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Transcript
Chapter 1
Introduction
CHAPTER-I
INTRODUCTION
1.1.
ORAL DRUG DELIVERY
The desired site of drug action, systemic or localized, is a major factor for
consideration in deciding the route of drug administration. Systemic routes of drug
administration are traditionally classified into enteral and parenteral routes
(Hughes et al., 2005). Enteral routes are those involving the gastrointestinal tract
(GIT) which include oral ingestion, sublingual, buccal and rectal administration
while parenteral drug delivery routes include intra-arterial, intravenous,
intrathecal, intramuscular, intracardiac, cutaneous and subcutaneous injections,
surgical site-specific implantations, and inhalational routes (Yadav and Prakashan,
2008). Drugs intended for local actions are administered through topical
application on the skin and mucosal membranes of the eye, ear, rectum and the
anus. The choice of route of drug administration is decided by a number of factors
including the physicochemical properties of the drug, biopsychosocial condition
of the patient, the desired site and onset of drug action, dosage frequency as well
as ease and convenience of administration (Strang et al., 2006). For toxicological
considerations, the possibility of reverse administration like gastric lavage and
stimulation of emesis are extreme considerations in the choice of route of drug
administration (Rathbone et al., 1994). The choice of route of drug administration
has a significant influence on patient compliance, therapeutic efficacy and
manifestation of side-effects (Liu et al., 1997; Sterling et al., 1997; Schwartzman
and Morgan, 2004).
Oral drug delivery remains the most favorable and preferred route of drug
administration both by patient and physicians (Wong et al., 2006). Oral
administration is generally accepted, easy and convenient; and offers the patient
the possibility of self administration requiring no expertise (De Jong et al., 2007).
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Introduction
Compared to injectables and implants, pharmaceutical products intended for oral
administration are cheaper and currently >60% of drugs are marketed as oral
products (Pretorius and Bouic, 2009). Researchers and pharmaceutical companies
are increasingly aware of the need for earlier assessment of new drug entities for
their potential as oral candidates (Davis and Wilding, 2001). The merits of new
drugs are measured in their delivery convenience in addition to their therapeutic
efficacy (Breimer, 1999). The possibility of self-administration, patient
compliance and less risk of irreversible side-effects has placed the oral route as a
standard in drug delivery (Sastry et al., 2000; Tong, 2007).
Because it is the easiest and most convenient way of non-invasive
administration, the oral route has always, been the preferred way of dosing. Oral
drug delivery systems also being the most cost-effective to manufacture, they have
always lead the worldwide drug delivery market.
Figure 1.1. Percent sales of orally administered drugs for the 50 most sold
pharmaceutical products in US and Europe (from IMS Health 2001)
1.1.1. Drug absorption from the gastrointestinal tract
Drug transposition from its dosage form into the general circulation, when
considering oral administration of immediate-release dosage forms, is a multi-step
process involving:
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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- Disintegration: the process by which the dosage form breaks up into
primary particles, drug and excipients, when exposed to the dissolution media.
- Dissolution: the process by which drug molecules leave the solid drug
particle and enter into the nearby dissolution media to form a solution.
- Absorption: the process by which dissolved drug molecules pass through
the membranes of the gastrointestinal tract to reach the systemic circulation.
Figure 1.2. Processes involved in getting a drug into solution in the
gastrointestinal tract so that absorption may take place. Heavy arrows
indicate primary pathways that the majority of drugs administered in a
particular dosage form undergo. Dashed arrows indicate that the drug is
administered in this state in the dosage form. Thin continuous arrows
indicate secondary pathways, which are usually inconsequential in achieving
therapeutic efficacy. (Reproduced from Hoener and Benet, 2002)
As we can clearly see in Figure 1.2., drug absorption following its oral
uptake can thus find a limitation either from the drug release from its
pharmaceutical form (i.e. solubilization – dissolution) and/or in the permeation
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Introduction
across the gastro intestinal tract (GIT) membranes; tablet or capsule disintegration
being generally a well-controlled manufacturing parameter.
As the overall rate of absorption of a drug is dictated by its solubility and
permeability characteristics, a classification system based on those parameters has
been introduced as the biopharmaceutical classification system (BCS).
1.1.2. Biopharmaceutical Classification System (BCS)
The Biopharmaceutics Classification System is a guide for predicting the
intestinal drug absorption provided by the United States Food and Drug
Administration (USFDA CDER Guidance, 2000). The fundamental basis for the
BCS was established by Dr. Gordon Amidon who was presented with a
Distinguished Science Award at the August 2006, International Pharmaceutical
Federation (IPF) congress in Salvador, Brazil.
The “Waiver of In-vivo Bioavailability and Bioequivalence Studies for
Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics
Classification System” is an FDA guidance document, which allows
pharmaceutical companies to forego clinical bioequivalence studies, if their drug
product meets the specification detailed in the guidance (FDA CDER Guidance,
2000). The principles of the BCS classification system can be applied to NDA and
ANDA approvals as well as to scale-up and post approval changes in drug
manufacturing. BCS classification can therefore save pharmaceutical companies a
significant amount of development time and reduce costs.
The BCS is based on the scientific rationale that, if the highest dose of a
drug candidate is readily soluble in the fluid volume on average present in the
stomach (250 mL) and the drug is more than >90% absorbed, then the in-vitro
drug product dissolution profiles should allow assessment of the equivalence of
different drug formulations. Solubility and dissolution can be easily measured invitro. Extent of absorption has historically been determined by conducting mass
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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balance studies both preclinically and clinically. However, the work of BCS and
that of collaborators has demonstrated that the effective intestinal permeability
(Peff) of therapeutic agents correlates well with total fraction absorbed in both
humans, rats and to a lesser extent in-vitro tissue culture systems. Based on these
studies a drug candidate can fall into one of four BCS categories, with category I,
High Permeability and High Solubility, being the subject of the BCS guidance.
The World Health Organization (WHO) has recently recommended bio waivers
for Class III and some Class II drugs and American Association of Pharmaceutical
Scientists (AAPS-FDA) scientific conferences have recommended bio waivers for
Class III compounds as well.
Figure 1.3. BCS Classification of Drugs
There are products in the market with molecules from each class depending
on the bioavailability requirement for the therapeutic response. However,
currently 40% of the New Chemical Entities (NCE)'s fall in class II and class IV
due to poor solubility. Formulating such a molecule into a suitable oral dosage
form for a desired therapeutic response poses a challenge to the formulation
scientist. There are a number of technologies to improve the solubility.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Solubility: a drug substance is considered highly soluble when the highest dose
strength is soluble in 250 mL or less of aqueous media over a pH range of 1 to 7.5
(equilibrium solubility at 37°C).
Permeability: in the absence of evidence suggesting instability in the
gastrointestinal tract, a drug substance is considered highly permeable when the
extent of absorption in humans is determined to be 90% or more of an
administered dose based on mass balance determination or in comparison to an
intravenous reference dose (absolute bioavailability study). The permeability class
of a drug may also be determined using in-vivo intestinal perfusion approaches
(human or appropriate animal models) or in-vitro permeation studies (excised
human or animal intestinal tissues or monolayers of cultured intestinal cells).
Specifications regarding the dissolution of the immediate release (IR) drug
product are also added to this classification.
Dissolution: an immediate release drug product is considered rapidly dissolving
when no less than 85% of the labelled amount of the drug substance dissolves
within 30 min using USP type I apparatus at 100 rpm (or USP type II at 50 rpm)
in a volume of 900 ml or less in each of the following media: (1) HCl 0.1N or
USP SGF without enzymes, (2) a pH 4.5 buffer and (3) a pH 6.8 buffer or USP
SIF without enzymes.
An in vitro-in vivo correlation (IVIVC) has been defined by the FDA as a
predictive mathematical model describing the relationship between an in-vitro
property of a dosage form and an in-vivo response. The objective behind the
development and the evaluation of an IVIVC is to establish the dissolution test as
a surrogate for human bioequivalence studies (i.e. biowaver – permission to
replace pharmacokinetic studies by dissolution testing). Biowavers can actually be
requested for solid, orally administered immediate-release products meeting the
dissolution requirements described above and containing highly soluble and
highly permeable drugs (Class I compound). For information, IVIVC can be
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Introduction
expected for Class I drugs if the dissolution rate is slower than the gastric
emptying rate (otherwise limited or no correlation) and for Class II drugs if the invitro dissolution rate is similar to the in-vivo dissolution rate (unless the dose is
very high); limited or no correlations being expected for Class III and IV
compounds as permeability is the rate controlling step in drug absorption (Amidon
et al., 1995; Löbenberg and Amidon, 2000).
A well developed review by Lindenberg et al. made in association with the
World Health Organization (WHO) (Lindenberg et al., 2004) establishes a
classification of drugs belonging to the WHO model list of Essential Medicines.
Examples of this classification are shown in Table 1.1.
Table 1.1. Classification of orally administered drugs on the WHO model list
of Essential Medicines according to the BCS (Lindenberg et al., 2004). (NB:
Class III drugs in bold are drugs with permeabilities corresponding to at
least 80% absorption).
