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A New Transdermal Delivery System Molecular Film Fabrics For Skin Management

INDEX

THE MANUFACTURER 2

THE TECHNOLOGY 3

THE PATHOLOGIES 6

SKIN MANAGEMENT IN DIABETIC FOOT 6

SKIN MANAGEMENT IN CHRONIC ULCERS 8

SKIN MANAGEMENT IN AMPUTEES 11

THE SYSTEM (VEHICLES AND REFILL) 12

MODE OF USE 14

MKT STRATEGY 15

REGULATORI ASPECTS 16

THE BIBLIOGRAFY 17

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THE MANUFACTURER

LVM TECHNOLOGIES (Bologna, Italy) is a group or research and development of new

technologies and products to improve quality of life.

The initial development has been addressed to the acquisition of a deep knowledge in the area

of skin care and its treatment with the goal of developing scientifically valid product using the

available technological opportunities.

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THE TECHNOLOGY

The microencapsulation process has numberless present and potential applications in the

textile sector from the pharmacological up to the cosmetic field. This technology is strongly

taken into consideration particularly in those case where delayed action is essential. A typical

example could be in medicine, where a slow release of an active principle from a textile

product guarantees a constant and extended action. The technology we apply consists in the

production of a molecular film containing microcapsules, which completely wraps the textile

yarns.

DIFOPREV® system are used for SKIN MANAGEMENT in pathologies where the skin

deteriorates due to different reasons.

DIFOPREV® system have been developed by microencapsulation of a natural ingredient

(glycoprotein) in high concentrations capable of repairing minor surface lesions of the skin,

decreasing keratosis, providing it with suppleness, elasticity and hydration and increasing

growth of type I and IV Collagen, Elastin.

Millions of microcapsules filled with glycoprotein are contained in a molecular film coating

the yarns of fabrics (vehicles). The microcapsules open when the vehicles come in contact

with the skin and start a gradual and constant transdermal delivery of the agent to the skin.

Dermal penetration is deep thanks to the monolayer structure of the molecular film. To

guarantee a high patient compliance, vehicles are available in different sizes and colour and

can be easily refilled by patients at home during washing process once emptied.

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Untreated fabric

Main advantages of this Technology:

Gradual and constant delivery of the active principle as long as vehicles are worn with

increase of therapeutic index

Possibility to focus the active principle in a particular area of the body

Three days application of microencapsulated active principles equal the content of 100

g cream (no risk of wound breakdown due to excessive moisture)

No gastric/metabolic damage.

Protection of the active principle against possible environmental degradations

High patient compliance

Foto Lanzara

Treated fabric

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DIFOPREV system have been developed in cooperation with:

Prof. Alberto Piaggesi Dr. Roberto Brambilla Prof. Tancredi Andrea Moscato Head of the Diabetic Foot Division Head of Cutaneous Ulcers Center Center for the Experimentation and Metabolic Disease and Diabetology Istituti Clinici Zucchi Monza Italy Application of prosthesis Department I.N.A.I.L., Budrio, Italy Pisa University Hospital, Italy Dr. Giacomo Clerici Dr. Vincenzo Gasbarro Dr. Gerardo Corigliano Centre for Prevention & treatment of Phlebology Research Center Head of Diabetic Unit the Diabetic Foot Ferrara University, Italy ASL,Naples, Italy

Dr.Leonardo Aluigi Dr. Steve Young Prof. Antonella Tosti Cardio Vascular Diseases High Frequency Diagnostic Ultrasound Head of Dermatology Dept. Maggiore Hospital, Bologna Italy Cambridge University, UK Sant’Orsola Hospital, Bologna, Italy Dr.Govind Singh Bisht Dr. Sanjoy Paul Dr. Anupma Dubay MBBS CPP (Fellowship in Podiatry) Consultant diabetologist Maharshi Diabetes and Foot Care centre

USA,Foot Care Specialist Dr.Mohan’s Diabetes Specialities Indore, MP, India Sitaram Bhartiya Institute Sri Balaji Action Medical Institute Delhi Diabetic Research Center India Dr. Lily Rodrigues Dr.Vilma Urbancic,MD,PHd Dr.Antonio Carlos de Souza DNB (MED) Assist.Prof.of Medicine Vascular Surgeon, Angiology Surakshaka Hospital,Hyderabad,India University Medical Centre, Dept of Angiomedi Clinic,Brasilia, Brasil Endocrinology Ljublijana,Slovenia Prof.Luca Avagnina Science of Rehabilitation Sport Podiatrist Specialist (President of Italian Ass. Of Sport Podiatry)

