INTRODUCTION:
At present about 40% of the drugs being in the
development pipelines are poorly soluble, even up to 60% of compounds coming
directly from synthesis are poorly soluble [1].Aqueous solubility is
one of the key determinants in development technologies, such as combinational
chemistry and high throughput screening are based on the basic principles of
medicinal chemistry, teaching that the most reliable method to increase in
vitro potency is to add lipophilic moiety at appropriate positions of the lead
structure. This has led to an increase in number of lipophilic and poorly
soluble molecules
being investigated for their therapeutic activity.
Various formulation techniques are applied to compensate for their
insolubility, slow dissolution rate consequently poor therapeutic efficacy.
These include formulation of the amorphous solid form, nanoparticles,
microemulsions, solid dispersions, melt extrusion, salt formation and formation
of water soluble complexes [2].
Poor
solubility is not only a problem for the formulation development and clinical
testing; it is also an obstacle at the very beginning when screening new
compounds for pharmacological activity. From this, there is a definite need for
smart technological formulation approaches to make such poorly soluble drugs
bioavailable. Making such drugs bioavailable means that they show sufficiently
high absorption after oral administration, or they can alternatively be
injected intravenously [3].
Since
many years the approaches to increase drug solubility are solubilisation by
surfactants, complex formation (e. g. cyclodextrin, macromolecules) self-emulsifying
drug delivery systems (SEDDS), microemulsions and especially for oral
administration micronisation of drug powders [4]. Micronization,
meaning the transfer of drug powders into the size range between typically 1-10
μm. However, nowadays many drugs are so poorly soluble that micronization
is not sufficient. The increase in surface area, and thus consequently in
dissolution velocity, is not sufficient to overcome the bioavailability
problems of very poorly soluble drugs of the biopharmaceutical specification
class II.
A
consequent next step was to move from micronization to nanonization. At the
beginning of the 1990s the drug nanocrystals were developed as more efficient
approach to increase drug solubility and dissolution velocity. Instead of
micronising the drug powder, it is nanonised leading to nanocrystals with a
typical size of about less than 1000 nm. Drug nanocrystals can be used for a
chemical stabilization of chemically labile drugs [5].
NANOCRYSTAL TECHNOLOGY
Preparation
of drug nanocrystals is basically a nanosizing method, which is utilized to
enhance the oral bioavailability of poorly water-soluble drugs. Drug
nanocrystals are nanoscopic crystals of the drug with dimensions less than 1000
nm as defined in the first patents in this field [6-8]. Nanocrystal
dispersions contain dispersion media (water, aqueous solutions or nonaqueous
media), active drug substances and surface active agents or polymers required
for stabilization [9]. If necessary, other substances such as
buffers, salts and sugars can be added.
ADVANTAGES OF NANOCRYSTAL
FORMULATIONS
•
Increased rate of absorption,
•
Increased oral bioavailability,
•
Rapid effect,
•
Improved dose proportionality,
•
Reduction in required dose,
•
Applicability to all routes of administration in any dosage form. Contrary to
micronized drugs, nanocrystals can be administered via several routes. Oral
administration is possible in the form of tablets, capsules, sachets or powder;
preferably in the form of a tablet. Nanosuspensions can also be administered
via the intravenous route due to very small particle size, and in this way,
bioavailability can reach 100 %.
•
Reduction in fed/fasted variability,
•
Rapid, simple and cheap formulation development.
•
Possibility of high amounts (30-40 %) of drug loading,
• Increased reliability. Usually side
effects are proportional to drug concentration, so decreasing the concentration
of active drug substances leads to an increased reliability for patients
[10, 11].
•
Sustained crystal structure. Nanocrystal technology leads to an increase in
dissolution rate depending on the increase in surface area obtained by
reduction of the particle size of the active drug substance down to the nano
size range preserving the crystal morphology of the drug [12].
• Improved
stability. They are stable systems because of the use of a stabilizer that
prevents reaggregation of active drug substances during preparation [13].
Suspension of drug nanocrystals in liquid can be stabilized by adding surface
active substances or polymers.
•
Applicability to all poorly soluble drugs because all these drugs could be
directly disintegrated into nanometer-sized particles.