Although the Class IV is the most problematic, interest will be concentrated
primarily on BCS Class II drugs, since it is the most common combination as poor
solubility of many drugs is directly associated with good lipophilicity which in
turn ensures good membrane permeability. For BCS Class II drugs, the dissolution
of the drug product is the rate limiting step to absorption as it is the parameter that
changes the actual drug concentration in solution over time and that there is no
limitation permeability-wise.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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1.1.3. Barriers to oral drug administration
The most significant limitation to oral drug administration is the resulting
poor systemic bioavailability of various drugs as a result of first-pass metabolism
(DeMario and Ratain, 1998; Veber et al., 2002). In numerous instances,
significant allowances are made for pre-systemic drug loss in the design of the
dosage regimen and the drug delivery system. Previous studies on structurally
diverse drugs have also revealed that subject variableness in bioavailability was
indirectly proportional to the extent of bioavailability which implies higher subject
variability for poorer bioavailable drugs (Hellriegel et al., 1996; Gidal et al., 2000;
Ezzet et al., 2005). This variation and the resulting poor control of plasma drug
concentrations would particularly be of concern for drugs that have a narrow
therapeutic window or a precipitous dose-effect profile (Aungst, 2000). Prominent
among impediments to oral absorption are intestinal efflux proteins (Chang et al.,
2004; Takano et al., 2006; Yamagata et al., 2007), physicochemical stability of the
drug in the various compartments of the gastrointestinal tract (Tong, 2007),
insufficient contact time in transit (Severijnen et al., 2004), poor permeability
across the gastrointestinal mucosa (Thanou et al., 2001; Wu and Benet, 2005) and
digestive and metabolic enzyme activity (Jeong et al., 2005; Cao et al., 2006). The
extremely poor solubility of certain drugs such as the bisphosphonates can make
their oral delivery difficult. This challenge is even greater when the required dose
is high (Veber et al., 2002; Hu et al., 2004).
In addition to digesting and absorbing nutrients, the GIT wall forms a
physiological barrier against the invasion of foreign substances including
pathogens, antigens, toxins and poisons (Brenchley and Douek, 2008). This
barrier comprises the cell membranes, tight junctions between adjacent epithelial
cells, the mucus layer, catabolic enzymes and the efflux proteins that propel
molecules back into the GIT lumen after oral administration (Wang et al., 2005).
Drug molecules are often recognized as foreign substances and therefore, the
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Chapter 1
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absorption of drug is also inhibited (Hamman et al., 2007). Overcoming these
challenges in oral drug delivery has been one of the most challenging endeavors
facing the pharmaceutical industry for decades.
When drugs are administered orally, apart from their exposure to possible
physical degradation, chemical inactivation or microbial biotransformation, the
anatomical proximity of the liver to the GIT necessitates the passage of absorbed
drug through the liver where drugs are metabolized to varying degrees by a
process known as the first-pass effect (Gibaldi et al., 1971; Kwan, 1997; Back and
Rogers, 2007). The most important of all the factors responsible for poor oral drug
bioavailability is the cytochrome P450 (CYP)-mediated first-pass metabolism. In
a few cases, >90% of administered drug is lost to pre-systemic metabolism
(Ghilzai, 2004; Hamman et al., 2005; Leonard et al., 2006; Majumdar and Mitra,
2006). The human CYP enzyme system present in the intestines and liver is
responsible for the metabolism of a wider range of drugs (Fang and Xiao-yin,
2005). A sub-family of this enzyme system CYP 3A is responsible for the
metabolism of >50% of marketed drugs to a large extent (Rendic, 2002). The
ability of CYP 3A to metabolize numerous structurally unrelated compounds apart
from being responsible for the poor oral bioavailability of numerous drugs is
responsible for the large number of documented drug-drug and drug-food
interactions (Quintieri et al., 2008). Successful inhibition of the metabolic activity
of these enzymes on orally administered drug may enhance the drug oral
bioavailability.
Various strategies have been employed to improve the systemic availability
of orally administered drugs (Gomez-Orellana, 2005). The principles are generally
based on the modification of the physicochemical properties of the drug (Delie
and Blanco-Prieto, 2005), addition of novel functionality to the molecular
structure of the drug to enhance intestinal wall penetration (Hajduk and Greer,
2007) and modification of pharmaceutical formulation technology by the use of
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Chapter 1
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novel drug delivery carrier systems such as microparticles (Muhrer et al., 2006;
Ozeki et al., 2005), nanoparticles (Mohanraj and Chen, 2006; Bawarski et al.,
2008) and dry emulsions (Morishita and Peppas, 2006).
Due to changes in the composition and thickness of the GIT mucus layer,
the GIT regional pH as well as the surface area and enzyme activity, certain drugs
undergo site-specific absorption (Hamman et al. 2005). The most significant site
of GIT drug absorption is the small intestine (Lacombe et al. 2004, Masaoka et al.,
2006). Although the small surface area and short residence time of most drugs in
the stomach limits gastric absorption, gastro-retentive drug delivery systems have
been used to enhance the local action of drugs in the stomach such as antidiarrheals (Connor et al., 2001), antacids (Fabregas et al., 1994), anti-ulcer agents
like misoprostol (Oth et al., 2004), and to facilitate absorption of furosemide in the
stomach and the upper small intestine (Streubel et al. 2006). Gastroretentive drug
delivery systems are also crucial for drugs such as captopril and ranitidine that are
unstable in the intestine and colon (Drummer and Jarrott, 2006) and diazepam that
exhibits low solubility at high pH values (Castrol et al. 1999).
1.2.
POORLY SOLUBLE DRUGS
The advancement in high throughput screening technology in recent drug
development era yields small molecules with characteristics like rocks. The
clinical requirement for such molecules in order to elicit the therapeutic response
in humans is that it needs to be dosed more than 20mg/kg/day. Because of the
poor physiochemical and biopharmaceutical properties of such molecules, it is
very difficult for the formulation scientist to come up with a suitable dosage form.
In the case of therapeutic indications, such as HIV and cancer, it is more important
to cure the disease or extend the life than the compliance. For such diseases, it can
be possible to have a very high dose formulation. However, for diseases such as
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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arthritis, diabetes and hypertension, it is very important to have a low dose
formulation because it has to be taken every day for the rest of the patient's life.
Over one third of drugs listed in the U.S. Pharmacopoeia and about 50% of
new chemical entities (NCEs) are insoluble or poorly soluble in water. Over 40%
of drug molecules and drug compounds are insoluble in the human body. In spite
of this, lipophilic drug substances having low water solubility are a growing drug
class having increasing applicability in a variety of therapeutic areas and for a
variety of pathologies. There are over 2500 large molecules in various stages of
development today, and over 5500 small molecules in development. Each of the
existing companies focusing on these large and small molecules has its own
restriction and limitations with regard to both large and small molecules on which
they focus.
Figure 1.4. Current market share of drugs based on BCS classification
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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1.3.
Introduction
SOLUBILIZATION OF POORLY SOLUBLE DRUGS
Therapeutic effectiveness of a drug depends upon the bioavailability and
ultimately upon the solubility of drug molecules. Solubility is one of the important
parameter to achieve desired concentration of drug in systemic circulation for
pharmacological response to be shown. Currently only 8% of new drug candidates
have both high solubility and permeability (Conference, June 2005, Thistle
Marble Arch, London, UK).
The solubility of a solute is the maximum quantity of solute that can
dissolve in a certain quantity of solvent or quantity of solution at a specified
temperature (Solubility. http://www.sciencebyjones.com/). In other words the
solubility can also be defined as the ability of one substance to form a solution
with another substance. The substance to be dissolved is called as solute and the
dissolving fluid in which the solute dissolve is called as solvent, which together
form a solution. The process of dissolving solute into solvent is called as solution
or hydration if the solvent is water (http://en.wikipedia.org/wiki/Solubility).
Table 1.2. Solubility definitions
Definition
Parts of solvent required for one part of solute
Very soluble
<1
Freely soluble
1 - 10
Soluble
10 - 30
Sparingly soluble
30 - 100
Slightly soluble
100 - 1000
Very slightly soluble
1000 - 10,000
Insoluble
> 10,000
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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1.3.1. Process of solubilisation
The process of solubilisation involves the breaking of inter-ionic or
intermolecular bonds in the solute, the separation of the molecules of the solvent
to provide space in the solvent for the solute, interaction between the solvent and
the solute molecule or ion.
Step 1: Holes opens in the solvent
Step 2: Molecules of the solid breaks away from the bulk
Step 3: The freed solid molecule is intergrated into the hole in the solvent
Figure 1.5. Steps involved in the process of solubilization
1.3.2. Factors affecting solubility
The solubility depends on the physical form of the solid, the nature and
composition of solvent medium as well as temperature and pressure of system
(James, Solubility and related properties, Marcel Dekker).
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Particle Size
The size of the solid particle influences the solubility because as a particle
becomes smaller, the surface area to volume ratio increases. The larger surface
area allows a greater interaction with the solvent. The effect of particle size on
solubility can be described by
Where,
S is the solubility of infinitely large particles
S0 is the solubility of fine particles
V is molar volume
γ is the surface tension of the solid
r is the radius of the fine particle
T is the absolute temp in degree kelvin
R is the universal gas constant
Temperature
Temperature will affect solubility. If the solution process absorbs energy
then the solubility will be increased as the temperature is increased. If the solution
process releases energy then the solubility will decrease with increasing
temperature. Generally, an increase in the temperature of the solution increases
the solubility of a solid solute. A few solid solutes are less soluble in warm
solutions. For all gases, solubility decreases as the temperature of the solution
increases.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Pressure
For gaseous solutes, an increase in pressure increases solubility and a
decrease in pressure decrease the solubility. For solids and liquid solutes, changes
in pressure have practically no effect on solubility.
Nature of the solute and solvent
While only 1 gram of lead (II) chloride can be dissolved in 100 grams of
water at room temperature, 200 grams of zinc chloride can be dissolved. The great
difference in the solubilities of these two substances is the result of differences in
their natures.
Molecular size
Molecular size will affect the solubility. The larger the molecule or the
higher its molecular weight the less soluble the substance. Larger molecules are
more difficult to surround with solvent molecules in order to solvate the
substance. In the case of organic compounds the amount of carbon branching will
increase the solubility since more branching will reduce the size (or volume) of
the molecule and make it easier to solvate the molecules with solvent.
