Ultrasonic Drug Delivery Encapsulation Systems PO Box 759 Broomall, PA 19008 USA Ph: 484-343 343-2506 / Fax 610-356 356-1866 Bruce K. Redding Jr.
Non-Invasive Insulin Delivery
U-Wand Designed to Fit a Women s Grip
U-Strip Insulin Patch & U-Wand Skin Transport Mechanism
Transdermal drug delivery The three principal layers of the skin Stratum corneum 15 μm Epidermis Dermis Hair follicle 50 μm
ICG Fluorescence Mode Imaging Another 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. ~ 5 µm ~ 10 µm 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.
Drug Delivery Pathway Lipid bilayers. keratinocyte
U-Strip Insulin Patch Physics
Cavitation Could Lead To Drug Damage
Ultrasonic Massaging Action Effected By Alternating Waveform Enlarges Pore Size Homogenization Skin Transport Sawtooth waveform Square waveform
Sonic Waveform Duty Cycles The alternating waveform Duty Cycle means the time in milliseconds the signal is on a particular waveform. Example, U-Strip U insulin delivery is generally 50 msecs on sawtooth followed by 50 msecs on square wave. There is a 2 msec gap between the next sequence. At the start the skin is primed on sawtooth for 30 seconds. The U-Wand, U designed to deliver skin care compounds just under the SC layer, Sub-Dermal delivery, operates with no Priming, and a 80 msec sawtooth,, 20 msec squarewave. The A-Wand, A designed to compounds transdermally, to the dermis, operates with no Priming, and a 20 msec sawtooth,, 80 msec squarewave,, but uses a higher sonic intensity than the U-Wand. U
Duty Cycle Comparisons Product Application Delivery Transdermal vs. Sub-Dermal Device Freq. (khz) Intensity (mw/ sq.cm) Skin Priming Sawtooth Wave Duty Cycle msecs Square Wave Duty Cycle msecs Gap Timing Between Next Signal series msecs 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
U-Strip Treated Insulin
U-Strip Insulin Patch & U-Wand Engineering A A New Form of TDD Electronics
Patch design P Transdermal Delivery Device with Ultrasound Backbone material Semi-permeable film Insulin Sonic membrane Absorbent Peel-away film
Absorbent Pad Liberation Factors
Patch-Cap
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 Bonding layers Cavity End cap PZT End cap Transducer Delivers alternating sonic waveform: 1/5 the power of a sonic toothbrush, 20-30 khz at 125 mw/sq. cm intensity
U-Strip Device Miniaturization
A-Wand
A-Wand with Pouch Cap Compatibility: Model No. BKR-1011-149 Pouch-Cap with Foam Border Activation Tab on Cap Activation Receiver on Wand Cap Snap On Tabs Indicator Lamp Activation Control Wand Will Not Activate Unless Proper Cap Is Affixed
A-Wand with Pouch Cap Compatibility: Model No. BKR-1011 1011-149149 View of Wand Plastic Housing Cross-Section Cap Attachment Transducer Array Block Battery Compartment 9 VDC Battery Wand Housing Circuit Compartment Battery Cover
Pouch-Cap Design: BKR-1011 1011-121121 Peel Away Film Perforated Film Layer Cream Storage Drum with Sonic Membrane at Bottom Foam Ring Activation Tab Cap Housing Activation Insert
Delivery of Copaxone via A-Wand 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
U-Strip Insulin Patch Clinical Summary
Clinical History in the order they were accomplished HPT-1A: Calibration trial with 5 healthy normal volunteers using saline instead of insulin as a model drug to determine ultrasonic settings. HPT-1B: Calibration trial with 4 healthy normal volunteers. Trial demonstrated ability to deliver 1 unit/hour insulin. Diabetes & Glandular Research Assocs. HPT-3: Skin Irritation study conducted on 25 Type-2 diabetic, males and females, wearing insulin patch on abdomen & upper left arm for 5 hour period. No skin irritation found. KGL Skin Labs. HPT-4: Skin Irritation study conducted on 25 Type-2 diabetic, males and females, of exposure to U-Strip U ultrasound on abdomen & upper left arm for 5 hour period. No skin irritation found. KGL Skin Labs.
