162 Recent Patents on Drug Delivery & Formulation 2009, 3, 162-173

Recent Trends in Oral Drug Delivery: A Review

Himanshu Gupta1*, Dinesh Bhandari2 and Aarti Sharma1

1
Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India; 2D. J. College of Pharmacy,
Modinagar, U.P., India

Received: January 22, 2009; Accepted: February 12, 2009; Revised: February 14, 2009
Abstract: There are many ways to deliver drugs into the body, viz oral (through swallowing), sub mucosal (through
buccal and sublingual mucosa), parenteral (through injection), transdermal (through skin), pulmonary (through inhalation)
etc. Among these deliveries oral delivery (by swallowing) is widely accepted. In oral drug delivery, many scientific
challenges and breakthrough technologies are required to generate novel dosage forms raising drug delivery to higher
level. Some are self emulsifying systems, solid self nanoemulsion, polymeric micelles, spray freezing, pH controlled
systems, time delayed system, osmotic pumps, prodrugs etc. This paper reviews recent patents, technologies and products
with their importance, manufacturing and novel approaches implemented till date to overcome the challenges in oral drug
delivery systems.
Keywords: Orally disintegrating tablets, controlled drug delivery, gastroretentive formulation, colon targeting, osmotic pumps,
prodrugs, nanoemulsion, microemulsion.

INTRODUCTION
Oral drug delivery formulation and technologies are
mainly focused on the following areas of gastro intestinal
tract (GIT) Fig. (1). [1]. Various challenges associated with
oral route include:
• Pill-swallowing difficulty
• Irritant and unpalatable drugs are not given by this route
• Gastrointestinal (GI) destruction of labile molecules
• Low levels of macromolecular absorption; absorption of
drugs may be affected by food in the stomach
• Slow onset of action
• Very little control over release of the drug; non-specific
delivery site & side effects
As oral drug delivery is simple, most convenient, safest,
noninvasive and most economical, it continues to be the
preferential route of administration and researchers are
Code Area Property
seeking ways to incorporate various technologies in oral
formulations; even small improvements in drug delivery A Oral pH 6.8, small surface area, lipophilic, neutral
technology can make significant differences in enhancing and basic drugs absorbed directly into the
patient compliance and drug bioavailability. systemic circulation

A. Oral Delivery, Ease of Administration B Stomach pH 1-3, not too large surface area, lipophilic,
neutral and acidic drugs absorbed but lesser
The most facing challenges in oral delivery are to than that from intestine
overcome problems like pill-swallowing difficulty, delivery
of unpalatable drugs, and reducing dosing frequency. Pill- C Small pH 5-7.5, very large surface area, major site
swallowing difficulty primarily affects the patients having Intestine for absorption of all types of drugs(lipophilic,
dysphagia, geriatric and pediatric populations; besides these neutral, acidic or basic drugs)
a middle-aged woman undergoing radiation therapy for D Colon pH 7.9-8, small surface area, all types of drugs
breast cancer may find it too nauseous to swallow a H2 - are absorbed but to a lesser extent

*Address correspondence to this author at the Department of Pharmaceutics,

Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi- Fig. (1). Different components of GIT (Gastro Intestinal Tract).
110062, India; Tel: 91-11-23828282; Fax: 91-11-23828282;
E-mail: [email protected]; [email protected]

1872-2113/09 $100.00+.00 © 2009 Bentham Science Publishers Ltd.

Oral Drug Delivery Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 2 163

blocker) [2]. To eliminate these problems associated with moldability saccharide (a saccharide that produces a hard
swallowing difficulties, a new dosage form, known as fast- compact) to granulate a low-moldability saccharide (poorly
dissolving tablets (FDT), has been developed. The fast- compressible saccharide) which provides quick, convenient
dissolving tablets are also called fast-melt or fast disinte- and consistent dosing [8]. Despite of patented products,
grating or orally disintegrating tablets (ODT). The orally many other relevant researches include development of
disintegrating tablets (ODT) are of optimal mechanical rapidly disintegrating tablets as an oral dosage form for
strength and disintegrate within 60 seconds in the oral cavity elderly patients with impaired swallowing using agar
[3]. Oral disintegrating tablets (ODT) are gaining popularity powders (AG) or treated agar powders (TAG) [9]. OraSolv
over conventional tablets due to their convenience in technology (Cima Labs Inc.) is an oral dosage form, which
administration and suitability for patients having dysphagia combines taste-masked drug ingredients with a fast-
[4]. Moreover no water is required for swallowing the tablets dissolving system that contains a low level of effervescence.
and hence suitable for geriatric, pediatric and traveling The ‘OraSolv’ tablet dissolves quickly without chewing and
patients. need for water. Taste-masking coatings coats the active
compound, permitting the active ingredients to be swallowed
In 1986, the first lyophilized fast-dissolving tablet Zydis®
before they comes in contact with taste buds [10].
were introduced by Cardinal, after that there was a
continuous growth in names by different companies, now a DuraSolv (Cima Labs Inc.) is a highly compact, more
number of fast-dissolving formulations are in market and the durable, solid oral dosage system formulated to achieve the
technology is still improving. Table 1, different ODT tablets primary benefits of the OraSolv fast-dissolve dosage form,
were prepared by different technologies. Zydis® is manu- but capable of being packaged in conventional packaging
factured by lyophilisation whereas AdvaTab tablets are such as foil pouches or bottles at much higher production
compressed using a patented external lubrication system in rates and with lower packaging costs. DuraSolv is an
which the lubricant is only applied to the tablet surface. As a appropriate technology for drug products requiring lower
result, the tablets are hard and durable, do not require high levels of active ingredient [11]. The taste of the active
compression forces during manufacturing and do not repel ingredient in these products (OraSolv & DuraSolv) is
liquids such as saliva when ingested. Consequently, masked by the use of an appropriate coating over the drug
AdvaTab tablets are robust, disintegrate rapidly in the oral particles in conjunction with effective flavoring agents and
cavity and the tablet compression step does not lead to an artificial sweetener.
breakage of the drug particles [5]. Akina has developed a Ozeki and coworkers in 2003 examined acidified brewers
new fast-melting tablet technology, called "Frosta®." A
yeast cell wall (AYC) with respect to novel applications as it
Frosta tablet melts in about 10 seconds after placing it in the
can be used as an aqueous coating material for tablets and
mouth. The Frosta® approach utilizes conventional wet
granules. AYC is a unique pharmaceutical additive posses-
granulation processing for cost-effective production [6]. SPI
sing opposing functions with respect to binding and
Pharma’s Pharmaburst is a co-processed excipient system
disintegration [12]. Fukami et al. in 2005 formulated a fast
with specific excipients, which allows rapid disintegration disintegrating compressed tablet using amino acids, such as
and low adhesion to punch faces while another Advantol
L-lysine HCl, L-alanine, glycine and L-tyrosine as disinteg-
platform uses proprietary co-processing technology of
ration accelerator [13]. In another study a rapid disinteg-
directly compressible excipient system [7]. It can be used to
ration tablet in the oral cavity was prepared using glycine as
develop a “soft-chew” or a “quick-melt” solid dosage form
a disintegrant. It was also suggested in the study that
for nutraceutical applications. The next in the series is
carboxymethylcellulose [14] (NS-300) possessed excellent
WOWTAB™. It is the first patented, without water quick- wetting nature and resulted in the rapid disintegration of
dissolve tablet technology of Yamanouchi Pharma, accom-
tablet [15]. Directly compressible rapidly disintegrating
modating both hydrophilic and hydrophobic drugs.
tablets of fenoverine with lower friability, acceptable taste,
WOWTAB™ technology uses a solution of a high-
and shorter disintegration times were obtained using cros-

