a novel topical transdermal delivery system mark s. nestor, m.d., ph.d. director center for clinical...

A Novel Topical Transdermal A Novel Topical Transdermal Delivery SystemDelivery System

Mark S. Nestor, M.D., Ph.D.Mark S. Nestor, M.D., Ph.D.DirectorDirector

Center for Clinical and Cosmetic Center for Clinical and Cosmetic ResearchResearch

Aventura FloridaAventura Florida

Topical Drug and Cosmetic DeliveryTopical Drug and Cosmetic Delivery The skin is a formidable barrier against environmental assaults The skin is a formidable barrier against environmental assaults

as well as topical drug deliveryas well as topical drug delivery A variety of active compounds have significant activity in the A variety of active compounds have significant activity in the

skin, subcutaneous tissue or muscle but cannot adequately skin, subcutaneous tissue or muscle but cannot adequately permeate the intact skin permeate the intact skin

Diseases such as acne, psoriasis, rosacea, and melasma as well Diseases such as acne, psoriasis, rosacea, and melasma as well as cutaneous aesthetic enhancement could dramatically benefit as cutaneous aesthetic enhancement could dramatically benefit from our ability to better transport active compounds to target from our ability to better transport active compounds to target tissue tissue

Solutions to a 100+ billion dollar marketSolutions to a 100+ billion dollar market Ionic Nano Particle Technology (InParT) is a novel and unique Ionic Nano Particle Technology (InParT) is a novel and unique

passive delivery system that can be utilized to assist the passive delivery system that can be utilized to assist the transport of a variety of active compounds to target sites in the transport of a variety of active compounds to target sites in the skin and beyondskin and beyond

InParT Drug Delivery SystemInParT Drug Delivery SystemIonic Nano Particle Technology IIonic Nano Particle Technology I

NovelNovel, , commercially viable trans commercially viable trans dermal non-invasive drug delivery dermal non-invasive drug delivery technology that technology that enables delivery and enables delivery and absorption of active compounds absorption of active compounds through the stratum corneum and through the stratum corneum and throughout the skin and sub throughout the skin and sub cutaneous tissue without any cutaneous tissue without any cutaneous toxicitycutaneous toxicity

InParT Drug Delivery SystemInParT Drug Delivery SystemIonic Nano Particle Technology IIIonic Nano Particle Technology II

Nano particles are made from combinations of Nano particles are made from combinations of micelles (surfactants and protein solubilizers), micelles (surfactants and protein solubilizers), coated with lipid molecules coated with lipid molecules

Nano paticles size; less than 1-10 nano meters Nano paticles size; less than 1-10 nano meters smaller than the skin poressmaller than the skin pores

Nano Particles Physically entraps active without any Nano Particles Physically entraps active without any changes in the chemical compositionchanges in the chemical composition

Stabilizes the actives: shelf stable at room Stabilizes the actives: shelf stable at room temperature for extended period of time without temperature for extended period of time without refrigeration)refrigeration)

Uses all FDA approved ingredientsUses all FDA approved ingredients

InParT Drug Delivery SystemInParT Drug Delivery SystemIonic Nano Particle Technology IIIIonic Nano Particle Technology III

INParT technology is highly adaptable to most high INParT technology is highly adaptable to most high molecular weight drugs, proteins, peptides and molecular weight drugs, proteins, peptides and insoluble hydrophobic moleculesinsoluble hydrophobic molecules

Capable of delivering more than one therapeutic agent Capable of delivering more than one therapeutic agent at a timeat a time

Offers high market value by featuring maximum Offers high market value by featuring maximum functionality at minimum system complexity and costfunctionality at minimum system complexity and cost

The technology is easily scalable to any size without The technology is easily scalable to any size without any complex new equipments need (no capital any complex new equipments need (no capital expenditure, commercially viable)expenditure, commercially viable)

SEM-Photograph- 250x SEM-Photograph- 1000x

InParT Drug Delivery SystemInParT Drug Delivery SystemClinical InvestigationClinical Investigation

Topical Hyaluronic AcidTopical Hyaluronic Acid Topical LidocaineTopical Lidocaine AcneAcne

Benzoyl Peroxide (BP)Benzoyl Peroxide (BP) Topical Botulinum Neurotoxin Type A (BoNTA)Topical Botulinum Neurotoxin Type A (BoNTA)

RhytidsRhytids HyperhidrosisHyperhidrosis

Future Developments and PartnershipsFuture Developments and Partnerships

Topical Hyaluronic Acid Topical Hyaluronic Acid (HA)(HA)

InParT Drug Delivery SystemInParT Drug Delivery SystemTopical Hyaluronic Acid (HA)Topical Hyaluronic Acid (HA)

HA crosslinked or non crosslinked difficult to HA crosslinked or non crosslinked difficult to adequately penetrate the stratum corneum adequately penetrate the stratum corneum

If adequate penetration can be achieved topical If adequate penetration can be achieved topical cross linked HA can significantly improve fine cross linked HA can significantly improve fine lines as well as skin texturelines as well as skin texture Painless applicationPainless application Companion treatment to injectable crosslinked HACompanion treatment to injectable crosslinked HA Topical cosmecuticalTopical cosmecutical

Topical Hyaluronic Acid (HA)Topical Hyaluronic Acid (HA) Clinical Model Clinical Model

The stabilized cream is applied topically onto the The stabilized cream is applied topically onto the skin containing crosslinked (non crosslinked) skin containing crosslinked (non crosslinked) HAHA

The nano-spheres helps penetrate the skin layers The nano-spheres helps penetrate the skin layers with the aid of absorption enhancers and with the aid of absorption enhancers and releases the HA into the deep layers of the skinreleases the HA into the deep layers of the skin

HA incorporated into the dermis (rapid aesthetic HA incorporated into the dermis (rapid aesthetic benefit) and induces long term collagen benefit) and induces long term collagen synthesissynthesis

A Double Blind Vehicle Controlled Trial A Double Blind Vehicle Controlled Trial to Investigate the efficacy and to Investigate the efficacy and tolerance of Transdermal CL1 tolerance of Transdermal CL1

(Restylane) versus non-CL1 (Non (Restylane) versus non-CL1 (Non Crossed Linked HA) in the appearance Crossed Linked HA) in the appearance

of photodamaged skinof photodamaged skin

Topical Hyaluronic Acid (HA)Topical Hyaluronic Acid (HA)Clinical Trial IClinical Trial I

100 subjects 2 sites: Women 35 – 65 with 100 subjects 2 sites: Women 35 – 65 with moderate to severe photodamage: 40 CL1 moderate to severe photodamage: 40 CL1 (crosslinked HA – Restylane), 40 NCL1 (Non (crosslinked HA – Restylane), 40 NCL1 (Non crossed linked HA), 20 Vehiclecrossed linked HA), 20 Vehicle

2 US sites2 US sitesSubjects and investigators blindedSubjects and investigators blinded2 week wash out, 12 week trail (evaluations 2,6 2 week wash out, 12 week trail (evaluations 2,6

and 12 weeks), 4 week post treatment and 12 weeks), 4 week post treatment (washout)(washout)

Apply twice a day clean faceApply twice a day clean face..

Topical Hyaluronic Acid (HA)Topical Hyaluronic Acid (HA)Clinical Trial IIClinical Trial II

Visia camera systemVisia camera systemObjective evaluationsObjective evaluations

Goldman-Rao” photographic scale in 5 Goldman-Rao” photographic scale in 5 gradesgrades

Evaluation of skin roughness, skin Evaluation of skin roughness, skin hydration, skin radiance, smoothing effect, hydration, skin radiance, smoothing effect, overall efficacy and toleranceoverall efficacy and tolerance

Subjective Questionnaires :Subjective Questionnaires : Product Qualities Product Qualities Subjective improvementSubjective improvement

..