Clinical History in the order they were accomplished HPT-2A: Comparison study between insulin pump and insulin patch using 6 male type-2 2 diabetics over a 5 hour study period. HPT-2B: Comparison of insulin patch vs. fasting level (no type-2 2 medication) during daytime evaluation to determine which system was more effective in glucose reduction and control. HPT-2C: Comparison of insulin patch vs. type-2 2 medication during night time evaluation to determine which system was more effective in glucose reduction and control. HPT-2D: Comparison of insulin patch vs. type-2 2 medication during daytime evaluation to determine which system was more effective in glucose reduction and control. HPT-5: Confocal imaging of insulin & Dye mixture to determine pathway through the skin using U-Strip. U
HPT-2 2 Pump Profile Volunteer is placed on Insulin pump/ Continuous Glucometer (Mini-Med Med Paradigm Real time 722 CSII) and a glucose profile with insulin injection is developed. Continuous Glucometer feature of the 722 insulin pump measures glucose readings every 5 minutes. Pump profile was used as a comparison for the U-Strip U patch.
Goal-1: Drop the Glucose Level of a Type-2 2 Diabetic to Mild or Safe Range Physiologic Insulin Secretion: 24-Hour Profile Insulin (µu/ml) 50 25 0 Basal Insulin 150 Breakfast Lunch Dinner Glucose (mg/dl) 100 50 0 7 8 9 101112 1 2 3 4 5 6 7 8 9 A.M. P.M. Time of Day Basal Glucose
HPT-2A STUDY SCHEDULE VISIT ACTIVITY 1 Informed consent 2 Medical tests and histories 3 Insulin pump & glucose profile 4 U-Strip system: Max Trial 5 U-Strip system: Max Trial 6 RUN STUDY 7 RUN STUDY NOTES Cellulose Pad, 5-5 hour study Nylon Pad, 5-5 hour study Best Performing Patch Material Low Profile Patch
Six Check Points 1. Real Time Glucometer Readings of Patients Serum Glucose Levels: a Real Time Indicator of U-strip U Performance 2. Serum Blood Analysis: Humalog Levels 3. Serum Blood Analysis: C-peptide C Levels 4. Serum Blood Analysis: Glucose Levels 5. Weight Reduction in Transdermal Delivery Device 6. Skin Scans of Test Area.
HPT-2 Patch vs. Insulin Pump Volunteer Pump Patch ID Ending Ending Drop % Drop % 1-24% -20% SR 2-43% -21% DD 3-55% -36% FB 4-30% -23% TN 5-27% -14% CD 6-47% -25% PM
Vol. 2: Glucose via CSII, Lispro Concentration and C-Peptide C Curves of G L U C O S E, M G /D L 180 160 140 120 100 80 60 40 20 0 0 100 200 300 400 TIME, MIN BASELINE, U- STRIP GLUCOSE PROFILE, U- STRIP SYSTEM BASELINE, PUMP GLUCOSE PROFILE, PUMP uu/ml of Insulin Found 25 20 15 10 C-Peptide Values 5 0 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 Start Hr-1 Hr-2 Hr-3 Hr-4 Hr-5 Time Interval Start Hr-1 Hr-2 Hr-3 Time Hr-4 Hr-5 Serum Insulin via Pump Serum Insulin via U- Strip Human C- Peptide via Pump Human C- Peptide via U- Strip
Serum Blood Analysis: Vol-1 Time Serum Insulin Serum Insulin via Pump via Patch Time Serum C-Peptide Serum C-Peptide via Pump via Patch Start 2.7 3.2 Hr-1 8.5 3.9 Hr-2 12.1 2.6 Hr-3 16.3 3 Hr-4 20.4 2.8 Hr-5 20.4 4.5 Start 3.9 4.5 Hr-1 3.8 4.4 Hr-2 3.5 3.9 Hr-3 2.9 4.3 Hr-4 2.5 3.7 Hr-5 1.9 3.5 Time Serum Glucose Serum Glucose via Pump via Patch Start 137 143 Hr-1 129 131 Hr-2 120 119 Hr-3 106 117 Hr-4 103 111 Hr-5 95 110
Vol-1: Comparative 2-hr 2 % Drop in Glucose and C-Peptide C Levels Glucose Glucose via Pump via Patch Starting 137 143 Hour 2 120 119 Drop 17 24 Drop % 12.4% 16.8% C-Peptide C-Peptide via Pump via Patch Starting 3.9 4.5 Hour 2 3.5 3.9 Drop 0.4 0.6 Drop % 10.3% 13.3%