Table 1. List of Currently Available Fast-Melting Tablet Technologies

Formulation Key Attributes Company

Zydis® Freeze-dried wafers RP Scherer (Cardinal)

®
Advatab Direct compression using external lubrication system Eurand
®
Frosta Direct compression of granules Akina

Pharmabrust Direct compression of powder mixture SPI Pharma

Advantol™ 200 Directly compressible excipient system SPI Pharma

®
WOWTAB High- and low-moldability saccharides Yamanouchi Pharma

OraSolv Low compression force and an effervescent couple as a water-soluble disintegrating agent Cima Labs Inc.

DuraSolv Direct compression using water-soluble excipients Cima Labs Inc.

164 Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 2 Gupta et al.

povidone and other excipients at optimum concentrations to prostol, antacids, antibiotics against Helicobacter pylori),
assist patients palatability of any age group [16]. As have an absorption window in the stomach or in the upper
compared to direct compression tablets, Kollidon CL small intestine, (e.g. L-DOPA, p-aminobenzoic acid,
excipient base was observed to have maximum drug release furosemide, riboflavin etc), unstable in the intestinal or
and minimum disintegration time showing the superiority of colonic environment (e.g., captopril), exhibit low solubility
the spray dried excipient base technique [17]. Direct com- at high pH values (e.g., diazepam, chlordiazepoxide, vera-
pression has been applied to prepare mouth-dissolving pamil HCl). Currently, there are a number of drugs that can
tablets of Metformin HCl using various superdisintegrants be delivered using once-daily formulations. This is possible
and tablet containing crosscarmellose and crosspovidone at only for drugs that are well absorbed throughout the GI tract
5% w/w concentration showed disintegration time of less or typically have long elimination half-lives. There are a
than 60 seconds along with rapid in vitro dissolution (95% large number of drugs that are not absorbed to the same
drug release in 5 min.) [18]. extent once they pass the upper small intestine, and thus,
once-daily formulations are elusive for these drugs. To
Oral Controlled Release Drug Delivery Systems (OCRDDS) overcome the fast GI transit, maintenance of dosage form in
the stomach for extended periods of time is development of
OCRDDS is considered as the solution to second gastric retention platforms. Various attempts have been made
challenge in oral delivery i.e. for reducing dosing frequency. to develop gastroretentive delivery systems. There are 3
OCRDDS have many advantages over a conventional dosage ways by which this can be achieved, altering the density of
form like improved patient compliance; reduction in the drug particles, use of mucoadhesive polymers and altering
steady state level of drug hence better control of disease the size of dosage form [24]. The composition of the coated
condition and reduced level of local or systemic side effects. controlled release polymer particles includes a polymer core
It also increases the safety margin of high potency drugs due encapsulating the active agent and a mucoadhesive coating
to better control of plasma levels, increased bioavailability around the core [25]. The density of GI fluid is around 1.4
and therefore reduction in total amount of dose administered. g/cc. Use of drug pellets having density greater than this
This leads to shorter treatment period, meanwhile reduction value, preferable above 1.6 g/cc, results in prolonged GI
in the personnel time to dispense, administer and monitor residence that is unaffected by food. Iron oxide, titanium
patients etc. which ultimately leads to reduction in health dioxide and barium sulphate have been used to increase the
care costs through this improved therapy like Geomatrix™ density of drug pellets. The drug is coated on the heavy core
technology [19]. It allows producing tablets with a wide and then covered by a diffusion controlled membrane [24].
range of predictable and reproducible drug release profiles, Intestinal Protective Drug Absorption System (IPDAS®
to achieve customized levels of controlled release of specific Technology) is a high density multiparticulate tablet tech-
drugs or it can achieve simultaneous release of two different nology, intended for use with GI irritant compounds. The
drugs at different rates from a single tablet. It can deliver an IPDAS® technology is composed of numerous high density
initial burst of a drug for fast therapeutic effect, followed by controlled release beads, which are compressed into a tablet
controlled release at a constant rate, or deliver a drug to form. Once an IPDAS® tablet is ingested, it rapidly
specific sites within the patient's digestive system. The disintegrates and disperses drug containing beads in the
controlled release is achieved by constructing a multilayered stomach, which subsequently pass into the duodenum and
tablet having a water soluble, swelling as well as erosion resides in the gastrointestinal tract in a controlled and
occurs simultaneously and both of them contribute to the gradual manner, independent of the feeding state [26].
overall drug release [20]. Polymer matrix such as hydroxyl-
propyl methylcellulose (HPMC) can be used. Povidone can Low Density pellets can also be called as hydro-
be included into the coating dispersion as stabilizer pH of dynamically balanced systems, such pellets having density
polymers also possess an important property when drug is to less than that of GI fluids, float on the gastric juice for an
be delivered to the targeted area e.g. Gastrointestinal tract or extended period of time while slowly releasing the drug.
in the colon [21]. Barrier layers delay the interaction Globular shells such as that of poprice and cellulose have
between core and dissolution medium [22], and hence, in been used to lower the density of system. A swellable gum
general, linear release profiles can be obtained by applying like HPMC was also used [24]. Manufacturing process
hydrophilic barrier layers on both faces of a hydrophobic include granulating a drug with 20 to 80% of hydrogel such
matrix tablet or vice-versa [23]. Some Geomatrix™ products as HPMC, HEC and HPC. On contact with the GI fluids, the
in the market are, Sular®, ZYFLO CR™, Coruno®, diclo- tablet swells and forms a diffusible gel barrier that lowers the
fenac-ratiopharm-uno® and Madopar DR® [19]. density of system to less than 1 which allows it to float [26].
Lipophilic polymers such as silicon elastomer can also be
B. Stomach modified to have swelling properties. This is achieved by
impregnating a water miscible liquid such as glycerol or a
One of the challenge in oral drug delivery is to develop water-soluble salt such as sodium chloride in the lipophilic
gastric retention platforms for long-term (ranging from 6 to matrix. On contact with aqueous medium, the modified
24 h) delivery of drugs by oral administration. lipophilic polymer swells due to absorption of water by the
hydrophilic additives in the matrix. A gas filled flotation
Need for Gastro-Retentive Drug Delivery chamber can be attached to a membrane coated tablet for
making it buoyant [26]. Scintigraphic studies in non-fasting
A controlled drug delivery system with prolonged
human volunteers confirms that the intra gastric buoyancy of
residence time in the stomach is of particular interest for
the floating forms is the main process determining their
drugs which are locally active in the stomach (e.g., miso-
Oral Drug Delivery Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 2 165

