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Development of Biopharmaceuticals and Biosimilar Drug Delivery

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Development of Biopharmaceuticals and Biosimilar Drug Delivery Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D KLE University s College of Pharmacy Belgaum-590010 – PowerPoint PPT presentation

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Title: Development of Biopharmaceuticals and Biosimilar Drug Delivery


1
Development of Biopharmaceuticals and Biosimilar
Drug Delivery
  • Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D
  • KLE Universitys College of Pharmacy
  • Belgaum-590010
  • E-mail bknanjwade_at_yahoo.co.in
  • Cell No 00919742431000

2
Development of NDA and BLA
3
What are Biopharmaceuticals
  • Biopharmaceuticals are defined as pharmaceuticals
    manufactured by biotechnology methods, with the
    products having biological sources, usually
    involving live organisms or their active
    components
  • Biopharmaceuticals are protein or nucleic acid
    based pharmaceuticals (substance used for
    therapeutic or in vivo diagnostic purpose), which
    are produced by mean other than direct extraction
    from a native biological source.

4
Pharmaceutical Biotechnology
  • The methods and techniques that involve the use
    of living organisms (such as cells, bacteria,
    yeast and others) are tools to perform specific
    industrial or manufacturing process are called
    biotechnology
  • Pharmaceutical Biotechnology will continue to
    provide new breakthroughs in medical research in
    the years to come, leading to treatment in field
    which have previously eluded us (including AIDS,
    cancer asthma, Parkinsons disease, Alzheimer
    disease)

5
Pharmaceutical Biotechnology
  • Biotechnology offers better product-targeting for
    specific diseases and patient groups, through the
    use of innovative technologies, in particular,
    genetics. Examples include, amongst others,
    treatment for rare diseases and cancers.
  • Some products are not naturally created in
    sufficient quantities for therapeutics purpose.
  • Biotechnology makes large-scale production of
    existing substances possible, for example,
    insulin in the field of diabetes treatment

6
Biopharmaceuticals history
7
Protein and peptide
  • Proteins - Chains of amino acids, each joined
    together by a specific type of covalent bond
  • Proteins formed by joining same 20 amino acids in
    many different combinations and sequences
  • Protein gt 50 amino acids
  • peptide lt 50 amino acids
  • Function of a protein determined by its
    non-covalent 3D structure

8
Covalently linked Amino Acids
Polypeptides
Amino Acids
9
Peptide Synthesis
10
Protein Structure
Lactate Dehydrogenase Mixed a / b
Immunoglobulin Fold b
Hemoglobin B Chain a
11
Classification of Proteins
  • According to their biological roles
  • - Enzymes Catalyses virtually all chemical
    reactions i.e. 6GDH
  • - Transport proteins i.e. Haemoglobin of
    erythrocytes
  • - Contractile or Motile proteins i.e. Actin and
    Myosin
  • - Structural proteins i.e.Collagen
  • - Defense proteins i.e. Immunoglobulins and
    Antibodies
  • - Regulatory proteins i.e. insulin
  • - Nutrient and storage proteins i.e. Ovalbumin

12
Protein Therapeutics
  • Proteins/peptides are gaining prominence
  • Proteins - ideal drugs as they carry out
    essentially all biologic processes and reactions
  • Recombinant DNA, hybridoma techniques, scale
    fermentation and purification processes brought
    new series of Proteins/peptides

13
Protein Pharmaceuticals
  • Insulin (diabetes)
  • Interferon b (relapsing MS)
  • Interferon g (granulomatous)
  • TPA (heart attack)

14
Protein Pharmaceuticals
  • Epogen
  • Regranex (PDGF)
  • Novoseven (F VIIa)
  • Intron-A
  • Neupogen
  • Pulmozyme
  • Infergen
  • Actimmune (If g)
  • Activase (TPA)
  • BeneFix (F IX)
  • Betaseron (If b)
  • Humulin
  • Novolin
  • Pegademase (AD)

15
Protein Pharmaceuticals
  • 77 FDA approved protein drugs
  • 66/77 are recombinant proteins
  • Protein pharmaceutical sales currently approach
    25 billion/yr
  • By 2012 they are expected to reach 60 billion/yr

16
Challenges with Proteins
  • Very large and unstable molecules
  • Structure is held together by weak non-covalent
    forces
  • Easily destroyed by relatively mild storage
    conditions
  • Easily destroyed/eliminated by the body
  • Hard to obtain in large quantities