PROPERTIES
OF NANOCRYSTALS [9]
The
main reasons for the increased dissolution velocity and thus increased bioavailability
are:
Increase
of dissolution velocity by surface area enlargement
The
size reduction leads to an increased surface area and thus according to the
Noyes-Whitney equation (Noyes and Whitney 1897) to an increased dissolution
velocity. Therefore micronization is a suitable way to successfully enhance the
bioavailability of drugs where the dissolution velocity is the rate limiting
step. By moving from micronization further down to nanonization, the particle
surface is further increased and thus the dissolution velocity increases too.
In most cases, a low dissolution velocity is correlated with low saturation
solubility.
Increase
in saturation solubility
The
general textbook statement is that the saturation solubility cs is a constant
depending on the compound, the dissolution medium and the temperature. This is
valid for powders of daily life with a size in the micrometer range or above.
However, below a critical size of 1–2 μm, the saturation solubility is
also a function of the particle size.
It
increases with decreasing particle size below 1000 nm. Therefore, drug
nanocrystals possess increased saturation solubility. This has two advantages:
1. According to Noyes and
Whitney (1897), the dissolution velocity is further enhanced because dc/dt is
proportional to the concentration gradient (cs-cx)/h (cs- saturation
solubility, cx - bulk concentration, h - diffusional distance).
2. Due to the increased
saturation solubility the concentration gradient between gut lumen and blood is
increased, consequently the absorption by passive diffusion.
NANOCRYSTAL PREPARATION METHODS
Drug
nanocrystals can be produced by bottom up techniques (precipitation methods) or
top down techniques (size reduction by milling or high pressure
homogenization). In case of bottom-up technologies, one starts with molecules
in the solution and moves via association of these molecules to form solid
particles, i.e. it is a classical precipitation process. The top down
techniques are based on size reduction of relatively large particles into
smaller particles by mechanical attrition. For industrial production, all
products are prepared by top down technique. The basic techniques currently
used by different companies are:
1.
Bottom-up technique (Precipitation method):
This
is also known as hydrosol technology. This was developed by Sucker and
the intellectual property is owned by Sandoz (nowadays Novartis) [14, 15]
.In this technique the drug is dissolved in a solvent and then this
solution is added to a non solvent leading to the precipitation of the finely
dispersed drug nanocrystals. The precipitation technique is simple and requires
low cost equipments. For example, the solvent can be poured into the
non-solvent with a constant velocity in the presence of a high-speed stirrer.
Main approaches include the use of static mixers or micro-mixers, which
simulate the precipitation conditions in a small volume. In the case of
micro-mixers, scaling up can be performed in a simple way by arranging many
micro-mixers in parallel. This equipment is relatively simple and of relatively
low cost.
The
drawbacks of this technique are that the drug needs to be soluble in at least
one solvent. This however, is problematic for newly developed drugs which are
generally insoluble in both aqueous and organic media.
Secondly,
this solvent needs to be miscible with at least one non solvent. Solvent
residues need to be removed, thus increasing production costs. In case of
nanocrystals, care needs to be exercised to ensure that the crystals do not
grow in size and remain stabilized at the nanosize.
Spray
drying and lyophilization are the techniques recommended to preserve the
particle size in nano range [16]. Another alternative to preserve
the size of nanocrystals is the use of polymeric growth inhibitors. Various
stabilizers like sodium dodecyl sulfate (SDS), polyvinyl alcohol (PVA), tween®
80 and polyxamer® 188 have been employed to prepare nanocrystals [17].
Figure 1. Production of Drug
Nanocrystals.
2.
Top-down techniques
2.1
Pearl/Ball milling:
In
this technique, the drug along with the milling media, dispersion media
(generally water) and the stabilizer is fed into the milling chamber. Milling
balls or small pearls are used as milling media. The movement of milling media
generates high shear forces and forces of impact which leads to particle size
reduction. This technology was developed by Merisko-Liversidge et al. (2003) [18].
The pearls or balls comprise of ceramic (cerium or yttrium stabilized zirconium
dioxide), glass, stainless steel or highly cross-linked polystyrene resin
coated beads. The two basic principles of milling are employed. Either the
milling material can be moved by an agitator or the complete container may be
moved in a complex movement. In the latter method large batches are difficult
to process, so mills using agitators are generally preferred for large batches.