prolonged gastro retentive time (GRT) and protecting them Approaches to Enhancing Delivery of Poorly Water-
from random gastric emptying related to antral peristaltism Soluble Drugs
[27]. Retention time of the drugs can be increased to more
Solid dispersion refers to the dispersion of one or more
than 12 hours by utilizing floating or hydrodynamically
active ingredients in an inert carrier or matrix in solid state
controlled drug delivery systems, such as using cellulose
acetate microspheres as floating depot systems increases prepared by the hot melt extrusion, co-preciptation or the
melting-solvent method [33]. A controlled release phar-
gastric retention of antidiabetic drug [28]. These
maceutical composition for oral use can be comprised of a
formulations, with their reduced frequency of administration
solid dispersion of an active substance, a polymer that has
and better control over drug disposition, may provide an
plasticizing properties, a stabilizing agent, then at least one
economic benefit to the user as compared to market available
active substance having a limited water solubility [34]. It has
products. Microspheres based mucoadhesive formulation are
extensively evaluated and characterized to determine diffu- also been defined as the product formed by converting a
fluid drug carrier combination to the solid state[35]. Solid
sion parameters and drug retention in the stomach mem-
dispersions can be classified as Solid solutions; glass
brane. Such as chitosan microspheres appear, technically
solutions of suspensions (A glass solution is a homogeneous
promising mucoadhesive drug delivery systems for
system in which a glassy or a vitreous form of the carrier
delivering clarithromycin to treat stomach ulcers [29]. It
solubilizes drug molecules); compound or complex for-
demonstrates good mucoadhesion of the microspheres with
the stomach mucosa as well as higher accumulation of drug mation between the drug and the carriers; amorphous
precipitations of drug in crystalline carrier.
in the stomach membrane. Microspheres also exhibited
sustained release of drug. Amoxicillin mucoadhesive micros- Solid solutions consist of a solid solute dissolved in a
pheres, pH-sensitive excipient composition microspheres solid solvent. The particle size in solid solution is reduced to
were prepared containing chitosan [30] (used as polymer) molecular level. Successful solubilization of Itraconazole has
and glutaraldehyde as a cross-linking agent by simple been achieved using solid solution technique [35]. Solid
emulsification phase separation technique. These micro- solutions of lower drug concentrations generally give faster
spheres were systematically evaluated and showed that they dissolution rate. Drug dissolution improves considerably
were able to reside in the gastrointestinal tract for an with an increase in molecular weight of a water soluble
extended period of time for a more effective H. pylori polymer such as polyethylene glycol. Gris-PEG® (Pedinol
eradication and hence treating gastric and duodenal ulcers Inc.) is another example of solid dispersion which contains
which were associated with Helicobacter pylori. The results ultramicrosize griseofulvin, colloidal silicon dioxide,
showed a more complete H. pylori clearance effect in case of polyethylene glycol 400 and 8000 [36]. The technique of
amoxicillin mucoadhesive microspheres as compared to solid dispersion is used for increasing the dissolution
amoxicillin powder. In conclusion, the prolonged gastroin- performance of glyburide tablets in polyethylene glycol
testinal residence time and enhanced amoxicillin stability (high hydrophilic carrier). The possibility of developing
[31]. The use of Chitosan, thiolated chitosan, Carbopol 71G solid dispersion of glyburide tablets (a poorly water-soluble
and Methocel K15M as mucoadhesive microspheres prolon- oral hypoglycemic agent) with fast, efficient, reproducible,
ged the delivery of acyclovir with significant improvement and markedly higher drug dissolution rate and dissolution
in oral bioavailability due to enhanced retension in upper GI efficiency; clearly better than those from various commercial
tract [32]. tablets [37]. Compound or complex formation between the
drug and the carriers system is characterized by com-
Size based systems relies on the fact that gastric
plexation of two components in a binary system during solid
emptying of a dosage form can be delayed in the fed state if
its size is greater than 2mm. Dosage form of size 2.5 cm or dispersion preparation. The availability of a drug from the
complex is dependent on the solubility, dissociation constant
large is often required to delay emptying time long enough to
and the intrinsic absorption rate of the complex.   and 
allow once daily dosing. Such forms are however difficult to
CD (cyclodextrine) in combination with polyethylene glycol
swallow [26].
(PEG) 6000 have been used to formulate such systems.
Amorphous precipitation occurs when the drug precipitates
C. Small Intestine as an amorphous form in the inert carrier. The high-energy
Challenges related to delivery to small intestine include state of the drug in this system generally produces much
development of formulations of poorly soluble and high greater dissolution rates than the corresponding crystalline
molecular weight drugs and delivering of protein peptides forms of the drug [35].
due to their instability in GI environment. Solubility of drug Microemulsions are liquid dispersions of water and oil
is an important factor concerned with development of con- that are made homogenous, transparent, and stable by the
trolled release formulations. The first step in drug absorption addition of relatively large amounts of a surfactant and co-
is dissolution of a drug in an aqueous environment. Drugs surfactants [38]. Micelles can solubilize hydrophobic
with low solubility are those requiring more than 250 mL of therapeutic agents effectively and are safe for human use.
water to dissolve the highest dose. Volume of 250 mL is not Micelles formed from amphiphilic block copolymers such as
easy to find in the intestine. Only a limited number of com- poly(ethylene glycol) as a hydrophile and poly(propylene
mercial formulations are available for poorly water soluble sulfide) (PPS) as a hydrophobe, using the immunosup-
drug. pressive drug cyclosporin A (a highly hydrophobic drug)
was developed. These micelles demonstrate interesting
solubilization characteristics, due to the low glass transition
166 Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 2 Gupta et al.

