Pharmaceutics Lecture On Biopharmaceuticals I

Front 1

Biotech Market Size and Growth
and Leading Corps

Back 1

see slide 2 thru 5

Front 2

what are biopharmaceuticals?

Back 2

pharmaceuticals manufactured by biotechnology methods, obtained from biological sources, and usually involving live organisms or their components.

Front 3

biopharmaceuticals include:

Back 3

-recombinant proteins
-(monoclonal) antibodies
-non-recombinant culture-derived -proteins
-vaccines
-blood/plasma-derived products
-cultured cells and tissues…
* last 3 are biologics *

Front 4

what are biologics?

Back 4

drug products derived from living sources, such as humans, animals, and microorganisms. Most biologics are complex mixtures that are not easily characterized. Many biologics are manufactured using biotechnology.

Front 5

biologics include:

Back 5

vaccines
viruses
therapeutic serum products
toxins and antitoxins or analogous products
blood or plasma components or derivatives…

Front 6

Biologics are regulated by:

Back 6

the FDA Center for Biologics Evaluation and Research (CBER).

Front 7

Biopharmaceuticals exhibit a large range of purities:

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comparatively pure peptides, proteins, and monoclonal antibodies (especially if manufactured by recombinant technologies leading to high concentrations of the product)- regulated by the FDA Center for Drug Evaluation and Research (CDER)
and
complex mixtures – vaccines, therapeutic serum products, blood- or plasma-derived products and other biologics

Front 8

Even comparatively pure biopharmaceuticals are difficult to characterize because of :

Back 8

the macromolecular structures (primary --> quaternary structures in proteins) that are sensitive to the environment

Front 9

Difficult characterization causes problems with

Back 9

the approval of “generic” biopharmaceuticals

Front 10

how are pharmaceuticals discovered?

Back 10

by screening of natural or synthetic products and the follow-up structure optimization

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Biopharmaceuticals are often components (or parts of the components) of the metabolic or hormonal pathways, which are found to participate in etiology of the disease by the techniques of molecular and cellular biology or molecular pharmacology

Back 11

true

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While the discovery process is more straightforward, biological origin of biopharmaceuticals causes problems with

Back 12

administration – limited membrane permeability, mostly administered by IV or SQ injections
stability – susceptibility to the environment and enzymes
immunogenicity – factors related to product and host

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physical instability of proteins

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protein denaturation & aggregation – ions, pH, temperature

Front 14

chemical/metabolic instability of proteins

Back 14

fragmentation
deamination
oxidation
L-D isomerization

Front 15

sterilization requirements

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terminal sterilization is impossible because of instability
aseptic process is the only option
challenges of purification from living organisms, which may contain prions, viruses or mycoplasmas

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Most biopharmaceuticals induce

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immune responses

Front 17

Immunogenicity (IG) canbecome a problem,especially for human-derived products

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true

Front 18

Product-related IG depends on

Back 18

sequence variation
glycosylation degree
antigens in excipients

Front 19

host related factors

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genetic predisposition
illness of kidney or liver

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Biopharmaceuticals and Biosimilars

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After patent expiration, non-inventor companies intend to produce biopharmaceuticals.
FDA calls these products Follow-on Proteins (FOP) or Follow-on Biologics (FOB).
The process would decrease the cost of therapies.
The shortened approval process (ANDA) available for pharmaceuticals based on structure and bioequivalence.
Cannot be directly applied to biopharmaceuticals - it is difficult to prove equivalence because of their
complex structure
composition
possible immunogenicity
Ongoing discussion on biosimilars and biocomparability

Front 21

Biopharmaceuticals (types)

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Anticoagulant Drugs
Clotting factors
Colony stimulating factors
Erythropoietin derivatives
Growth factors
Human growth hormone
Interferons
Interleukins
Tissue plasminogen activators
Monoclonal antibodies (MAb)…

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what is insulin?

