Health-Chem Tech Review

1
TD GlucoseTM Monitoring SystemTechnical
Review
2
Overview

• Brief introduction to Health-Chems RD
  Philosophy
• Product oriented approach
• Show videos
• Update on current clinical results
• Show representative clinical examples
• Review general basic understanding
• Transdermal Drug Delivery (TDD)
• Relate basic TDD facts
• TD Glucose Monitoring System (TD-G) information
• Hypothesize on underlying product mechanisms
• Q A

3
RD PHILOSOPHY

• 100 Product-Oriented RD focus
• NO academic research to prove and investigate
  theoretical concepts
• All RD efforts are focused solely on product
  development
• Assure that product works and introduce into
  market fast
• After product introduction, theoretical concepts
  will be investigated and researched by academia
  or other organizations
• Health-Chem supports these efforts, but will not
  take on a leading role

4
ASSURE PRODUCT FUNCTIONALITY

• Mainly Lab Work
• Produce product and demonstrate that it achieves
  desired goal and objective
• Generate all pertinent information required for
  FDA approval
• supported by Theoretical Review
• Assure that theoretical mechanisms and available
  scientific background information can explain or
  support the feasibility of the new product

5
VIDEOS

• BBC - Weekly Science and Technology Program
• Tomorrows World (6/2/99) 1
• CBS Ch4 - St. Louis Station KMOV-TV
• On local News Segment (8/5/99) 2
• CBS - Nationwide The Early Show
• HealthWatch Segment (11/17/99) 3

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UPDATE CLINICAL DATA

• WashU Study Objective
• Confirm patch performance in hypo hyperglycemic
  range
• Triggered by Barcelona, Spain, Presentation 9/98
  (Dr.s Office)
• Basic Study Design
• Enrolled 13 patients (3 Type I 10 Type II)
• Hospitalized, under constant medical supervision
• Infusion lines for glucose and insulin delivery
• Catheter for venous blood sampling
• Glucose Measurements
• Venous blood glucose was analyzed w/ YSI gt
  mg/dL
• Capillary blood w/Fingerstick (OneTouch) gt
  mg/dL
• TD-G patch gt mV
• Develop correlation model, evaluate best fit
  parameters

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MATHEMATICAL CORRELATION

• Fit TDG Data to corresponding REFERENCE data
• Simple 2-parameter Model
• TDG (INT - mV)MPL
• Choose correlation model parameters (INT MPL)
• GOAL Correlation curve on centerline in Clarke
  ERROR Grid Slope 1, Intercept 0
• Evaluate feasibility of UNIVERSAL Correlation

8
PATCH METER SYSTEM

• Patch
• Proprietary detection membrane
• All patch materials
• can be easily mass produced
• very cost efficient
• GMP
• track record with FDA (cosmetic or medical use)
• Patch assembly still manual
• Meter
• Dual optics
• Operator Error correcting software not
  implemented, yet!

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PATIENT GF-WU4R
Glucose Profile (YSI, Fingerstick Patch) Model
Parameters 810 - 3.4
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PATIENT RF-WU5
Glucose Profile (YSI, Fingerstick Patch) Model
Parameters 798 - 4.8
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PATIENT CM-WU9
Glucose Profile (YSI, Fingerstick Patch) Model
Parameters 796 - 5.3
12
PATIENT RL-WU14
Glucose Profile (YSI, Fingerstick Patch) Model
Parameters 809 - 4.8
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SUMMARY INDIVIDUAL
Each patient individually fitted
600
B
A
E
C
550
WU4 - 16
500
A
y 1.00x 0.27
R
2
0.93
450
400
B
350
TDG (mg/dL)
300
250
200
150
D
D
100
50
E
C
0
0
100
200
300
400
500
600
YSI
Reference Blood Glucose -

(mg/dL)
outliers
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MODEL PARAMETER ANALYSIS

• Found excellent prediction/correlation
• Both parameters vary from patient-to-patient
• INT parameter varies less then MPL
  parameterlt1 compared to ?17
• Reasons for variations?
• Variety of causes
• electronics related issues
• physiological differences (skin)
• else!
• Overall, small fluctuation
• Universal Calibration?

