Ultrasonic Drug DeliveryUltrasonic Drug Delivery

Encapsulation SystemsEncapsulation SystemsPO Box 759PO Box 759

Broomall, PA 19008 USABroomall, PA 19008 USAPh: 484Ph: 484--343343--2506 / Fax 6102506 / Fax 610--356356--18661866

Bruce K. Redding Jr. Bruce K. Redding Jr.

Non-Invasive Insulin Delivery

UU--Wand Designed to Fit a WomenWand Designed to Fit a Women’’s s GripGrip

UU--Strip Insulin Patch Strip Insulin Patch & &

UU--WandWand

Skin Transport MechanismSkin Transport Mechanism

Transdermal drug deliveryThe three principal layers of the skin

Dermis

Stratum corneum

Epidermis

Hair

follicle

50 μm

15 μm

ICG Fluorescence Mode ImagingAnother feature that we looked for in the images was temporary increases in the diameter of pores or hair follicles. The images below are of the same sweat duct before and after treatment. They are not conclusive, but may indicate a slight increase.

Fluorescence 500 µm x 500 µm image at 10µm depth at time 0hr.

Fluorescence 500 µm x 500 µm image at 10µm depth after 1hr treatment.

~ 5 µm

~ 10 µm

keratinocyte

Lipid bilayers

.

Drug Delivery Pathway

UU--Strip Insulin PatchStrip Insulin PatchPhysicsPhysics

Cavitation Could Lead To Cavitation Could Lead To Drug DamageDrug Damage

Ultrasonic Massaging Action Effected By Alternating Waveform

Enlarges Pore Size

Homogenization Skin Transport

Sawtooth waveform Square waveform

Sonic Waveform Duty CyclesSonic Waveform Duty CyclesThe alternating waveform Duty Cycle means the time in The alternating waveform Duty Cycle means the time in milliseconds the signal is on a particular waveform.milliseconds the signal is on a particular waveform.Example, UExample, U--Strip insulin delivery is generally 50 Strip insulin delivery is generally 50 msecsmsecs on on sawtoothsawtooth followed by 50 followed by 50 msecsmsecs on square wave. There is a on square wave. There is a 2 2 msecmsec gap between the next sequence. At the start the gap between the next sequence. At the start the skin is primed on skin is primed on sawtoothsawtooth for 30 seconds.for 30 seconds.The UThe U--Wand, designed to deliver skin care compounds just Wand, designed to deliver skin care compounds just under the SC layer, Subunder the SC layer, Sub--Dermal delivery, operates with no Dermal delivery, operates with no Priming, and a 80 Priming, and a 80 msecmsec sawtoothsawtooth, 20 , 20 msecmsec squarewavesquarewave..The AThe A--Wand, designed to compounds transdermally, to the Wand, designed to compounds transdermally, to the dermis, operates with no Priming, and a 20 dermis, operates with no Priming, and a 20 msecmsecsawtoothsawtooth, 80 , 80 msecmsec squarewavesquarewave, but uses a higher sonic , but uses a higher sonic intensity than the Uintensity than the U--Wand.Wand.

Duty Cycle ComparisonsDuty Cycle ComparisonsProduct

ApplicationDelivery

Transdermal vs. Sub-Dermal

Device Freq.(kHz)

Intensity(mW/ sq.cm)

Skin Priming

Sawtooth Wave Duty

Cyclemsecs

Square Wave Duty Cyclemsecs

Gap Timing Between

Next Signal seriesmsecs

Insulin Delivery- Humulin

Transdermal U-Strip 23 125 30 seconds 50 50 2

Insulin Delivery- Humalog

Transdermal U-Strip 23 125 30 seconds 50 50 2

Insulin Delivery- Humulin

Transdermal A-Wand 30 225 0 50 50 2

Betadyne Transdermal A-Wand 30 225 0 20 80 2

Capoxone Transdermal A-Wand 30 225 0 20 80 2

Eucerin Sub-Dermal U-Wand 30 225 0 80 20 2

UU--Strip Treated InsulinStrip Treated Insulin

UU--Strip Insulin Patch Strip Insulin Patch &&

UU--WandWand

EngineeringEngineeringA New Form of TDDA New Form of TDDElectronicsElectronics

Peel-away filmSemi-permeable film

Sonic membraneBackbone material

Absorbent

Ultrasound

Insulin

Transdermal Delivery Device withP

Patch design

Absorbent Pad Liberation Absorbent Pad Liberation FactorsFactors

PatchPatch--CapCap

Low Profile Transdermal Patch

•Center absorbent pad holds drug.•No Risk of adhesive contamination.•Plastic components pass through ultrasound.•On/Off Function •Rate Control, Limitation•Designed for both Low and High molecular weight drugs. Bottom View