Polarity
Polarity of the solute and solvent molecules will affect the solubility.
Generally non-polar solute molecules will dissolve in non-polar solvents and polar
solute molecules will dissolve in polar solvents. The polar solute molecules have a
positive and a negative end to the molecule. If the solvent molecule is also polar,
then positive ends of solvent molecules will attract negative ends of solute
molecules. This is a type of intermolecular force known as dipole-dipole
interaction. All molecules also have a type of intermolecular force much weaker
than the other forces called London Dispersion forces where the positive nuclei of
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Chapter 1
Introduction
the atoms of the solute molecule will attract the negative electrons of the atoms of
a solvent molecule. This gives the non-polar solvent a chance to solvate the solute
molecules.
Polymorphs
A solid has a rigid form and a definite shape. The shape or habit of a
crystal of a given substance may vary but the angles between the faces are always
constant. A crystal is made up of atoms, ions, or molecules in a regular geometric
arrangement or lattice constantly repeated in three dimensions. This repeating
pattern is known as the unit cell. The capacity for a substance to crystallize in
more than one crystalline form is polymorphism. It is possible that all crystals can
crystallize in different forms or polymorphs. If the change from one polymorph to
another is reversible, the process is called enantiotropic. If the system is
monotropic, there is a transition point above the melting points of both
polymorphs. The two polymorphs cannot be converted from one another without
undergoing a phase transition. Polymorphs can vary in melting point. Since the
melting point of the solid is related to solubility, so polymorphs will have different
solubilities. Generally the range of solubility differences between different
polymorphs is only 2-3 folds due to relatively small differences in free energy
(Singhal and Curatolo, 2004).
1.3.3. Techniques Of Solubility Enhancement
There are various techniques available to improve the solubility of poorly
soluble drugs. Some of the approaches to improve the solubility are (Pinnamaneni
et al, 2002):
I. Physical Modifications
A. Particle size reduction
a. Micronization
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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b. Nanosuspension
B. Modification of the crystal habit
a. Polymorphs
b. Pseudopolymorphs
C. Drug dispersion in carriers
a. Eutectic mixtures
b. Solid dispersions
c. Solid solutions
D. Complexation
a. Use of complexing agents
E. Solubilization by surfactants:
a. Microemulsions
b. Self microemulsifying drug delivery systems
c. Self nanoemulsifying drug delivery systems
II. Chemical Modifications
A. Salt Formation
B. Co-crystallization
C. Co-solvency
D. Hydrotropic
E. Solubilizing agent
F. Nanotechnology
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
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I. Physical Modifications
A. Particle size reduction
Particle size reduction can be achieved by micronisation and nanosuspension.
Each technique utilizes different equipments for reduction of the particle size.
a. Micronization
The solubility of drug is often intrinsically related to drug particle size. By
reducing the particle size, the increased surface area improves the dissolution
properties of the drug. Conventional methods of particle size reduction, such as
comminution and spray drying, rely upon mechanical stress to disaggregate the
active compound. The micronisation is used to increased surface area for
dissolution (Chaumeil, 1998).
Micronisation increases the dissolution rate of drugs through increased
surface area, it does not increase equilibrium solubility (Blagden et al, 2007).
Micronization of drugs is done by milling techniques using jet mill, rotor stator
colloid mills etc. Micronization is not suitable for drugs having a high dose
number because it does not change the saturation solubility of the drug.
b. Nanosuspension
Nanosuspensions are sub-micron colloidal dispersion of pure particles of
drug, which are stabilised by surfactants. The advantages offered by
nanosuspension is increased dissolution rate is due to larger surface area exposed,
while absence of Ostwald ripening is due to the uniform and narrow particle size
range obtained, which eliminates the concentration gradient factor.
Techniques for the production of nanosuspensions:
1) Homogenization
The suspension is forced under pressure through a valve that has nano
aperture. This causes bubbles of water to form which collapses as they come out
of valves. This mechanism cracks the particles.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Three types of homogenizers are commonly used for particle size
reduction in the pharmaceutical and biotechnology industries: conventional
homogenizers, sonicators, and high shear fluid processors.
2) Wet milling
Active drug in the presence of surfactant is defragmented by milling.
Other technique involves the spraying of a drug solution in a volatile
organic solvent into a heated aqueous solution. Rapid solvent evaporation
produces drug precipitation in the presence of surfactants.
The nanosuspension approach has been employed for drugs including
tarazepide, atovaquone, amphotericin B, paclitaxel and bupravaquone. All the
formulations are in the research stage. One major concern related to particle size
reduction is the eventual conversion of the high-energy polymorph to a low
energy crystalline form, which may not be therapeutically active one
(Pinnamaneni et al, 2002, Aulton, Pharmaceutics, The science of dosage form
design). Drying of nanosuspensions can be done by lyophilisation or spray drying.
Other techniques for reduction of the particle size:
1) Sonocrystallisation
Recrystallization of poorly soluble materials using liquid solvents and
antisolvents has also been employed successfully to reduce particle size (Michael
Hite, 2003). The novel approach for particle size reduction on the basis of
crystallisation by using ultrasound is Sonocrystallisation.
Sonocrystallisation utilizes ultrasound power characterised by a frequency
range of 20–100 kHz for inducing crystallisation. It’s not only enhances the
nucleation rate but also an effective means of size reduction and controlling size
distribution of the active pharmaceutical ingredients (API) (Sheere Banga, 2004).
Most applications use ultrasound in the range 20 kHz-5 MHz.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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2) Supercritical fluid process
Novel nanosizing and solubilization technology whose application has
increased particle size reduction via supercritical fluid (SCF) processes (Vasu
Kumar et al., 2004). A supercritical fluid (SF) can be defined as a dense
noncondensable fluid (Irene Pasquali et al, 2006). Supercritical fluids are fluids
whose temperature and pressure are greater than its critical temperature (Tc) and
critical pressure (Tp). Through manipulation of the pressure of SCFs, the
favorable characteristics of gases- high diffusivity, low viscosity and low surface
tension may be imparted upon liquids to precisely control the solubilisation of a
drug with a supercritical fluid. SCFs are high compressible, allowing moderate
changes in pressure to greatly alter the density and mass transport characteristics
of fluid that largely determine its solvents power. Once the drug particles are
solubilised within SCFs, they may be recrystalised at greatly reduced particle
sizes. A SCF process allows micronisation of drug particles within narrow range
of particle size, often to sub-micron levels. Current SCF processes have
demonstrated the ability to create nanoparticulate suspensions of particles 5 to
2,000 nm in diameter.
The most widely employed methods of SCF processing for micronized
particles are rapid expansion of supercritical solutions (RESS) and gas
antisolvents recrystallisation (GAS), both of which are employed by the
pharmaceutical industry using carbon dioxide (CO2) as the SCF due to its
favourable processing characteristics like its low critical temperature (Tc = 31.1C) and pressure (Pc = 73.8 bar) (Hamsaraj Karanth et al, 2006).
RESS involves solubilising a drug or a drug-polymer mixture in SCF and
subsequently spraying the SCF solution into a lower pressure environment via a
conventional nozzle or capillary tube. The rapid expansion undergone by the
solution reduces the density of the CO2, correspondingly reducing its solvent
power and supersaturating the lower pressure solution. This supersaturation results
in the recrystallisation and precipitation of pure drug or drug-polymer particles of
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
20
Chapter 1
Introduction
greatly reduced size, narrow size distribution and high purity. The solubility of
nifedipine has been improved by RESS (Perrut et al, 2005).
GAS processing requires the drug or drug-polymer mixture be solubilised
via conventional means into a solvent that is then sprayed into an SCF; the drug
should be insoluble in the SCF, while the SCF should be miscible with the organic
solvent. The SCF diffuses into the spray droplets, causing expansion of the solvent
present and precipitation of the drug particles.
The low solubility of poorly water-soluble drugs and surfactants in
supercritical CO2 and the high pressure required for these processes restrict the
utility of this technology in the pharmaceutical industry (Bhupendra et al,
http://www.pharmaquality.com/).
3) Spray drying
Spray drying is a commonly used method of drying a liquid feed through a
hot gas. Typically, this hot gas is air but sensitive materials such as
pharmaceuticals and solvents like ethanol require oxygen-free drying and nitrogen
gas is used instead. The liquid feed varies depending on the material being dried
and is not limited to food or pharmaceutical products and may be a solution,
colloid or a suspension. This process of drying is a one step rapid process and
eliminates additional processing. Spray drying of the acid dispersed in acacia
solutions resulted in as much as a 50% improvement in the solubility of poorly
water soluble salicylic acid (Kawashima et al, 1975).
B. Modification of the crystal habit
Polymorphism is the ability of an element or compound to crystallize in
more then one crystalline form. Different polymorphs of drugs are chemically
identical, but they exhibit different physicochemical properties including
solubility, melting point, density, texture, stability etc. Broadly polymorphs can be
classified as enantiotropes and monotropes based on thermodynamic properties. In
the case of an enantiotropic system, one polymorphs form can change reversibly
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
21
Chapter 1
Introduction
into another at a definite transition temperature below the melting point, while no
reversible transition is possible for monotropes. Once the drug has been
characterized under one of this category, further study involves the detection of
metastable form of crystal. Metastable forms are associated with higher energy
and thus higher solubility. Similarly the amorphous form of drug is always more
suited than crystalline form due to higher energy associated and increase surface
area.
Generally, the anhydrous form of a drug has greater solubility than the
hydrates. This is because the hydrates are already in interaction with water and
therefore have less energy for crystal breakup in comparison to the anhydrates (i.e.
thermodynamically higher energy state) for further interaction with water. On the
other hand, the organic (nonaqueous) solvates have greater solubility than the
nonsolvates.