INT
MPL
Wu4
812
3.3
Wu5
798
4.8
Wu6
789
5.2
Wu7
793
5
Wu8
802
4.4
Wu9
796
5.3
5
Wu10
808
Wu11
793
5.6
Wu12
798
5
Wu13
794
6.7
Wu14
809
4.8
5.4
Wu15
809
Wu16
802
6.7
800
5.2
7
0.9
0.9
17.1
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Summary UNIVERSAL
Every patient fitted with AVG Model parameters
600
B
A
E
C
550
WU4 - 16
y 1.01x - 0.52
500
A
R
2
0.84
450
400
B
350
TDG (mg/dL)
300
250
200
D
D
150
Universal Parameters
100
800/5.2
50
E
C
0
0
100
200
300
400
500
600
YSI
Reference Blood Glucose -
(mg/dL)
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DISCUSSION

• Scatter probably related to non-optimized product
  
• Worst case scenario
• Hand-made patches compared to fully automated MFG
  
• Meter software not fully implemented (correction
  algorithms) slide
• Individual calibration resulted in excellent
  correlation between TDG and YSI or Fingerstick
• NEXT STEP Compare to Cygnus
• UNIVERSAL calibration?
• Acceptable for FDA approval? Likely, need more
  data!

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CONCLUSION CLINICAL DATA

• TD Glucose System is successful in predicting
  hypo hyperglycemic range
• Accuracy of prediction is similar to YSI and
  Fingerstick
• Recent data suggest that UNIVERSAL patient
  calibration may be achievable

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THEORY SECTION

• Where is the Glucose - collected in the patch -
  coming from?

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ASSUMPTION
TD-G based ondermal or transdermalmechanisms
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THEORETICAL CONCEPT

• Glucose partitions into / exchanges between
  compartments
• Blood, ISF Skin Tissues

21
GLUCOSE AND SKIN

• Non-invasive blood glucose monitoring systems
  under development using skin as portal
• Electro transport
• Infrared technique
• Light absorption
• reverse transdermal
• Conventional
• Health-Chem
• Rationale Prevent lancing the skin to draw blood
• Inconvenient and distressful (daily basis,
  several times a day)
• Allow for more frequent daily monitoring

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GLUCOSE AND SKIN (contd)

• TD-G based on the facts that
• Glucose levels equilibrate between blood and
  interstitial fluids(Lonnroth et. al., Am. J. of
  Physiology, 253 E228-31, 1987)
• Skin glucose varies in synchrony with blood
  glucose levels during tolerance testing(Fusaro
  et. al., J. Invest. Dermatol., 42 359, 1964)
• Skin tissue when immersed into glucose solutions
  equilibrates linearly with external glucose
  concentration (Halprin et. al., J. Invest.
  Dermatol., 49(6) 561, 1967)
• Available information supports concept of a
  dermal or transdermal type mechanism

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Transdermal Drug Delivery

• Typically focus on enhancer formulations to
  facilitate
• partitioning into and diffusion through skin
  layer (Ficks Law)
• in particular SC and epidermis

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Schematic Transport Routes Equations
Compartments
TD-G Patch Gel SC ISF/(Epi)Dermis Blood
JP
JD
Glucose exchanges between compartments
Total Transport Sum of transports
through dense and porous sections DENSE
membrane JD PD?cD POROUS membrane
JP PP?cP c(1-?) Jv Jv
Lp(?p-????g)
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Porous Membrane Concept
JP PP?cP c(1-?) Jv
JP PP?cP
JP cLp?p (at steady state)
Patch Reservoir SC ISF/(Epi)Dermis Blood
SUCTION
JP,c
JP,d
Permeability PP is proportional to number of
pores
Permeability LP is proportional to porosity,
tortuosity, etc.
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SKIN HYDRATION

• Sweating may have impact on glucose transport to
  the skin surface
• Pores, sweat ducts, hair follicle shafts, etc.
• Transcellular route (swollen keratinocytes)
• Intracellular route via water section of the
  lipid bilayer
• Clinical data supports this thinking
• Patients under hypoglycemic stress experience
  profuse sweating
• Measurements at this extreme condition typically
  show stronger meter responses suggesting more
  glucose was transported to skin surface via
  transpiration
• Needs continued research to develop appropriate
  counter measures

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Dense Membrane Concept (JP 0)
Skin Area with NO Pores diffusive
JD PD?cD
Ficks Law (Steady State)
JD
Permeability PD can be modified by skin
permeation enhancers
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WHAT IS THE ACTUAL TRANSPORT PROCESS?