Topical Hyaluronic Acid (HA)Topical Hyaluronic Acid (HA)Clinical Trial - WashoutClinical Trial - Washout

Evaluation of sustained effect of topical Evaluation of sustained effect of topical HAHA

Patient discontinued all Topicals at day 90 Patient discontinued all Topicals at day 90 and were evaluated for sustained effects and were evaluated for sustained effects at day 120at day 120

Visia photographsVisia photographsClinical evaluationsClinical evaluations

..

Trial DataTrial Data

Blinded Investigator AssessmentsBlinded Investigator Assessments

Clinical Evaluation: Skin RoughnessClinical Evaluation: Skin Roughness

CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

Clinical Evaluation: Skin Roughness

1.3

1.6

2

1.1

1.4

1.7

1.3 1.3

1.5

1.71.8

2.8*

2.6*

2.4+2.3+

1

1.5

2

2.5

3

day 0 day 15 day 45 day 90 day 120

CL1 NCL1 Control

* CL1 vs Control at .001+NCL1 vs Control at .001

Clinical Evaluation: Skin RoughnessClinical Evaluation: Skin Roughness

Clinical Evaluation: Skin Roughness (% Rated Smooth & Very Smooth)

41

61.6

87.2

20

41

71.1

35 35

5055 55.4

95.9*100*

88+85.1

0

10

20

30

40

50

60

70

80

90

100

% Day 0 % Day 15 % Day 45 % Day 90 %Day 120

Cl1 NCl1 Control*CL1 Vs Control at .001+*NCL1 vs Control at .001


Clinical Evaluation: Skin HydrationClinical Evaluation: Skin HydrationClinical Evaluation: Skin Hydration

1

1.9 1.9

1

1.5

2.2

1

1.41.5

1.9

1.8

2.5*2.4*

2.1

1.9*/+

1

1.5

2

2.5


CL1 NCL1 Control*CL1 vs Control at .001+NCL1 vs Control

2.4


Clinical Evaluation: Skin HydrationClinical Evaluation: Skin Hydration

Clinical Evaluation: Skin Hydration (% Rated Hydrated or Very Hydrated)

15.4 15

65.4

5

35

45

60

87.2*

94.9* 97.4* 100*

86.8+89.5+

86.6+

52.4

0

10

20

30

40

50

60

70

80

90

100

% Day 0 % Day 15 % Day 45 % Day 90 %Day 120

Cl1 NCl1 Control*CL1 vs NCL1 & Control at .001+NCL1 vs Control at .001


Clinical Evaluation: Skin ElasticityClinical Evaluation: Skin Elasticity

Clinical Evaluation: Skin Elasticity

3.8

4

4.3

3.43.3

3.5

3.7

3.5

43.9

4.14

3.4

4.6*4.7*

3

3.5

4

4.5

5


CL1 NCL1 Control *CL1 vs NCL1 & Control at .001


Clinical Evaluation: Skin Elasticity (% Rated Good or Excellent)

31.4

21.326.8

30.835

40.738.1

21.8

47.3*

63.3*

78*

27.4

0

10

20

30

40

50

60

70

80

90

% Day 15 % Day 45 % Day 90 % Day 120

Cl1 NCl1 Control *CL1 vs NCL1 & Control at .001

Clinical Evaluation: Skin ElasticityClinical Evaluation: Skin Elasticity


Clinical Evaluation: Skin Radiance

1.1

1.3

1.6

1.1

1.3

1.5

1.8

1.21.3 1.3 1.3

1.5

1

2*1.9*

0

0.5

1

1.5

2


CL1 NCL1 Control *CL1 vs NCL1 & Control at .001


Clinical Evaluation: Skin RadianceClinical Evaluation: Skin Radiance

Clinical Evaluation: Skin RadianceClinical Evaluation: Skin Radiance

Clinical Evaluation: Skin Radiance (% Rated Radiant or Very Radiant)

59

76.9

94.9

50

69.2

89.2

78.975 75

80

50

32

100* 100*

59+

0

10

20

30

40

50

60

70

80

90

100

% Day 0 % Day 15 % Day 45 % Day 90 % Day 120

Cl1 NCl1 Control*CL1 vs Control at .001+NCL1 vs Control at .001


Clinical Evaluation: Smoothing EffectClinical Evaluation: Smoothing Effect


Clinical Evaluation: Smoothing Effect

1.1

0.9

00.1

0.40.5

2.1*

1.8*

1.5* 1.5+

1.3+

1.1+

0

0.5

1

1.5

2

2.5

day 15 day 45 day 90 day 120

CL1 NCL1 Control*CL1 vs Control at .001+NCL1 vs Control at

Clinical Evaluation: Smoothing EffectClinical Evaluation: Smoothing Effect


Clinical Evaluation: Smoothing Effect (% Rated Significant or Very Significant)

10.3

2.6

10.5

0 0 0 0

48.7*

72.3*79.1*

28.9+

38.0+

0

10

20

30

40

50

60

70

80

90

% Day 15 % Day 45 % Day 90 % Day 120

Cl1 NCl1 Control*CL1 vs NCL1 & Control at .001+NCL1 vs Control at .001

Clinical Evaluation: Overall EfficacyClinical Evaluation: Overall Efficacy


Clinical Evaluation: Overall Efficacy

1.1

1.5

0.8

1.1

0.05 0.1

0.4 0.4

1.9*

2.2*

1.3+

1.6+

0

0.5

1

1.5

2

2.5

day 15 day 45 day 90 day 120

CL1 NCL1 Control

*CL1 vs Control at .001+NCL1 vs Control at .001

Clinical Evaluation: Overall EfficacyClinical Evaluation: Overall EfficacyClinical Evaluation: Overall Efficacy (% Rated Good or

Excellent)

12.8

48.7

5.1

18.4

0 0 0 0

93.3*

76*

35+

27.5+

0

10

20

30

40

50

60

70

80

90

100

% day 15 % day 45 % day 90 % day 120

Cl1 NCl1 Control*CL1 vs NCl1 & Control at .001+NCL1 vs Control at .001


Clinical Evaluation: ToleranceClinical Evaluation: Tolerance


Clinical Evaluation: Local Tolerance (% Rated Excellent)

100 100 100100 100 100100 100 100

0

10

20

30

40

50

60

70

80

90

100

day 15 day 45 day 90

CL1 NCL1 Control

Blinded Subjective AssessmentsBlinded Subjective Assessments

Subjective Evaluation: Wrinkle ImprovementSubjective Evaluation: Wrinkle Improvement


Subjective: Wrinkle Improvement (% Rated Good or Excellent)

10

47.4

10

28

40

20

32.4

25

50.5*

0

10

20

30

40

50

60

% day 15 % day 45 % day 90

Cl1 NCl1 Control *CL1 vs Control

Subjective Evaluation: Elasticity and TightnessSubjective Evaluation: Elasticity and Tightness

Subjective: Elasticity & Tightness

0.8

1.5

0.8

1.1

1.3

0.8

0.6

1

1.4*

0

0.5

1

1.5

2


CL1 NCL1 Control *CL1 vs Control at .05


Subjective Evaluation: Elasticity and TightnessSubjective Evaluation: Elasticity and Tightness

Subjective: Elasticity & Tightness (% Rated Good or Excellent )

17.916

26.5

36.9

1917

25

43.6*

48.7*

0

5

10

15

20

25

30

35

40

45

50

% Day 15 % Day 45 % Day 90

Cl1 NCl1 Control * CL1 vs Control at .05


Subjective Evaluation: Texture ImprovementSubjective Evaluation: Texture Improvement

Subjective: Skin Texture

0.90.9

1.2

1.4

0.7

0.9

1.1

1.9*

1.6*

0

0.5

1

1.5

2




Subjective: Skin Texture (% Rated Good or Excellent)

23

15.4

24.1

50

1521

25

71.8*

51.3*

0

10

20

30

40

50

60

70

80

% Day 15 % Day 45 % Day 90

Cl1 NCl1 Control*CL1 vs. NCL1 & Control at .05

Subjective Evaluation: Texture ImprovementSubjective Evaluation: Texture Improvement


Subjective Evaluation: Skin Hydration ImprovementSubjective Evaluation: Skin Hydration Improvement