Milling time, however, depends upon various factors such as hardness of the
drugs, surfactant contents, viscosity, temperature, energy input and size of
the milling media. The milling time can last from 30 minutes to several hours [18].
Advantages
of Pearl milling include low cost, simple technology and ability for large
scale production.
The
disadvantages associated with this process are erosion from the milling material
leading to product contamination, adherence of the product to the inner surface
of the mill and to the surface of the milling pearls, long milling times(in
case of hard drugs), potential growth of germs in the water phase (when milling
for a longtime), time and costs associated with the separation procedure of the
milling material from the drug nanoparticle suspension, especially when
producing parenteral sterile products.
Buchmann
et al (1996) [19] reported the formation of glass micro particles when
using glass beads as the milling media. The erosion from the glass beads could
be reduced when these were coated with highly cross linked polystyrene resin.
The wastage of the drug due to adherence to milling surface is of significance
in case of very expensive drugs, particularly when very small quantities are
processed.
The
first four marketed products containing nanocrystals such as Rapamune®, Emend®,
Tricor®, Megace ES® were prepared by Pearl mill technology by Elan nanosystems.
Table 1. List
of Drugs Developed With
Nanocrystal Technology
|
Product
|
Drug
|
Technology
by / licensed to
|
|
Rapamune
|
Sirolimus
|
Elan / Wyeth
|
|
Emend
|
Aprepitant
|
Elan / Merck
|
|
Tricor
|
Fenofibrate
|
Elan / Abbot
|
|
Triglide
|
Fenofibrate
|
SkyePharma / First
Horizon Pharmaceuticals
|
2.2
High Pressure Homogenization Technique
This
Technique has been applied for many years for the production of emulsions and
suspensions. A distinct advantage of this technology is its ease for scale up.
There
are three important technologies for producing nanocrystals using
homogenization methods:
2.2.1.
Microfluidizer technology (IDD-PTM technology)
2.2.2.
Piston gap homogenization in water (Dissocubes® technology)
2.2.3.
Piston gap homogenization in water mixtures or in non-aqueous medium (Nanopure®
technology)
2.2.1
Microfluidizer technology:
This
technology is based on the jet-stream principle. Two streams of liquid with
high velocity (upto 1000 m/sec) collide frontally under high pressures (upto
1700 bars) [20]. The particle size is reduced due to high shear
force particle collision and cavitation. The same can be achieved using jet
stream homogenizers such as micro-fluidizer (Microfluidizer® Microfluidics
Inc.). The collision chamber can be either Y-type or Z-type in shape.
Surfactants or phospholipids are required to stabilize the desired particle
size. Microfluidizer can be used for the production of drug nanosuspensions for
soft drugs. However, this technique is not very convenient for large scale
production as a large number of cycles (50 to 100 passes) are required for
sufficient particle size reduction [21, 22]. This technique is being
utilized by SkyePharma Canada Inc. for production of submicron particles of
poorly soluble drugs and named it IDD-PTM (Insoluble Drug Delivery- Particle
technology).
2.2.2
Piston gap homogenization in water: (Dissocubes® technology).
Piston
gap homogenization technology was developed by Müller et al.
[23], and acquired by SkyePharma in 1999.
3.1.
NANOEDGE® Technology: (Microprecipitation and Homogenization).
NANOEDGE®
Technology was introduced by Baxter, and this involves a combination of
precipitation followed by annealing process. Annealing process is carried out
using high energy such as high shear forces and/or thermal energy [31].
When drug nanoparticles are produced by precipitation method alone, the
precipitated nanoparticles have a tendency to grow. Also, the precipitated
particles may be amorphous or partially amorphous. Upon keeping, the amorphous
particles may re-crystallize and this may lead to a decreased bioavailability of
the drug. Combination technology on the other hand has the potential to
overcome these problems, firstly, by prevention of crystal growth and secondly
by reducing the uncertainty of formation of either crystalline or amorphous
state as the annealing process converts all precipitated particles to
crystalline state.
3.2.