• At the time not absolutely defined
• Safe to speculate that glucose partitions into
  the adjoining tissues
• How it gets there is with high probability a mix
  of
• Regular intracellular and extra-cellular
  diffusive transport
• Shunt transport through
• Hair follicles
• Sweat ducts
• Other? Hydration, ionic convection (see Cygnus),
  etc.
• References for glucose skin flux

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GLUCOSE SKIN FLUX

• Examples
• US5,139,023
• gt 4 ?g/cm2min
• flux f(c)
• Cygnus
• ? 6 ng/cm2min
• Private conversation

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THEORETICAL ESTIMATION

• Melting Point Theory
• Baker, R., Kochinke, F., 1988. "Transdermal Drug
  Delivery Systems", Controlled Release of Drugs
  Polymers and Aggregate Systems. VCH, 277-305
• mp ? 150C
• ? 0.1 mg/cm2hr
• ? 2 ng/cm2min

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CONCLUSION / ANSWER

• Glucose collected in the patch originates from
  skin
• We dont know the exact pathways and related
  transport parameters
• Glucose travels along regular transdermal routes
• Experimentally and theoretically determined
  glucose skin flux values are very different
• Qualitatively, data suggest glucose is crossing
  the skin
• Quantitatively?

32
ADD DATA TO THEORY
What and How Much is the Patch measuring?
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QUALITY CONTROL TESTING

• Patches are charged with defined glucose
  quantities
• 40 ml gel with increasing finite amounts of
  glucose
• 3 patches per STD
• STD span the complete range of in vivo elicited
  responses

1
850
2
INT (?)
3
Patch Average (STD 0.8)
linear (Patch Average)
750
In Vivo
Meter Reading (mV)
finite Glucose amount from Skin
650
y -0.2705x 789.26
2
R
0.9962
550
0
100
200
300
400
500
Standards (ng/40ml)
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CALCULATED GLUCOSE FLUX

• STD Calibration Testing (less than 5 minutes)
• 20 to 300 ng per 0.5 cm2 ? 40 to 600 ng/cm2
• Corresponding flux value 8 120 ng/cm2min

• Hypothesis
• Membrane response can be elicited by
• a STEADY glucose skin flux or
• the glucose already partitioned into and
  available to the patch from the outermost skin
  layers

35
STEADY FLUX ?

• Membrane reaction has an Endpoint
• Endpoint suggests a limited or finite amount
  of glucose is detected by the membrane
• Reaction is concentration-dependent
• STEADY Skin Flux would NOT allow Endpoint
• Constant supply of glucose, reaction would
  continue
• In addition, lag time does not allow STEADY flux
  in the initial time interval

36
LAG TIME

• Certain time for the steady state flux to
  develop Lag Time Time interval to establish
  steady state flux
• Before SS Flux reachedimmediateleachable
  amount
• Cant measure reliably(poor assay sensitivity)
• Health-Chem membrane can!
• Within 3 minutes
• 0.34 mg through 1.89 cm2
• ? 180 ng/cm2
• Comparable amount to Health-Chem findings
  compare

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PARTITIONING

• Glucose equilibrates between compartments
• Leachable amount increases with rising blood
  level

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REVERSE TRANSDERMAL MECHANISMS

• Conventional
• Measure in steady state region
• e.g. Cygnus
• Health-Chem
• Very sensitive device
• Capable to measure immediate leachable amount

Conventional methods CAN distinguish
Conventional methods CANT distinguish
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SUMMARY

• The actual glucose skin transport mechanisms all
  the way up to the patch membrane are yet to be
  determined
• Health-Chems TD-G system is assumed to function
  based on basic reverse transdermal mechanisms.
• Health-Chems glucose reaction membrane is
  extremely sensitive (only small and finite
  glucose amounts are required to generate
  enzymatic color change)
• Measures outside of conventional understanding
  of transdermal transport modality (steady state
  flux vs. within lag time interval)
• Requires New Thinking Approach

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TD GlucoseTM Monitoring SystemTechnical
Review