temperature of the PPS block and low melting temperature anionic (eg, sodium dodecyl sulfate), cationic (eg, trialkyl-
of the block polymer, highly hydrophobic nature, and good ammonium) and zwitterionic (eg, glycine and proteins) [47].
solvent properties of it enable the use of such a simple drug Among these the most commonly used ones are the anionic
encapsulation technique [39]. Amphiphilic ABC triblock and non-ionic surfactants. Since the process of solubilization
copolymers composed of monomethoxy-capped poly occurs due to presence of micelles, generally high concen-
(ethylene glycol) (MPEG), poly(2-(dimethylamino)ethyl trations of surfactants are needed to significantly improve
methacrylate) (DMA), and poly(2-(diethylamino)ethyl drug solubility. One example of surfactant based solution is
methacrylate) (DEA) have been used for pH-induced Taxol (paclitaxel), an anticancer drug that is solubilized in
micellization for solubilization and controlled release of a 50% solution of Cremophor. Other examples include Valru-
hydrophobic drug dipyridamole [40]. bicin in 50% Cremophor and Cyclosporin in 65%
Self-Emulsifying Systems, a novel self-emulsifying drug Cremophor [35].
delivery system (SEDDS) is useful for the adminis-tration of Wet milling reduces the particle size to nano-sized
a water-insoluble drug. The SEDDS comprises a hydrophilic through attrition in the presence of some stabilizing agents
surfactant with hydrophilic-lipophilic balance (HLB) value [48]. Various technologies such as Elan's NanoCrystal®
greater than 10 [41]. These formulations have also attracted Technology is a drug enablement and optimization tech-
interest because they can improve the bioavailability of nology applicable to poorly water-soluble compounds.
compounds that fall into Class II of the biopharmaceutical Similarly, NanoCrystal® Particles are very small particles of
classification system (BCS). Class II compounds are poor drug substance, of the order of less than 1,000 nanometers
water soluble and highly permeable [42]. The IDD®-SE (nm) in diameter, particles of this diameter are produced by
(Self-Emulsifying) technology (Skyepharma) constitutes a milling the drug substance using a proprietary, wet-milling
special class of the IDD® systems due to their production. technique. The NanoCrystal® particles of the drug are
The particles of IDD®-P and IDD®-D formulations result stabilized against agglomeration by stabilizers such as
from application of a physical or mechanical process. On the surface adsorption of selected GRAS (Generally Regarded
other hand, surface stabilised micrometre to submicrometre As Safe) stabilizers. The result is the formation of
sized particles or droplets are self generated when a dosage NanoCrystal Colloidal DispersionTM solution, which can be
form containing IDD®-SE formulation is exposed to an processed into finished dosage forms for all routes of
aqueous medium such as those present in gastrointestinal or administration [49].
vascular compartments [43]. A self-microemulsifying system
(SMES) consisting of ethyl oleate, Cremophor® RH 40 and Nano and Microparticle Approach
Labrasol® with hydroxy-propylmethylcellulose (HPMC) is
used to control the in vitro release of poorly soluble drugs Recently, the nano and microparticle approach [50] has
from solid oral dosage forms [44]. The control of the release become popular. A decrease in particle size results in
of water-insoluble drugs from pellet formulations by increased surface area, resulting in faster dissolution,
incorporating them into self-emulsifying systems, which normally by a small order of magnitude. In some cases, this
enhances their rate of release and then, by applying a water- may be enough to result in increased bioavailability.
insoluble polymer containing water soluble plasticizer and Eurand's novel Biorise® technology can be applied to a wide
talc, reduce the rate of drug release. A sample of pellets range of compounds to enhance bioavailability and solu-
containing methyl paraben in the self-emulsifying system bility. Biorise is based on the fact that the solubility of
was pre-coated with a film of hydroxypropylmethyl cellulose nanocrystalline and amorphous forms of drugs is higher than
from an aqueous solution and then coated. The application of that of unmodified or even micronized forms. Therefore, if
a sub-coating of hydroxypropylmethyl cellulose was able to drug permeability is sufficient, the absorption rate and
reduce the release rate of methyl paraben self-emulsifying absolute bioavailability of a drug can be increased by
pellet system coated with ethyl cellulose. Thus, the enhancing solubility and solubilization. Biorise creates New
formulation approach offers the possibility of formulating Physical Entities (NPEs) by physically breaking down a
and controlling the in vitro release of water-insoluble drugs drug's crystal lattice. This results in drug nanocrystals and/or
from solid oral dosage forms [45]. amorphous drug, which are then stabilized with biologically
inert carriers. The carriers used in the Biorise system are
biocompatible and readily disperse in the body's GI fluids.
Solid Self-Nanoemulsifying Systems (SSNES)
The final product is a free-flowing powder that can be
Solidification of these liquid systems to yield solid self- incorporated into a variety of dosage forms to achieve the
nanoemulsifying systems (SSNES) offer a possible solution most effective delivery [51]. The insoluble drug delivery
over Conventional SNES which consist of liquid forms filled (IDD®) platform (Skye pharma) consists technologies to
in hard or soft gelatin capsules, which are least preferred due address formulation and delivery problems originating from
to leaching and leakage phenomenon, interaction with poor solubility of biologically active compounds [52]. These
capsule shell components, handling difficulties, machina- IDD® technologies feature easily dispersible narrow particle
bility, and stability problems, and that is why these systems size distribution dosage forms derived from surface modified
have attracted wide attention [46]. Surfactants are molecules micrometer to sub micrometer sized particles or droplets
with well defined polar and non-polar regions that allow stabilized by surface modifiers, preferably phospholipids.
them to aggregate in solution to form micelles. Non-polar The IDD® platform is different to other drug delivery
drugs can partition into these micelles and can be made systems as its effectiveness is dependant on the physi-
solubilized. Depending on the nature of the polar area, cochemical properties of the drug rather than the chemical
surfactants can be non-ionic (eg, polyethylene glycol), structure and reactivity [43].
Oral Drug Delivery Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 2 167