The U-Strip Transducer

Bondinglayers Cavity

End cap

PZT

End capTransducer Delivers alternating sonic waveform: 1/5 the power of a sonic toothbrush, 20-30 kHz at 125 mW/sq. cm intensity

UU--Strip Device MiniaturizationStrip Device Miniaturization

A-Wand

Pouch-Cap with Foam Border

Activation Tab on Cap

Activation Receiver on

Wand

Indicator Lamp

Activation Control

Cap Snap On Tabs

A-Wand with Pouch Cap Compatibility: Model No. BKR-1011-149

Wand Will Not Activate Unless Proper Cap Is Affixed

AA--Wand with Pouch Cap Compatibility: Model Wand with Pouch Cap Compatibility: Model No. BKRNo. BKR--10111011--149149

View of Wand Plastic Housing CrossView of Wand Plastic Housing Cross--SectionSection

Cap Attachment

Transducer Array Block

Wand Housing

Circuit Compartment

Battery Compartment

9 VDC Battery

Battery Cover

PouchPouch--Cap Design: Cap Design: BKRBKR--10111011--121121

Peel Away Film

Perforated Film Layer

Cream Storage Drum with Sonic

Membrane at Bottom

Foam Ring

Cap Housing

Activation Tab

Activation Insert

Delivery of Delivery of CopaxoneCopaxone via via AA--WandWand

Before After, Note deposition under SC Layer

Originally designed for Application of Cosmetics under the skin a new more powerful version, the A-Wand, has demonstrated a match for Sub-Q delivery via hypodermic needle, Non-invasively, for MS

UU--Strip Insulin PatchStrip Insulin Patch

Clinical SummaryClinical Summary

Clinical History in the order they Clinical History in the order they were accomplishedwere accomplished

HPTHPT--1A: Calibration trial with 5 healthy normal volunteers 1A: Calibration trial with 5 healthy normal volunteers using saline instead of insulin as a model drug to determine using saline instead of insulin as a model drug to determine ultrasonic settings.ultrasonic settings.HPTHPT--1B: Calibration trial with 4 healthy normal volunteers. 1B: Calibration trial with 4 healthy normal volunteers. Trial demonstrated ability to deliver 1 unit/hour insulin. Trial demonstrated ability to deliver 1 unit/hour insulin. Diabetes & Glandular Research Assocs.Diabetes & Glandular Research Assocs.HPTHPT--3: Skin Irritation study conducted on 25 Type3: Skin Irritation study conducted on 25 Type--2 2 diabetic, males and females, wearing insulin patch on diabetic, males and females, wearing insulin patch on abdomen & upper left arm for 5 hour period. No skin abdomen & upper left arm for 5 hour period. No skin irritation found. KGL Skin Labs.irritation found. KGL Skin Labs.HPTHPT--4: Skin Irritation study conducted on 25 Type4: Skin Irritation study conducted on 25 Type--2 2 diabetic, males and females, of exposure to Udiabetic, males and females, of exposure to U--Strip Strip ultrasound on abdomen & upper left arm for 5 hour period. ultrasound on abdomen & upper left arm for 5 hour period. No skin irritation found. KGL Skin Labs.No skin irritation found. KGL Skin Labs.

Clinical History in the order Clinical History in the order they were accomplishedthey were accomplished

HPTHPT--2A: Comparison study between insulin pump and 2A: Comparison study between insulin pump and insulin patch using 6 male typeinsulin patch using 6 male type--2 diabetics over a 5 hour 2 diabetics over a 5 hour study period.study period.HPTHPT--2B: Comparison of insulin patch vs. fasting level (no 2B: Comparison of insulin patch vs. fasting level (no typetype--2 medication) during daytime evaluation to determine 2 medication) during daytime evaluation to determine which system was more effective in glucose reduction and which system was more effective in glucose reduction and control.control.HPTHPT--2C: Comparison of insulin patch vs. type2C: Comparison of insulin patch vs. type--2 medication 2 medication during night time evaluation to determine which system during night time evaluation to determine which system was more effective in glucose reduction and control.was more effective in glucose reduction and control.HPTHPT--2D: Comparison of insulin patch vs. type2D: Comparison of insulin patch vs. type--2 medication 2 medication during daytime evaluation to determine which system was during daytime evaluation to determine which system was more effective in glucose reduction and control.more effective in glucose reduction and control.HPTHPT--5: Confocal imaging of insulin & Dye mixture to 5: Confocal imaging of insulin & Dye mixture to determine pathway through the skin using Udetermine pathway through the skin using U--Strip.Strip.