Subjective: Skin Hydration

1.1

1.8

1

1.3

1.5

1

1.2

1.5

1.7*

1

1.25

1.5

1.75

2




Subjective Evaluation: Skin Hydration ImprovementSubjective Evaluation: Skin Hydration Improvement

Subjective: Skin Hydration (% Rated Good or Excellent)

18

52.6

3026.4

55

66.6*71.8*

30.8

42.1

0

10

20

30

40

50

60

70

80

% Day 15 % Day 45 % Day 90

Cl1 NCl1 Control

*CL1 vs NCL1 & Control at .05*CL1 vs NCL1 & Control at .05


Subjective Evaluation: Global Appearance ImprovementSubjective Evaluation: Global Appearance Improvement

Subjective: Global Skin Appearance Improvement

10.8

1.11.2

0.7 0.7

1.1

1.8*

1.5*

0

0.5

1

1.5

2




Subjective Evaluation: Global Appearance ImprovementSubjective Evaluation: Global Appearance Improvement

Subjective: Global Skin Appearance (% Rated Good or Excellent)

23.1

12.8

34.2

42.1

20

10.5

30

61.5*

51.3*

0

10

20

30

40

50

60

70

% Day 15 % Day 45 % Day 90

Cl1 NCl1 Control *Cl1 vs Control at .001


Subjective Evaluation: Overall EfficacySubjective Evaluation: Overall Efficacy

Subjective Overall Efficacy of the Product

1.4

1.9

1.3

1.5

1.6

1.4

1.1

1.5

1.8*

1

1.25

1.5

1.75

2




Subjective Evaluation: Overall EfficacySubjective Evaluation: Overall Efficacy

Subjective: Product Efficacy (% Rated Good or Excellent)

43.6

35.9

47.4 5045

26.5

45

70*67*

0

10

20

30

40

50

60

70

80

% Day 15 % Day 45 % Day 90

Cl1 NCl1 Control

*Cl1 vs Control at .05


Product QualitiesProduct Qualities

Assessment of ProductAssessment of ProductSmellSmell

Subjective: Smell of Product (% Rated Satisfactory & Very Satisfactory)

95 92.186.9

92.5

74.4 76.9

95100

95

0

10

20

30

40

50

60

70

80

90

100


CL1 NCL1 Control

Assessment of ProductAssessment of ProductColorColor

Subjective: Color of Product (% Rated Satisfactory & Very Satisfactory)

97

86.9 89.595

82.1 82

100 100 100

0

10

20

30

40

50

60

70

80

90

100


CL1 NCL1 Control

Assessment of ProductAssessment of ProductTextureTexture

Subjective: Texture of Product (% Rated Satisfactory & Very Satisfactory)

92.1 94.8 94.895

84.7 82.1

100 100 100

0

10

20

30

40

50

60

70

80

90

100


CL1 NCL1 Control

Assessment of ProductAssessment of ProductEasiness of ApplicationEasiness of Application

Easiness of Application of the Product (% Rated Satisfactory & Very Satisfactory)

9098 97.499

92 92.3100 100 100

0

10

20

30

40

50

60

70

80

90

100


CL1 NCL1 Control

Assessment of ProductAssessment of ProductPenetrationPenetration

Easiness of Penetration of the Product (% Rated Satisfactory & Very Satisfactory)

9197.4 94.892.5 92.3 92.3

100 100 100

0

10

20

30

40

50

60

70

80

90

100


CL1 NCL1 Control

Assessment of ProductAssessment of ProductOverallOverall Qualities of the Cream Qualities of the Cream

Subjective: Overall Assessment of Product (% Rated Satisfactory & Very Satisfactory)

76

86.9 86.990

69.276.9

95

80

70

0

10

20

30

40

50

60

70

80

90

100


CL1 NCL1 Control

Topical Hyaluronic Acid (HA)Topical Hyaluronic Acid (HA) 90 Day Results Summary I 90 Day Results Summary I

Blinded Investigator evaluations showed highly Blinded Investigator evaluations showed highly statistically significant improvement using the topical statistically significant improvement using the topical crosslinked HA (Restylane) over time and vs the non cross crosslinked HA (Restylane) over time and vs the non cross linked and vehicle in Skin Roughness, Hydration, linked and vehicle in Skin Roughness, Hydration, Elasticity, Radiance, Smoothing Effect and Overall Elasticity, Radiance, Smoothing Effect and Overall Efficacy. Most dramatic differences with Smoothing Efficacy. Most dramatic differences with Smoothing Effect and Overall EfficacyEffect and Overall Efficacy

Blinded subjective evaluations showed highly statistically Blinded subjective evaluations showed highly statistically significant improvement using the topical crosslinked HA significant improvement using the topical crosslinked HA (Restylane) over time and vs the non cross linked and (Restylane) over time and vs the non cross linked and vehicle in, Hydration, Elasticity and tightness, Texture vehicle in, Hydration, Elasticity and tightness, Texture improvement,, Global Appearance Improvement and improvement,, Global Appearance Improvement and Overall EfficacyOverall Efficacy

..

Topical Hyaluronic Acid (HA)Topical Hyaluronic Acid (HA) 90 Day Results Summary II 90 Day Results Summary II

Overall the non crosslinked HA showed better Overall the non crosslinked HA showed better efficiency than the vehicle but was inferior to the efficiency than the vehicle but was inferior to the crosslinked HAcrosslinked HA

Wrinkle evaluation using Goldman-Rao scale was Wrinkle evaluation using Goldman-Rao scale was to course a measurement to show statistical to course a measurement to show statistical differences but clinical photos showed significant differences but clinical photos showed significant improvement using the crosslinked HAimprovement using the crosslinked HA

Tolerance: 97 out of 100 patients finished the Tolerance: 97 out of 100 patients finished the trial. No dropout because of tolerance issues. No trial. No dropout because of tolerance issues. No significant complaints of irritation, dryness, significant complaints of irritation, dryness, itching or redness. No investigator observed itching or redness. No investigator observed untoward effects. Subjects liked the product untoward effects. Subjects liked the product texture, color, penetration, and ease of applicationtexture, color, penetration, and ease of application

..

Topical Hyaluronic Acid (HA)Topical Hyaluronic Acid (HA) Washout Results Summary Washout Results Summary

Blinded Investigator evaluations showed Blinded Investigator evaluations showed highly statistically significant continued highly statistically significant continued improvement after 30 day washout using the improvement after 30 day washout using the topical crosslinked HA (Restylane) vs the non topical crosslinked HA (Restylane) vs the non cross linked and vehicle which overall lost cross linked and vehicle which overall lost significant ground on improvementsignificant ground on improvement

Dramatic clinical improvement after washout Dramatic clinical improvement after washout period in categories of skin roughness, period in categories of skin roughness, smoothing effect and overall efficiency smoothing effect and overall efficiency

..

Topical Hyaluronic Acid (HA)Topical Hyaluronic Acid (HA) Discussion Discussion

Topical crosslinked HA (Restylane) and non crosslinked HA appears Topical crosslinked HA (Restylane) and non crosslinked HA appears penetrate the skin using the unique Ionic Nano Particle Technology penetrate the skin using the unique Ionic Nano Particle Technology (InParT) delivery system(InParT) delivery system

Topical crosslinked HA (Restylane) and to a lesser extent non Topical crosslinked HA (Restylane) and to a lesser extent non crosslinked HA appear to have significant aesthetic enhancement crosslinked HA appear to have significant aesthetic enhancement effect in this double blind vehicle controlled trial in virtually every effect in this double blind vehicle controlled trial in virtually every category of blinded investigator evaluations and subjective category of blinded investigator evaluations and subjective evaluations as well as in clinical photographic assessmentsevaluations as well as in clinical photographic assessments

The benefits of the topical crosslinked HA (Restylane) continue to The benefits of the topical crosslinked HA (Restylane) continue to improve even when the product is discontinued perhaps indicating a improve even when the product is discontinued perhaps indicating a long term benefit to the skin brought forth by collagen remodelinglong term benefit to the skin brought forth by collagen remodeling

Early discussion with regulatory attorneys indicates that topical Early discussion with regulatory attorneys indicates that topical crosslinked HA probably does not need an NDA and can be sold as a crosslinked HA probably does not need an NDA and can be sold as a cosmecuticalcosmecutical..

