 Implementing Nanotechnology and Novel Drug Delivery Systems to Improve Dissolution and

Solubilization

Implementing Nanotechnology and Novel Drug

Delivery Systems to Improve Dissolution and
Solubilization
Monday, December 10, 2012

 Email
 Print
 Comments (0)

126889 <li class="privacy

Clare Hoskins
Woei Ping Cheng

Introduction
Drug efficacy and bioavailability are largely dependent on drug physicochemical properties such as

water solubility, pKa and Log P. Today it is widely recognized that up to 60% of new drugs in the

developmental stage are water insoluble [1] and this presents a major challenge to the

pharmaceutical industry. For drugs to be administered intravenously, drugs formulated as aqueous-

based injections are most desirable. Thus drug aqueous solubility is a prerequisite [2]. For oral drug

delivery, drugs must be able to dissolve in the aqueous gastrointestinal fluid before absorption can

take place in the gastrointestinal tract (GIT) [3]. Therefore, for drugs which have high permeability but

with poor solubility (Class II according to Biopharmaceutics Classification System), rate of dissolution

is a major rate limiting step for the absorption of these drugs via oral administration. As a result, this

undesirable property often leads to poor oral bioavailability and erratic GIT absorption.

Conventional excipients such as surfactants, cosolvents are often added to improve drug solubility for

both oral and parenteral routes. Complexation with cyclodextrins or formulating oil in water emulsions

are also employed to improve poorly soluble drugs. Today the growing demand to fabricate drug

delivery systems capable of encapsulating high levels of active ingredients with additional benefits

such as drug targeting capability has resulted in a plethora of technologies exploiting the unique
physical properties of nano-sized structures. Nanotechnologies such as nano-crystals, solid lipid

nanoparticles (SLN), nano-emulsion, polymeric nanoparticles, liposomes and polymeric self-

assemblies have been employed to enhance drug solubilization. In this review, we will focus on four

types; namely nano-crystals, SLN, liposomes and polymeric self-assemblies.

Nano-crystals
Nano-crystals technology essentially involves a nano-sizing method, in which large insoluble drug

crystals are milled to form nano-sized particles with less than 2000nm as defined in the first patents in

this field (Table 1) [4]. To prevent particle aggregation, excipients such as surface active agents and

polymers are normally required for stabilization [5]. The decrease in drug particle size to nanoscopic

crystals results in an increased surface area to volume ratio [4] (Fig 1). According to Noyes Whitney

equation, the dissolution rate is proportional to the surface area of the drug particles in contact with

the dissolution medium [3]:

is the rate of dissolution of a solid, Cs is the saturation solubility of the dissolution layer, D is the

diffusion coefficient of the dissolved solute, σ is the thickness of the diffusion layer and A is the

surface area of the solid.

Figure 1. Surface Area Enlargement by Particle Size Reduction [4]

Therefore, the increased surface area of nano-crystals will consequently result in an enhanced

dissolution rate of hydrophobic drugs. This leads to an improvement in oral bioavailability and rate of

oral absorption.

Additionally, this technology can also be employed for intravenous administration where nano-

crystals can be formulated as nano-suspensions for injections. Today, there are a number of

products utilizing this technology that have been approved by FDA (Table 2).

Solid Lipid Nanoparticles (SLN)

Solid lipid nanoparticles (SLN) have been investigated since the early nineties as one of nano-sized

drug delivery systems for hydrophobic drugs (Table 1). These particles typically have a mean particle

size of 50-1000nm and composed of three essential components (solid lipids, surfactants and water)

[6,7]. Different types of solid lipids such as glycerides, waxes, and fatty acids have been used in the

fabrication of SLN. Depending on the fabrication method, the type, concentration of the drug,

surfactant and lipid, poorly soluble drugs can be molecularly dispersed within the lipid matrix or

formed a core-shell model (drug-enriched shell or drug enriched core)[6].

The advantages of using SLN include the versatility in using these delivery systems for various

routes of administrations such as oral, parenteral, dermal, ocular and the manipulation of different

solid lipids and production parameters to achieve optimal drug loading and release profiles. However,

there are limitations such as poor loading capacity and risk of instability during storage.

Table 1. Types of Nanotechnologies used to Improve Drug Solubility

 Zo
om In

Liposomes
Liposomes are spherical structures composed of a phospholipid bilayer surrounding an aqueous

reservoir [8]. Liposome vesicles are composed of unilamellar or multilamellar lipid bilayers which have

alternate aqueous layers sandwiched between the bilayers [9] (Table 1). Upon aggregation,

multilayered liposomes are formed but are easily converted to unilamellar entities by sonication [10].