HPTHPT--2 Pump Profile2 Pump Profile

Volunteer is placed on Insulin pump/ Volunteer is placed on Insulin pump/ Continuous Glucometer Continuous Glucometer (Mini(Mini--Med Med Paradigm Real time 722 CSII) and a Paradigm Real time 722 CSII) and a glucose profile with insulin injection is glucose profile with insulin injection is developeddeveloped..Continuous Glucometer feature of the Continuous Glucometer feature of the ’’722 722 insulin pump measures glucose readings insulin pump measures glucose readings every 5 minutes. every 5 minutes. Pump profile was used as a comparison Pump profile was used as a comparison for the Ufor the U--Strip patch.Strip patch.

GoalGoal--1: Drop the Glucose Level of a 1: Drop the Glucose Level of a TypeType--2 Diabetic to Mild or Safe Range2 Diabetic to Mild or Safe Range

Physiologic Insulin Secretion: 24-Hour Profile

Insulin(µU/mL)

Glucose(mg/dL)

150

100

50

07 8 9 10 11 12 1 2 3 4 5 6 7 8 9

A.M. P.M.

Basal Glucose

Time of Day

50

25

0 Basal Insulin

Breakfast Lunch Dinner

HPTHPT--2A STUDY SCHEDULE2A STUDY SCHEDULEVISITVISIT ACTIVITYACTIVITY NOTESNOTES

11 Informed consent Informed consent

22 Medical tests and Medical tests and histories histories

33 Insulin pump & Insulin pump & glucose profileglucose profile

44 UU--Strip system:Strip system: Max TrialMax Trial

Cellulose Pad, 5Cellulose Pad, 5-- hour studyhour study

55 UU--Strip system:Strip system: Max TrialMax Trial

Nylon Pad, 5Nylon Pad, 5-- hour studyhour study

66 RUN STUDYRUN STUDY Best Best Performing Performing

Patch MaterialPatch Material

77 RUN STUDYRUN STUDY Low Profile Low Profile PatchPatch

Six Check PointsSix Check Points1.1. Real Time Glucometer Readings of Real Time Glucometer Readings of

Patients Serum Glucose Levels: a Real Patients Serum Glucose Levels: a Real Time Indicator of UTime Indicator of U--strip Performancestrip Performance

2.2. Serum Blood Analysis: Humalog LevelsSerum Blood Analysis: Humalog Levels3.3. Serum Blood Analysis: CSerum Blood Analysis: C--peptide Levelspeptide Levels4.4. Serum Blood Analysis: Glucose LevelsSerum Blood Analysis: Glucose Levels5.5. Weight Reduction in Transdermal Weight Reduction in Transdermal

Delivery DeviceDelivery Device6.6. Skin Scans of Test Area.Skin Scans of Test Area.

HPTHPT--22 Patch vs. Insulin PumpPatch vs. Insulin Pump

Volunteer Pump Patch IDEnding EndingDrop % Drop %

1 -24% -20% SR2 -43% -21% DD3 -55% -36% FB4 -30% -23% TN5 -27% -14% CD6 -47% -25% PM

Vol. 2: Glucose via CSII, Lispro Vol. 2: Glucose via CSII, Lispro Concentration and CConcentration and C--Peptide Curves ofPeptide Curves of