90 Day Photos90 Day Photos

33

BEFORE

33

BEFORE

BEFORE

AFTER

NTL4: The Next Generation Topical AnestheticNTL4: The Next Generation Topical Anesthetic

Optimized 4% Topical Lidocaine in a Unique Nano Optimized 4% Topical Lidocaine in a Unique Nano Technology Delivery SystemTechnology Delivery System

Results of Clinical Trials Comparing NTL4 to LMX4Results of Clinical Trials Comparing NTL4 to LMX4

Protocols NProtocols N°° 1002510025

10025.110025.1

Center for Clinical and Cosmetic Research (CCCR), Aventura, Florida

Mark S. Nestor, M.D., Ph.D.

NTL4 is an experimental topical Anesthetic owned by NTL4 is an experimental topical Anesthetic owned by Innovatech, Inc.Innovatech, Inc.

LMX4 is a commercially available topical anesthetic LMX4 is a commercially available topical anesthetic owned by Ferndale Laboratoriesowned by Ferndale Laboratories

Clinical studies results in this presentation are preliminaryClinical studies results in this presentation are preliminary Studies preformed at CCCR in Aventura, Florida and Studies preformed at CCCR in Aventura, Florida and

Manhattan Beach, California. Mark S. Nestor, M.D., Manhattan Beach, California. Mark S. Nestor, M.D., Ph.D., Principle Investigator, Glynis Ablon, M.D., Co Ph.D., Principle Investigator, Glynis Ablon, M.D., Co InvestigatorInvestigator

Funding provided by a Research Grant from Innovatech, Funding provided by a Research Grant from Innovatech, Inc.Inc.

DisclosureDisclosure

NTL4 is a unique 4% Lidocaine TA based on the INParT drug NTL4 is a unique 4% Lidocaine TA based on the INParT drug delivery systemdelivery system

The INParT drug delivery system allows for rapid and The INParT drug delivery system allows for rapid and efficient transfer of the Lidocaine through the stratum efficient transfer of the Lidocaine through the stratum cornenum, epidermis and dermis to the sensory nervescornenum, epidermis and dermis to the sensory nerves

4% lidocaine is ideal because of it OTC FDA indication4% lidocaine is ideal because of it OTC FDA indication Clinical trails were conducted to test efficacy and safety of Clinical trails were conducted to test efficacy and safety of

NTL4 as a TA in patients receiving Restylane injections in the NTL4 as a TA in patients receiving Restylane injections in the NLF. The trails utilized LMX4 (the market leader in NLF. The trails utilized LMX4 (the market leader in commercially available 4% lidocaine) in the contra lateral commercially available 4% lidocaine) in the contra lateral NLF as an active controlNLF as an active control

The initial trial investigated the efficacy and safety comparing The initial trial investigated the efficacy and safety comparing a 20 minute application of both productsa 20 minute application of both products

The second trial accessed early onset efficacy at 5, 10, and 15 The second trial accessed early onset efficacy at 5, 10, and 15 minute application of both productsminute application of both products

NTL4NTL4

CCCR Protocol 10025CCCR Protocol 10025

Double Blind, Randomized, Split-Face Study to Double Blind, Randomized, Split-Face Study to Evaluate the Efficacy, Safety and Subject Evaluate the Efficacy, Safety and Subject Satisfaction of Pain Management Utilizing NTL4 Satisfaction of Pain Management Utilizing NTL4 (Topical 4% Lidocaine in a Novel Nano (Topical 4% Lidocaine in a Novel Nano Technology Delivery System) vs. LMX 4 (4% Technology Delivery System) vs. LMX 4 (4% Lidocaine cream) During and After Restylane® Lidocaine cream) During and After Restylane® Dermal Filler Injections for the Correction of Dermal Filler Injections for the Correction of Nasolabial FoldsNasolabial Folds

Study Design: Protocol 10025Study Design: Protocol 10025 Two-center, randomized, split-face, double-blind pilot trial to Two-center, randomized, split-face, double-blind pilot trial to

evaluate the effectiveness of a test product NTL4 versus L-M-evaluate the effectiveness of a test product NTL4 versus L-M-X4® topical anesthetic immediately post, one and three hours X4® topical anesthetic immediately post, one and three hours after Restylane® injections in the NLF. after Restylane® injections in the NLF.

2-day study 2-day study 30 patients total for 2 sites randomized left and right to NLT4 30 patients total for 2 sites randomized left and right to NLT4

or LMX4, respectively, randomly applied (20 second massage) or LMX4, respectively, randomly applied (20 second massage) to each NLF for 20 minutes and removedto each NLF for 20 minutes and removed

Investigator and patient assessments completed at screening Investigator and patient assessments completed at screening /injection immediately upon injection, at 1 hour and 3 hours at /injection immediately upon injection, at 1 hour and 3 hours at visit 1visit 1

Follow-up assessments completed at Visit 2 (next day)Follow-up assessments completed at Visit 2 (next day) AE and concomitant medication review / update at each visitAE and concomitant medication review / update at each visit

AE, adverse event.

Results Summary: Protocol 10025Results Summary: Protocol 10025 Subjective mean VAS scores for the 30 subjects indicated Subjective mean VAS scores for the 30 subjects indicated

significantly less pain upon injection (p=0.04), one hour after significantly less pain upon injection (p=0.04), one hour after injection (p< 0.01) and trend at 3 hours (p=0.06) favoring NTL4 injection (p< 0.01) and trend at 3 hours (p=0.06) favoring NTL4 over LMX4over LMX4

Subjective assessment of level of pain indicated clear but not Subjective assessment of level of pain indicated clear but not significant trend favoring NTL4 over LMX4 significant trend favoring NTL4 over LMX4

Subjects preference of topical anesthetic significantly favored Subjects preference of topical anesthetic significantly favored NTL4 over LMX4 (p=0.002)NTL4 over LMX4 (p=0.002)

Blinded investigator assessment of pain indicated significantly Blinded investigator assessment of pain indicated significantly less pain on the NTL4 treated vs. LMX4 treated side (p=0.002)less pain on the NTL4 treated vs. LMX4 treated side (p=0.002)

Blinded investigators overall satisfaction (adequate anesthesia) Blinded investigators overall satisfaction (adequate anesthesia) significantly favored NTL4 over LMX4 (p< 0.001)significantly favored NTL4 over LMX4 (p< 0.001)

Results Summary: Protocol 10025Results Summary: Protocol 10025

AE’s were all classified as minor and AE’s were all classified as minor and included tenderness, bruising and edema included tenderness, bruising and edema all of which were considered to be related all of which were considered to be related to the Restylane injectionsto the Restylane injections

There were no apparent differences in the There were no apparent differences in the injection related AE’s for either NTL4 or injection related AE’s for either NTL4 or LMX4LMX4

CCCR Protocol 10025.1CCCR Protocol 10025.1

Double Blind, Randomized, Split-Face Double Blind, Randomized, Split-Face Study to Evaluate the Onset of Topical Study to Evaluate the Onset of Topical 4% Lidocaine in a Novel Nano 4% Lidocaine in a Novel Nano Technology Delivery System vs. LMX 4 Technology Delivery System vs. LMX 4 (4% Lidocaine cream) During and (4% Lidocaine cream) During and After Restylane® Dermal Filler After Restylane® Dermal Filler Injections for the Correction of Injections for the Correction of Nasolabial FoldsNasolabial Folds

Study Design: Protocol 10025.1Study Design: Protocol 10025.1 Two-center, randomized, split-face, double-blind pilot trial to Two-center, randomized, split-face, double-blind pilot trial to

evaluate the effectiveness of a test product NTL4 versus L-M-evaluate the effectiveness of a test product NTL4 versus L-M-X4® topical anesthetic immediately post, one and three hours X4® topical anesthetic immediately post, one and three hours after Restylane® injections in the NLF. after Restylane® injections in the NLF.