17
Problem with Proteins (in vivo in the body)
  • Elimination by B and T cells
  • Proteolysis by endo/exo peptidases
  • Small proteins (lt 30 kD) filtered out by the
    kidneys very quickly
  • Unwanted allergic reactions may develop (even
    toxicity)
  • Loss due to insolubility/adsorption

18
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19
Problem with Proteins (in vitro in the bottle)
  • Noncovalent Covalent
  • - Denaturation - Deamidation
  • - Aggregation - Oxidation
  • - Precipitation - Disulfide exchange
  • - Adsorption - Proteolysis

20
Noncovalent Processes

Denaturation
Adsorption
Aggregation
Precipitation
21
Covalent processes
  • Deamidation - conversion of Asn-Gly sequences to
    a-Asp-Gly or b-Asp-Gly
  • Oxidation - conversion RSR to RSOR, RSO2R or
    RSO3R (Met Cys)
  • Disulfide exchange - RS- RS-SR goes to
    RS-SR RS- (Cys)
  • Proteolysis - Asp-Pro, Trypsin (at Lys) or
    Chymotrypsin (at Phe/Tyr)

22
How to Deal with These Problems
  • Storage

Formulation
Delivery
23
Storage
  • Refrigeration
  • Packaging
  • Additives
  • Freeze-Drying

24
Storage (additives)
  • Addition of stabilizing salts or ions (Zn for
    insulin)
  • Addition of polyols (glycerol and/or polyethylene
    glycol) to solubilize
  • Addition of sugars or dextran to displace water
    or reduce microbe growth
  • Use of surfactants (CHAPS) to reduce adsorption
    and aggregation

25
Storage (Freeze Drying)
  • Freeze liquid sample in container
  • Place under strong vacuum
  • Solvent sublimates leaving only solid or
    nonvolatile compounds
  • Reduces moisture content to lt0.1

26
How to Deal with These Problems
Storage
  • Formulation

Delivery
27
Protein Formulation
  • Protein sequence modification (site directed
    mutagenisis)
  • PEGylation
  • Proteinylation
  • Peptide Micelles
  • Formulating with permeabilizers

28
Site Directed Mutagenesis
E343H
29
Site Directed Mutagenesis
  • Allows amino acid substitutions at specific sites
    in a protein
  • i.e. substituting a Met to a Leu will reduce
    likelihood of oxidation
  • Strategic placement of cysteines to produce
    disulfides to increase Tm
  • Protein engineering (size, shape, etc.)

30
PEGylation

CH-CH-CH-CH-CH-CH-CH-CH-CH-CH
OH OH OH
OH OH OH OH OH OH OH
31
PEGylation
  • PEG is a non-toxic, hydrophilic, FDA approved,
    uncharged polymer
  • Increases in vivo half life (4-400X)
  • Decreases immunogenicity
  • Increases protease resistance
  • Increases solubility stability
  • Reduces depot loss at injection sites

32
Peptide-PEG monomers
Hydrophobic block
Hydrophobic block
Peptide
Peptide
33
Proteinylation

Protein Drug ScFv (antibody)
34
Proteinylation
  • Attachment of additional or secondary
    (nonimmunogenic) proteins for in vivo protection
  • Increases in vivo half life (10X)
  • Cross-linking with Serum Albumin
  • Cross-linking or connecting by protein
    engineering with antibody fragments

35
Peptide Micelles
36
Peptide Micelles
37
Targeted Micelles
38
Formulation with permeabilizers
  • Salicylates (aspirin)
  • Fatty acids
  • Metal chelators (EDTA)
  • Anything that is known to punch holes into the
    intestine or lumen

39
How to Deal with These Problems
Storage
Formulation
  • Delivery

40
Drug Delivery
  • Non-conventional way of administering drugs
    (novel drug delivery)
  • Conventional way
  • Oral (Tablets, Capsules)
  • Parenteral (IV injections)

41
Conventional
  • ORAL
  • Ease of administration
  • Patient Compliance
  • Exposure to extremely acidic pH
  • Poor absorption of larger drugs
  • Degradation by enzymes
  • INTRAVENOUS
  • Fast action
  • No absorption issues
  • Lesser patient compliance
  • Fast clearance of drugs

