march 2008 lisapharma – confidential 1. 2 company introduction & proprietary technologies

March 2008 Lisapharma – Confidential 1


Company Introduction

&

Proprietary Technologies


LISAPHARMA at a glance

Fully owned by Italian capital

Family-ruled business from its foundation to today

Manufacturing plant of dosage forms in full GMP compliance, including β-lactam ceph derivatives dedicated line

Driven to technological developments throughout strong liaisons with different university bodies

Operative on the Italian and international markets through a portfolio of proprietary medicines


Milestones

1925: Lisapharma is established in Bologna

1949: HHQQ and plant moved to actual site of Erba (Co)

1968: first export business to Taiwan

1970: establishment of international production units in Nicaragua & Costarica

1993: first manufacturing activity as toll manufacturer with Novartis

2000: start of phase-out of production of oral solid non-sterile products

2002: establishment of the j.-v. with Omicron for the manufacture of oral solid non-sterile products


Key facts & figures

Fully owned Italian manufacturing plant for sterile injection products, non-sterile liquids, semisolids

J.-V. participation in Omicron plant (Italy) for oral solid non-sterile production

148 total headcounts, out of which 80 reps

International customers portfolio of 81 accounts

International sales in 32 different countries worldwide

Intellectual property of 18 patents covering original technologies

Development & RA expenditure up to 5.60% of company revenues


Goals

To consolidate the presence in the Italian market

To improve the penetration in existing countries outside Italy and to expand to further new markets its business partneriships

To enlarge the toll manufacturing activities for renowned international companies

BY………………………..


Strategy

In-house development of generic registration dossiers focusing on niche products (injectable class,…)

Partnering and/or tightening strategic alliances allowing the best exploitation of the in-house developed patented technologies (Sucralfate Gel, Dome Matrix™, Patch-non-Patch™, Chimerical Agglomerates™)

Diversification of the product portfolio to include additional non-RX compounds “dedicated” to specialists (food supplements, medical devices,…)

Strengthening the existing collaborations through the proven high standard of quality and service provided, by doing so attracting new potential customers too


PROPRIETARY TECHNOLOGIES


Proprietary technologies

Long-lasting cooperation between Lisapharma and well reputable Universities in Italy

Focusing in the development of novel delivery systems, due to the increased market demand for drug delivery technology

Aiming to develop versatility in drug delivery, as much as adaptability to different drugs to inhance patient compliance

ALL THIS LED TO


Proprietary technologies

Dome Matrix™, oral platform

Patch-non-Patch™, transdermal platform

Chimerical Agglomerates™, inhalation nasal platform

Sucralfate Gel, as unti-ulcer for GI tract and skin wounds

FOUR PLATFORMS

The technologies are covered by patents and available for discussions


The Platform Concept in DDS

• More than 15% of the total pharma market – in excess of U$ 80 billion - is covered by drug delivery technolgies

• Future belongs to biotech drugs, to old drugs to be revaluated, to new drugs offered with appropriate dds, and to generics

• The systems invented shall posses not only versatility in delivery, but also adaptability to different drugs

• The term platform indicates a delivery system capable to be adapted to various drugs, strenghts, mechanisms of delivery, in order to control not only the time but also the site of delivery


DOME MATRIX®


Dome Matrix®

• The system is based on tablets (modules) with a peculiar shape made of swellable polymer for controlling the release rate

• The typical shape of the module is a cylindrical tablet having one concave and one convex base designed to allow the convex base to be inserted in the concave

• The shape permits to put together several modules to create different assembled release systems


Dome Matrix®


Dome Matrix®

• A peculiar assembly can be obtained by fitting the concave base of two modules allowing the construction of a floating system able to keep the release of the substance into the stomach


Dome Matrix®

• Piled configurations can be obtained by staking the modules convex face into concave face


Dome Matrix®

• Dome Matrix® finds its ideal application whenever there is a need for:

a prolonged release of solid dosage forms and it may represent an effective answer to the need to have versatility in the substance release kinetics

modulation of dose administered

association of different substances in one modular system

improving the efficacy of the substance delivered, providing a time-and-space controlled release system