Some insoluble drug delivery approaches are, IDD®-P particles. The choice of solvent system and processing
(MicroParticle) a microparticulate variation of the IDD® conditions, determines particle morphology of particles. In
drug delivery system, which consists of a pure solid drug in the isolation step, the nitrogen and solvent were removed to
the core of the particle [43]. IDD®-D formulations avoid agglomeration or ripening of the drug particles [55].
(MicroDroplet), the core is constituted of essentially liquid Evaporative Precipitation into Aqueous Solutions
drug substance. IDD®-P and IDD®-D formulations are (EPAS), a technology that creates nanostructured drug
produced by application of high shear, cavitations or particles with rapid dissolution performance. For this
impaction (e.g. attrition, homogenization, microfluidisation, technology, the drug is dissolved in a hydrophobic solvent
milling, ultrasonication, etc.) to reduce the drug particle size and atomized into water at a temperature above the boiling
in the presence of phospholipids (and/or other surface point of the solvent. The rapid expansion and atomization of
modifiers) that associate at the freshly generated drug the solvent in the water phase cause the formation of nano-
surface. A particle size reduction from approximately 100- structured drug particles. The solvent and/or water phase
200
m to about1
m is achieved resulting in a very homo- contains the stabilizers for the particles. The evaporated
geneous and stable formulation [43]. Flamel’s Medusa® solvent is recovered, and the stabilized particles are isolated
delivery system is a versatile nanotechnology which can from the aqueous phase by standard techniques [55]. RR01,
accommodate the physicochemical specifications and the a new highly lipophilic drug showing extremely low water
delivery therapeutic-requirements of a wide variety of solubility and poor oral bioavailability, has been incor-
protein drugs. Medusa® nanocarrier is also suitable for the porated into pH-dependent dissolving particles made of a
efficient delivery of insoluble (i.e. hydrophobic) small poly(methacrylic acid-co-ethylacrylate) copolymer these pH-
molecule drugs and could be applied to peptides [53]. dependent dissolving particles have a great potential as oral
Polymeric nanoparticles and nanoparticles-in-microsphere delivery systems for drugs with low water solubility and
oral system (NiMOS) are useful for systemic and oral gene acceptable permeation properties [59]. A novel cubic liquid
therapy, respectively [54]. crystalline phase is described within the pseudoternary
system comprising lauric acid, monolaurin, and simulated
Particle engineering technologies [55] includes tech-
endogenous intestinal fluid (SEIF). This cubic phase may
nologies from BioAqueous solubilization services (Dow
potentially be of benefit in the delivery of poorly water-
pharma) modify drug substances, changing particle size,
soluble compounds due to its high loading capacity and
surface area or morphology to yield stabilized, isolated
potential for sustained release [60].
redispersible powders with enhanced dissolution charac-
teristics. These powders can be readily formulated into final Polymeric micelles are Amphiphilic polymers assemble
dosage forms. Some of these techniques are reviewed briefly into nanoscopic supramolecular core-shell structures, which
as Controlled Precipitation, a technology that creates crys- are under extensive study for drug delivery [61]. Potential of
talline nanostructured drug particles with rapid dissolution polymeric micelles for the solubilization and delivery of
rates [56]. With this technology, the drug is dissolved in a STAT3 inhibitor cucurbitacins in solid tumors has been
water-miscible solvent and dispersed into water. Nano- shown by Molavi O et al. [62]. A very low water soluble
structured drug particles are formed from the solvent drug Propofol (99.7%) was added directly to an aqueous
droplets as the solvent dissolves into the water phase. Stabi- solution of poly(N-vinyl-2-pyrrolidone)-block-poly(d,l-
lizers are added to the water and/or solvent to control particle lactide) copo-lymers (PVP-PLA) block copolymers and
growth and to stabilize the final particles. The stabilized stirred in order to obtain a clear solution. This formulation
particles are isolated as dry powders by standard techniques was filtered sterile and then lyophilized to its solid form
[55]. Template Emulsion, a technology that creates Propofol-PM (propofol polymeric micelle) which recons-
nanostructured drug particles with controlled particle size titutes to a propofol 1%w/v (10 mg ml-1) clear aqueous
distribution and yielding rapid dissolution performance [57]. solution of 30-60 nm propofol-containing micelles [63].
With this technology, an oil-in-water emulsion is prepared
Some patented technologies Table 2 are Polymeric
then swelled with a nonaqueous solution of the drug and
Nano-Delivery System™ (PNDS) technologies (Labopharm)
stabilizers. The particle size distribution of the drug particles
are an excellent complement to Contramid because they
is a direct result of the size of the emulsion droplets prior to allow optimized delivery of water-insoluble drugs with poor
loading with drug, a property which can be controlled and
bioavailability or safety profiles. PNDS are a library of block
optimized in this process. Furthermore, through selected use
copolymers designed to address the unmet needs of insoluble
of solvents and stabilizers, emulsion stability is achieved
drug delivery. Comprising hydrophobic and hydrophilic
with no or suppressed ostwald ripening. Subsequently, the
GRAS (Generally Recognized As Safe) subunits fused as
solvent and water are removed, and the stabilized
novel molecular entities, PNDS can be simply manufactured
nanostructured drug particles are recovered. Various particle to form stable nano-vehicles or micelles that entrap insoluble
morphologies can be achieved by appropriate control of
drugs, making them available for oral or parenteral adminis-
processing conditions [55]. Spray Freezing into Liquid
tration in safe and convenient forms [64]. OraVescent
(SFL), [58] a novel, cryogenic technology to create nano-
technology to improve the transport of poorly absorbed and
structured drug particles with greatly enhanced surface area.
large molecule active drugs across mucosal membranes in
This technology consists of an organic or organo-aqueous
the oral cavity or the gastrointestinal tract has been deve-
solution of a drug with stabilizers, which is injected into a loped by Cima Lab [65]. .Akina Inc. has developed concepts
cryogenic liquid, such as liquid nitrogen. The droplets of the
of hydrotropic polymer (Hytrop®), hydrotropic hydrogel
drug solution freeze at a rate sufficient to minimize crystal-
(HyTrogel®), and hydrotropic polymer micelle (Hytro
lization and particle growth, thus forming nano-structured
Cell™) for delivery of poorly water-soluble drugs. Hytrops,
168 Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 2 Gupta et al.