Some drugs can exist in amorphous form (i.e. having no internal crystal
structure). Such drugs represent the highest energy state and can be considered as
super cooled liquids. They have greater aqueous solubility than the crystalline
forms because they require less energy to transfer a molecule into solvent. Thus,
the order for dissolution of different solid forms of drug is
Amorphous >Metastable polymorph >Stable polymorph
Melting followed by a rapid cooling or recrystallization from different
solvents can be produce metastable forms of a drug.
C. Drug dispersion in carriers
The solid dispersion approach to reduce particle size and therefore increase
the dissolution rate and absorption of drugs was first recognised in 1961
(Sekiguchi and Obi, 1961).The term “solid dispersions” refers to the dispersion of
one or more active ingredients in an inert carrier in a solid state, frequently
prepared by the melting (fusion) method, solvent method, or fusion solventmethod (Chiou and Riegelman, 1971). Novel additional preparation techniques
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Chapter 1
Introduction
have included rapid precipitation by freeze drying (Emara et al, 2002) and using
supercritical fluids (Juppo et al, 2003) and spray drying (Kai et al, 1996), often in
the presence of amorphous hydrophilic polymers and also using methods such as
melt extrusion (Forster et al, 2001). The most commonly used hydrophilic carriers
for solid dispersions include polyvinylpyrrolidone (Ambike et al, 2004; Paradkar
et al, 2004), polyethylene glycols (Doshi et al, 1967), Plasdone-S630 (Alazar et al,
2007). Many times surfactants may also used in the formation of solid dispersion.
Surfactants like Tween-80, Docusate sodium, Myrj-52, Pluronic-F68 and Sodium
Lauryl Sulphate used.
The solubility of etoposide, glyburide, itraconazole, ampelopsin,
valdecoxib, celecoxib, halofantrine can be improved by solid dispersion using
suitable hydrophilic carriers.
The eutectic combination of chloramphenicol/urea and sulphathiazole/
urea served as examples for the preparation of a poorly soluble drug in a highly
water soluble carrier.
1) Hot Melt method
Sekiguchi and Obi used a hot melt method to prepare solid dispersion.
Sulphathiazole and urea were melted together and then cooled in an ice bath. The
resultant solid mass was then milled to reduce the particle size. Cooling leads to
supersaturation, but due to solidification the dispersed drug becomes trapped
within the carrier matrix. A molecular dispersion can be achieved or not, depends
on the degree of supersaturation and rate of cooling used in the process (Christian
Leuner and Jennifer Dressman, 2000). An important requisite for the formation of
solid dispersion by the hot melt method is the miscibility of the drug and the
carrier in the molten form. When there are miscibility gaps in the phase diagram,
this usually leads to a product that is not molecularly dispersed. Another important
requisite is the thermostability of the drug and carrier.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Chapter 1
Introduction
2) Solvent Evaporation Method
Tachibana and Nakumara, 1965 were the first to dissolve both the drug
and the carrier in a common solvent and then evaporate the solvent under vacuum
to produce a solid solution. This enabled them to produce a solid solution of the
highly
lipophilic
β-carotene
in
the
highly
water
soluble
carrier
polyvinylpyrrolidone. An important prerequisite for the manufacture of a solid
dispersion using the solvent method is that both the drug and the carrier are
sufficiently soluble in the solvent (Christian Leuner and Jennifer Dressman,
2000). The solvent can be removed by various methods like by spray-drying or by
freeze-drying. Temperatures used for solvent evaporation generally lie in the
range 23-65ºC.
The solid dispersion of the 5- lipoxygenase/cyclooxygenase inhibitor ER34122 shown improved in-vitro dissolution rate compared to the crystalline drug
substance which was prepared by solvent evaporation (Kushida et al, 2002). These
techniques have problems such as negative effects of the solvents on the
environment and high cost of production due to extra facility for removal of
solvents (Serajuddin, 1999). Due to the toxicity potential of organic solvents
employed in the solvent evaporation method, hot melt extrusion method is
preferred in preparing solid solutions.
3) Hot-melt Extrusion
Melt extrusion was used as a manufacturing tool in the pharmaceutical
industry as early as 1971 (el-Egakey et al, 1971). It has been reported that melt
extrusion of miscible components results in amorphous solid solution formation,
whereas extrusion of an immiscible component leads to amorphous drug dispersed
in crystalline excipient (Breitenbach, 2002). The process has been useful in the
preparation of solid dispersions in a single step.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Chapter 1
Introduction
4) Melting –solvent method
A drug is first dissolved in a suitable liquid solvent and then this solution
is incorporated into the melt of polyethylene glycol, obtainable below 70ºC
without removing the liquid solvent. The selected solvent or dissolved drug may
not be miscible with the melt of the polyethylene glycol. Also polymorphic form
of the drug precipitated in the solid dispersion may get affected by the liquid
solvent used.
Table 1.3. Carriers for Solid Dispersions
Sr. No.
Chemical Class
Examples
1
Acids
Citric acid, Tartaric acid, Succinic acid
2
Sugars
Dextrose, Sorbitol, Sucrose, Maltose,
Galactose, Xylitol
3
Polymeric Materials
Polyvinylpyrrolidone, PEG-4000, PEG6000, Carboxymethyl cellulose,
Hydroxypropyl cellulose,
Guar gum, Xanthan gum, Sodium
alginate, Methylcellulose, HPMC,
Dextrin, Cyclodextrins,
Galactomannan
4
Surfactants
Polyoxyethylene stearate, Poloxamer,
Deoxycholic acid, Tweens and Spans,
Gelucire 44/14, Vitamine E TPGS NF
5
Miscellaneous
Pentaerythritol, Urea, Urethane,
Hydroxyalkyl xanthines
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
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Chapter 1
Introduction
D. Complexation
Complexation is the association between two or more molecules to form a
nonbonded entity with a well defined stichiometry. Complexation relies on
relatively weak forces such as London forces, hydrogen bonding and hydrophobic
interactions. There are many types of complexing agents and a partial list can be
found in below table.
Table 1.4. List of Complexing Agents
Sr.No.
Types
Examples
1
Inorganic
IB-
2
Coordination
Hexamine cobalt(III) chloride
3
Chelates
EDTA, EGTA
4
Metal-Olefin
Ferrocene
5
Inclusion
Cyclodextrins, Choleic acid
6
Molecular Complexes
Polymers
1) Staching complexation
Staching complexes are formed by the overlap of the planar regions of
aromatic molecules. Nonpolar moieties tend to be squeezed out of water by the
strong hydrogen bonding interactions of water. This causes some molecules to
minimize the contact with water by aggregation of their hydrocarbon moieties.
This aggregation is favored by large planar nonpolar regions in the molecule.
Stached complexes can be homogeneous or mixed. The former is known as self
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Chapter 1
Introduction
association and latter as complexation. Some compounds that are known to form
staching complexes are as follows:
Nicotinamide, Anthracene, Pyrene, Methylene blue, Benzoic acid,
Salicylic acid, Ferulic acid, Gentisic acid, Purine, Theobromine, Caffeine, and
Naphthalene etc.
Higuchi and Kristiansen, 1970 proposed a model according to which the
compounds capable of undergoing stacking can be classified into two classes
(classes A and B) based on their structure. The compounds in class A have higher
affinity for compounds in class B than for those in class A and vice versa
(Rajewski and Stella, 1996).
2) Inclusion complexation
Inclusion complexes are formed by the insertion of the nonpolar molecule
or the nonpolar region of one molecule (known as guest) into the cavity of another
molecule or group of molecules (known as host). The major structural requirement
for inclusion complexation is a snug fit of the guest into the cavity of host
molecule. The cavity of host must be large enough to accommodate the guest and
small enough to eliminate water, so that the total contact between the water and
the nonpolar regions of the host and the guest is reduced.
The most commonly used host molecules are cyclodextrins. The enzymatic
degradation of starch by cyclodextrin-glycosyltransferase (CGT) produces cyclic
oligomers, Cyclodextrins. Cyclodextrins are non-reducing, crystalline, water
soluble, cyclic, oligosaccharides. Cyclodextrins consist of glucose monomers
arranged in a donut shape ring. Three naturally occurring CDs are α-Cyclodextrin,
β-Cyclodextrin, and γ- Cyclodextrin. The complexation with cyclodextrins is used
for enhancement of solubility (Kaneto Uekama et al, 1998). Cyclodextrin
inclusion is a molecular phenomenon in which usually only one guest molecule
interacts with the cavity of a cyclodextrin molecule to become entrapped and form
a stable association. The internal surface of cavity is hydrophobic and external is
hydrophilic, this is due to the arrangement of hydroxyl group within the molecule.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Chapter 1
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Molecules or functional groups of molecules those are less hydrophilic
than water, can be included in the cyclodextrin cavity in the presence of water. In
order to become complex, the "guest molecules" should fit into the cyclodextrin
(CD) cavity. The cavity sizes as well as possible chemical modifications
determine the affinity of cyclodextrins to the various molecules.
The kinetics of cyclodextrin inclusion complexation has been usually
analyzed in terms of a one-step reaction or a consecutive two-step reaction
involving intracomplex structural transformation as a second step. Cyclodextrins
is to enhance aqueous solubility of drugs through inclusion complexation. It was
found that cyclodextrins increased the paclitaxel solubility by 950 fold (Anil
Singla et al, 2002). Complex formation of rofecoxib, celecoxib, clofibrate,
melarsoprol, taxol, cyclosporin A etc. with cyclodextrins improves the solubility
of particular drugs.
