Introduction Advantages & Disadvantages Manufacturing of Nanosponges Evaluation of Nanosponges Applications

1. 1
Nanosponges
Dr. Anil Pethe
Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management,
SVKM’S NMIMS, Mumbai

2. Introduction
Advantages & Disadvantages
Manufacturing of Nanosponges
Evaluation of Nanosponges
Applications
Contents

3. • Targeting the drug delivery has long been a problem for medical researchers
how to get them to the right place in the body and how to control the
release of the drug to prevent overdose.
• The development of new and complex molecules called Nanosponges has
the potential to solve these problems.
• Nanosponge is a novel and emerging technology which play a vital role in
targeting drug delivery in a controlled manner.
• Nanosponges are a new class of materials and made of microscopic particles
with few nanometres wide cavities in which a large variety of substances can
be encapsulated.
Introduction

4. • A wide variety of drugs can be loaded into
nanosponge for targeting drug delivery.
• These particles are capable of carrying both
lipophilic and hydrophilic substances and of
improving the solubility of poorly water soluble
molecule.
• Nanosponges are tiny mesh like structures is about
the size of a virus with a backbone of naturally
degradable polyester.
• They cross link segments of the polyester to form a
spherical shape that has many pockets / cavities
where drug can be stored.
Introduction (Cont.)

5. • The nanosponges are solid in nature and can be formulated as oral,
parenteral, topical or inhalational dosage forms.
• For oral administration, these may be dispersed in a matrix of excipients,
diluents, lubricants which is suitable for the preparation of tablets or
capsules.
• For parenteral administration, these can be simply mixed with sterile
water, saline or other aqueous solutions.
• For topical administration, they can be effectively incorporated into topical
hydro gel.
Introduction (Cont.)

6. • Nanosponges are tiny sponges with a size of about a virus (250nm – 1μm), which consist
of cavities that can be filled with a wide variety of drugs.
• The sponge acts as a three-dimensional network or scaffold, which consist of the
backbone known as long-length polyester.
• It is mixed in solution with cross-linkers to form the polymer.
Definition

8. • It provides improved elegance, stability and formulation flexibility
• The drug is protected from degradation
• It is non-mutagenic,Non-irritating, non-toxic
• Improve aqueous solubility of lipophilic drugs
• This technology provide entrapment of active contents and side effects are less
• It can be used to mask unpleasant flavours
• Nanosponges can significantly reduce the irritation of drugs without reducing their
efficacy
• Improving patient compliance by prolonging dosing intervals
• Biodegradable
• Predictable release
• Easy scale-up for commercial production
Advantages

9. Disadvantages
 The main disadvantage of these nanosponges is their ability to
include only small molecules
 The nanosponges could be either paracrystalline or in crystalline
form. The loading capacity of nanosponges depends mainly on degree
of crystallisation. Paracrystalline nanosponges can show different
loading capacities.

10. • Polymers : Hyper cross linked polystyrenes, ethyl cellulose, 2-hydroxy
proply β – cyclodextrins, poly valerol actone, Eudragit RS 100, acrylic
polymers
• Cross linkers : Carbonyl diimidazoles, Carboxylic acid dianhydrides, Di
aryl carbonates, Dichloromethane, Diisocyanates, Di phenyl Carbonate,
Epichloridine, Gluteraldehyde,Pyro mellitic anhydride, 2,2-bis
(acrylamido)Acetic acid.
• Co Polymers :Poly(valerolactoneallylvalerol actone),Poly(valerol actone-
allylvalerol actone oxepanedione),Ethyl Cellulose, Poly vinyl alcohol.
Materials used for Nanosponges

11. 1.Type of polymer :
• Type of polymer used can influence the formation as well as the
performance of Nanosponges. For complexation, the cavity size of
nanosponge should be suitable to accommodate a drug molecule of
particular size.
2.Type of drugs :
• Molecules to be complexed with nanosponges should have certain
characteristics mentioned below
 Molecular weight between 100 – 400 Da .
 Drug molecule consists of less than five condensed rings .
 Solubility in water is less than 10mg/mL .
 Melting point of the substance is below 250°C.
Factors influencing the formation of Nanosponges

12. 3.Temperature :
• Increasing in the temperature decreases the stability of the
drug/nanosponge complex, may be due to a result of possible reduction of
drug/nanosponge interaction forces.
4.Method of preparation :
• The method of loading the drug into the nanosponge can affect
rug/Nanosponge complexation. However, the effectiveness of a method
depends on the nature of the drug and polymer, in many cases freeze drying
was found to be most effective for drug complexation
5.Degree of substitution :
• The complexation ability of the nanosponge may be greatly affected by type,
number and position of the substituent on the parent molecule.
Factors influencing the formation of Nanosponges (cont.)