SmartCrystal® Technology
This
technology was first developed by PharmaSol GmbH and was later acquired by
Abbott. It is a tool-box of different combination processes in which process
variations can be chosen depending upon the physical characteristics of the
drug (such as hardness). The process H42 involves a combination of spray-drying
and HPH. Drug nanocrystals can be produced much faster in one to a few
homogenization cycles. Process H69 (Precipitation and HPH) and H96
(lyophilization and HPH) yield nanocrystals of amphotericin B within a size
range of about 50 nm [32].
S.
Kobierski et al. (2008) [33] produced nanocrystals in a two-step
process i.e. pre- milling followed by high pressure homogenization (HPH).
Nanosuspensions of cosmetic active hesperidin were produced by ball-milling
process and with combination process. Nanosuspension prepared using
SmartCrystal® technology was found to be of a smaller size indicating better
physical stability. Also combination technique is faster and more economical as
compared to HPH alone.
Möschwitzer
and Müller (2005) [34] prepared spraydried hydrocortisone acetate
powder from nanosuspension produced by HPH with a micron LAB 40 and planetary
monomill “pulverisette 6”. The number of cycles required could be distinctly
reduced. Additionally, a smaller particle size and better particle size
distribution could be obtained. Another finding of the study was that the
application of different homogenization pressures (e.g. 300 and 500 bar) was
equally efficient. Therefore, during large scale production, low homogenization
pressures (300 bars) may be preferred to reduce wearing of the machine [35].
APPLICATIONS
OF NANOCRYSTALS BY VARIOUS ROUTES OF ADMINISTRATION [36, 37]
1. Oral
administration:
Nanosizing of drug leads to dramatic increase in their
oral absorption and subsequent bioavailability. Aqueous nanosuspension can be
used directly in liquid dosage form and as tablets and hard gelatin capsule
with pellets.
2.
Parenteral administration:
Drug nanocrystals in the form of nanosuspensions can
be administered via Different parenteral administration route ranging from
intra articular via. Intraperitoneal to intravenous injection. Nanosuspension
has been found to increase the efficacy of Parenteral administered drugs.
3.
Pulmonary drug delivery:
Poorly
soluble drugs can be delivered directly to the lungs by nebulizing the aqueous
nanosuspensions using mechanical or ultrasonic nebulizers. Using nanoparticles,
drug is more evenly distributed in droplets. All aerosol droplets are likely to
contain drug nanocrystals. Budenoside, poorly water soluble corticosteroid, has
been successfully prepared as a nanosuspension for pulmonary delivery. It
showed long term stability. No particle growth and aggregates formed over a
period of one year. In addition, Buparvaquone nanosuspension was formulated for
an alternative treatment of lung infection (pneumonia) to deliver the drug at
the site of lung infection using nebulization. Administration to infected
guinea pigs of nebulized rifampin, isoniazid and pyrazinamide encapsulated in
wheat germ agglutinin-functionalized PLG nanoparticles was much more effective.
Three doses administered fortnightly for 45 days were sufficient to produce a
sterilizing effect in lungs and spleen. Drug nanocrystals showed an increased
mucoadhesiveness leading to a prolonged residence time at the lung mucosa.
4.
Dermal application:
Dermal
nanosuspensions are mainly of interest if conventional approaches fail.
Nanocrystals can increase the penetration of poorly soluble cosmetic and
pharmaceutical substances into skin. This happens because increased saturation
solubility increases the concentration gradient. Juvena launched first four
Nanocrystal cosmetic products with rutin.
5.
Ophthalmic drug delivery:
Nanosuspensions
can prove beneficial for drugs that have poor solubility in lachrymal fluids.
Nanosuspensions offer advantage of prolonged retention time in the eye, most
likely due to their adhesive properties. Another advantage of nanosuspensions
is high drug loading which avoids high tonicity created by water soluble drugs.
6.
Targeted drug delivery:
Nanocrystals
can have deep excess to the human body because of particle size and control of
surface properties. So they can also be used for targeted drug delivery.
Nanoparticles offer a promising new cancer treatment that may one day replace
radiation and chemotherapy. Kangius RF therapy attaches microscopic
nanoparticles to cancer cells and then cooks tumors inside the body with radio
waves that heat only the nanoparticles and the adjacent cancerous cells.
