERAL AGENT
Reel/Frame 074050/0573 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 9, 2023
From: NOVARTIS AG
To: BAUSCH + LOMB IRELAND LIMITED
Reel/Frame 065531/0583 →
CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNMENT AGREEMENT PREVIOUSLY RECORDED ON REEL 062116 FRAME 0917. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Jul 10, 2023
From: KEDALION THERAPEUTICS, INC.
To: NOVARTIS AG
Reel/Frame 064237/0507 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 13, 2022
From: KEDALION THERAPEUTICS, INC.
To: NOVARTIS AG
Reel/Frame 062116/0917 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 1, 2020
From: BLUMENKRANZ, MARK S.; IVRI, YEHUDA; QUINTANA, REYNALDO; PALANKER, DANIEL V.
To: KEDALION THERAPEUTICS, INC.
Reel/Frame 054507/0869 →
Continuity (6)
Provisional Application 63049582 · Jul 8, 2020
Provisional Application 63049110 · Jul 7, 2020
Provisional Application 63011808 · Apr 17, 2020
Provisional Application 63011800 · Apr 17, 2020
Provisional Application 62951903 · Dec 20, 2019
Provisional Application 62934225 · Nov 12, 2019
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