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19 Iajps19062017 PDF
19 Iajps19062017 PDF
Please cite this article in press as A. Deevan Paul et al, Challenges in Nanotechnology Drug Delivery Systems -
State of Art Technologies, Indo Am. J. P. Sci, 2017; 4(06).
because incomplete freezing or collapse may occur accumulate a large quantity of drug. However, this
with water soluble drugs at low eutectic freezing process is not suitable for thermolabile drugs (13).
temperature. (10) used a mixture of mannitol and
natural gum such as acacia gum, guar gum, xanthan Compaction:
gum or tragacanth as carrier material for preparation In the compaction process, a mixture of particulate
of an open matrix network structure. The mannitol matter is fed to a compression device which promotes
concentration in stable ODT was reported to be at agglomeration due to pressure. Continuous sheets of
least 50 % (m/m) and the natural gum concentration solid material or solid forms such as briquettes or
of the solid dosage form was about 0.07 to 3.2 % tablets are produced. Compaction processes range
(m/m). This study revealed an improvement in the from confined compression devices such as tableting
properties of ODTs when the open matrix structure to continuous devices such as roll presses, briquetting
comprised mainly mannitol. machines and extrusion. The following different
techniques are based on the compaction mechanism.
Molding:
ODTs prepared by molding, also known as solid Crystalline transition process:
dispersion, disintegrate within 5 to 15 s. Compression ODTs are prepared by crystalline transition through
molding and heat molding is the two approaches to compressing two saccharides having high and low
preparing ODTs by the molding technique. compressibility/mold ability indices and are then
Compression molding involves moistening of the subjected to the conditioning process (14). Transition
powder blend with a hydro-alcoholic solvent, from the amorphous to crystalline state is
followed by compression into mold plates to form a intentionally done by the conditioning process after
wetted mass. The wetted mass is then air-dried to tablet compression to achieve sufficient hardness and
remove the solvent. The compression force involved fast disintegration time. Fluidized bed granulator is
in compression molding is lower than that used for commonly used for the crystalline transition process.
conventional tablet and hence molded tablets are less
compact than conventional compressed tablets and a Phase transition:
possess highly porous structure, which in turn The manufacturing ODTs using phase transition of
increases disintegration and dissolution rates. In the sugar alcohol (SA). This method was mainly
heat molding process for the preparation of ODTs, dependent upon the melting point of SA. The process
molten mass containing a dispersed drug and/or involves compressing the powder containing two SAs
dissolved drug is used (11). The disintegration time of high and low melting points and subsequently
and dissolution rate of ODTs prepared using molding heating the compressed mass at the temperature
depend upon the dissolution or dispersion type of the between their melting points. However, in case of
drug. Hence, it can be said that the ODTs preparation talc, oral disintegration time did not change with an
using the molding process is easy and convenient at increase in hardness. Among the three lubricants
an industrial scale although cannot achieve studied, i.e., magnesium stearate, sodium stearyl
disintegration time compared to that of lyophilized fumarate and talc, talc was recommended as the most
forms. The molded tablets typically do not possess desirable lubricant for preparation of ODTs by phase
great mechanical strength and can break during transition of SA (16) .
handling or when blister packs are opened. However,
the addition of binders (acacia, polyvinyl Sublimation:
pyrrolidone, PEG) gives sufficient consistency to the Conventional tablets with high water-soluble
formulation and prevents tablet breaking (12). ingredients fail to disintegrate rapidly because of
Cotton candy process: their low porosity and this suggests that the presence
Cotton candy process utilizes a unique spinning of a highly porous particle structure in the tablet
mechanism to produce floss of crystalline structure. matrix is an important factor for fast disintegration of
The process involves formation of a matrix of ODT. In the sublimation process, volatile substances
saccharides or polysaccharides by simultaneous flash like camphor, ammonium carbonate, ammonium
melting and spinning. This results into formation of bicarbonate, benzoic acid, hexamethonium tetramine,
the candy floss matrix, which is then milled and naphthalene, phthalic anhydride, urea and urethane
blended with active ingredients and excipients and were used along with other excipients. Solvents such
subsequently compressed into ODTs. To improve the as cyclohexane/benzene were sometimes also used
flow properties and compressibility, the candy floss for further enhancement in the porous matrix
matrix may sometimes partially recrystallize, which formation. Volatilization of these materials
imparts good mechanical strength and can eliminates the complicated process associated with
dispersed throughout the particles. Although both lipid particle matrix. This matrix gives much more
types of active ingredients may be incorporated, most room to incorporate drugs, the drug loading is
often they are hydrophilic in the case of nanospheres increased. To achieve this, spatially very different
and lipophilic in the case of nanocapsules. Polymeric lipid molecules are used for particle production. The
nanoparticles including nanospheres and old SLN are made from a solid lipid and
nanocapsules can be prepared according to numerous subsequent melting and homogenization. The NLC
methods. are made by mixing a solid lipid with a liquid lipid
The major disadvantages of polymeric nanoparticles (oil), these lipid molecules are spatially so different
are their relatively slow biodegradability, which that they form imperfect matrices. Of course, the
might cause systemic toxicity. Apart from polymer blend needs to be chosen in a way that after
accumulation on repeated administration, toxic homogenization and cooling the blend solidifies and
metabolites may be formed during the is solid at body temperature.