0

20

40

60

80

100

120

140

160

180

0 100 200 300 400TIME, MIN

GLU

CO

SE,M

G/D

L

BASELINE, U-STRIP

GLUCOSEPROFILE, U-STRIPSYSTEMBASELINE,PUMP

GLUCOSEPROFILE,PUMP

0

5

10

15

20

25

Start Hr-1 Hr-2 Hr-3 Hr-4 Hr-5

Time Interval

uU/m

l of I

nsul

in F

ound

SerumInsulinvia Pump

SerumInsulinvia U-Strip

00.5

11.5

22.5

33.5

44.5

5

StartHr-1 Hr-2 Hr-3 Hr-4 Hr-5

Time

C-P

eptid

e V

alue

s Human C-Peptide viaPumpHuman C-Peptide via U-Strip

Serum Blood Analysis: VolSerum Blood Analysis: Vol--11

Time Serum C-Peptide Serum C-Peptidevia Pump via Patch

Start 3.9 4.5Hr-1 3.8 4.4Hr-2 3.5 3.9Hr-3 2.9 4.3Hr-4 2.5 3.7Hr-5 1.9 3.5

Time Serum Insulin Serum Insulinvia Pump via Patch

Start 2.7 3.2Hr-1 8.5 3.9Hr-2 12.1 2.6Hr-3 16.3 3Hr-4 20.4 2.8Hr-5 20.4 4.5

Time Serum Glucose Serum Glucosevia Pump via Patch

Start 137 143Hr-1 129 131Hr-2 120 119Hr-3 106 117Hr-4 103 111Hr-5 95 110

VolVol--1: Comparative 21: Comparative 2--hr % Drop hr % Drop in Glucose and Cin Glucose and C--Peptide LevelsPeptide Levels

Glucose Glucosevia Pump via Patch

Starting 137 143Hour 2 120 119Drop 17 24Drop % 12.4% 16.8%

C-Peptide C-Peptidevia Pump via Patch

Starting 3.9 4.5Hour 2 3.5 3.9Drop 0.4 0.6Drop % 10.3% 13.3%

Glucose Drops Pump vs. PatchGlucose Drops Pump vs. PatchHPT-2 Vol-1 Glucose Comparison

Pump Vs. Patch

020406080

100120140160180

1 2 3 4 5 6

Time in Hours

Glu

cose

(mg/

dl)

CGMS BaselineGlucoseCGMS on Pump

Patch Baseline

Glucose on Patch

HPT-2 U-Strip/Insulin Vol-2 Glucose Comparison Pump vs Patch

0

50

100

150

200

1 2 3 4 5 6

Time in Hours

Glu

cose

(mg/

dl)

CGMSBaselineGlucose

CGMS onPump

Patch DayBaseline

Glucose onPatch

HPT-2 Vol-3 Glucose Comparison Pump vs. Patch

0

50

100

150

200

250

300

1 2 3 4 5 6

Time in Hours

Glu

cose

(mg/

dl)

CGMSBaselineGlucose

CGMS onPump

PatchBaselin

Glucose onPatch

HPT-2 Vol-4 Glucose Comparison Pump Vs. Patch

0

50

100

150

200

250

300

1 2 3 4 5 6

Time in Hours

Glu

cose

(mg/

dl)

CGMS BaselineGlucose

CGMS on Pump

Patch Baseline

Glucose onPatch

HPT-2 Vol-5 Glucose Comparison Pump Vs. Patch

0

50

100

150

200

250

300

1 2 3 4 5 6

Time in Hours

Glu

cose

(mg/

dl)

CGMS BaselineGlucose

CGMS on Pump

Patch Baseline

Glucose onPatch

HPT-2 Vol-6 Glucose Comparison

0

50

100

150

200

250

1 2 3 4 5 6

Time in HoursG

luco

se (m

g/dl

)

CGMSBaselineGlucose

CGMS onPump

PatchBaseline

Glucoseon Patch

HPTHPT--2B U2B U--Strip vs. Fasting Strip vs. Fasting GlucoseGlucose

220

225

230

235

240

245

250

255

260

265

270

0 50 100 150 200 250 300 350

Time (min)

Glu

cose

(mg/

dL)

FastingU-Strip

100

120

140

160

180

200

220

0 50 100 150 200 250 300 350

Time (min)

Glu

cose

(mg/

dL)

FastingU-Strip

Vol.4 Vol.-5

Vol. 1 2 3 4 5 6

Metformin X X X X X

Avandia X X X X

Exubera X

Byetta X

HPTHPT--2C U2C U--Strip vs. Medication Strip vs. Medication Night Time ComparisonNight Time Comparison

200

220

240

260

280

300

320

0 50 100 150 200 250 300 350

Time (min)

Glu

cose

(mg/

dL)

