Methods for Enhancing

Oral Bioavailability of a
Drug undergoing Extensive
First Pass Metabolism

SAT Presentation

Submitted To : Submitted By :

Dr. Akash Chaurasiya Tanishka

M.Pharm 3rd Sem
H20181460229H
 First Pass Metabolism
• Low systemic Availability of drug as a result of significant metabolism.
• Can occur in intestine, uterus, etc.; more often observed in hepatocytes (hepatic first pass metabolism)
• Occurs when drug absorbed from GI tract is metabolized by enzyme within liver to an extent that most of
active ingredient is lost and does not reach systemic circulation.

Outcomes of FPM :
• Active drug becomes inactive after getting metabolized.

Eg. Codeine Morphine

• Lipid drug Water- soluble (Easy excretion )

Strategies to overcome fpm

Pro Drug approach

Nanotechnology Nanoparticles
Liposomes
approaches

SMEDDS

Buccal and
Sublingual
 SMEDDS – SELF micro emulsifying drug delivery
system
• Isotropic mixture of natural or synthetic oils, solid and liquid surfactants.
• One or more hydrophilic solvents and co-solvents/ surfactants ; forming fine oil in water micro emulsion
upon mild agitation followed by dilution in aqueous media, such as GI fluids.

Types of SMEDDS :

1. O/W microemulsion
2. W/O microemulsion
 Composition

Oils Surfactant Co-Solvent Co-Surfactant

A. Oil- Phase :
• Natural oils are non-toxic and easily by m/o (thus, can be used)
• Vegetable oils

B. Surfactant :
• Usually, non-ionic surfactant with high HLB value used in formulation.
C. Co- Solvents :
• Mainly PG and PEG are used.

D. Co- Surfactant :
• It is used to reduce the concentration of Surfactant.
• Mainly used are Propylene Glycol, Ethanol, Isopropyl Alcohol etc.

Method of Preparation :

1. Phase-Titration Method :
2. Phase- Inversion Method
 IBRUTINIB – The Drug
 Available dosage forms : Capsules (For MCL and MZL)
Dosage : 560mg OD
420mg OD

Tablets
Dosage : 140mg, 280mg, 420mg and 560mg

Available reviews for the drug

1. Mean 27.7 % lower Cmax observed for 560 mg tablet compared to four 140 mg tablets.
2. Flat dose-exposure response relationship for clinical response was also found equal to and above dose 2.5mg/kg.
3. Comparable Cmax for 560 mg tablet and four 140 mg capsules under fed conditions.
4. Comparable Ctrough concentration of tablet and capsule.
Lipid excipients for drug delivery

Excipient Form
Gelucire 44/14 Block
Gelucire 48/16 Pellets
Gelucire 50/12 Pellets
Labrafil M1944 CS Liquid
Labrafil M2126 CS Liquid
Lauroglycol 90 Liquid
Sedefos 75 Pellets
 Gelucire

Gelucire 48/16 (Pellets)

Pure water-soluble surfactant
Used in different types of liquid-based formulations
Forms a micellar solution when used alone in a binary formulation with active ingredients
Can combined with oils, surfactants and solvents to form type III formulation

Gelucire 44/14 (Block)

Non-ionic water dispersible surfactant
Increase the aqueous solubility and oral bioavalibility
 Use of gattefosse excipients in lipid-based
formulations

Lipophilic Hydrophilic
+
Type I Type II Type III Type IV
(Oils) (SEDDS) Co-surfactants (SMEDDS) (Micellar)

Maisine/Peceol Labrafil M 1944 CS Capryol 90, Lauroglycol 90 Gelucire 44/14 Gelucire 448/16
Labrafac Lipophile WL 1349 Labrafil M 2125 CS Plurol oleique, Gelucire 50/13 Transcutol HP (6-10%)
Transcutol HP (6-10%) Labrasol ALF
Formulation with high
Formulation with low HLB Self-emulsifying These formulations will be They are generally
HLB excipitents will be
lipid excipients will be excipient with more lipophilic or more suitable for
hydrophilic, containing
lipophilic, thus providing medium HLB can hydrophilic depending on active ingredients
mostly water soluble
greater solubilizing be used to form the excipients composition with medium logP
surfactants and are
potential for lipophilic type II and type III
useful for active
{high LogP} active formulations
ingredients with low
ingredients
logP
Composition and Characteristics
Formulation Composition Formulation characteristics

Type I oils 100% Non-disersible

Oils 40-80% SEDDS without water-soluble components

Type II
Low HIB surfactants
Oils
Type III High HLB surfactants
Hydrophillic cosolvents
Low HIB surfactants
Type IV High HLB surfactants
Hydrophillic cosolvents
20-60% Opaque emulsion (200nm- 10μm)
<20-80% SEDDS/SMEDDS with water-soluble
20-50% components
0-50% Ulterfine dispersion (10-200 nm)
0-20%
Transparent micellar
30-80%
solution/nanosystem (2-10 nm).
0-50%
Recommendations for seDds formulations
 Development of multi-excipient SEDDS and
SMEDDS
Three main steps :-
• Assessment of API solubility in individual excipients to slecect the excipients with high
solubilisation capacity.
• Perform miscibility, dispersion testing and ternary phase diagramming to select the best
excipient combinations and define ratio to develop the formulations.
• Undertaking in vitro lipolysis testing to assess if the drug is maintained in a solubilized state
throughout the digestion process and select the best formulation.