42
Parenteral Delivery of Proteins
  • Intravenous
  • Intramuscular
  • Subcutaneous
  • Intradermal

43
Parenteral Delivery of Proteins
  • Route of delivery for 95 of proteins
  • Allows rapid and complete absorption
  • Allows smaller dose size (less waste)
  • Avoids first pass metabolism
  • Avoids protein unfriendly zones
  • Problems with overdosing, necrosis
  • Local tissue reactions/hypersensitivity
  • Everyone hates getting a needle

44
Drug Delivery
45
Novel Drug Delivery
  • Useful for following types of drugs
  • Short half-life
  • Insulin t1/2 lt 25 min
  • Growth hormone t1/2 lt 25 min
  • High systemic toxicity (causing side effects)
  • Carmustine causes nausea, hair loss
  • Frequent dosing
  • Growth hormone Daily dosage required
  • Expensive drugs

46
Novel Drug Delivery
  • Adverse Drug Effects
  • 15 of hospital admissions
  • 100,000 deaths
  • 136 billion in health care costs
  • Less patient compliance
  • 10 hospital admissions
  • Novel Drug delivery sales
  • 14 billion in 1997 53 billion in 2002

47
Polymeric Drug Delivery
  • Frequency of doses reduced
  • Drug utilized more effectively
  • Drug stabilized inside the polymer matrix
  • Reduced side effects
  • Possibility of dose-dumping
  • De-activation of drug inside polymer

48
Polymeric Drug Delivery
  • Controlled Release of drugs

49
Polymeric Drug Delivery
  • Polymers should be
  • Biodegradable
  • Bio-compatible
  • Non-toxic
  • Examples
  • Polylactides/glycolides
  • Polyanhydrides
  • Polyphosphoesters

50
Polymeric Drug Delivery
  • Diffusion of drug out of the polymer
  • Governing equation Ficks laws of diffusion
  • Drug release is concentration dependant
  • Less applicable for large molecules

51
Polymeric Drug Delivery
  • Drug Release by Polymer Degradation
  • Polymer degradation by
  • Hydrolysis
  • Enzymatic (Phosphotases Proteases etc.)

52
Microsphere Encapsulation
100 mm
53
Encapsulation
  • Process involves encapsulating protein or peptide
    drugs in small porous particles for protection
    from insults and for sustained release
  • Two types of microspheres
  • nonbiodegradable
  • biodegradable

54
Types of Microspheres
  • Nonbiodegradable
  • ceramic particles
  • polyethylene co-vinyl acetate
  • polymethacrylic acid/PEG
  • Biodegradable (preferred)
  • gelatin
  • polylactic-co-glycolic acid (PLGA)

55
Microsphere Release
  • Hydrophilic (i.e. gelatin)
  • best for burst release
  • Hydrophobic (i.e. PLGA)
  • good sustained release (esp. vaccines)
  • tends to denature proteins
  • Hybrid (amphipathic)
  • good sustained release
  • keeps proteins native/active

56
Polymer Scaffolds
  • Incorporate drug into polymeric matrix
  • Protection of drug from enzymatic degradation
    particularly
  • Applicable to peptide and protein drugs
  • Release drug at known rate over prolonged
    duration
  • Drug dispersed or dissolved in suitable polymer
  • Release
  • - diffusion of drug through polymer
  • - diffusion through pores in polymer structure
  • - therefore different release profiles result
    (dissolved or
  • dispersed)

57
Release Mechanisms
58
Magnetic Targeted Carriers (MTCs)
  • Microparticles, composed of elemental iron and
    activated carbon
  • Drug is adsorbed into the MTCs and transported
  • The drug attaches to the carbon component
  • The particles serve as delivery vehicles to the
    area of the tumor for site-specific targeting

59
Magnetic Targeted Carriers (MTCs)
Source http//www.magneticsmagazine.com/e-prints/
FeRx.htm
60
Magnetic Targeted Carriers (MTCs)
  • FeRx Inc. is the leader in the development in
    this innovative technology
  • Founder of FeRx and pioneer of magnetic targeted
    drug delivery is Dr. Kenneth Widder
  • Began with albumin microspheres containing
    encapsulated drugs, and lead to present MTC
    technology
  • Present clinical trials by FeRx show that drug
    remains for 28-days with no redistribution from
    the targeted site