Factors affecting complexation:
1. Steric effects
2. Electronic effects
a. Effect of proximity of charge to CD cavity
b. Effect of charge density
c. Effect of charge state of CD and drug
3. Temperature, additives and cosolvent effects
E. Solubilization by surfactants
Surfactants are molecules with distinct polar and nonpolar regions. Most
surfactants consist of a hydrocarbon segment connected to a polar group. The
polar group can be anionic, cationic, zwitterionic or non-ionic (Swarbrick and
Boylan, 2002). When small apolar molecules are added they can accumulate in the
hydrophobic core of the micelles. This process of solubilization is very important
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Introduction
in industrial and biological processes. The presence of surfactants may lower the
surface tension and increase the solubility of the drug within an organic solvent.
Microemulsion
The term microemulsion was first used by Jack H. Shulman in 1959. A
microemulsion is a four-component system composed of external phase, internal
phase, surfactant and cosurfactant. The addition of surfactant, which is
predominately soluble in the internal phase unlike the cosurfactant, results in the
formation of an optically clear, isotropic, thermodynamically stable emulsion. It is
termed as microemulsion because of the internal or dispersed phase is < 0.1 μ
droplet diameter. The formation of microemulsion is spontaneous and does not
involve the input of external energy as in case of coarse emulsions. The surfactant
and the cosurfactant alternate each other and form a mixed film at the interface,
which contributes to the stability of the microemulsions (Lawrence and Rees,
2000). Non-ionic surfactants, such as Tweens (polysorbates) and Labrafil
(polyoxyethylated oleic glycerides), with high hyrophile-lipophile balances are
often used to ensure immediate formation of oil-in-water droplets during
production.
Advantages of microemulsion over coarse emulsion include its ease of
preparation due to spontaneous formation, thermodynamic stability, transparent
and elegant appearance, increased drug loading, enhanced penetration through the
biological membranes, increased bioavailability (Tenjarla, 1999), and less interand intra-individual variability in drug pharmacokinetics (Kovarik et al, 1994).
II. Chemical Modifications
A. Salt Formation
It is the most common and effective method of increasing solubility and
dissolution rates of acidic and basic drugs. Acidic or basic drug converted into salt
having more solubility than respective drug. Ex. Aspirin, Theophylline,
Barbiturates (Sinko, 2006).
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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B. Co-crystallisation
The new approach available for the enhancement of drug solubility is
through the application of the co-crystals, it is also referred as molecular
complexes. If the solvent is an integral part of the network structure and forms at
least two component crystal, then it may be termed as co-crystal. If the solvent
does not participate directly in the network itself, as in open framework structures,
then it is termed as clathrate (inclusion complex). A co-crystal may be defined as
a crystalline material that consists of two or more molecular (and electrically
neutral) species held together by non-covalent forces (Aakeröy, 1997).
Co-crystals are more stable, particularly as the co-crystallizing agents are
solids at room temperature. Only three of the co-crystallizing agents are classified
as generally recognised as safe (GRAS) it includes saccharin, nicotinamide and
acetic acid limiting the pharmaceutical applications. Co-crystallisation between
two active pharmaceutical ingredients has also been reported. This may require
the use of subtherapeutic amounts of drug substances such as aspirin or
acetaminophen (Almarsson and Zaworotko, 2004). At least 20 have been reported
to date, including caffeine and glutaric acid polymorphic co-crystals (Trask et al,
2004). Co-crystals can be prepared by evaporation of a heteromeric solution or by
grinding the components together. Another technique for the preparation of cocrystals includes sublimation, growth from the melt, and slurry preparation
(Zaworotko, 2005). The formation of molecular complexes and co-crystals is
becoming increasingly important as an alternative to salt formation, particularly
for neutral compounds or those having weakly ionizable groups.
C. Co-solvency
The solubilisation of drugs in co-solvents is another technique for
improving the solubility of poorly soluble drug (Amin et al, 2004). It is wellknown that the addition of an organic cosolvent to water can dramatically change
the solubility of drugs (Yalkowsky,S.H. and Roseman, 1981).
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Weak electrolytes and nonpolar molecules have poor water solubility and
it can be improved by altering polarity of the solvent. This can be achieved by
addition of another solvent. This process is known as cosolvency. Solvent used to
increase solubility known as cosolvent. Cosolvent system works by reducing the
interfacial tension between the aqueous solution and hydrophobic solute. It is also
commonly referred to as solvent blending (Joseph, 2002).
Most cosolvents have hydrogen bond donor and/or acceptor groups as well
as small hydrocarbon regions. Their hydrophilic hydrogen bonding groups ensure
water miscibility, while their hydrophobic hydrocarbon regions interfere with
waters hydrogen bonding network, reducing the overall intermolecular attraction
of water. By disrupting waters self-association, cosolvents reduce waters ability to
squeeze out non-polar, hydrophobic compounds, thus increasing solubility. A
different perspective is that by simply making the polar water environment more
non-polar like the solute, cosolvents facilitate solubilization (Jeffrey et al., 2002).
Solubility enhancement as high as 500-fold is achieved using 20% of 2pyrrolidone.
D. Hydrotrophy
Hydrotrophy designate the increase in solubility in water due to the
presence of large amount of additives. The mechanism by which it improves
solubility is more closely related to complexation involving a weak interaction
between the hydrotrophic agents (sodium benzoate, sodium acetate, sodium
alginate, and urea) and the solute.
Example: Solubilisation of Theophylline with sodium acetate and sodium alginate
E. Solubilizing agents
The solubility of poorly soluble drug can also be improved by various
solubilizing
materials.
PEG
400
is
improving
the
solubility
of
hydrochlorthiazide85. Modified gum karaya (MGK), a recently developed
excipient was evaluated as carrier for dissolution enhancement of poorly soluble
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Chapter 1
Introduction
drug, nimodipine (Murali Mohan Babu et al., 2002). The aqueous solubility of the
antimalarial agent halofantrine is increased by the addition of caffeine and
nicotinamide (Lee-Yong Lim and Mei-Lin Go, 2000).
F. Nanotechnology approaches
Nanotechnology will be used to improve drugs that currently have poor
solubility. Nanotechnology refers broadly to the study and use of materials and
structures at the nanoscale level of approximately 100 nanometers (nm) or less.
For many new chemical entities of very low solubility, oral bioavailability
enhancement by micronisation is not sufficient because micronized product has
the tendency of agglomeration, which leads to decreased effective surface area for
dissolution and the next step taken was Nanonisation.
a. Nanocrystal
A nanocrystal is a crystalline material with dimensions measured in
nanometers; a nanoparticle with a structure that is mostly crystalline. The
nanocrystallization is defined as a way of diminishing drug particles to the size
range of 1-1000 nanometers.
Nanocrystallization is thought to be a universal method that can be applied
to any drug (Radtke, 2001).
There are two distinct methods used for producing nanocrystals; ’bottomup’ and ’top-down’ development. The top-down methods (i.e. Milling and High
pressure homogenization) start milling down from macroscopic level, e.g. from a
powder that is micron sized. In bottom-up methods (i.e. Precipitation and Cryovacuum method), nanoscale materials are chemically composed from atomic and
molecular components.
1) Milling
Nanoscale particles can be produced by wet-milling process. In ball mills,
particle size reduction is achieved by using both impact and attrition forces. The
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Introduction
most common models are a tumbling ball mill and a stirred media mill. One
problem of this method is the degradation of mill surfaces and subsequent
suspension contamination.
2) High pressure homogenization
In high pressure homogenization, an aqueous dispersion of the crystalline
drug particles is passed with high pressure through a narrow homogenization gap
with a very high velocity. Homogenisation can be performed in water
(DissoCubes) or alternatively in non-aqueous media or water-reduced media
(Nanopure). The particles are disintegrated by cavitation and shear forces. The
static pressure exerted on the liquid causes the liquid to boil forming gas bubbles.
When exiting from the gap, gas bubbles collapse under normal air pressure. This
produces shock waves which make the crystals collide, leading to particle
disintegration. A heat exchanger should be used when operating on temperature
sensitive materials because high pressure homogenization causes increase in the
sample temperature. The particle size obtained during the homogenization process
depends primarily on the nature of the drug, the pressure applied and the number
of homogenization cycles.
3) Precipitation
In the precipitation method a dilute solution is first produced by dissolving
the substance in a solvent where its dissolution is good. The solution with the drug
is then injected into water, which acts as a bad solvent. At the time of injection,
the water has to be stirred efficiently so that the substance will precipitate as
nanocrystals. Nanocrystals can be removed from the solution by filtering and then
dried in air.
4) Cryo-vacuum method
In the cryo-vacuum method the active ingredient to be nanonized is first
dissolved in water to attain a quasi-saturated solution (Salvadori et al., 2006). The
method is based on sudden cooling of a solvent by immersing the solution in
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Introduction
liquid nitrogen (-196ºC). Rapid cooling causes a very fast rise in the degree of
saturation based on the decrease of solubility and development of ice crystals
when the temperature drops below 0ºC. This leads to a fast nucleation of the
dissolved substance at the edges of the ice crystals. The solvent must be
completely frozen before the vessel is removed from the liquid nitrogen. Next the
solvent is removed by sublimation in a lyophilization chamber where the
temperature is kept at constant -22ºC and the pressure is lowered to 10-2 mbar.
Cryo-assisted sublimation makes it possible to remove the solvent without
changing the size and habit of the particles produced, so they will remain
crystalline. The method yields very pure nanocrystals since there is no need to use
surfactants or harmful reagents.
b. NanoMorph
The NanoMorph technology is to convert drug substances with low watersolubility from a coarse crystalline state into amorphous nanoparticles. A
suspension of drug substance in solvent is fed into a chamber, where it is rapidly
mixed with another solvent. Immediately the drug substance suspension is
converted into a true molecular solution. The admixture of an aqueous solution of
a polymer induces precipitation of the drug substance. The polymer keeps the
drug substance particles in their nanoparticulate state and prevents them from
aggregation or growth. Water redispersable dry powders can be obtained from the
nanosized dispersion by conventional methods, e.g. spray-drying.