HyTrogels, and HytroCelles are able to increase the aqueous form or biological integrity [70]. The eligen® technology is
solubilities of poorly soluble drugs by 2-4 orders of applicable to a diverse group of drug molecules (e.g., pro-
magnitudes. Hydrotropic polymer micelle (HytroCell™); teins, peptides and other poorly absorbed compounds).
HytroCelles based on PEG-b-poly (2-(4-vinylbenzyloxy)- Molecules ranging in size from 500 Daltons to >150,000
N,N-diethylnicotinamide) (PEG-b-PVBDENA) can dissolve Daltons can be delivered easily [70].
paclitaxel more than 30%wt and yet they are stable in
aqueous solution for weeks. Such HytroCelles can be D. Targeting to the Colon
formulated for oral administration of paclitaxel [66]. Lip'ral
is a patented technology (Lipocine Inc) based on lipidic Targeted delivery of drugs to the colon become popular
compositions which form the optimal dispersed phase in the in recent years to achieve one or more of four objectives. (a)
gastrointestinal environment for improved absorption of the to reduce dosing frequency; (b) to achieve high local
insoluble drug. Lip'ral presents insoluble drugs efficiently to concentrations of drug in the treatment of diseases of the
the intestinal absorption site, thus bringing the absorption distal gut e.g. ulcerative colitis or Chron’s disease; (c) to
process under formulation control and making the product delay delivery to a time appropriate to treat acute phases of
robust to physiological variables such as dilution, pH, and disease (chronotherapy); and finally, (d) to deliver drug to a
food effects. Lip'ral can be extended with Lipocine's region that is less hostile metabolically, e.g. to facilitate
Synchronized Solubilizer Release technology, Lip'ral-SSR, absorption of acid and enzymatically labile materials,
to enable controlled release of insoluble drugs and drugs especially peptides. Colon is also rich in lymphoid tissue so
with pH-sensitive solubility [67] uptake of antigens into the mast cells of the colonic mucosa
produces rapid local production of antibodies thus helping in
Approaches to Enhancing Delivery of Highly Water vaccine delivery [71].
Soluble, Poorly Permeable Drugs
For low molecular weight drugs, aqueous solubility plays
Hydroance technology (Lipocine Inc.) enables oral an important role. Drugs with high solubility may
delivery of compounds that are currently delivered only by prematurely release before reaching the colon. Preventing
the invasive route, such as conventional polar organics premature release would require a very thick coating which
(MW<1000), Polysaccharides, Peptides, Peptidomimetics, may result in incomplete drug release in the colon. Drugs
Oligonucleotides, Genetic materials, Cytokines, and Proteins with poor solubility may not dissolve in the colon where
(vaccines). Hydroance customizes lipid based carriers for the there is not as much fluid as in the upper portion of the GI
optimal availability of the drug and absorption at the site, tract. The current technologies are mainly focused on
thus enabling absorption of the drug across the epithelial cell delayed release, i.e. no release until the dosage form reaches
membranes of the intestinal tract [67]. the colon. The time-delay approach relies on drug release
following a predetermined lag time and would therefore be
Delivery of Proteinous Drugs less dependable. Combinations of time-delay and enzyme-
degradable systems would seem be more reliable. Common
A major challenge with large molecules such as proteins
approaches used for colon targeting are listed in Table 3.
is the vast number of functional groups that can be the
subject of chemical degradation as well as the complex pH Controlled system relies on the fact that the pH in
structure of the individual proteins. Generally, it is important the terminal ileum and colon (except ascending colon) is
to develop efficient techniques for characterization and higher than in any other region of the GI tract. Thus a dosage
profiling of these complex protein samples. Even a small form that disintegrates preferentially at high pH levels has
conformational change may have a detrimental effect on the good potential for site-specific delivery into this region. A
function of the protein. Therefore, efforts to correctly rapidly disintegrating tablets coated with a model pH
characterize as well as creating a suitable and stable dosage depedent polymer, Eudragit S®, have been investigated
form of each therapeutic protein have to be made such as in vivo, using gamma scintigraphy, to assess its suitability
microparticles of protein, polypeptide and peptide drugs for use in colonic drug delivery [72]. In spite of the
[68]. limitation of change in luminal pH due to disease state, such
pH dependent systems are still very commonly investigated
Bovine serum albumin (BSA) as a protein model drug
for colon targeting. A system for colonic targeting of
was loaded in Thiolated Eudragit-coated CMs (TECMs) to metronidazole was developed by coating the drug-containing
study the release character of the delivery system. Results
capsules with azoaromatic and pH-sensitive polymers that
indicated that TECMs have potentials to be an oral protein
are prone to selective degradation in the colon environment.
drug carrier [69]. Emisphere’s broad-based oral drug
These polymers were characterized for physical attributes,
delivery technology platform, known as the eligen® tech-
namely film-forming properties, effect of colon bacterial
nology, is based on the use of proprietary, synthetic chemical
flora, and pH [73]. A novel formulation for oral adminis-
compounds, known as EMISPHERE® delivery agents, or tration using pH-enzyme Di-dependent chitosan mciro-
“carriers.” These delivery agents facilitate or enable trans-
spheres (MS) and 5-Fu as a model drug has been inves-
port of therapeutic macromolecules across biological mem-
tigated for colon-specific drug delivery by the emulsifi-
branes such as those of the gastrointestinal tract, allowing the
cation/chemical cross-linking and coating technique,
therapeutic molecules to exert their desired pharmacological
respectively and results clearly demonstrated that the pH-
effect. The delivery agents have no known pharmacological
enzyme Di-dependent chitosan MS is potential system for
activity themselves at the intended clinical dose levels.
Emisphere’s eligen® technology makes it possible to orally
deliver a therapeutic molecule without altering its chemical
Oral Drug Delivery Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 2 169