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THE PATHOLOGIES

Skin Management in The Diabetic Foot

It is estimated that around 10 to 15% of the total diabetic population is at risk of developing complications in the lower limbs, with skin getting hard and easily cracked. Such patients cannot notice the skin getting cracked due to peripheral neuropathy (loss of sensitivity). In Diabetic Foot doctor (endocrinologist, diabetologists, vascular surgeon, GP’s, podiatrists, etc.) should use the DIFOPREV® system with the objective of maintaining the skin moisturised, hydrated, soft and to reduce keratosis (hard skin) being the cause of cracks that might lead to ulcers, gangrene and ultimately amputations. It’s a preventative prophylaxis to be used in both Primary and Secondary Prevention.

A few examples taken from one of the Efficacy Tests in the Diabetic Foot

BASELINE After 30 DAYS

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The indications

DIFOPREV® is indicated in all dysidrosis conditions of the lower limbs, and especially in

elderly patients, in patients affected by venous diseases or diabetes mellitus and in xerotic

skin pathologies.

In presence of lower limbs pathology deriving from diabetes mellitus, DIFOPREV® is

indicated in patients with neuropathy and/or peripheral arteriopathy and in patients with

previous foot ulcerations and more broadly speaking in all patients with at leas 10 years of

disease.

Patients over 60 years of age with type 1 and type 2 diabetes should use two pairs of socks

per year with adequate refills for a month treatment every four months ,thus three month

cycles per year.

At risk patients with type 1 diabetes should be supplied two pairs of socks per year with

adequate refills for a month treatment every three month, thus four month cycles per year.

Patients with type 1 or type 2 diabetes with and elevated risk, those who have developed

lesions or undergone amputations in the past or those with lower limb ischemia with ABPI ‹

0,8 should be supplied whit two pairs of socks per year with refills for two month treatment

every four months, thus three cycles of two months per year.

Disease and

Socks/Patient/Year

Month/Patient/Year

Objective

Diabetes type 2 2 3

Skin hydration and suppleness

Diabetes type 1›60 years

2 3

DM1 at risk 2 4

DM1 with elevated risk 2 6

Complete skin integrity and regeneration

DM2 with elevated risk 2 6

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Skin Management in chronic cutaneous ulcers

Leg ulcers are a chronic condition caused by two main problems in developed countries. The two commonest causes of ulceration are diseases of the veins and diseases of the arteries. As many as 75% of patients have a significant venous component to their leg ulcers. Arterial ulceration and mixed arterio-venous ulcers (ulcers due to a combination of venous and arterial disease) constitute the second major group of leg ulceration patients (14%). Diabetes mellitus can also cause ulceration, but predominantly in the foot. Venous and arterial problems can also occur in patients with diabetes.

Key Points

The skin surrounding a wound is particularly vulnerable and although it may appear healthy, periwound problems occur frequently. Periwound skin damage can exacerbate pain, increase wound size and delay healing.

All periwound skin can become vulnerable and requires careful assessment and management to prevent or reduce further damage.

DIFOPREV CP is an effective system for preventing and managing peri-ulcer skin lesions .

Applied over the top of any wound dressing be worn under bandage or compression stocking, as an integration and improvement of our usual approach to chronic cutaneous lesions. The device is capable of resolving a key aspect of the problem, the peri-ulcer skin, being of primary importance though often underestimated and still without alternative solutions. Do not use in direct contact with open wounds or sores.

The simplicity of use of the device has to be underlined, facilitating its use even in “difficult” patients such as those affected by skin ulcers.

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A few example taken fron one of the Efficacy Tests in the Peri-Ulcer Skin management

BASELINE AFTER 1st TREATMENT

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Skin Management in Trans-Tibial and Trans-Femoral Amputees Major Amputations (calf and above knee) are performed due to different causes such as

traumas or diabetes.

The stump in lower limb amputees is prone to skin problems because it is exposed to several

unnatural conditions (shear and stress forces and increase humidity) when a prosthesis is

used. The main disorders are acroangiodermatitis, allergic contact dermatitis, bullous

diseases, epidermal hyperplasia, hyperhidrosis, infection, malignancies and ulcerations.

The pressure, the stress and the weight leaning on the prosthesis deteriorates the skin of the

stump, sometimes resulting in a rejection of the prosthesis itself. Patients can wear a

DIFOPREV® Stump Cover overnight, when the prosthesis is not in place.