Using this technology the coarse crystalline drug substances are transformed into
a nanodispersed amorphous state, without any physical milling or grinding
procedures. It leads to the preparation of amorphous nanoparticles.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Table 1.5. Nanotechnology approaches to improve the solubility of
hydrophobic drugs
Company
Nanoparticulate Description
Technologies
Elan
NanoCrystal
NanoCrystal drug particles (<1,000 nm)
produced by wet-milling and stabilised
against agglomeration through surface
adsorption of stabilisers; applied to NMEs
eg aprepitant/reformulation of existing
drugs eg. sirolimus
Eurand
Biorise
Nanocrystals/amorphous drug produced
by physical breakdown of the crystal
lattice and stabilised with biocompatible
carriers (swellable microparticles or
cyclodextrins)
SkyePharma
IDD
Insoluble Drug Delivery: micro-nm
particulate/droplet water-insoluble drug
core stabilised by phospholipids;
formulations are produced by high shear,
cavitation or impaction
BioSante
CAP
Calcium Phosphate-based nanoparticles:
for improved oral bioavailability of
hormones/proteins such as insulin; also as
vaccine adjuvant
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
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American
Introduction
NAB
Bioscience
Nanoparticle Albumin-Bound technology:
injectable suspension of biocompatible
protein with drug improves
solubility/removes need for toxic solvents;
eg paclitaxel-albumin nanoparticles
Nanoparticle Albumin-Bound technology:
injectable suspension of biocompatible
protein with drug improves
solubility/removes need for toxic solvents;
eg paclitaxel-albumin nanoparticles
Baxter
Nanoedge
Nanoedge technology: drug particle size
reduction to nanorange by platforms
including direct homogenisation,
microprecipitation, lipid emulsions and
other dispersed-phase technology
Company
Nanostructuring Description
Technologies
pSivida
BioSilicon
Drug particles are structured within the
nano-width pores of biocompatible
BioSilicon microparticles, membranes or
fibres; gives controlled release/improves
solubility of hydrophobic drugs
iMEDD
NanoGate
Silicon membrane with nano-width pores
(10-100 nm) used as part of an
implantable system for drug delivery and
biofiltration
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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PharmaSol
NLC8
Nanostructured Lipid Carriers:
nanostructured lipid particle dispersions
with solid contents produced by highpressure homogenisation; lipid-drug
conjugate nanoparticles provide highloading capacity for hydrophilic drugs for
oral delivery
1.3.4. Need of Solubility Enhancement
The better characterization of biochemical targets increasingly drives drug
development; these targets are generally cell-based and access to them in these
models is relatively straightforward. This has led to the widely discussed
proliferation
of
highly
active
compounds
that
have
physicochemical
characteristics that are poorly suited to delivery to a whole organism: at the head
of this list of undesirable characteristics is poor water solubility (Perrett and
Venkatesh, 2006).
According to recent estimates, nearly 40% of new chemical entities are
rejected because of poor solubility i.e. biopharmaceutical properties. Solubility is
one of the important parameter to achieve desired concentration of drug in
systemic circulation for pharmacological response to be shown.
Poor aqueous solubility is caused by two main factors
1) High lipophilicity and
2) Strong intermolecular interactions which make the solubilisation of the solid
energetically costly.
Solubility of active pharmaceutical ingredients (APIs) has always been a
concern for formulators, since inadequate aqueous solubility may hamper
development of products and limit bioavailability of oral products. Solubility
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Introduction
plays an essential role in drug disposition, since the maximum rate of passive drug
transport across a biological membrane, the main pathway for drug absorption, is
the product of permeability and solubility. Among the five key physicochemical
screens in early compound screening, pKa, solubility, permeability, stability and
lipophilicity, poor solubility tops of the list of undesirable compound properties.
Compounds with insufficient solubility carry a higher risk of failure during
discovery and development since insufficient solubility may compromise other
properties, influence both pharmacokinetic and pharmacodynamic properties of
the compound, and finally may affect the ability of the compound to develop as
API .
Poorly water-soluble drug candidates often emerge from contemporary
drug discovery programs, and present formulators with considerable technical
challenges (Pouton, 2006). The poor solubility and low dissolution rate of poorly
water soluble drugs in the aqueous gastro-intestinal fluids often cause insufficient
bioavailability.
Especially
for
class
II
substances
according
to
the
Biopharmaceutics Classification System (BCS), the bioavailability may be
enhanced by increasing the solubility and dissolution rate of the drug in the
gastro-intestinal fluids (Urbanetz, 2006). Consideration of the modified NoyesWhitney equation provides some hints as to how the dissolution rate of even very
poorly soluble compounds might be improved to minimize the limitations to oral
availability:
dC/ dt = AD (Cs - C)/ h
Where, dC/dt is the rate of dissolution, A is the surface area available for
dissolution, D is the diffusion coefficient of the compound, Cs is the solubility of
the compound in the dissolution medium, C is the concentration of drug in the
medium at time t, h is the thickness of the diffusion boundary layer adjacent to the
surface of the dissolving compound.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
38
Chapter 1
Introduction
The main possibilities for improving dissolution according to this analysis
are to increase the surface area available for dissolution by decreasing the particle
size of the solid compound and/or by optimizing the wetting characteristics of the
compound surface, to decrease the boundary layer thickness, to ensure sink
conditions for dissolution and, last but definitely not least, to improve the apparent
solubility of the drug under physiologically relevant conditions.
Larger the surface area, higher will be the dissolution rate. Since the
surface area increases with decreasing particle size, which can be accomplished by
conventional methods like trituration, grinding, ball milling, fluid energy
micronization, salt formation and controlled precipitation. Although these
conventional methods have been used commonly to increase dissolution rate of
drug, there are practical limitation with these techniques as the desired
bioavailability enhancement may not always be achieved. Therefore, formulation
approaches are being explored to enhance bioavailability of poorly soluble drugs.
One such formulation approach that has been shown to significantly enhance
absorption of such drugs is to formulate self emulsifying drug delivery system
(SEDDS).
1.4.
SELF-EMULSIFYING/ MICROEMULSIFYING DRUG DELIVERY
SYSTEMS
Self-Emulsifying / Microemulsifying drug delivery systems (S(M)EDDS)
are isotropic mixtures of oil, hydrophilic surfactant and/or a cosurfactant, and a
solubilized drug. They can be encapsulated in hard or soft gelatin capsules or can
be converted to solid state (Solid SEDDS/SMEDDS). These formulations
spontaneously form a fine oil-in-water emulsion in case of SEDDS and a
nanoemulsion in the case of SMEDDS upon dilution with water. In the GI tract,
they are readily dispersed, where the motility of the stomach and small intestine
provides the gentle agitation necessary for emulsification. SEDDS produces
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
39
Chapter 1
Introduction
coarse emulsions while SMEDDS produces droplets of size less than 100 nm.
This property of S(M)EDDS makes them a natural choice for delivery of
hydrophobic drugs that have adequate solubility in oil-surfactant blends.
S(M)EDDS improves the rate and extent of absorption of hydrophobic drugs,
whose absorption is considered to be dissolution rate-limited. Upon aqueous
dilution the drug remains in the oil droplets or as a micellar solution since the
surfactant concentration is very high in such formulations (Pouton and Porter,
2008). The drug in the oil droplet may partition out in the intestinal fluid as shown
in figure 1.6.
Figure 1.6. Mechanism of drug partitioning in S(M)EDDS
Potential advantages of these systems include;
1. Enhanced oral bioavailability enabling reduction in dose,
2. More consistent temporal profiles of drug absorption,
3. Selective targeting of drug(s) toward specific absorption window in GIT,
4. Protection of drug(s) from the hostile environment in gut.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
40
Chapter 1
Introduction
5. Control of delivery profiles
6. Reduced variability including food effects
7. Protective of sensitive drug substances
8. High drug payloads
9. Liquid or solid dosage forms
1.4.1. Excipient selection for lipid based formulations
Chemically, lipids are considered as one of the most versatile excipient
classes available today. There are various subcategories of lipids available and
there is a constant influx of new lipid based excipients in the market. This
provides flexibility to the formulator in terms of selecting a suitable excipient, but
at the same time the formulator should be cautious while selecting a particular
excipient. Pouton et al. described few factors that should be considered while
selecting a lipid excipient. They are: (a) regulatory issues-irritancy, toxicity (b)
solvent capacity (c) miscibility (d) morphology at room temperature (e) selfdispersibility (f) digestibility and fate of digested products (g) capsule
compatibility (h) purity, chemical stability and (i) cost.
The following description on lipid based excipients is in relation to the
S(M)EDDS.
1.4.1.1.
Oils
Oils play a critical role in S(M)EDDS because it is responsible for
solubilization of the hydrophobic drug, aiding in self-emulsification and moreover
contributes to the intestinal lymphatic transport of the drug. The emulsification
property of the oil is said to be dependent on the molecular structure of the oil
(Kimura et al., 1994). Oils used in self-dispersing systems can be classified into
three categories.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Chapter 1
Introduction
Triglyceride vegetable oils: They are easily ingested, digested and absorbed
presenting no safety issues. Depending on the vegetable source, they can have
different proportions of long chain triglycerides (LCT) and medium chain
triglycerides (MCT). Generally vegetable oils are rich in unsaturated LCT with the
exception of coconut oil and palm kernel oil which are rich in saturated MCT.
They are highly lipophilic and their effective concentration of ester group
determines its solvent capacity. MCT’s are preferred over LCT’s in lipid based
drug delivery owing to its good solvent capacity and resistance to oxidation.