61
Liposomes
Spherical vesicles with a phospholipid bilayer
Hydrophilic
Hydrophobic
62
Liposomes Drug Delivery
  • Potential of liposomes in drug delivery has now
    realized
  • Bloemycin encapsulated in thermosensitive
    liposomes enhanced antitumor activity and
    reduced normal tissue toxicity
  • S.C injection of negatively charged liposomes
    produced a prolonged hypoglycemic effect in
    diabetic dogs
  • Liposomes have recently been used successfully as
    vehicles for vaccines

63
Hydrogel Based Drug Delivery
  • Hydrogels are three dimensional networks of
    hydrophilic
  • polymers that are insoluble

64
Hydrogel Based Drug Delivery
  • Hydrogels can swell as a result of changes in
    pH, Temp., ionic strength, solvent composition,
    pressure and the application of electric fields

Insulin has been one drug that has been
incorporated in hydrogels and investigated
by researchers extensively
65
Proteins in Pumps
Infusaid Model 400 Implantable Pump
66
Proteins in Pumps
Mechanical Insulin Pumps
67
Proteins in Pumps
  • Formulation is the beginning of successful drug
    delivery
  • Multiple potential interactions between the
    protein and the pump
  • Control of the material interface is most
    important
  • Device design and formulation need to work
    together and be regulated together

68
Oral Protein Delivery
69
Oral Insulin
  • Buccal aerosol delivery system developed by
    Generex
  • Insulin is absorbed through thin tissue layers in
    mouth and throat
  • Insulin is formulated with a variety of additives
    and stabilizers to prevent denaturation on
    aerosolization and to stabilize aerosol particles

70
Oral Delivery by Microsphere
pH 2 pH 7
71
pH Sensitive Microspheres
  • Gel/Microsphere system with polymethacrylic acid
    PEG
  • In stomach (pH 2) pores in the polymer shrink and
    prevent protein release
  • In neutral pH (found in small intestine) the
    pores swell and release protein
  • Process of shrinking and swelling is called
    complexation (smart materials)

72
Nasal Delivery of Proteins
  • Extensive microcirculation network underneath the
    nasal mucosa
  • Drug absorbed nasally can directly enter the
    systemic circulation before passing through the
    hepatic circulation
  • The nasal administration of peptides has
    attracted much interest now a days due to
  • - Relatively rapid absorption of drug
  • - Little metabolic degradation
  • - Relative ease of administration
  • - Selective to peptide structure and size

73
Nasal Delivery of Proteins
  • Enhancement of nasal absorption of insulin using
    polyacrylic acid as a vehicle
  • Enhancement in the nasal absorption of insulin
    entrapped in liposomes through the nasal mucosa
    of rabbits
  • Administration of insulin (1 IU/ kg) via the
    nasal route caused a significant decrease in the
    plasma glucose level
  • The nasal route appears to be a viable means of
    systemically delivering many small peptides

74
Pulmonary Delivery
  • Deep lung, an attractive site of protein delivery
    due to
  • - Relatively large surface area (100m2)
  • - Rapid absorption of drug into the blood
    stream through the alveoli
  • Dura and Inhale developed dry powder delivery
    systems for proteins
  • 40 of the insulin administered in an aerosol, to
    the trachea of anaesthetized rabbit was absorbed
  • Albumin was largely absorbed within 48 hours of
    instillation into the lungs of guinea pigs and
    dogs

75
Rectal Delivery
  • The rectal delivery offers many advantages
  • - Avoidance of drug dilution prior to reaching
    the systemic circulation
  • - Reduction in first-pass metabolism
  • - Rapid systemic absorption
  • - Safe and convenient especially in case of
    neonates and infants
  • - Greater dose may be administered
  • - Withdrawal of drug is possible in case of
    adverse effects
  • Administration of insulin using the rectal route
    shows systemic absorption

76
Occular Delivery
  • Gelfoam eye device enhances the absorption of
    sodium insulin with an absorption enhancer
  • Many proteins and peptides that have been
    investigated for ocular delivery
  • - Enkephalins
  • - Thyrotropin releasing hormones,
  • - Leutanizing hormone-releasing hormone,
  • - Glucagon and Insulin
  • All these peptides were absorbed into the blood
    stream to some extent

77
Patch Delivery
78
Mucoadhesive Patch
  • Adheres to specific region of GI tract
  • Ethylcellulose film protects drugs from
    proteolytic degradation
  • Composed of 4 layers
  • Ethylcellulose backing
  • Drug container (cellulose, citric acid)
  • Mucoadhesive glue (polyacrylic acid/PEG)
  • pH Surface layer (HP-55/Eudragit)