2-day study 2-day study 20 patients total for 2 sites randomized left and right to NLT4 or 20 patients total for 2 sites randomized left and right to NLT4 or

LMX4, respectively (30 second massage) LMX4, respectively (30 second massage) 3 group randomization for onset of effectiveness: 15, 10 and 5 3 group randomization for onset of effectiveness: 15, 10 and 5

minute duration of topical cream prior to injectionminute duration of topical cream prior to injection Investigator and patient assessments completed at Investigator and patient assessments completed at

screening/injection Immediately upon injection, at 1 hour and 3 screening/injection Immediately upon injection, at 1 hour and 3 hours at Visit 1hours at Visit 1

Follow-up assessments completed at Visit 2 (next day)Follow-up assessments completed at Visit 2 (next day) AE and concomitant medication review / update at each visitAE and concomitant medication review / update at each visit

AE, adverse event.

Results Summary I: Protocol 10025.1Results Summary I: Protocol 10025.1 Subjective mean VAS scores for the 20 subjects Subjective mean VAS scores for the 20 subjects

(combined early onset) indicated significantly less (combined early onset) indicated significantly less pain upon injection (p<0.001), with trends at one hour pain upon injection (p<0.001), with trends at one hour after injection and trend at 3 hours favoring NTL4 after injection and trend at 3 hours favoring NTL4 over LMX4. VAS immediate injection score lower for over LMX4. VAS immediate injection score lower for NTL4 in early onset trial vs original 20 minute trial NTL4 in early onset trial vs original 20 minute trial (1.57 vs 1.99) but higher for the LMX4 (3.86 vs (1.57 vs 1.99) but higher for the LMX4 (3.86 vs 3.02) .Mean Individual onset groups: significantly less 3.02) .Mean Individual onset groups: significantly less pain favoring NTL4 over LMX4 for 15 minute and 5 pain favoring NTL4 over LMX4 for 15 minute and 5 minute incubations (p=0.04) with trend favoring NTL4 minute incubations (p=0.04) with trend favoring NTL4 at 10 minutes. Trends favoring NTL4 at one and three at 10 minutes. Trends favoring NTL4 at one and three hours in all groupshours in all groups

Results Summary II: Protocol 10025.1Results Summary II: Protocol 10025.1 Subjective assessment for the 20 subjects (combined early onset) of Subjective assessment for the 20 subjects (combined early onset) of

level of pain indicated significant less pain on NTL4 over LMX4 level of pain indicated significant less pain on NTL4 over LMX4 (p<0.001). Individual onset groups: significantly less pain favoring (p<0.001). Individual onset groups: significantly less pain favoring NTL4 over LMX4 for 15 minute and 5 minute incubations (p=0.01, NTL4 over LMX4 for 15 minute and 5 minute incubations (p=0.01, p=0.006) with trend favoring NTL4 at 10 minutes. p=0.006) with trend favoring NTL4 at 10 minutes.

Subjects preference of topical anesthetic for the 20 subjects Subjects preference of topical anesthetic for the 20 subjects (combined early onset) significantly favored NTL4 over LMX4 (combined early onset) significantly favored NTL4 over LMX4 (p=0.002). Individual onset groups: significant preference favoring (p=0.002). Individual onset groups: significant preference favoring NTL4 over LMX4 for 15 minute 10 minute and 5 minute incubations NTL4 over LMX4 for 15 minute 10 minute and 5 minute incubations (p=0.001, p= 0.05, p=0.02)(p=0.001, p= 0.05, p=0.02)

Blinded investigator assessment of pain for the 20 subjects (combined Blinded investigator assessment of pain for the 20 subjects (combined early onset) indicated significantly less pain on the NTL4 treated vs. early onset) indicated significantly less pain on the NTL4 treated vs. LMX4 treated side (p=0.001) Individual onset groups: significantly LMX4 treated side (p=0.001) Individual onset groups: significantly less pain favoring NTL4 over LMX4 for 15 minute (p=0.02) with less pain favoring NTL4 over LMX4 for 15 minute (p=0.02) with trends favoring NTL4 for the 10 minute and 5 minute incubations trends favoring NTL4 for the 10 minute and 5 minute incubations

Results Summary III: Protocol 10025.1Results Summary III: Protocol 10025.1 Blinded investigators overall satisfaction (adequate Blinded investigators overall satisfaction (adequate

anesthesia) for the 20 subjects (combined early onset) anesthesia) for the 20 subjects (combined early onset) significantly favored NTL4 over LMX4 (p<0.001). significantly favored NTL4 over LMX4 (p<0.001). Individual onset groups: significant preference favoring Individual onset groups: significant preference favoring NTL4 over LMX4 for 15 minute 10 minute and 5 minute NTL4 over LMX4 for 15 minute 10 minute and 5 minute incubations (p= 0.05)incubations (p= 0.05)

AE’s were all classified as minor and included tenderness, AE’s were all classified as minor and included tenderness, bruising and edema all of which were considered to be bruising and edema all of which were considered to be related to the Restylane injections. One patient (15 related to the Restylane injections. One patient (15 minute) demonstrated erythema and edema lasting 4 days, minute) demonstrated erythema and edema lasting 4 days, initially bilateral and then unilateral (NTL4 side). Cleared initially bilateral and then unilateral (NTL4 side). Cleared with topical cortisone. Thought to be reaction to with topical cortisone. Thought to be reaction to Lidocaine.Lidocaine.

Efficacy Results: Subjective VAS Efficacy Results: Subjective VAS Early Onset (5 Minutes) (N=6)Early Onset (5 Minutes) (N=6)

N=6 N=6 N=6

p=0.045 p=0.309 p=0.643

d=0.61 (Large) d=0.27 (Small)

X Axis: Time After InjectionY Axis: VAS Scale

0

1

2

3

4

5

Immediate 1 Hour 3 Hour

NTL4

LMX4

Subjective Level of PainSubjective Level of Pain Early Onset (5 Minutes) (N=6) Early Onset (5 Minutes) (N=6)

P=0.079

LMX4NTL4

Product_Randomization

4

3

2

1

0

Co

un

t

Moderate PainMild PainMinimal PainNo Pain

Subject_Level_of_Pain

Bar Chart

Subject Satisfaction Data: Overall PreferenceSubject Satisfaction Data: Overall Preference Early Onset (5 Minutes) (N=6) Early Onset (5 Minutes) (N=6)

0

1

2

3

4

5

6

NTL4 LMX4 NoPreference

Subject Preference

P=0.02Preference Rates:NTL4 = 83% (5/6)LMX4 = 16% (1/6)No Preference = 0% (0/8)

Blinded Investigator’s Evaluation of PainBlinded Investigator’s Evaluation of PainEarly Onset (5 Minutes) (N=6)Early Onset (5 Minutes) (N=6)

P=0.076

LMX4NTL4

Product_Randomization

4

3

2

1

0

Co

un

t

Mild PainMinimal PainNo Pain

Subject_Level_of_Pain

Bar Chart

VAS Comparison: OnsetVAS Comparison: OnsetImmediate Post InjectionImmediate Post Injection

0

1

2

3

4

5

20 minutes 15 minutes 10 minutes 5 minutes

NTL4

LMX4

N=30 N=6 N=8 N=6p=0.044 p=0.004 p=0.068 p=0.045

d=0.98 (Large)X Axis: Duration of ApplicationY Axis: VAS Scale

Discussion IDiscussion I Trails compared subjective and blinded investigator assessment Trails compared subjective and blinded investigator assessment

pain, as well as preference following Restylane injections in the pain, as well as preference following Restylane injections in the NLF comparing a novel 4 % lidocaine in nano technology delivery NLF comparing a novel 4 % lidocaine in nano technology delivery system (NTL4) to commercially available LMX4 system (NTL4) to commercially available LMX4