This prophylaxis has the purpose of improving skin conditions all around the stump.

As a matter of fact, around 70% of major amputations are due to diabetes, and it is estimated

that around 20% of diabetic amputees have skin related problems in the stump.

The same problems are experienced by patients who underwent amputations for other

reasons.

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A few examples taken from one of the Efficacy Tests in

Trans-femoral Amputees

BASELINE AFTER 1sr TREATMENT (30 days)

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THE VEHICLES ACCORDING TO THE PATHOLOGIES

DIABETIC FOOT Compression-free socks, made in Meryl. Available models:

MAJOR AMPUTEES Stump covers. Available in 1 size that fits all.

“30-day kit” pack containing a pre-filled pair of vehicles (3 days) along with 9 refill capsules (27 days))

Refill Capsule 9’s (27 days) One pair of pre-filled vehicles (3days)

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THE VEHICLES ACCORDING TO THE PATHOLOGIES

PERI-WOUND SKIN Tubolar made in Meryl. Available in 2 size.

The vehicles are DISPOSABLE.

One pack contain n. 10 pre-filled pair of vehicles.

(The liner Is removed and thrown away when replacing the dressing (usually every 4-5 days) and replaced with a new. )

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MODE OF USE In the Diabetic Foot patients will wear the socks just like ordinary socks, either during day time or overnight. Treatment cycles last 30 days each, to be repeated during the year depending on doctor’s advice. Every 3 days the socks have released completely the glycoprotein and have to be refilled. Socks can be washed with ordinary washing machine programs (30°) on a daily basis, without washing off the microcapsules. Major Amputees shall wear the stump cover overnight, when they remove the prosthesis, as long as the doctor advise to do so. The vehicles can be refilled.

To recharge the socks,

After standard washing, take a bowl large enough to accommodate both

socks/stump cover.

Pour a small quantity of lukewarm (not hot) water into the bowl.

Add the gel contained in the refill capsule into the water, making sure you

empty completely the capsule.

Mix thoroughly until a homogenous solution is obtained. Pour enough

lukewarm water to soak completely both socks/stump cover

Soak them into the bowl.

leave it there for 20 minutes, after which the socks/stump cover will be

automatically refilled again.

Dry away from heat sources, no ironing.

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MARKETING STRATEGY

Taking into account that DIFOPREV® nowadays do not have competition being a unique

technology, we can support international distributors with:

Free products for local test or for participation in local congresses/seminars

Avalaibility of Italian specialist to give lectures in local congresses/seminars

Avalaibility of local doctors for training courses in Italian clinics

We request from our International Distributors:

Promotion and detailing to appropriate doctors to generate

prescriptions/recommendation

Partecipation in local congresses/seminars

Application for listing in the health insurance (where existing)

Capillary distribution through retail pharmacy shops or other appropriate channels.

Sales channels might vary from country to country involving pharmacy retail shops, clinic,

hospitals, podiatrist, etc…Sales should always be generated by a doctor’s prescription or

recommendation thus requiring not only a good sales reps network, but also a capillary

medical reps network.

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REGULATORY ASPECTS DIFOPREV® is manufactured in Italy and has been classified as Class IIa Medical Deviced in

accordance with the 93/42/EEC and carries relevant CE number and Declaration of

Conformity.

DIFOPREV is protected by European Patent No. EP 1700947.

Within UE Countries, DIFOPREV® does not need to undergo registration process and

maintains its original classification as Class IIa Medical Device with a simple notification to the

local MOH.

Outside UE Countries, DIFOPREV® requires a registration process which is different from

Country to Country. Some authorities even reject the original classification and want to

register it as a Cosmetic or as a Drug. There are usually obstacles that have to be overcome by

the distributor relying on the documentation provided by us.