Vegetable oils are not widely used in SEDDS because of their poor solubility for
the hydrophobic drug and due to poor self dispersing property.
Vegetable oils derivatives: Popular vegetable oil derivatives are hydrogenated
vegetable oil, mixed glycerides, polyoxylglycerides, ethoxylated glycerides and
esters of fatty acids with various alcohols. Hydrogenated vegetable oils are
produced by hydrogenation of the unsaturated bonds present in the oil. Usually
vegetable oils are hydrogenated before they are transformed into their derivatives
since hydrogenation increases chemical stability. Examples of such oils are
hydrogenated cottonseed oil (Lubritab), hydrogenated palm oil (Dynasan),
hydrogenated castor oil (Cutina HR) and hydrogenated soybean oil (Lipo).
Mixed Partial Glycerides: They are formed by partial hydrolysis of triglycerides
present in the vegetable oil resulting in a mixture of mono-,di- and tri-glycerides.
The physical state, melt characteristics, and the HLB of the partial glycerides
depend on the nature of the fatty acid present and the degree of esterification.
Glycerides with medium chain or unsaturated fatty acids are used for improving
bioavailability, while ones with saturated long chain fatty acids are used for
sustained-release purposes (Jannin et al., 2008). Examples of glycerides with
medium chain fatty acids are glyceryl monocaprylocaprate (Capmul MCM) and
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
42
Chapter 1
Introduction
ones with long chain fatty acids are glyceryl monoleate (Peceol) and glyceryl
monolinoleate (Maisine 35-1).
Polyoxylglycerides / Macrogolglycerides: They are formed by polyglycolysis of
vegetable oil (hydrogenated or not hydrogenated) with polyethylene glycols
(PEG) of a particular molecular weight. It has a fixed composition of a mixture of
mono-, di- and triglycerides and mono and diesters of PEG. They are readily
dispersible in water making them a good choice for SEDDS. Like glycerides, they
may be composed of unsaturated long chain fatty acids such as oleyl
polyoxylglycerides (Labrafil 1944CS) and linoleyl polyoxylglycerides (Labrafil
M
2125CS)
or
medium
chain
fatty
acids
such
as
caprylocaproyl
polyoxylglycerides (Labrasol) and lauroyl polyoxylglycerides (Gelucire 44/14).
Ethoxylated glycerides: They are formed from ethoxylation (etherification) of
ricinoleic acid (present in glyceride) of castor oil. This reaction makes the oil
hydrophilic.
Examples of such glycerides are ethoxylated castor oil (Cremphor EL) and
ethoxylated hydrogenated castor oil (Cremophor RH40 and Cremophor RH 60).
Because of its amphiphilic nature, Cremophor’s are widely used as surfactants in
the formulation of SEDDS. Moreover, they can dissolve large quantities of drugs,
have good self-emuslification property, and their degradation products are similar
to those obtained from intestinal digestion (Gershanik and
Benita, 2000;
Constantinides, 1995).
Polyalcohol esters of fatty acids: These are newer oil derivatives that possess
surfactant properties because of its amphiphilic nature and are effective in
replacing conventionally used oils. Their composition is based on nature of
alcohol used. They can be polyglycerol (Plurol Oleique CC 497), and propylene
glycol (Capryol), and polyoxyethylene glycol (Mirj).
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
43
Chapter 1
1.4.1.2.
Introduction
Surfactants
Surfactants are surface active molecules which concentrate at the oil-water
interface and stabilize the internal phase in an emulsion. Surfactants are critical
components of S(M)EDDS systems since they are responsible for forming a stable
emulsion upon aqueous dilution. Nonionic surfactants are commonly used in this
type of formulation. Proper selection of the surfactant is based on its Hydrophilic
Lipophilic Balance (HLB) value and safety considerations. Nonionic surfactants
with high hydrophilicity are required for SEDDS. A surfactant with an HLB value
of more than 12 is necessary in SMEDDS to spontaneously form a fine oil-inwater nanoemulsion when dispersed in the GI tract fluids. Surfactants used in lipid
based drug delivery are usually polyethoxylated lipid derivatives (Pouton, 2007).
These lipids can be fatty acids, alcohols or glycerides which are linked to a certain
number of repeating polyexthylene oxide units through ester linkage (fatty acids
and glycerides) and ether linkage (alcohols). The polyethylene groups provide
hydrophilic characteristics to the surfactant. Examples of such surfactants are
polyethoxylated fatty acid ester (Myrj and Solutol HS 15), polyethoxylated alkyl
ethers(Brij), polyethoxylated sorbitan esters (Tweens), and polyethoxylated
glycerides (Cremphors, Labrasol). The most commonly used surfactants in
SMEDDS are Tweens, Cremophors, and Labrasols. Block copolymers such as
Pluronics have also been used in SEDDS (Singh et al, 2009). Emulsifiers of
natural origin are preferred due to safety considerations but are not widely used
because of their poor self emulsification property (Constantinides, 1995).
Nonionic surfactants are less toxic and possess good emulsion stability over wider
range of ionic strength and pH than ionic surfactants (Tenjarla, 1999), but may
cause changes in intestinal lumen permeability (Swenson et al, 1994). The
surfactant concentration necessary to form a stable S(M)EDDS ranges from
30%w/w to 60%w/w (Fanun, 2010). The least possible surfactant concentration
should be used so as to prevent gastric irritation. Extremely small droplet size
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
44
Chapter 1
Introduction
produced in case of SMEDDS promotes rapid gastric emptying and low local
concentration of surfactant, thereby reducing the gastric irritation (Charman et al.,
1992). The surfactant concentration is shown to have varied effects on emulsion
droplet size. Increase in surfactant concentration causes a decrease in droplet size
associated with stabilization of surfactant molecules at the oil-water interface
(Neslihan Gursoy and Benita, 2004), while the reverse is possible due to enhanced
water penetration into oil droplets leading to breakdown of oil droplets (Pouton,
1997). The surfactants being amphiphilic can dissolve large quantities of the
hydrophobic drug. They can contribute to the total solubility of the drug in
S(M)EDDS, thus preventing drug precipitation upon aqueous dilution and keep
the drug in solubilized state in GI tract for further absorption (Neslihan Gursoy
and Benita, 2004).
1.4.1.3.
Cosolvents
Water soluble cosolvents are widely used in lipid based dosage forms.
Ethanol, polyethylene glycol (PEG), propylene glycol, and glycerol are examples
of cosolvents used. Their role is: (a) to increase the solvent capacity of the drugs
which are freely soluble in them. But this is associated with the risk of drug
precipitation when S(M)EDDS are dispersed in water, (b) to dissolve large
quantities of the hydrophilic surfactant in the oil. S(M)EDDS requires use of high
concentration of surfactants to ensure proper dispersion of the formulation, (c) to
increase the stability of nanoemulsion by wedging themselves between surfactant
molecules (Benita, 2006). There are several key issues that have to be considered
before using a particular cosolvent. The cosolvents are miscible with the oil only
up to a certain limit. There are some incompatibilities of using alcohol since it
may penetrate into soft and hard gelatin shell causing precipitation of the drug.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
45
Chapter 1
Introduction
1.4.2. Role of SEDDS/SMEDDS in improvement of oral absorption
S(M)EDDS partially avoids the additional drug dissolution step prior to
absorption in the GI tract. They increase the amount of solubilized drug in the
intestinal fluids resulting in good drug absorption. Apart from this, absorption of
the drug may also be enhanced by using lipid based excipients in the formulation.
There are several mechanisms through which increased absorption can be
achieved; the following schematic diagram describes these mechanisms.
Figure 1.7. Pathways for drug absorption from lipid based formulations
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
46
Chapter 1
Introduction
Retardation of gastric emptying time: Surfactants are believed to play a role in
retardation of gastric transit time, thereby increasing the time available for the
drug to dissolve and get absorbed. Surfactants may slow down gastric emptying
for a period of time by formation of viscous mass in the gastric and intestinal
lumen. Labrasol (a caprylocaproyl macrogolglyceride) was shown to improve
bioavailability of an investigational compound by retarding gastric emptying time
(Chang and Shojaei, 2004).
Increase in effective drug solubility in lumen: When exogenous lipid excipients
are encountered in the gastric environment, they are digested by gastric lipases.
Triglycerides are digested to di-glycerides and fatty acids. The duodenum secretes
bile salts (BS), phosphatidylcholine (PL) and cholesterol (Ch) from the gall
bladder and pancreatic lipases from pancreas. These agents in combination with
lipid digestion products get adsorbed to the surface of emulsion droplet and
transform into small, stable droplets. They also produce a series of colloidal
particles such as micelles, mixed micelles, and vesicles as shown in figure 1.6.
The drug contained in the oil droplet partitions into these micellar structures
making them a drug reservoir at the absorption site. This results in an increased
solubilization capacity of the drug in the GI tract. This capacity is dependent on
the type (medium chain or long chain triglycerides) and quantity of the lipids,
presence of additional lipid excipients such as surfactants and cosurfactants, and
the level of endogenous BS and PL present (Porter et al., 2008). The micelles and
nanoemulsions can be absorbed through following mechanisms: pinocytosis,
diffusion, or endocytosis. The partition of the drug from the oil droplets depends
on their size and polarity. Nano sized droplets will result in faster partitioning
since the drug can diffuse faster from smaller droplets (Shah et al., 1994). In case
of SMEDDS, it has been shown that digestion of the resultant nanoemulsion acts
independently of bile salts (Trull et al., 1995) and the polarity of the oil droplets is
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Chapter 1
Introduction
not significant because the drug reaches the capillaries within the oil droplets
(Benita, 2006).