Glucose Drops Pump vs. Patch HPT-2 Vol-1 Glucose Comparison Pump Vs. Patch HPT-2 U-Strip/Insulin Vol-2 Glucose Comparison Pump vs Patch HPT-2 Vol-3 Glucose Comparison Pump vs. Patch Glucose (mg/dl) 180 160 140 120 100 80 60 40 20 0 1 2 3 4 5 6 Time in Hours CGMS Baseline Glucose CGMS on Pump Patch Baseline Glucose on Patch Glucose (mg/dl) 200 150 100 50 0 1 2 3 4 5 6 Time in Hours CGMS Baseline Glucose CGMS on Pump Patch Day Baseline Glucose on Patch Glucose (mg/dl) 300 250 200 150 100 50 0 1 2 3 4 5 6 Time in Hours CGMS Baseline Glucose CGMS on Pump Patch Baselin Glucose on Patch HPT-2 Vol-4 Glucose Comparison Pump Vs. Patch HPT-2 Vol-5 Glucose Comparison Pump Vs. Patch HPT-2 Vol-6 Glucose Comparison Glucose (mg/dl) 300 250 200 150 100 50 0 1 2 3 4 5 6 CGMS Baseline Glucose CGMS on Pump Patch Baseline Glucose on Patch Glucose (mg/dl) 300 250 200 150 100 50 0 1 2 3 4 5 6 CGMS Baseline Glucose CGMS on Pump Patch Baseline Glucose on Patch Glucose (mg/dl) 250 200 150 100 50 0 1 2 3 4 5 6 CGMS Baseline Glucose CGMS on Pump Patch Baseline Glucose on Patch Time in Hours Time in Hours Time in Hours
HPT-2B U-Strip U vs. Fasting Glucose Vol.4 Vol.-5 270 220 265 260 200 Glucose (mg/dl) 255 250 245 240 235 230 225 Fasting U-Strip Glucose (mg/dl) 180 160 140 120 Fasting U-Strip 220 0 50 100 150 200 250 300 350 Time (min) 100 0 50 100 150 200 250 300 350 Time (min) Vol. 1 2 3 4 5 6 Metformin X X X X X Avandia X X X X Exubera X Byetta X
HPT-2C U-Strip U vs. Medication Night Time Comparison Vol.-5 Vol.-6 320 220 300 200 Glucose (mg/dl) 280 260 240 Medication U-Strip Glucose ( m g /d L ) 180 160 140 Medication U-Strip 220 120 200 0 50 100 150 200 250 300 350 100 0 50 100 150 200 250 300 350 Time (min) Time (min) Vol. 1 2 3 4 5 6 Metformin X X X X X Avandia X X X X Exubera X Byetta X
HPT-2D U-Strip U vs. Medication Daytime Comparison Vol.-5 Vol.-6 280 220 Glucose (mg/dl) 260 240 220 200 180 160 140 120 Day Medication U-Strip Glucose (mg/dl) 200 180 160 140 120 Day Medication U-Strip 100 0 50 100 150 200 250 300 350 100 0 50 100 150 200 250 300 350 Time (min) Time (min) 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/ml Pump Vs. Patch Time, hr SR Vol-1 DD Vol-2 FB Vol-3 TN Vol-4 CD Vol-5 Mean Vol-6 0 0.0/3.2 0.0 0.0 0.0 0.0 0.0 1 3.5/3.9 1.5 10.1 4.7 5.2 5.0 2 7.1/2.6 5.6 13.3 7.5 18.7 8.4 3 11.3/3.0 7.8 15.4 10.9 19.8 11.4 4 15.4/2.8 7.7 16.6 16.2 17.7 14.0 5 15.4/4.5 8.9 17.0 18.1 34.2 14.9
Lispro Blood Concentration, uu/ml after Transdermal USTRIP Time, hr SR DD FB TN CD Mean Baseline 0 3.2 4.1 3.8 4.5 7.9 4.7 5 1 3.9 3.1 4.7 11.7 2.9 5.3 5 2 2.6 3.4 5.3 7.7 27.0 9.2 5 3 3.0 2.5 8.1 6.5 25.3 9.1 5 4 2.8 2.8 3.8 2.6 10.3 4.5 5 5 4.5 4.0 4.8 2.7 47.8 12.8 5
Conclusions: The U-Strip U effected a better reduction in glucose within the first two hours of the study - at a rate faster (8.5mg/dl/hr) than for the insulin pump (6mg/dl/hr) The U-Strip U was superior to the pump in suppressing endogenous insulin production within the first 2-hour 2 period (higher % C-C peptide drop/hr). See Table 5. An important advantage offered by U-Strip U is that a better degree of the intracellular drug uptake may be achieved at a substantially lower drug concentration in the blood. In comparison to oral meds for Ty-2 s s the U-U Strip was more reliable in both daytime and night time glucose control.
Range of Molecular Size Passive TDD Requires Assistance U-Strip Capable Range Unknown Insulin rpa tpa Up to 500 Da Up to 1000 Da 6000 Da 36 kda 75 kda Greater than 125 kda Molecular Size U-strip Is Theorized to Be Capable of Delivering From 0 to 125,000 Mol Wt. Compounds
Non-Invasive Insulin Delivery