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… an endocrine hormone secretedby the beta cells of the pancreas

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insulin initiates recruitment of

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GLUT-4 to cell membrane (3), glycogensynthesis (4), glycolysis (5), and fatty acid synthesis (6)

** see slide 14 **

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insulin structure

Back 24

see slide 15

Front 25

Insulin: Production Sources
animal derived

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bovine insulin
porcine insulin
(not clinically used in the US)
-- from the pancrease

Front 26

Insulin: Production Sources
recombinant (biosynthetic)

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human insulin

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Insulin: Production Sources
insulin analogs (biosynthetic)

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structure differs slightly to change the onset and duration of action

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insulin administration

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--various insulin injections available
--various insulin pumps available
--the closed-loop computerized system with glucose sensors dosing insulin and glucagon (artificial pancreas) under development at MIT

Front 29

Formulations of Insulin Products

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1.Short-acting (regular)
2.Rapid-acting insulin
3.Intermediate-acting insulin
4.Long-acting insulin
5.Intermediate-acting and short-
acting insulin mixtures

**These formulations are available to cover differing needs of patients.
Additional details: Ansel’s 9th ed., pp 469-475

Front 30

Insulin Products: Pharmacokinetics

Back 30

see slide 18

Front 31

short acting (regular) insulin

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Human insulin - Humulin R (for regular)
Zinc insulin crystal dissolved in neutral solution
The only form administered by IV injection
All other forms are given by subcutaneous injection

peaks in 2 to 4 hrs and tapers off
see slide 18

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rapid acting insulin
Lispro (humalog)

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alternation of Lys29 and Pro28 provides a faster onset and shorter duration

** see slide 18

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rapid acting insulin
insulin aspart (novolog)

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Replacement of Pro28 by aspartic acid (Pro28=>Asp) provides a rapid onset and shorter duration

** see slide 18

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rapid acting insuling
(other...)

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Insulin Glulisine injection (Apidra®)
Inhaled Insulin Exubera®

Front 35

Intermediate acting insulin
NPH (Neutral Protamine Human) Insulin (Isophane insulin suspension, Humulin N):

Back 35

contains protamine (small basic proteins with anti-coagulation effects) and zinc insulin crystals
buffered to pH 7.1 to 7.4
available as premixes with Humulin (Humulin mix)

** see slide 18

Front 36

Intermediate acting insulin
Insulin zinc suspension - Humulin L (lente)

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contains crystalline (slower effect)and amorphous (quicker effect)
contains zinc chloride

** see slide 18

Front 37

Intermediate acting insulin
Insulin Detemir injection (Levemir®):

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acylated analog of soluble regular insulin
available in 2006 as intermediate or long acting insulin

Front 38

Long acting insulin
Extended insulin zinc suspension (Ultralente® U; Ultralente Insulin):

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a large, crystalline from of zinc insulin buffered to pH 7.2-7.5

** see slide 23

Front 39

Long acting insulin
Insulin Glargine:

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several residue alternations cause a decreased solubility at physiological pH
precipitation and delayed absorption following subcutaneous injection

Front 40

. Mixtures of Intermediate-acting and Short-acting Insulin

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see slide 23

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Delivery of Insulin
storage

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room temperature or refrigerator, the currently used vial can be stored at room temperature (comfort of injection)
freezing and heat should be avoided

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Delivery of Insulin
Injection

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needle (normally subcutaneous; clear solution may be used IV – typically only regular insulin)
needle-free: jet injection www.mediject.com

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Delivery of Insulin
other routes:

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Exubera - a powdered form of recombinant human insulin
delivered through an inhaler into the lungs
absorption as good as after injection but expensive
dose variability
marketed by Pfizer in 2006, discontinued in 2007

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Insulin injection devices

Back 44

see slide 25

Front 45

Insulin infusion pumps

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MiniMed infusion pump and several others available
Delivers short acting insulin
Pump gives better control than injections - programmed
Unique safety concerns: skin infections
** see slide 26

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Patient Education and Counseling

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--Storage – refrigerator and room temperature
--Self-administration and aseptic techniques
--Rotation of injection sites
frequent injections give rise to avascular, spongy tissue
here the injection is less painful but also the drug is absorbed slowly
--Disposal of needle and syringes