Table 2. List of Various Patents on Oral Delivery

S. No. Patent No. Contents

1. EP2001450 (2008) Orally disintegrating tablets dissolve very fast,have optimal mechanical strength and disintegrate within 60 sec

2. EP0346507 CMC

3. WO2006123364 (2006) Oral drug delivery system is in the form of a coated tablet which includes after a predetermined delay the coating
is reliably removed fully or partially from one or more of the tablet surfaces and controlled drug release

4. WO2007001448 (2007) Coated controlled release polymer particles encapsulate the active agent and a mucoadhesive coating disposed
about the core

5. WO2008075448 (2008) A chitosan coating solution is so safe that it is capable of oral administration in the fields of foods and medicines

6. US2008293787 (2008) Solid dispersions of poorly soluble compounds formed by co-precipitation resulted in improved stability

7. US2008234352 (2008) Solid dispersions contain atleast one active substance, polymer with plasticizing properties and stabilizing agent.

8. MX9801755 (1998) Microemulsions contain a polar phase containing water, a non-polar phase consisting of oil, mixture of
hydrophilic and hydrophobic surfactant

9. WO2005037250 (2005) Self-emulsifying drug delivery system comprises of hydrophilic surfactant, oil, and a non-aqueous protic solvent.

10. CA2579382 (2008) Controlled release delivery device comprises excipients such as diluents, filler, plasticizer, compression agents,
glidants, lubricants, solubilizers, wetting agents, surfactants etc

11. US2008212402 (2008) Process for the production of microparticles or nanoparticles

12. EP1974726 (2008) A novel matrix composition has been designed where an insoluble active substance is employed and improved
bioavailability is desired

13. WO03059319 (2003) Template emulsion preparation in which micron or submicron-sized drug particles are disclosed

14. WO02060411 (2002) Production of microparticles and nanoparticles using spray which generates frozen particles

15. US5637319 (1997) Controlled release preparations are suitable to deliver drugs to different sites of gastrointestinal tract and control
the release rate of drugs

16. US2007128280 (2007) Oral osmotic drug delivery system provide controlled and sustained drug delivery

17. WO2005105049 (2005) Wet milling reduce the particle size

18. WO2004012710 (2004) Crystalline drug particles prepared using controlled precipitation

19. WO2006107903 (2007) Polymeric micelles are particularly attractive due to their ability to deliver large payloads of a variety of drugs

20. WO2008132727 (2008) Oral delivery of proteins and peptides

Table 3. Common Approaches Used for Colon Targeting

Technology Used for Colon Targeting Mechanism

pH Controlled systems A series of polymers which dissolve and/or swell by sequential changes in pH and enzymes

Time delayed systems Drug release following a predetermined time period

Modified enteric coating Thick enteric coating dissolves at pH more than 5

Swellable (Biodegradable) polymers Polysaccharides degraded by enzymes in the colon

Prodrug Approach Altering biological properties of drugs to enhance their efficacy and to reduce their toxicity

Microbially controlled systems Relies on the unique enzymatic ability of the colonic micro flora

Nanoparticulate systems Enhance drug’s solubility, permeability and bioavailability

Pressure controlled systems This particular delivery system is in the form of a capsule, which is resistant to the pressures of the
upper GI tract but is collapsed in the large intestine due to increased pressure
170 Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 2 Gupta et al.