Results indicate that NTL4 is significantly superior to LMX4 Results indicate that NTL4 is significantly superior to LMX4 according to blinded subjective bilateral comparisons and blinded according to blinded subjective bilateral comparisons and blinded investigator observations. Results consistent at one hour and three investigator observations. Results consistent at one hour and three hours after injection and is related to both half life of lidocaine and hours after injection and is related to both half life of lidocaine and decreased initial paindecreased initial pain

NTL4 appears to have significant efficiency with extremely short NTL4 appears to have significant efficiency with extremely short incubation (15,10 and 5 minutes) after 30 second massage incubation (15,10 and 5 minutes) after 30 second massage application. Variations in significance of individual onset groups application. Variations in significance of individual onset groups secondary to small n in each group. Differences between initial and secondary to small n in each group. Differences between initial and early onset study (apparent enhanced effect of NTL4 may be due to early onset study (apparent enhanced effect of NTL4 may be due to 30 vs 20 second application massage)30 vs 20 second application massage)

Discussion IIDiscussion II AE’s mild and appear associated with injections except for one AE’s mild and appear associated with injections except for one

subject. Erythema and edema started bilaterally and continued in subject. Erythema and edema started bilaterally and continued in NTL4 treatment side. Probable cause is lidocaine topical sensitivity.NTL4 treatment side. Probable cause is lidocaine topical sensitivity.

NTL4 show significant promise as a next generation topical NTL4 show significant promise as a next generation topical anesthetic having significantly enhanced effect and early onset abilityanesthetic having significantly enhanced effect and early onset ability

Nano technology allows for enhanced rapid penetration of lidocaine Nano technology allows for enhanced rapid penetration of lidocaine through the stratum corneum, epidermis and dermis to the sensory through the stratum corneum, epidermis and dermis to the sensory nervesnerves

4% lidocaine allows for OTC status: both as a physician used 4% lidocaine allows for OTC status: both as a physician used (dispensed) and general consumer use (dispensed) and general consumer use

Short incubation times (early onset) will be very attractive to Short incubation times (early onset) will be very attractive to dermatologists and pediatriciansdermatologists and pediatricians

Commercial launch of OTC within months (just need stability testing)Commercial launch of OTC within months (just need stability testing)

NTL4 (4% Topical Lidocaine NTL4 (4% Topical Lidocaine Anesthetic Utilizing a Novel Micelle Anesthetic Utilizing a Novel Micelle Nano Technology Delivery System): Nano Technology Delivery System): Anesthetic Properties and Lidocaine Anesthetic Properties and Lidocaine

Toxicity Toxicity

Mark S. Nestor, M.D., Ph.D.Mark S. Nestor, M.D., Ph.D.

Glynis R. Ablon, M.D.Glynis R. Ablon, M.D.

Center for Clinical and Cosmetic ResearchCenter for Clinical and Cosmetic Research

Introduction IIntroduction I

• A recent study showed that NTL4 (Innovatec, A recent study showed that NTL4 (Innovatec, Inc), a new topical nanotechnology lidocaine Inc), a new topical nanotechnology lidocaine preparation, was significantly more effective than preparation, was significantly more effective than L.M.X.4® (Ferndale laboratories), a L.M.X.4® (Ferndale laboratories), a commercially available topical lidocaine commercially available topical lidocaine preparation at decreasing pain upon injection of preparation at decreasing pain upon injection of Restylane in the nasolabial folds. Restylane in the nasolabial folds.

• The preparation worked in as little as 5 minutes. The preparation worked in as little as 5 minutes. • Because of the improved capabilities of NTL4 Because of the improved capabilities of NTL4

this study will evaluate absorption and potential this study will evaluate absorption and potential systemic effects of lidocaine. systemic effects of lidocaine.

Introduction IIIntroduction II The objective of this clinical study is the The objective of this clinical study is the

detection of lidocaine levels in blood after the detection of lidocaine levels in blood after the application of up to 60 grams of NTL4 under application of up to 60 grams of NTL4 under occlusion for 60 minutes on the face, abdomen occlusion for 60 minutes on the face, abdomen or thighs of ten study participants. or thighs of ten study participants.

Additionally a needle stick test using a Additionally a needle stick test using a subjective VAS pain scale will be used to subjective VAS pain scale will be used to determine efficacy of the NTL4. Analysis will determine efficacy of the NTL4. Analysis will include comparison of mean VAS scores for the include comparison of mean VAS scores for the treated and non treated areas. treated and non treated areas.

Methods IMethods I

• 10 subjects between 25 and 6510 subjects between 25 and 65• Blood samples (approximately 3-5cc each) were drawn Blood samples (approximately 3-5cc each) were drawn

from each participant at baseline (before NTL4 cream is from each participant at baseline (before NTL4 cream is applied*) following central laboratory instructions. applied*) following central laboratory instructions.

• NTL4 cream was applied (30 grams) on the whole face of NTL4 cream was applied (30 grams) on the whole face of 4 volunteers. Three volunteers had 60 grams of the cream 4 volunteers. Three volunteers had 60 grams of the cream applied on a 600 cm2 area on their abdomen and the applied on a 600 cm2 area on their abdomen and the remaining three on their thighs under plastic wrap remaining three on their thighs under plastic wrap occlusion occlusion

• The cream was applied on different areas of the body to The cream was applied on different areas of the body to determine differences in absorption.determine differences in absorption.

Methods IIMethods II

NTL4 cream was left on the area for at least 60 minutes. After NTL4 cream was left on the area for at least 60 minutes. After the 60 minutes, the cream was completely removed using the 60 minutes, the cream was completely removed using tongue depressors and lint-free wipes as well as alcohol wipes. tongue depressors and lint-free wipes as well as alcohol wipes. A second blood sample was taken at this time. A second blood sample was taken at this time.

Blood samples were taken again at 2, 6 and 24 hours post Blood samples were taken again at 2, 6 and 24 hours post initial application of the anesthetic creaminitial application of the anesthetic cream

The VAS (Visual Analog Pain) scale was used to determine the The VAS (Visual Analog Pain) scale was used to determine the effectiveness of the topical anestheticeffectiveness of the topical anesthetic

The subject was asked to evaluate the pain experienced at The subject was asked to evaluate the pain experienced at needle stick in the area covered by the topical anesthetic as needle stick in the area covered by the topical anesthetic as well as an untreated adjacent area, by responding to a pain well as an untreated adjacent area, by responding to a pain intensity scale. intensity scale.

ResultsResults

Results IResults I

Patients’ lab results were negative for any level of lidocaine or Patients’ lab results were negative for any level of lidocaine or lidocaine metabolites. lidocaine metabolites.

No neurological, cardiovascular, or gastrointestinal indications No neurological, cardiovascular, or gastrointestinal indications of lidocaine toxicity were observed. of lidocaine toxicity were observed.

In 100% of the patients raw scores of the VAS showed that In 100% of the patients raw scores of the VAS showed that patients reported less pain upon needle stick on the treated patients reported less pain upon needle stick on the treated area when compared to the non-treated area. Table 1 illustrates area when compared to the non-treated area. Table 1 illustrates descriptive data for number of patients, mean scores, and descriptive data for number of patients, mean scores, and standard deviations for VAS scores on treated and non-treated standard deviations for VAS scores on treated and non-treated areas areas

Table 1.

VAS Scores

N

M

SD

Treated

10

1.1

.95Non Treated

10

4.9

2.46

A one-way analysis of variance was used to test mean differences between the 2 areas. Results indicated that a significant difference exists between the treated and non-treated areas (F [1,18] = 21.0, p<.001).