Muco-adhesive pellets or nanoparticles have been used as specific carrier
systems for oral administration.
CONCLUSION:
Drug
nanocrystals, regardless of their production method, can be applied to all the
poorly soluble drugs to overcome the solubility and bioavailability problems,
because all the poorly soluble drugs can be disintegrated into nanocrystals. In
some cases, besides improving drug dissolution, drug nanocrystals also show
other biological activities, such as realization of a sustained release and
targeting to the special tissues or organs. An important advantage of the drug
nanocrystals is that they can be applied to various administration routes, such
as oral, parenteral, ocular, and pulmonary delivery, and have shown great
superiority over the counterparts of the traditional formulation products in
every administration route. The fact that nanocrystal technology has many
advantages; such easy production and scale up, and low cost, make this approach
a very attractive means for solving a very serious problem of drugs, poor
water-solubility in conjunction with low oral absorption and bioavailability.
REFERENCES:
1. Garg Mukesh, Srivastava
B., Kohli Kanchan, Bedi Simrata and Sharma Pankaj. Performance enhancement of
water insoluble drugs using novel formulation technique. International Journal
of Drug Delivery Technology. 4(3); 2014: 1-5.
2. Loftsson T, Hreinsdottir
D. and Masson M. Evaluation of cyclodextrin solubilization of drugs. Int J
pharm. 302; 2005: 18-28.
3. Lipinski C. Poor aqueous
solubility— an industry wide problem in drug discovery. Am. Pharm. Rev.
5; 2002: 82–85.
4. Keck C, Kobierski S,
Mauludin R and Muller RH. Second generation of drug nanocrystals for delivery
of poorly soluble drugs: smartcrystals technology. D O S I S. 24(2);
2008: 125-127.
5. Troester F. Cremophor-free
aqueous paclitaxel nanosuspension—production and chemical stability. Controlled
Release Society 31st annual meeting, Honolulu, HI, 2004.
6. Hovey D, Pruiit J and Ryde
T, inventors; Elan Pharma International Limited, assignee. Nanoparticulate
megestrol formulations. US patent 7,101,576. 2006 September 5.
7. Liversidge G and Jenkins
S, inventors; Elan Pharma International Limited, assignee. Nanoparticulate
candesartan formulations. WO 074218. 2006 July 13.
8. Ruddy SB and Ryde NP,
inventors; Elan Pharma International Limited, assignee. Solid dose
nanoparticulate compositions. WO 666,539. 2002 March 28.
9. Junghanns JUAH and Muller
AH. Nanocrystal technology, drug delivery and clinical applications. International
Journal of Nanomedicine. 3(3); 2008: 295–309.
10. Coppola D. Nanocrystal
Technology Targets Poorly Water-soluble Drugs. Pharm Tech. 27; 2003: 20.
11. Riehemann K, Schneider SW,
Luger TA, Godin B, Ferrari MF and Fuchs H. Nanomedicine - challenge and
perspectives. Angew Chem Int Ed. 48; 2009: 872-897.
12. Waard H, Hinrichs WLJ and
Frijlink HW. A Novel Bottom-Up Process to Produce Drug Nanocrystals: Controlled
Crystallization During Freeze-Drying. J Control Release. 128; 2008:
179-183.
13. Technology focus helping you
bring products to market. Serial online: 23 March 2007 available from:
URL:http://www.elan.com/Images/Elan_Technology_07v1_tcm3-17145.pdf
14. Gassmann, P. and Schweitzer
A. Hydrosols – alternatives for the parenteral application of poorly water
soluble drugs. Eur. J. Pharm. Biopharm. 40; 1994: 64–72.
15. List, M.A., and Sucker H.
Pat No. GB 2200048.1988, Great Britian.
16. Speiser, P.P. 1998. Poorly
soluble drugs, a challenge in drug delivery, In Müller, R.H., Benita, S., Bohm,
B. (eds.), Emulsions and Nanosuspensions for the Formulation of Poorly Soluble
Drugs, Medpharm Stuttgart. Scientific Publishers: 15-28
17. Mauludin, R., Möschwitzer,
J. and Müller, R. H. Comparison of Ibuprofen Drug Nanocrystals Produced by High
Pressure Homogenization (HPH) versus Ball Milling, AAPS Annual Meeting,
Nashville, T2217, 2005.