MedicationU-Strip

100

120

140

160

180

200

220

0 50 100 150 200 250 300 350

Time (min)

Glu

cose

(mg/

dL)

MedicationU-Strip

Vol.-5 Vol.-6

Vol. 1 2 3 4 5 6

Metformin X X X X X

Avandia X X X X

Exubera X

Byetta X

HPTHPT--2D U2D U--Strip vs. Medication Strip vs. Medication Daytime ComparisonDaytime Comparison

100

120

140

160

180

200

220

240

260

280

0 50 100 150 200 250 300 350

Time (min)

Glu

cose

(mg/

dL)

Day MedicationU-Strip

100

120

140

160

180

200

220

0 50 100 150 200 250 300 350

Time (min)

Glu

cose

(mg/

dL)

Day MedicationU-Strip

Vol.-5 Vol.-6

Vol. 1 2 3 4 5 6

Metformin X X X X X

Avandia X X X X

Exubera X

Byetta X

Lispro Blood Concentration, uU/mLLispro Blood Concentration, uU/mL Pump Vs. PatchPump Vs. Patch

Time, Time, hrhr SRSR DDDD FBFB TNTN CDCD MeanMean

VolVol--11 VolVol--22 VolVol--33 VolVol--44 VolVol--55 VolVol--66

00 0.0/3.20.0/3.2 0.00.0 0.00.0 0.00.0 0.00.0 0.00.0

11 3.5/3.93.5/3.9 1.51.5 10.110.1 4.74.7 5.25.2 5.05.0

22 7.1/2.67.1/2.6 5.65.6 13.313.3 7.57.5 18.718.7 8.48.4

33 11.3/3.011.3/3.0 7.87.8 15.415.4 10.910.9 19.819.8 11.411.4

44 15.4/2.815.4/2.8 7.77.7 16.616.6 16.216.2 17.717.7 14.014.0

55 15.4/4.515.4/4.5 8.98.9 17.017.0 18.118.1 34.234.2 14.914.9

Lispro Blood Concentration, uU/mL Lispro Blood Concentration, uU/mL after Transdermal USTRIPafter Transdermal USTRIP

Time, Time, hrhr SRSR DDDD FBFB TNTN CDCD MeanMean BaselineBaseline

00 3.23.2 4.14.1 3.83.8 4.54.5 7.97.9 4.74.7 55

11 3.93.9 3.13.1 4.74.7 11.711.7 2.92.9 5.35.3 55

22 2.62.6 3.43.4 5.35.3 7.77.7 27.027.0 9.29.2 55

33 3.03.0 2.52.5 8.18.1 6.56.5 25.325.3 9.19.1 55

44 2.82.8 2.82.8 3.83.8 2.62.6 10.310.3 4.54.5 55

55 4.54.5 4.04.0 4.84.8 2.72.7 47.847.8 12.812.8 55

Conclusions:Conclusions:The UThe U--Strip effected a better reduction in Strip effected a better reduction in

glucose within the first two hours of the study glucose within the first two hours of the study -- at a rate faster (8.5mg/dl/hr) than for the at a rate faster (8.5mg/dl/hr) than for the insulin pump (6mg/dl/hr)insulin pump (6mg/dl/hr)The UThe U--Strip was superior to the pump in Strip was superior to the pump in suppressing endogenous insulin production suppressing endogenous insulin production within the first 2within the first 2--hour period (higher % Chour period (higher % C--peptide drop/hr). See Table 5.peptide drop/hr). See Table 5.An important advantage offered by UAn important advantage offered by U--Strip is Strip is that a better degree of the intracellular drug that a better degree of the intracellular drug uptake may be achieved at a substantially uptake may be achieved at a substantially lower drug concentration in the blood. lower drug concentration in the blood. In comparison to oral meds for TyIn comparison to oral meds for Ty--22’’s the Us the U--Strip was more reliable in both daytime and Strip was more reliable in both daytime and night time glucose control.night time glucose control.

Passive TDD

Insulin rPA tPA

RequiresAssistance

U-Strip CapableRange

Molecular Size

Unknown

Up to 500 Da Up to 1000 Da 6000 Da 36 kDa 75 kDa Greater than 125 kDa

Range of Molecular Size

U-strip Is Theorized to Be Capable of Delivering From 0 to 125,000 Mol Wt. Compounds

Non-Invasive Insulin Delivery