Dome Matrix®

• Dome Matrix® technology can be applied

To “old” products presented in innovative dosage forms

New compounds combined with an original and innovative delivery route

• Dome Matrix® industrial development is in progress

• Dome Matrix® is covered by patent, license or transfer could be considered


Patch-non-Patch®


Patch-non-Patch®

Patches vs. Traditional Systemic Formulations

• Constant plasma levels

• Lower incidence of side effectsvs Injection vs Oral

Non invasive Increased bioavailability

More acceptable Reduced dosing frequency

No need of specialized No drug interaction

personnel

• Limitation

Low skin permeability (daily dosing < 10 mg)


Patch-non-Patch®

Patches vs. Traditional Systemic Formulations

• Topical formulations (solutions, creams, gels,…) can:−Be accidentally removed – contact time

−Applied at the wrong dose

−Stick to cloths

• Patches guarantee control in:−Dose applied

−Area of application

−Contact time

−Release kinetics


Patch-non-Patch®

The Typical Structure of a Patch

• Multi-layer structures composed of:

−Backing

−Deposit of the active (solid/liquid)

−(Membrane)

−Adhesive

−Release linerBackingDepositMembraneAdhesiveLiner

Minitran®


Patch-non-Patch®

The Typical Structure of a Patch

• Plasters

−Backing (woven-non-woven)

−Thick adhesive hydrogel

containing the active

−Liner

• Gauzes soaked in gel/oil formulations

Lidoderm®

Medicell Patch®


Patch-non-Patch®: the Novelty

Backing

Active+Adhesive

Liner

Backing

Active+Adhesive

Liner Patch-non-Patch®

SEM Image


Patch-non-Patch®: Characteristics

• Dry

• Not self-adhesive

• Flexible, transparent

• Water permeable

• Electrically conductive

• Organic solvents not required

• Adhesive only on wet skin

• Washeable with water


Patch-non-Patch®


Patch-non-Patch®: Case Studies

Lidocaine Estradiol Hydrocortisone

Caffeine Nitroglycerin Herbal extracts

Thiocolchicoside Progesterone Rutin derivatives

Ibuprofen lysine Nicotine&Bupropion Ketoconazole

Diclofenac Sumatripan Clindamycin

Acyclovir

Clorexidine

Nicotinamide&Salicylic ac.

Thyroxine


Patch-non-Patch®: Production

• Solution (suspension) of all components in water

• Lamination on the release liner at predetermined time

• Oven drying (60-80°C)

• Cutting

• Thickness of 40-200 µm

• Different shapes/patterns possible


Patch-non-Patch®: The Cosmetic difference


Patch-non-Patch®: The Cosmetic advantage


Patch-non-Patch®: Advantages vs Competitors

FeatureFeature P-n-PP-n-P®® PatchPatch PlasterPlaster GelGel

% of active released High Low Low Low

Time lag No Yes Yes No

Duration of activity Long Long LongShort

Adaptation to skin surf. Yes No No ?

Occlusive No Yes Yes/No No

Water soluble Yes No ? Yes

Electrically conductive Yes No ? Yes/No

Cosmetically acceptableYes Yes/No No ?

Easy to be removed Yes No Yes/No Yes


Patch-non-Patch®: Advantages vs Competitors

FeatureFeature P-n-PP-n-P®® PatchPatch PlasterPlaster GelGel

Preservatives needed No No Yes Yes

Organic solvents requ. No Yes Yes/No No

Drying step critical No Yes Yes -

Active crystalliz.critical No Yes Yes Yes

Cost of production ++ ++++ +++ ++


Patch-non-Patch ®

Patch-non-Patch® is meant for pharmaceutical, cosmetic, medical device and medical industries

Patch-non-Patch® feasibility studies with different actives/prototypes are available and further can be added

Patch-non-Patch ® allows several potential applications including smoking cessation products, analgesic patches, caffeine-based cellulite treatments, among the others

Patch-non-Patch ® is covered by patent, license or transfer can be considered


Chimerical Agglomerates™



• Inhalation nasal platform

• A new nasal form as powder able to satisfy different technological requirements related to preparation and administration of powders through non-invasive routes such as oral, buccal and nasal ones

• The powder is made of agglomerates of micro-particles obtained by spray-drying process of an aqueous or hydro-alcoholic solution containing the substance and excipients



• In case of insufflation, the agglomerates dimension are useful for the dose metering of the powder into the insufflation device

• After insufflation, due to turbolence of air flow, agglomerates are broken into fragments of appropriate dimension for nasal or buccal administration which are rapidly deaggreagated in the primary micro-particles by water