18. Merisko-Liversidge, E.,
Liversidge, G.G. and Copper, E.R. Nanosizing: a formulation approach for
poorly-water-soluble compounds. Eur. J. Pharma. Sci. 18; 2003:
113–20.
19. Buchmann, S., Fischli, W.,
Thiel, F.P., Alex, R. Aqueous microsuspension, an alternative intravenous
formulation for animal studies. In: 42nd annual congress of the International
Association for Pharmaceutical Technology (APV), Mainz, 1996.
20. Bruno, R.P. and McIlwrick,
R. Microfluidizer processor technology for high performance particle size
reduction, mixing and dispersion. Eur. J. Pharm. Biopharm. 56;
1999: 29–36.
21. Parikh, I.S., Ulagaraj.1997.
Composition and method of preparing microparticles of water insoluble
substances 93969997.
22. Dearn, A.R. Atovaquone
pharmaceutical compositions. US, 08/974248, 6018080, 2000.
23. Rainbow, B.E.
Nanosuspensions in Drug Delivery. Nat. Rev. 3; 2004: 785-796.
24. Möschwitzer, J., Müller,
R.H. Application. Germany: 2005. Method for the production of ultrafine
submicron nanosuspensions. DE 10 2005 011 786.4.
25. Müller, R.H., Jacobs, C. and
Kayser, O. Nanosuspensions as particulate drug formulations in therapy:
Rationale for development and what we can expect for the future. Adv. Drug
Deliv. Rev. 471; 2001: 3–19.
26. Sahoo, N. G., Al Shaal, L.,
Kakran, M., Li, L., Müller, R. H. Artimisinin nanocrystals for improved oral
bioavailability in malaria treatment, AAPS Annual Meeting, T2154, New Orleans,
2010.
27. Sahoo, N. G., Al Shaal, L.,
Kakran, M., Li, L., Müller, R. H. Antioxident quercetin: preparation and
characterization of nanocrystals, AAPS Annual Meeting, W4134, New Orleans,
2010.
28. Fichera, M.A., Keck, C.M.
Müller, R.H. Nanopure Technology - Drug Nanocrystals for the Delivery of Poorly
Soluble Drugs, in Particles. Orlando, 2004.
29. Bushrab, N.F., Müller, R.H.
Nanocrystals of Poorly Soluble Drags for Oral Administration. New Drugs. 5;
2003: 20-22.
30. Keck, C.M., Bushrab, N.F.
Müller, R.H. Nanopure® Nanocrystals for Oral Delivery of Poorly Soluble Drugs,
in Particles. Orlando, 2004.
31. Kipp, J.E., Wong, J.C.T.,
Doty, M.J. Microprecipitation method for preparing submicron suspensions. US
Patent 6607784; USA, 2003.
32. Fichera, M.A., Wissing,
S.A., Müller, R.H. Effect of 4000 Bar Homogenisation Pressure on Particle
Diminution in Drug Suspensions, in APV. Niirnberg, 2004.
33. Kobierski, S., Hanisch, J.,
Mauludin, R., Müller, R. H., Keck, C. Nanocrystal production by smartCrystal
combination technology, Int. Symp. Control. Rel. Bioact. Mater. 35, #3239, New
York City, 2008.
34. Möschwitzer, J., Müller, R.
H. Development of a New Two-Step Process for the Effective Production Drug
Nanocrystals By, AAPS Annual Meeting, Nashville, W5124, 2005.
35. Möschwitzer, J., Müller, R.
H. Final Formulations for Drug Nanocrystals: Pellets, AAPS Pharmaceutics and
Drug Delivery Conference, Philadelphia, PA, 2004.
36. Lei G, Dianrui Z and Minghui
C. Drug nano crystals for the formulation of poorly soluble drugs and its
applications. A potential drug delivery system. Journal of Nano particle
Research, 10(5); 2001: 845-862.
37. Banavath H and Sivarama RK.
Nano suspension: An Attempt to enhance Bioavailability of poorly soluble drugs.
International Journal of Pharmaceutical Science and Research, 1(9);
2010: 1-11.