Lymphatic transport of the drug: Most of the drugs delivered using S(M)EDDS
are absorbed systematically via portal vein except for certain type of drugs.
Lymphatic transport of the drug occurs when the drug is highly lipophilic (logP
>5) and shows high solubility in triglycerides (>50mg/ml). Such drugs are
absorbed via lymph vessels in the intestine which are responsible for absorption of
lipids. Since the drug is cleared by the lymph vessels, they bypass the liver
metabolism. This results in an increased bioavailability of these drugs. The
bioavailability of Ontazolast, an extensively first-pass metabolized drug was
improved when delivered in a lipid based formulation. The drug was absorbed via
lymphatic pathway and thus bypassed first-pass metabolism (Hauss et al., 1998).
Enterocyte based drug transport: Few endogenous lipid transporters have been
identified which are responsible for intestinal passage of lipophilic drugs. At low
lipid concentrations drugs are actively transported, while at high lipid
concentrations drugs are passively permeated. P-glycoprotein (P-gp) is an efflux
transporter present in enterocytes that acts as a substrate for many lipophilic
drugs. Surfactants are reported to inhibit these P-gp efflux transporters resulting in
an increase in permeability of poorly permeated drugs (Porter et al., 2007).
Labrasol was identified as the most effective surfactant in inhibiting the P-gp.
Increasing membrane permeability: Lipids are responsible for causing
fluidization of intestinal cell membrane and opening of tight junctions resulting in
increased membrane permeability. Labrasol has a dual property of increasing
membrane permeability by both the mechanisms, while Cremphor EL and Tween
80 act by opening the tight junction barrier. Surfactants also penetrate into the
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
48
Chapter 1
Introduction
intestinal cell membrane and disrupt the structural organization of the membrane
leading to an increased permeability (Neslihan Gursoy and Benita, 2004).
1.4.3. Mechanism of Self-emulsification
Conventional emulsions are formed by mixing two immiscible liquids
namely water and oil stabilized by an emulsifying agent. When an emulsion is
formed surface area expansion is created between the two phases. The emulsion is
stabilized by the surfactant molecules that form a film around the internal phase
droplet. In conventional emulsion formation, the excess surface free energy is
dependent on the droplet size and the interfacial tension. If the emulsion is not
stabilized using surfactants, the two phases will separate reducing the interfacial
tension and the free energy (Craig et al., 1995). In case of S(M)EDDS, the free
energy of formation is very low and positive or even negative which results in
thermodynamic spontaneous emulsification. It has been suggested that self
emulsification occurs due to penetration of water into the Liquid Crystalline (LC)
phase that is formed at the oil/surfactant-water interface into which water can
penetrate assisted by gentle agitation during self-emulsification. After water
penetrates to a certain extent, there is disruption of the interface and a droplet
formation. This LC phase is considered to be responsible for the high stability of
the resulting nanoemulsion against coalescence (Groves and De Galindez, 1976;
Wakerly et al. 1986).
1.4.4. Stability of SMEDDS
SMEDDS is a thermodynamically stable system. The stability issue arises
mainly due to the supersaturation of the system at RT and when stored at low
temperature which may result in re-crystallisation of the active substance. This
phenomenon is more common in liquid SMEDDS.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
49
Chapter 1
Introduction
The stability of the SMEDDS to is influenced by the chemical
characteristics of the selected carriers at different storage conditions, the
interaction between the carrier and the active substances. SMEDDS in the form of
liquid crystal, semisolid and solid can remain stable at both room temperature and
4°C.
The factors which affect the stability of SMEDDS are as following:
Polarity of the lipophillic phase:
The polarity of the lipid phase is one of the main factors that govern the
drug release from the micro-emulsions. The polarity of the droplet is governed by
the HLB, the chain length and degree of unsaturation of the fatty acid, the
molecular weight of the hydrophilic portion and the concentration of the
emulsifier. In fact, the polarity reflects the affinity of the drug for oil and/or water,
and the type of forces formed. The high polarity will promote a rapid rate of
release of the drug into the aqueous phase. This is confirmed by the observations
of Sang-Cheol Chi, who observed that the rate of release of idebenone from
SMEDDS is dependent upon the polarity of the oil phase used. The highest release
was obtained with the formulation that had oil phase with highest polarity.
Nature and Dose of the Drug:
Drugs which are administered at very high dose are not suitable for
SEDDS unless they have extremely good solubility in at least one of the
components of SEDDS, preferably lipophillic phase. The drugs which have
limited or less solubility in water and lipids are most difficult to deliver by
SEDDS. The ability of SEDDS to maintain the drug in solubilised form is greatly
influenced by the solubility of the drug in oil phase. As mentioned above if
surfactant or co-surfactant is contributing to the greater extent in drug
solubilisation then there could be a risk of precipitation, as dilution of SEDDS will
lead to lowering of solvent capacity of the surfactant or co-surfactant. Equilibrium
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
50
Chapter 1
Introduction
solubility measurements can be carried out to anticipate potential cases of
precipitation in the gut. However, crystallisation could be slow in the solubilising
and colloidal stabilizing environment of the gut. Pouton’s study reveal that such
formulations can take up to five days to reach equilibrium and that the drug can
remain in a super-saturated state for up to 24 hours after the initial emulsification
event. It could thus be argued that such products are not likely to cause
precipitation of the drug in the gut before the drug is absorbed, and indeed that
super-saturation
could
actually
enhance
absorption
by
increasing
the
thermodynamic activity of the drug. There is a clear need for practical methods to
predict the fate of drugs after the dispersion of lipid systems in the gastrointestinal tract.
1.4.5. Toxicity of SMEDDS
Unfortunately, there is not enough research conducted to investigate
toxicity of SMEDDS. Researchers measured proliferation of keratinocytes in one
of the topical niosome formulations. The effect of surfactant type on toxicity was
investigated. It was determined that the ester type surfactants are less toxic than
ether type surfactants. This may be due to enzymatic degradation of ester bounds.
In general, the physical form of niosomes did not influence their toxicity as
evident in a study comparing the formulations prepared in the form of liquid
crystals and gels. However, nasal applications of these formulations caused
toxicity in the case of liquid crystal type niosomes. In some instances,
encapsulation of the drug by niosomes reduces the toxicity as demonstrated in the
study on preparation of niosomes containing vincristine. It decreased the
neurological toxicity, diarrhoea and alopecia following the intravenous
administration of vincristine and increased vincristine anti-tumor activity in S-180
sarcoma and Erlich ascites mouse models.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Chapter 1
1.5.
Introduction
ISOTRETINOIN- A POORLY SOLUBLE MODEL DRUG
The evolution of high throughput combinatorial chemistry and efficient
receptor based in-vitro activity screen has resulted in molecules with poor
physicochemical properties for absorption across the GIT, like Isotretinoin.
Isotretinoin was approved in the United States in 1982 as a treatment for
severe recalcitrant nodular (cystic) acne that is unresponsive to conventional
therapy including systemic antibiotics. Isotretinoin is 13-cis retinoic acid or 13
cis-Vitamin A, its isomers and some of its analogs are widely known to leave a
therapeutic activity in the treatment of several skin disorders like acne,
hypertropic lupus erythmatosus, keratinization disorders. Some evidences also
have been brought about the activity of Isotretinoin in basal cell carcinoma and
squamous cell carcinoma. Isotretinoin is a reddish orange powder. It decomposes
in the presence of light and atmospheric oxygen. Isotretinoin is very poorly
soluble in water what makes its bioavailability quite low after an oral intake of
about 25% in fasted condition and 40% in fed conditions. The maximum
concentration (Cmax) is reached after 2-4hrs, while the Cmax of the active
metabolite, 4-oxo-isotretinoin is reached after 6hrs. The elimination half life of
Isotretinoin is about 7 to 37 hrs while the half life t1/2 of active metabolite is of 11
to 50 hrs. The steady state concentration is reached after 1 week of treatment.
It is increasingly being recognized by the pharmaceutical industry that for
these molecules, drug delivery systems play an important role for improving
bioavailability. Isotretinoin is characterized by a low absolute bioavailability and a
high inter and intra individual variability. It also presents a wide range of side
effects among which some are severe (ocular, skin anemia, hepatic). It is
consequently of particular interest to dispose of a reliable, stable and highly
bioavailable formulation of Isotretinoin.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Chapter 1
Introduction
The drug is available in most markets in the form of a soft gelatin capsule
containing a fatty liquid formulation of Isotretinoin. The reported literatures show
a maximum in-vitro drug release of about 60-70% even after 5 h.
The commercially available marketed product constitutes batch to batch
variability which further contributes to the variability caused by the nature of the
molecule itself. This inadvertently created further hurdles in developing the
generic version of Roacutane 20mg soft gelatin capsule product.
This variation occurs mainly due to the particle size and solid state
characteristics of Isotretinoin. The particle size of the active is mainly controlled
by the API manufacturer during the recrystallization or purification step. The size
reduction of the bigger particles causes serious blow in the purity and its physical
characteristics due to the energy intensive milling process. Hence such process is
mostly discouraged in the formulation industry but the quality of the product is
built through the input and In-process controls by controlling the API particle size
in a narrow range at vendor level itself. This makes the condition more complex
and increases the cost of the active material and ultimately adds on the cost of the
final formulation and makes the treatment costlier.
Isotretinoin is a highly unstable molecule. It decomposes in the presence
of light and atmospheric oxygen. A novel composition which shall be
manufactured through easily scalable process at the formulation manufacturer site
without involving sophisticated and energy intensive milling process irrespective
of the particle size of the active material procured from the API manufacturer, to
enhance the oral bioavailability and to address the stability issues associated with
the Isotretinoin molecule would be welcome to the class of poorly soluble drugs.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
53