biotransformation of polymeric carriers, for example, Nanosuspensions (drug nanoparticles) for many
formaldehyde as a metabolite of polycyanoacrylates. decades drug carriers have represented the only
The formation of larger polymer particles and lumps group of colloidal drug administration systems.
cannot be avoided totally in large scale production of Nowadays a fundamentally different group of
nanoparticles. The system also suffers from the lack dispersions i.e. nanosuspensions (drug nanoparticles)
of a cost-effective large scale production method are also under investigation. Pharmaceutical
yielding a product of a quality being acceptable by nanosuspensions are usually very finely dispersed
the regulatory authorities. Also polymeric solid drug particles in an aqueous vehicle for both
nanoparticles possess limited drug loading capacity. oral and topical use or for parenteral and pulmonary
administration. The next development was
Solid lipid nanoparticles (SLN): transformation of a micronized drug powder into
Solid lipid nanoparticles have been developed as drug nanoparticles. In a nanosuspension, the overall
alternative delivery system to conventional polymeric bioavailability is improved by an increase in surface
nanoparticles. The solid lipid nanoparticles (SLN) are area and saturation solubility via particle size
sub-micron colloidal carriers (501000 nm) which reduction. The drug microparticles are ground to
are composed of a physiological lipid, dispersed in nanoparticles in between the moving milling pearls.
water or in an aqueous surfactant solution. Solid lipid Preparation of DissoCubes involves dispersion of
nanoparticles combine advantages of polymeric drug powder in a surfactant solution by a high-speed
nanoparticles, fat emulsions and liposomes, and stirrer. First, the particle size is reduced in a jet mill.
avoid some of their disadvantages. They are The obtained macro-suspension is passed through a
biodegradable, biocompatible and non-toxic. The high-speed homogenizer leading to the formation of a
possibility of large scale production of SLN is an nanosuspension. The cavitation forces experienced
important feature. are sufficient to disintegrate drug microparticles to
Advantages of SLN are: nanoparticles. The Table compares features of
1. Avoidance of coalescence leads to enhanced NanoCrystals and DissoCubes(19).
physical stability.
2. Reduced mobility of incorporated drug molecules NEW DEVELOPMENTS IN DRUG
leads to reduction of drug leakage. NANOCRYSTALS
3. Static interface solid/liquid facilitates surface DissoCubes are prepared by homogenizing drug
modification. powder dispersed in pure water. This is based on the
The drug release can be controlled by varying the fact that it was believed that cavitation is the major
carrier matrices as well as by the choice of force to disintegrate large particles to drug
emulsifier. Besides parenteral administration, solid nanocrystals. To obtain cavitation one needs to have
lipid nanoparticles are also suitable for other routes a liquid with a high vapour pressure, i.e. water.
of administration and might be an interesting carrier Cavitation should not be present or only present at a
system for the per oral administration of poorly very limited extent when homogenizing in liquids
water-soluble drugs with low per oral bioavailability. with a low vapour pressure, e.g. liquid oils (MCT) or
An advantage of the emulsified lipid particles might liquid PEG. Recently, a new patent application was
be their improved wet ability in gastrointestinal filed describing the production of drug NanoCrystals
fluids. in non-aqueous media. In addition, it is also claimed
This problem has been overcome by the new to produce drug NanoCrystals in mixtures of water
generation of solid lipid nanoparticles, the so called with water-miscible liquids (e.g. production in
nanostructured lipid carriers (NLC). These particles isotonic dispersions of glycerol-water).
are characterized as forming on purpose an imperfect
Drug NanoCrystals are produced in melted PEG, the opportunities for revitalizing marketed products with
obtained nanosuspension is then filled straight away suboptimal delivery.
as liquid at 70 _C in hard gealtin or HPMC capsules.
Cooling forms a solid matrix in the capsule which NANOPARTICLE FORMULATIONS
contains the drug nanocrystals in a finely dispersed No matter what approach is taken to generate drug
form. In addition, stock dispersions of water-sensitive nanoparticles, in comparison to particulates greater
drugs can be prepared. Such a stock suspension in than 1 micron, surface area is increased. This
e.g. glycerol can then be diluted prior to parenteral increase in surface area and surface interactions can
administration using sterile water to yield on isotonic be positively used to enhance the dissolution rate and
suspension provide a platform for controlling the
pharmacokinetic properties of the dosage form.