In general hydrophilic compounds are not well entrapped in aqueous core of liposomes compared to

hydrophobic compounds which are well retained within the phospholipid bilayers [9, 11]. Their major

disadvantage as drug carriers is their instability upon drug entrapment [12]. The inclusion of drug into

the lipid bilayer causes penetration and results in premature drug release [12, 13]. To combat this

problem, cholesterol is incorporated into the phospholipid bilayer, consequently the liposome possess

higher rigidity leading to more stable vesicles [14, 15]. Furthermore, poor stability is experienced on

storage in aqueous phase. However, lyophilization and cryoprotection of the liposomal formulation

have been reported to minimize this problem [12, 16]. Liposomes have been shown to improve the
therapeutic efficacy of pharmaceutical drugs including ibuprofen, amphotericin B and doxorubicin

[12,17,18]. Today, liposomes are one of the successful nano-delivery systems that have entered the

clinics. There are currently 12 liposomal products in the market, a number of which undergo various

phases of clinical trials (Table 2) [19]. The approved products are mainly administered intravenously

for cancer therapy or treatment of systemic fungal infection (Table 2).

Table 2. Types of Nanotechnology Products Approved on the Market/ in Clinical Trials.

(This list is not exhaustive. Please refer to [4, 19, 30] )

Zo
om In

Polymeric self-assemblies
Polymeric self-assemblies have been widely investigated since the early 1990s as promising delivery

systems for hydrophobic drugs [20]. They are formed spontaneously by amphiphilic polymers which

consist of hydrophobic and hydrophilic segments. In aqueous environments, a hydrophobic core is

formed spontaneously upon aggregation of the hydrophobic moieties while the hydrophilic segments

will remain in contact with the aqueous environment (Fig 2). Hydrophobic drugs are encapsulated in
the core via hydrophobic interactions and thus solubilization increases in aqueous environments [21].

The most common type of self-assemblies formed by amphiphilic polymers are polymeric micelles

[20, 21], although they have also been reported to form a wide range of nano-structures such as

vesicles and nanoparticles [22]. Amphiphilic polymers can be fabricated from diverse architectures,

such as block copolymers (the most common type) [23, 24], hydrophobically modified polymers [25,

26], star shaped polymers [27] and dendrimers [28]. Unlike micelles formed by traditional surfactants,

the polymeric micelles typically have significantly lower critical micellar concentration (CMC) (1x10 -6M)

compared to traditional micelles. As a result, they do not lose their payload upon dilution in vivo. This

unique characteristic has been utilized for delivering a wide range of hydrophobic drugs such as

paclitaxel, propofol, doxorubicin, etoposide and camptothecin via intravenous administration.

Recently,these structures have also shown to increase oral absorption of class II drugs in vivo [26]. To

date, a number of polymeric micelles have entered clinical trials (Table 2), although none have

reached the clinic yet due to the relative young age of this technology. However, this technology is

thought to advance further with the promising preclinical and clinical data demonstrated to date.

Drug targeting and Controlled Drug release

Capabilities
Unlike conventional excipients which generally only enhance the solubilization of hydrophobic drugs,

the use of nano-carriers has additional benefits of achieving site specific delivery especially for cancer

therapy. This capability is demonstrated by intravenous administration of liposomes and polymeric

micelles, where patients typically experience lower side effects compared to conventional formulations

[29, 30]. The reason being the nano-size of these carriers allow them to passively target tumors

through the phenomenon known as the enhanced permeability and retention effect (EPR). The blood

vessels supplying the blood to cancerous tissue are leaky and disorganized. The tumor tissues also

experience poor lymphatic drainage. Nano-structures (<120nm) are capable of entering the highly

permeable blood capillaries which supply the rapidly growing tumors [29]. This however does not

occur in normal tissue as the blood vessels are well formed and non-porous. Once inside the

capillaries, they accumulate and are retained in the tumor as a result of the poor lymphatic drainage.

Additionally, the versatility of nano-carriers enables the attachment of ligands for targeted delivery,

either for cancer therapy [31] or oral delivery to promote uptake by intestinal cells [32]. Newer

generations of these nano-carriers have been designed to precisely control the release of the drugs

based on stimuli release mechanism. A range of external and internal stimuli such as temperature,
magnetic, pH, reduced environment have been utilized to control the release of drugs demonstrating

the versatility of these nanocarriers [33].

Conclusions and Future Outlook

As shown in Table 2, liposomes were the earliest nanotechnology products approved in late 1990s

after the discovery in 1975 while the history of other nanotechnologies is relatively shorter than

liposomes. Within the next ten years it is expected that many clinical trials using nano-sized

formulations will be completed and their use in the clinics should improve treatments and patient’s

quality of life. The development of biocompatible polymers/ materials for the production of nano-

carriers, accompanied with advanced techniques to study the cellular uptake mechanisms and the

fate of nanocarriers will fuel greater exploitation of nanotechnology in drug delivery. In the future,

these new excipients could be part of the decision tree in the development and Formulation of new or

existing chemical entities for enhancing solubilization of these drugs.