20 µm20 µm

Prepared by spray drying

Ø 5-10 µm

Primary microparticles

200µm

Roundish shape Free flowing

Ø 106-850 µm

They break up into fragments during

insufflation

Chimeral Agglomerates

200µm

Fragments

Suitable size for nasal deposition

Prepared by spray drying

Ø 5-10 µm

Primary microparticles

200µm


Ø 106-850 µm


insufflation


200µm200µm


Ø 106-850 µm


insufflation


200µm

Fragments


200µm200µm

Fragments




• Chimerical Agglomerates™ is very versatile system since it is possible to prepare formulations of different substances by varying the composition of the micro-particles

• Chimerical Agglomerates™ scale of development is laboratory tested – scale up phase

• Chimerical Agglomerates™ is covered by patent, license or transfer could be considered



• Highly respirable insulin case study

Dry insulin powders have been prepared by using spray-drying process starting from suspensions or aqueous solutions of the active ingredient in acetic acid

As metering device has been used a commercial device able to administer 2 mg of insulin powder when activated by an air flow of 60 l/min

Stability study has been carried out for 12 months during which the powders have been kept in two different conditions: 25°C-60% RU and 2-8°C



• Highly respirable insulin case studyPowders obtained form insulin suspensions showed lower values

of FPF (10-30%) compared to those obtained by drying of solutions of insulin (60-80%)

Particles obtained applying this latter option have corrugated surface characteristics, when examined through SEM analysis

All powders showed a median volume diameter below 5 µm, therefore suitable for inhalatory administration

The chemical and physical stabilities of powders obtained starting from acetic acid solutions were the best one and the hydrolytic degradation products, the related substances as well as the covalent aggregation products remain within the spec limits described in EP, also when the powders were stored at 25°C up to 24 months



• Highly respirable insulin case study

By spray-drying process therefore is possible to obtain dry insulin powders characterized by high stability and suitable particle shape able to make the powders highly breathable and manageable for manufacturing

These powders show good flow properties which allow them to be easily charged in a adevice for insufflation

By this approach insulin crystals are transformed in micro-particles

The product does not contain excipients, so reducing the potential side effects associated to them

The room temperature stability of these pwders allows the product to be stored in non-refrigerated conditions


Sucralfate Gel


Sucralfate Gel

• Sucralfate is a safe and active antiulcer drug

• A new physical form of Sucralfate, named Sucralfate Gel, has been patented and developed and possesses colloidal properties due to the reduced particle size

• The material is a humid solid since the drying of the sucralfate gel causes the lost of the gel properties

• It has been demonstrated that sucralfate gel superior activity is due to a demonstrated strong bio-adhesion towards the oral and gastrointestinal mucosa, which allows the product to persist in contact with the tissue to be healed


Sucralfate Gel

• Other than the development of Sucralfate Gel as oral suspension for the treatment of GI ulcers, the peculiarity of this new material has suggested a series of further development.

• One of this has been the topical use of Sucralfate Gel for the treatment of the skin ulcers of various origin, which has got the CE approval as Medical Device

• This was made possible again by the bio-adhesion properties of the Sucralfate humid gel that allowed the preparation of a simplified and self-adherent topical preparation

• The topical preparation can be used also as a carrier for topical substances and it is patented


Sucralfate Gel


Sucralfate Gel

• There are already on the market in many countries various products based on the Sucralfate Gel technology including:

• Sucralfate gel topical 25% for the treatment of skin ulcers of various origin (Medical Device)

• Sucralfate gel oral suspension 1g/5ml sachet

• Sucralfate gel oral suspension 2g/10ml sachet

• Dried sucralfate gel tablets 1g (under registration)

• Dried sucralfate gel sequential tablets + ketoprofen

• Dried Sucralfate gel sequential tablets + aspirin


…Good tips to partnering with Lisapharma

Small though efficient and dedicated team group allowing quick decision process

Flexibility combined to first class service

Quick adaptation to market changes

Fast reacting to customers’ demands and needs

Commitment to innovation

Very promising tech package portfolio

Excellent expertise and know how in manufacturing of injection products

Independent company not belonging to any group

march 2008 lisapharma – confidential 1. 2 company introduction & proprietary technologies

Documents

lisapharma confidential

nonsterile liquids

italian manufacturing

sterile injection products

omicron plant italy

italian marketto

italian capitalfamily

international markets