The major advantages of nanosuspension technology However, unless properly dampened, this tremendous
are its general applicability to most drugs and its increase in surface energy can cause the nanometer-
simplicity. Interesting special features of sized drug particles to spontaneously aggregate into a
nanosuspensions are more thermodynamically stable state. It should be
emphasized that surface stabilization does not
a. Increase in saturation solubility and necessarily involve chemical grafting of the surface
consequently an increase in the dissolution rate of the stabilizer to the molecule. Stabilization is typically
drug. driven by the mere adsorption of the stabilizer to the
b. Increase in adhesive nature, thus resulting in surface of the poorly water-soluble compound.
enhanced bioavailability.
c. Increasing the amorphous fraction in the
particles, leading to a potential change in the
crystalline structure and higher solubility.
d. Absence of ostwald ripening, producing
physical longterm stability as an aqueous suspension.
e. Possibility of surface-modification of
nanosuspensions for site specific delivery.
f. Possibility of large-scale production, the
pre-requisite for the introduction of a delivery system
to the market.
3) A drug-to-stabilizer ratio on a weight basis structures that are up to several hundred nanometers
typically 10:1 or lower: 30% drug to 3% or lower in size and that are developed by top-down or
stabilizer concentration. bottom-up engineering of individual components.
4) Usefulness for all routes of administration: Herein, we focus on the application of
oral, pulmonary, intravenous, IM and ophthalmic. nanotechnology to drug delivery and highlight
5) The ability to be readily post processed into several areas of opportunity where current and
most commonly used dosage forms: tablets, capsules emerging nanotechnologies could enable entirely
and sterile products. novel classes of therapeutics. Orodispersable tablets
have better patient acceptance, compliance and
NANOPARTICLES: possibly will tender enhanced biopharmaceutical
IMPROVED PERFORMANCE properties, superior efficacy, and enhanced safety
The activity of a compound depends on its ability to compared to conventional oral dosage forms.
dissolve and interact with the relevant biological
target, either through dissolution and absorption or REFERENCES:
dissolution and receptor interaction. The poor 1.European Pharmacopoeia, 5th ed., Council of
bioavailability of poorly water-soluble molecules that Europe, Strasbourg, 2006, 628.
are not permeation-rate limited can be attributed to 2.V. Agarwal, B. H. Kothari, D. V. Moe and R. K.
dissolution- rate kinetics. The dissolution rate is Khankari, Drug delivery: Fast-dissolve Systems,
directly proportional to the surface area of the drug, inEncyclopedia of Pharmaceutical Technology (Ed.
according to the Noyes-Whitney model for James Swarbrick), Informa Healthcare, New
dissolution kinetics. Drug crystals reduced in size York2006, 11041114.
from 10 microns to 100-nm particles generate a 100- 3.S. V. Sastry, J. R. Nyshadham and J. A. Fix, Recent
fold increase in surface-area-to-volume ratio. If the technological advances in oral drug deliverya review,
bioavailability of a poorly water-soluble compound is Pharm. Sci. Tech. Today,2000; 3:138145.
dissolution- rate limited, approaches that afford DOI: 10.1016/S1461-5347(00)00247-9.
delivery using nanometer-sized particles of drug 4.P. Virely and R. Yarwood, Zydis a novel fast
improve bioavailability by enhancing dissolution. dissolving dosage form, Manuf. Chem.1990; 61: 36
This maximizes the amount of soluble drug that is 37.
free to be absorbed. This is especially true for poorly 5.S. W. Avery and D. M. Dellarosa, Approaches to
water-soluble compounds absorbed at a defined treating dysphagia in patients with brain injury, Am.
region of the gastrointestinal tract(20). J. Occup. Ther. 1994;48: 235239.
6.Douglas, S. J., Davis, S. S., and Illum, L.
Nanoparticles in drug delivery. Crit Rev Ther Drug
Carrier Syst 1987;3: 233-61.
7.Muller RH, Jacobs C, Kayser O., Nanosuspensions
as particulate drug formulations in therapy rationale
for development and what we can expect for the
future. Adv. Drug. Deliv. Rev. 2001;47: 319.
8.S. L. Nail, L. A. Gatlin, Freeze Drying: Principles
and Practice, in Pharmaceutical Dosage Forms
Parenteral Medications, Marcel Dekker, New York
1993, p. 163.
9.P. Kearney and S. K. Wong, Method of Making
Freeze Dried Drug Dosage Forms, U.S. Pat. 5 631
023, 20 May 1997.
10.P. Kearney, The Zydis Oral Fast Dissolving
Dosage Form, in Modified-release Drug Delivery
Technology (Eds. M. J. Rathbone, J. Hadgraft and M.
CONCLUSION: S. Roberts), Marcel Dekker Inc., New York 2003,
Nanotechnology is the engineering and
pp.191201.
manufacturing of materials at the atomic and
11.H. Seager, Drug delivery product and the Zydis
molecular scale. In its strictest definition from the
fast-dissolving dosage form, J. Pharm. Pharmacol.
National Nanotechnology Initiative, nanotechnology
1998;50: 375382.
refers to structures roughly in the 1100 nm size
DOI: 10.1111/j.2042-7158.
regime in at least one dimension. Despite this size
restriction, nanotechnology commonly refers to