Results IIResults II

DiscussionDiscussion

NTL4 is an extremely effective topical NTL4 is an extremely effective topical anestheticanesthetic

Moderate amounts of NTL4 (up to 60 grams Moderate amounts of NTL4 (up to 60 grams under plastic wrap occlusion) showed no under plastic wrap occlusion) showed no blood levels of lidocaine or metabolitesblood levels of lidocaine or metabolites

Dramatic reduction in VAS pain scale to Dramatic reduction in VAS pain scale to needle stickneedle stick

NTL4 safe and effective topical anestheticNTL4 safe and effective topical anesthetic

Topical BP CombinationTopical BP CombinationAcneAcne

InParT Drug Delivery SystemInParT Drug Delivery SystemTopical BP: Acne ITopical BP: Acne I

BP is one of the most effective and enduring acne BP is one of the most effective and enduring acne treatmentstreatments

BP dramatically reduces bacteria (p. acnes) BP dramatically reduces bacteria (p. acnes) without causing bacterial resistance and in fact without causing bacterial resistance and in fact can reduce bacterial resistance if this has arisen can reduce bacterial resistance if this has arisen from antibiotic therapy. from antibiotic therapy.

Reduces the number of yeasts on the skin surface. Reduces the number of yeasts on the skin surface. BP is an oxidizing agent and is keratolytic and BP is an oxidizing agent and is keratolytic and

comedolytic i.e. it reduces the number of comedolytic i.e. it reduces the number of comedonescomedones

Anti-inflammatory actionAnti-inflammatory action

InParT Drug Delivery SystemInParT Drug Delivery SystemTopical BP: Acne IITopical BP: Acne II

Insoluble BP causes skin to stain clothes need better Insoluble BP causes skin to stain clothes need better alternativesalternatives

Prescription strength BP is a Desi Drug. Rapid FDA Prescription strength BP is a Desi Drug. Rapid FDA approval but FDA transitioning to OTC designationapproval but FDA transitioning to OTC designation

OTC BP is a tremendous market opportunityOTC BP is a tremendous market opportunity The active ingredient in Proactiv product is BP: The active ingredient in Proactiv product is BP:

$500,000,000 in annual sales$500,000,000 in annual sales Total market OTC BP is approximately Total market OTC BP is approximately

$2,000,000,000$2,000,000,000 Low dose BP in InParT delivery can be more Low dose BP in InParT delivery can be more

effective with fewer side effects (irritation and effective with fewer side effects (irritation and dryness)dryness)

Topical BP: Acne Topical BP: Acne Clinical ModelClinical Model

InParT can theoretically maximize penetration InParT can theoretically maximize penetration and delivery of BP and delivery of BP

Improved efficiency Improved efficiency Minimal PB remains on skin surface to lighten Minimal PB remains on skin surface to lighten

skin and stain clothingskin and stain clothing Delivery system can also work with BP Delivery system can also work with BP

combination compoundscombination compounds

Topical BP: Acne Topical BP: Acne Pilot Clinical StudyPilot Clinical Study

ObjectiveObjective To evaluate the efficacy of the To evaluate the efficacy of the novel novel INParTINParT topical (BP 3.5%, 1.5% topical (BP 3.5%, 1.5% salicylic acid and 3% Hydrogen peroxide) salicylic acid and 3% Hydrogen peroxide) in moderate to severe acne vulgarisin moderate to severe acne vulgaris

Design Design open-label treatment phase, open-label treatment phase, randomized, parallel-group maintenance randomized, parallel-group maintenance phase in comparison with VC (placebo phase in comparison with VC (placebo treatment).treatment).


Subjects: Subjects: 26 patients (male/female 14/12) Duration acne was on 26 patients (male/female 14/12) Duration acne was on average 2-3 yearsaverage 2-3 years

Trial Duration: Trial Duration: 8 week Twice a day 8 week Twice a day Main Outcome Measures Main Outcome Measures Overall disease severity, global Overall disease severity, global

improvement, and lesion counts. Patients were seen at baseline, improvement, and lesion counts. Patients were seen at baseline, defined as the visit when treatment was initiated, and again at 2, 4, defined as the visit when treatment was initiated, and again at 2, 4, 8 weeks of treatment. Lesion count, global response and 8 weeks of treatment. Lesion count, global response and photographsphotographs

The global response to treatment scores were assessed by The global response to treatment scores were assessed by comparing the patient's condition with baseline photographs and comparing the patient's condition with baseline photographs and then were graded from 0 to 6 as follows: then were graded from 0 to 6 as follows:

0, completely cleared; 0, completely cleared; 1, approximately 90% improved; 1, approximately 90% improved; 2, approximately 75% improved; 2, approximately 75% improved; 3, approximately 50% improved; 3, approximately 50% improved; 4, approximately 25% improved; 4, approximately 25% improved; 5, no change; and 5, no change; and 6, exacerbation. 6, exacerbation.


Results:Results: After 8 weeks or less treatment the mean After 8 weeks or less treatment the mean

reductions from baseline in non inflammatory reductions from baseline in non inflammatory and inflammatory lesion count, were 66% and inflammatory lesion count, were 66% and 69% with this novel formulation in and 69% with this novel formulation in comparison with placebo where improvement comparison with placebo where improvement was 3.7% and 5.2%was 3.7% and 5.2%

At week 4, more than 80% of patients had At week 4, more than 80% of patients had maintained a 50% or greater global maintained a 50% or greater global improvement from baseline, and more than improvement from baseline, and more than 40% had maintained a 75% or greater global 40% had maintained a 75% or greater global improvement.improvement.


Results:Results: Overall disease severity score mean ± SD 3.7±1.7Overall disease severity score mean ± SD 3.7±1.7 Mean percentage (%) change in papules and pustulesMean percentage (%) change in papules and pustules

Baseline week 1 week 2 week 4 week 6 week 8 Baseline week 1 week 2 week 4 week 6 week 8 0 7.5 15.1 27.7 40.1 56.30 7.5 15.1 27.7 40.1 56.3

Incident of >50% global improvement from baseline 21/26Incident of >50% global improvement from baseline 21/26 Incident of >75% global improvement from baseline 14/26Incident of >75% global improvement from baseline 14/26 % change non-inflammatory lesions counts 64±22.2% change non-inflammatory lesions counts 64±22.2 % change inflammatory lesions counts 67±27.3% change inflammatory lesions counts 67±27.3


AEs:AEs: There were no SAEs observed There were no SAEs observed during this study over period during this study over period

Most subjects reported excess dryness Most subjects reported excess dryness (24/26). (24/26).

Redness and peeling at the site of Redness and peeling at the site of application (9/26). application (9/26).

Burning sensation when they applied the Burning sensation when they applied the treatment for the first time (5/26), faded treatment for the first time (5/26), faded after 5-7 days of the treatment. after 5-7 days of the treatment.

Clinical PhotographsClinical Photographs

Baseline 4 weeks


Baseline 6 weeks


Baseline 3 weeks 6 weeks

Topical Botulinum Topical Botulinum NeurotoxinNeurotoxin

HyperhidrosisHyperhidrosis

Introduction IIntroduction I

Hyperhidrosis is considered a chronic disorder Hyperhidrosis is considered a chronic disorder that is characterized by excessive sweating in the that is characterized by excessive sweating in the axilla, palm, soles, or faceaxilla, palm, soles, or face

Injection of abobotulinumtoxin, BotoxInjection of abobotulinumtoxin, Botox is is approved by the FDA for the treatment of severe approved by the FDA for the treatment of severe primary axillary hyperhidrosis but many patients primary axillary hyperhidrosis but many patients do not tolerate the extensive injectionsdo not tolerate the extensive injections

Additionally a large market exists for individuals Additionally a large market exists for individuals who would like to “cosmetically” stop who would like to “cosmetically” stop perspiration for an extended period of time perspiration for an extended period of time without the need for injections without the need for injections

Introduction IIIntroduction II

The InParT Transdermal Delivery System has The InParT Transdermal Delivery System has been shown to have significant efficacy for been shown to have significant efficacy for passively transporting botulinum toxin both passively transporting botulinum toxin both for aesthetic benefits as well as hyperhidrosisfor aesthetic benefits as well as hyperhidrosis

Multiple dose trials outside USMultiple dose trials outside US In US pilot study, 3 different FDA approved In US pilot study, 3 different FDA approved

toxins will be utilized in single dose treatment toxins will be utilized in single dose treatment regime to determine initial efficacy of the regime to determine initial efficacy of the delivery systemdelivery system