colon-specific drug delivery of 5-Fu [74]. Eudragit-coated function as colon specific coatings [81]. Amylose-
pectin microspheres are promising controlled release carriers ethylcellulose film coatings obtained from organic-based
for colon-targeted delivery of 5-fluorouracil (FU). The solvents were investigated as potential vehicles for colonic
release profile of FU from Eudragit-coated pectin drug delivery [82]. Enzyme controlled release pellets were
microspheres was pH dependent. In acidic medium, the prepared by a fluid bed coater,using ethylcellulose aqueous
release rate was much slower; however, the drug was dispersion(Surlease) and Amylose as the controlled coating
released quickly at pH 7.4 [75]. The formulation containing meterials,using diethyl phthalate as the plasticizer [83]. A
locust bean gum and chitosan in the ratio of 4:1 held a better novel colon targeted tablet formulation was developed using
dissolution profile, higher bioavailability and hence a natural polysaccharides such as chitosan and guar gum as
potential carrier for drug targeting to colon [76]. A novel carriers and diltiazem hydrochloride as model drug. The
colon targeted tablet formulation was developed using pectin prepared blend of polymer-drug tablets were coated with two
as carrier and diltiazem HCl and indomethacin as model layers, inulin as an inner coat followed by shellac as outer
drugs. These tablets were coated with inulin followed by coat. The study revealed that polysaccharides as carriers and
shellac. It was evaluated that this coating system limited the inulin and shellac as coating materials can be used
drug release in stomach and small intestinal environment and effectively for colon targeting of drugs for treating local as
released maximum amount of drug in the colonic environ- well as systemic disorders [84]. A novel tablet of protein
ment. The study revealed that polysaccharides as carriers and drug matrix for colon targeting was developed using resistant
inulin and shellac as a coating material can be used starch as a carrier prepared by pre-gelatinization and
effectively for colon targeting of both water soluble and crosslinking of starch [85]. A novel formulation for oral
insoluble drugs [77]. administration using coated calcium alginate gel beads-
entrapped liposome and bee venom peptide as a model drug
One of the example of time delayed system is the
has been investigated for colon-specific drug delivery
OCAS™ (Oral Controlled Absorption System) (Yamanouchi
pharma) drug delivery technology enables the gradual in vitro. The results clearly demonstrated that the coated
calcium alginate gel beads-entrapped liposome is a potential
release of drug active as the tablet system travels through the
system for colon-specific drug delivery [86]. System which
digestive tract, including the colon, where drug release is
consists of ketoprofen-loaded Zn-pectinate gel (ZPG)
difficult to achieve [78]. Modified enteric coating, allows
microparticles together with pectin/dextran mixtures in a
for a small portion of a drug dose to be released into the
tablet form has been investigated, in vitro and this approach
stomach, with the remainder of release occurring rapidly
upon passage of the dosage form into the small intestine. suggests that ZPG microparticles and their modified-release
formulations are promising as useful controlled-release
This release profile is particularly suited to drugs which
carriers for colon-targeted delivery of drugs [87]. Novel
demonstrate site specific absorption in the upper portion of
formulation consisting of cross-linked microspheres of guar
the GI tract (duodenum, jejunum), or where high dose drugs
gum has been investigated for colon-targeted delivery of
are being delivered which have narrow therapeutic indices.
metronidazole. An emulsification method involving the
These high volume formulations can result in prolonged
gastric retention times, which can then release drug close to dispersion of aqueous solution of guar gum in castor oil was
used to prepare spherical microspheres [88]. Prodrug
the time when the next dose is delivered, thereby resulting in
Approach includes chemical modification of a biologically
potential overdose of patients. Such a release profile can be
active compound that will liberate the active compound in
achieved through the use of hydrophilic pore formers in pH
vivo by enzymatic or chemical processes. The primary
dependent enteric coatings. Modified enteric coating is thus
purposes for designing prodrugs are improving physicoche-
another approach of colon targeting, colon targeting of ATL-
2502 (Prednisolone sodium metasulphobenzoate) is achieved mical properties of drugs to overcome formulation problems,
and altering biological properties to enhance their efficacy
by using colalTM coating [79].
and to reduce their toxicity. Azo-prodrugs such as
Swellable (Biodegradable) polymers, based on this sulphasalazine, olsalazine and balsalazide, have long been
approach, various polysaccharides have been investigated for used in managing inflammatory disorders of colon. After
colon-specific drug release. These polysaccharides include entry into the large intestine, the active species, 5-ASA, is
pectin, guar gum, amylose, inulin, dextran, chitosan, and released from the prodrug after the cleavage of the azo-
chondroitin sulphate. This family of natural polymers has an linkage [89]. Flurbiprofen beta-cyclodextrin (Fbp-beta-CyD)
appeal to drug delivery as it is comprised of polymers with a prodrug was found beneficial in treatment of inflammatory
large number of derivatizable groups, a wide range of bowel disease [90]. The experimental results showed the
molecular weights, varying chemical compositions, and, for good colon targeting property of dexamethasone succinate
the most part, low toxicity and biodegradability yet high dextran (DSD) prodrug compared with free dexamethasone
stability. The most favorable property of these materials is [91]. One strategy for targeting orally administered drugs to
their approval as pharmaceutical excipients [80]. The for- the colon exploits carriers that are degraded specifically by
mation of colonic digestible films of amylose and ethyl- colonic bacteria and utilizes microbially degradable
cellulose from aqueous dispersions at temperatures below polymers/drugs, especially azo-cross-linked polymers/drugs.
370C. This technique also demonstrated that the ethyl- Prodrugs utilizing azo linkages are sulfasalazine, ipsalazine,
cellulose and the amylose were not miscible. The ability of balsalazine, and olsalazine. These were developed for
faecal slurry to digest the films formed at low temperatures delivery of 5-amino salicylic acid to the colon for localized
was confirmed by the use of a batch fermenter. The extent of chemotherapy of inflammatory bowl disease. The azo-conju-
digestion was directly related to the amylose content of the gation approach utilizes the ability of the colonic environ-
films, ensuring the potential to provide films, which could ment to cleave these conjugates and protects the drug from
Oral Drug Delivery Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 2 171

absorption or degradation in the upper gastrointestinal tract. CONFLICT OF INTEREST

It is believed that flavin mediators present in the colon and
Authors do not have any conflict of interest for this
azo-reductase enzymes released from colonic bacteria are
article.
responsible for the degradation of azo-aromatic compounds
for site-specific delivery of the drug to the colon [92].
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