79
Patch Delivery
80
Transdermal Patches
Micro fabricated needles to facilitates
permeation of peptide drugs
81
Transdermal Patches
  • Proteins imbedded in a simple matrix with
    appropriate additives
  • Patch is coated with small needles that penetrate
    the dermal layer
  • Proteins diffuse directly into the blood stream
    via capillaries
  • Less painful form of parenteral drug delivery

82
Role of a Pharmaceutical Engineer
  • Modeling of drug delivery systems
  • Prediction of kinetics/thermodynamics
  • Novel polymer research
  • Temperature sensitive polymers pH sensitive
    polymers
  • Development of new drug delivery techniques
  • Novel techniques for new therapies
  • Development of purification processes
  • Solvent Removal Removal of impurities etc.
  • Process development
  • Design Development of robust processes GMP
    Validation
  • Scale-up of processes

83
Protein X
  • Natural protein
  • Specific enzymatic activity
  • Negligible side effects
  • Frequent injections (up to twice a day)
  • Expensive

84
Protein X delivery
  • Applicable alternative techniques
  • Pulmonary delivery
  • Non-invasive Good patient compliance
  • Poor efficiency Requires patient training
  • PEGylation
  • Improved stability reduced frequency of
    injections
  • Protein X activity?
  • Polymeric delivery
  • Long-term deliveryimproved patient compliance
  • May improve protein X utilization
  • Stability of protein X in polymer?

85
Protein X delivery
  • Economical advantages
  • Improved protein utilization
  • Less protein gets wasted
  • Drives down product cost
  • Improved patient compliance
  • Reduced frequency of dosing
  • Improved patient compliance
  • Less medical expenditure from
  • events due to missed doses

86
  • BIOSIMILARS

87
What is a biosimilar medicine
  • A biosimilar medicine is a medicine which is
    similar to a biological medicine that has already
    been authorized (the biological reference
    medicine)
  • The active substance of a biosimilar medicine is
    similar to the one of the biological reference
    medicine

88
What is a biosimilar medicine
  • Biosimilar and biological reference medicines are
    used in general at the same dose to treat the
    same disease
  • Since biosimilar and biological reference
    medicine are similar but not identical
  • The name, appearance and packaging of a
    biosimilar medicine differ to those of the
    biological reference medicine

89
What is a biosimilar medicine
  • As biosimilars are not generics, the generic
    substitution rules should not apply to
    biosimilars

90
Characteristics of therapeutic proteins
  • Size
  • - 100 500 times larger than classic drugs
  • - Can not be completely characterized by
    physico-
  • chemical methods
  • Immunogenicity
  • Structural heterogeneity
  • Relatively high biological activity
  • Relatively unstable

91
Factors influencing activity of therapeutic
proteins
  • Gene and promotor
  • Host cell
  • Culture conditions
  • Purification
  • Formulation
  • Storage and handling
  • Unknown factors

92
What is in a name
  • Biogenerics
  • Second entry biologicals
  • Subsequent entry biologicals
  • Off-patent biotech products
  • Multisource products
  • Follow-up biologics
  • Biosimilars
  • Similar biological medicinal products

93
(No Transcript)
94
Main elements CHMP guidelines concerning
biosimilars
  • The concept of similar biological products is
    applicable to any biological medicinal product.
    But it is more likely applied to highly purified
    products, which can be thoroughly characterized
  • In order to support pharmacovigilance monitoring,
    the specific product given to the patient should
    be clearly identified

95
Main elements CHMP guidelines concerning
biosimilars
  • The active substance of the biosimilar product
    must be similar in molecular and biological terms
    to the active substance of the reference
    medicinal product e. IFN alpha 2a is not similar
    to IFN alpha 2b
  • The same reference product throughout the
    comparability program
  • The pharmaceutical form, dose and route of
    administration of the biosimilar and the
    reference product should be the same

96
Main elements CHMP guidelines concerning
biosimilars
  • If the reference product has more than one
    indication, the safety and eficacy for all
    indications have to be justified or demonstrated
    for each indication separately
  • The clinical safety must be monitored on an
    ungoing basis after marketing approval
  • The issue of immunogenicity should always be
    addressed, and its long-term monitoring is
    necessary

97
Thank You
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