Company Introduction

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Company Introduction Proprietary Technologies
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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 ß-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

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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

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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

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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..

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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

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• PROPRIETARY TECHNOLOGIES

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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

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Proprietary technologies
FOUR PLATFORMS

• 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

The technologies are covered by patents and
available for discussions
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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

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• DOME MATRIX

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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

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Dome Matrix
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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

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Dome Matrix

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

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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

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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

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• Patch-non-Patch

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Patch-non-Patch

• Patches vs. Traditional Systemic Formulations
• Constant plasma levels
• Lower incidence of side effects
• vs 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 lt 10 mg)

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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

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Patch-non-Patch

• The Typical Structure of a Patch
• Multi-layer structures composed of
• Backing
• Deposit of the active (solid/liquid)
• (Membrane)
• Adhesive
• Release liner

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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

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Patch-non-Patch the Novelty
Patch-non-Patch
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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

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Patch-non-Patch
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Patch-non-Patch Case Studies

• Lidocaine Estradiol Hydrocortisone
• Caffeine Nitroglycerin Herbal extracts
• Thiocolchicoside Progesterone Rutin derivatives
• Ibuprofen lysine NicotineBupropion Ketoconazole
• Diclofenac Sumatripan Clindamycin
• Acyclovir
• Clorexidine NicotinamideSa
  licylic ac.
• Thyroxine

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Patch-non-Patch Production

• Solution (suspension) of all components in water
• Lamination on the release liner at predetermined
  time
• Oven drying (60-80C)
• Cutting
• Thickness of 40-200 µm
• Different shapes/patterns possible

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Patch-non-Patch The Cosmetic difference
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Patch-non-Patch The Cosmetic advantage
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Patch-non-Patch Advantages vs Competitors

• Feature P-n-P Patch Plaster Gel
• of active released High Low Low Low
• Time lag No Yes Yes No
• Duration of activity Long Long Long Short
• 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 acceptable Yes Yes/No No ?
• Easy to be removed Yes No Yes/No Yes

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Patch-non-Patch Advantages vs Competitors

• Feature P-n-P Patch Plaster Gel
• 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

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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

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• Chimerical Agglomerates

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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

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Chimerical Agglomerates

• 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

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Chimerical Agglomerates
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Chimerical Agglomerates

• 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

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Chimerical Agglomerates

• 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 25C-60 RU and 2-8C

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Chimerical Agglomerates

• Highly respirable insulin case study
• Powders 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 25C up to 24 months

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Chimerical Agglomerates

• 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

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• Sucralfate Gel

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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

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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

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Sucralfate Gel
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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

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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