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THE BIBLIOGRAPHY

001 L. Aluigi, G. Pirotta – Prevention of “DIABETIC FOOT” preliminary 2005 results of a new delivery system with cosmetic microcapsules- Podium presentation – IFSCC World Wide Wellness – Proceedings Cosmetics 2005 International conference – Firenze, 19-21 Settembre 2005 002 E. Banchellini, L. Ambrosini, A. Civitelli, S. Macchiarini, E. Leporati, V. Sciré, I. Teobaldi, A. Piaggesi – Valutazione del nuovo sistema DIFOPREV nella prevenzione e nel trattamento delle condizioni Pre-ulcerative nei pazienti con piede diabetico neuropatico: uno Studio prospettico randomizzato – Podium presentation – Congresso Piede Diabetico 2005 – Firenze 5-7 Dicembre 2005 2005 003 E. Banchellini, L. Ambrosini, A. Civitelli, S. Macchiarini, E. Leporati, V. Sciré, I. Teobaldi, A. Piaggesi – Applicazione delle nanotecnologie Alla gestione delle condizioni pre-ulcerative nel piede diabetico Neuropatico – Poster session – 21° Congresso Nazionale SID – Milano, 17-20 Maggio 2006. 2006 004 R.Piro, F.De Bernardinis, G.Grossi,S.Carnevale – Trattamento di Prevenzione e Ripristino della cute nel piede diabetico con sistema Difoprev – podium presentation – Piede diabetico la realtà centro- Meridionale – 19-21 Ottobre 2006 – Paola (CS) 2006 005 L. Aluigi – Educazione e prevenzione piede diabetico - Podium Presentation – Giornate Nazionali di angiologia XXVIII Congresso Nazionale SIAPAV – Roma Novembre 2006 2006 006 E. Banchellini, L. Ambrosini, V. Dini, L. Rizzo, M. Romanelli, A. Piaggesi – Nanotechnologies for the treatment of pre-ulcerative Condition of the diabetic foot – a prospective randomized trial – Podium presentation – V° International Symposium on the diabetic foot – 9-12 May 2007, Noordwijkerout – Netherands 2007 007 A. Piaggesi – Facing the challenge of prevention in the diabetic Foot – Podium presentation – 13° National Congress of Internal Medicine 8-13 Ottobre 2007 – Athens - Greece 2007 008 G. Pirotta – Skin delivery of active ingredient from fabric – Publication “Cosmetic&Toiletries” Allured Publishing Corporation USA, Aprile 2008 2008 009 E. Banchellini, S. Macchiarini, V. Dini, L. Rizzo, A. Tedeschi, A. Scatena, C. Goretti, F. Campi, M. Romanelli, A. Piaggesi – Use of nanotechnology- Designed footsock in the management of preulcerative conditions in the Diabetic foot: results of a single, blind randomized study – Publication The International Journal of Extremity Wounds - USA –Giugno 2008 2008 010 E. Banchellini, S. Macchiarini, V. Dini, L. Rizzo, L. Abruzzese, A. Tedeschi A. Scatena, C. Goretti, M. Romanelli, A. Piaggesi – Nanotechnologies for The management of pre-ulcerative conditions in the diabetic foot – Poster session – Seven meeting of DFSG – 11-14 Settembre 2008 Il Ciocco Castelvecchio Pascoli Italy 2008

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011 Douglas H. Richie jr., DPM- Therapeutic hosiery: An Essential Component Of Footwear for the Pathologic Foot – Publication Footwear & Podiatry- Podiatry Management – East Islip - NY USA - Ottobre 2008 2008 012 H. Hosalcar, MBMS, FCPS, DNB, J. Hsu, N.K.Pandya and M. A. Keenan – What’s new in Orthopaedic Rehabilitation – Publication The Journal of Bone And Joint Surgery – USA Ottobre 2008 2008 013 A.Piaggesi, L.Rizzo, A.Tedeschi, A.Scatena, C.Goretti, S.Del Prato - Measurements in Diabetic Foot – Publication Journal Of Wound Technology – Edition MF – Paris - France Gennaio 2009 2009 014 A.Piaggesi – Innovative approaches to Diabetic Foot care in Italy – Publication Wounds International – UK – Febbraio 2010 2010 015 S.Manfredelli, I.Martire, F.Passafiume, N.Di Tullio, A.Forte, A.Lorenzotti, V.Malagnino, A.Chiravalloti, M.Bezzi, F.Vietri, P.G.Pastore – Trattamento della Neuropatia autonomica nella prevenzione delle ulcere del piede diabetico- Pubblicazione Acta Vulnologica – Italia – Giugno 2010 2010 016 E.Banchellini, L.Abruzzese, L.Ambrosini Nobili, E.Leporati, S.Macchiarini, I.Teobaldi, A.Piaggesi – Nanotechnologies for the prevention and treatment of pre-ulcerative lesions of the ischemic foot – Podium presentation – VI° International Symposium on the diabetic foot – 11-14 May 2011, Noordwijkerhout, Netherlands 2011