InParT Drug Delivery SystemInParT Drug Delivery SystemTopical BoNTA: HyperhidrosisTopical BoNTA: Hyperhidrosis

Need for a topical neurotoxin for Need for a topical neurotoxin for HyperhidrosisHyperhidrosis Painless applicationPainless application Needle phobiaNeedle phobia

Coupled with application device for in office Coupled with application device for in office procedureprocedure

Allergan owns patent (2014) but can be used Allergan owns patent (2014) but can be used off labeloff label

Topical BoNTA: Hyperhidrosis Topical BoNTA: Hyperhidrosis Clinical ModelClinical Model

The stabilized cream is applied topically onto the skin The stabilized cream is applied topically onto the skin containing fixed (exact) amount of the Toxincontaining fixed (exact) amount of the Toxin

The nano-spheres helps penetrate the skin layers with The nano-spheres helps penetrate the skin layers with the aid of absorption enhancers and releases the the aid of absorption enhancers and releases the stabilized toxin into the deep layers of the skinstabilized toxin into the deep layers of the skin

Toxin diffuses into the eccrine glands (Smooth Toxin diffuses into the eccrine glands (Smooth muscles) inhibiting the release of acetylcholine and muscles) inhibiting the release of acetylcholine and reducing sweat productionreducing sweat production

Topical BoNTA: HyperhidrosisTopical BoNTA: HyperhidrosisPilot Clinical Study I*Pilot Clinical Study I*

Prospective open label study axillary and palmer hyperhidrosisProspective open label study axillary and palmer hyperhidrosis 24 subjects (18 – 59)24 subjects (18 – 59) Starch Iodine and Starch Iodine and Gravimetric Gravimetric teststests Botulinum toxin type A gel is applied, twice a day for 1 weeks, 6 units Botulinum toxin type A gel is applied, twice a day for 1 weeks, 6 units

per day. (42 units at the end of the study).per day. (42 units at the end of the study). Weekly follow up for 12-16 weeks, with picture records, colorimetric Weekly follow up for 12-16 weeks, with picture records, colorimetric

and gravimetric test at week 4 and at the end of the study.and gravimetric test at week 4 and at the end of the study. Adverse effects were recorded.Adverse effects were recorded. Patients answered a questionnaire of satisfaction at the end of the Patients answered a questionnaire of satisfaction at the end of the

study.study.

*Rogelio J, Morales O: HYPERHIDROSIS TREATMENT WITH TOPIC *Rogelio J, Morales O: HYPERHIDROSIS TREATMENT WITH TOPIC BOTULIN TOXIN TYPE A GEL SubmittedBOTULIN TOXIN TYPE A GEL Submitted..

Topical BoNTA: HyperhidrosisTopical BoNTA: HyperhidrosisPilot Clinical Study II*Pilot Clinical Study II*

Analysis Friedman Test: Analysis Friedman Test: mg/min: 79% reduction at mg/min: 79% reduction at 12 weeks for all areas 12 weeks for all areas P<0.0002P<0.0002

Analysis Friedman Test: Analysis Friedman Test: cm2: 89% reduction at 12 cm2: 89% reduction at 12 weeks for all areas P<0.004weeks for all areas P<0.004

High Satisfaction Low AE’s High Satisfaction Low AE’s mostly drynessmostly dryness

*Rogelio J, Morales O: HYPERHIDROSIS TREATMENT WITH TOPIC *Rogelio J, Morales O: HYPERHIDROSIS TREATMENT WITH TOPIC BOTULIN TOXIN TYPE A GEL SubmittedBOTULIN TOXIN TYPE A GEL Submitted..

Hyperhidrosis; Before and After ( at week 16)

Topical Botulinium Toxin Topical Botulinium Toxin in the Treatment of in the Treatment of

HyperhydrosisHyperhydrosis

Mark S. Nestor, M.D., Ph.D.Mark S. Nestor, M.D., Ph.D.Glynis R. Ablon, M.D.Glynis R. Ablon, M.D.

Center for Clinical and Cosmetic ResearchCenter for Clinical and Cosmetic Research

Confidential Preliminary DataConfidential Preliminary Data

MethodsMethods 15 subjects 2 US sites15 subjects 2 US sites Baseline axillary hyperhydrosis as defined by gravimetric Baseline axillary hyperhydrosis as defined by gravimetric

test (>50 mg sweat per 5 minutes)test (>50 mg sweat per 5 minutes) No antiperspirant or deodorant for 3 days before and during No antiperspirant or deodorant for 3 days before and during

trailtrail One axilla single topical treatment:One axilla single topical treatment:

• 5 subjects: 300 units of Dysport in InParT transport system5 subjects: 300 units of Dysport in InParT transport system• 5 subjects: 100 units of Botox in InParT transport system5 subjects: 100 units of Botox in InParT transport system• 5 subjects: 2500 units of Myobloc in InParT transport system5 subjects: 2500 units of Myobloc in InParT transport system

Contralateral axilla: InParT transport system aloneContralateral axilla: InParT transport system alone Under occlusion for 60 minutes Under occlusion for 60 minutes Evaluated at 15 and 30 days with gravimetric and starch Evaluated at 15 and 30 days with gravimetric and starch

iodineiodine

ResultsResults

Note: Relative change from control similar in Botox group

Patient 1Patient 1

Baseline hyperhydrosis as defined by gravimetric Baseline hyperhydrosis as defined by gravimetric test (>50 mg sweat per 5 minutes)test (>50 mg sweat per 5 minutes)

No antiperspirant or deodorant for 3 days before No antiperspirant or deodorant for 3 days before and during trailand during trail

One axilla single topical treatment with 300 units One axilla single topical treatment with 300 units of Dysport in unique InParT transport systemof Dysport in unique InParT transport system

Contralateral axilla treated with InParT transport Contralateral axilla treated with InParT transport system alonesystem alone

Both under occlusion for 60 minutes Both under occlusion for 60 minutes

Patient 1Patient 1BaselineBaseline

Control Topical Dysport

Gravimetric Tests129.0mg 102.9 mg

Patient 1Patient 1Day 8Day 8


Gravimetric Tests120.2 mg 13.7 mg



Gravimetric Tests128.1 mg 14.0mg



Gravimetric Tests128.1 mg 14.0 mg



Gravimetric Tests100.9 mg 26.3mg

DiscussionDiscussion

Pilot study with 3 toxins (Botox, Dysport and Pilot study with 3 toxins (Botox, Dysport and Myobloc) to determine effect of a single low dose Myobloc) to determine effect of a single low dose topical applicationtopical application

All three topical toxins showed effect All three topical toxins showed effect Overall a 20% decrease over control with 100% Overall a 20% decrease over control with 100%

of subjects having lower amounts of perspiration of subjects having lower amounts of perspiration on the treated side at day 15 and 80% at day 30on the treated side at day 15 and 80% at day 30

Individual subjects had up to 90% reduction at Individual subjects had up to 90% reduction at day 15 and 80% at day 30day 15 and 80% at day 30

Need further clinical trails to optimize dosing and Need further clinical trails to optimize dosing and applicationapplication

InParT Drug Delivery SystemInParT Drug Delivery SystemFuture ApplicationsFuture Applications

Hyperpigmentation and MelasmaHyperpigmentation and Melasma PsoriasisPsoriasis RosaceaRosacea Onychomycosis Onychomycosis XerosisXerosis CosmeuticalCosmeutical Hair GrowthHair Growth

InParT Drug Delivery SystemInParT Drug Delivery SystemOpportunitiesOpportunities

Partnership vs. License TechnologyPartnership vs. License Technology Enhance existing topical toxinEnhance existing topical toxin HAHA LidocaineLidocaine HydroquinoneHydroquinone

Collaborative effortCollaborative effort Strategic InvestmentStrategic Investment SaleSale

a novel topical transdermal delivery system mark s. nestor, m.d., ph.d. director center for clinical...

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topical drug delivery

skin pores nano particles

cosmetic delivery

variety of active compounds

inpart technology

absorption of active

skin pores nano paticles

unique passive delivery