13. 1. Solvent method
2. Hyper Cross- Linked β- Cyclodextrins
3. Emulsion Solvent Diffusion Method
4. Ultrasound-Assisted synthesis
Method of preparation of Nanosponges

14. Solvent Method
Polymer is mixed with suitable
solvent like polar aprotic solvent
The mixture is added to excess quantity of the
cross linker preferably in cross linker polymer
molar ratio of 1:4
Action is carried out at temperature ranging
from 10 oC to the reflux temperature of the
solvent, for time ranging from 1 to 48 hr.
After completion of the reaction, the solution is
cooled at room temperature and the product is
added to large excess of distilled water
The recovery of the product is done by
filtration under vacuum

15. • Nanosponges are obtained by reacting cyclodextrin with a
crosslinker such as di isocianates, diaryl carbonates, dimethyl
carbonate, diphenyl carbonate, and carbonyl diimidazoles.
• The average diameter of a Nanosponge is below 1 μm but fractions
below 500 nm can be selected.
Hyper Cross- Linked β- Cyclodextrins

16. Emulsion Solvent Diffusion Method
Organic internal phase containing
drug & polymer in solvent is
added to
External phase containing emulsifying agent
The mixture is stirred at 1000-2000 rpm
for 3 hrs at RT
Formed nanosponges were filtered, washed
& dried at RT

17. • In this method nanosponges can be obtained by reacting polymers with
cross-linkers in the absence of solvent and under sonication.
• The nanosponges obtained by this method will be spherical and uniform in
size.
• Mix the polymer and the cross-linker in a particular molar ratio in a flask.
• Place the flask in an ultrasound bath filled with water and heat it to 90°C.
• Sonicate the mixture for 5hours.
• Then allow the mixture to cool and break the product roughly.
• Wash the product with water to remove the nonreacted polymer and
subsequently purify by prolonged soxhlet extraction with ethanol.
• Dry the obtained product under vacuum and store at 25°C until further use
Ultrasound-Assisted synthesis

18. Loading of drug into nanosponges

19. 1. Particle Size Determination
2. Loading Efficiency
3. Entrapment efficiency
4. Saturation state interaction
5. Porosity
6. Zeta potential
7. SEM and TEM
8. Fourier transform-infrared spectroscopy (FTIR)
9. Powder X-ray diffraction (P-XRD)
10. Thermo gravimetric analysis (TGA)
11. Resiliency
12. Solubility studies
13. Swelling and water uptake
14. Drug release kinetics
Evaluation of nanosponges

20. 1. Particle Size Determination
Particle size can be determined by laser light diffractometry or Zeta seizer.
2. Loading Efficiency
The loading efficiency (%) of Nanosponge can be determined by,
Actual drug content
Loading Efficiency = ---------------------------------- X 100
Theoretical drug content

21. • To calculate the entrapment efficiency, weigh accurate quantity of
nanosponges into a suitable solvent in a volumetric flask & flask was
shaken for 1 min. using vortex mixer.
• The volume was made up to 10 ml with solvent. Then the solution was
filtered and diluted with the concentration of drugs was determined by
using uv-spectrometer.
• The yield of nano particles can be determined by calculating initial
weight of nanosponges.
3. Entrapment efficiency:

22. • UV spectroscopy is used to carry out the saturated solution
interaction study.
• Increasing concentrations of nanosponge solutions (1– 80 ppm) are
added to fixed concentrations of the drug.
• The samples are kept overnight for interaction and finally filtered
solutions are scanned for λmax and absorbance is measured.
• Drug loading is interpreted by taking scans of the formulation in the
UV range and analyzing the shift of the absorbance maxima in the
spectra compared to pure drug.
4. Saturation state interaction

23. 5. Porosity:
6. Zeta potential
7.SEM and TEM
8.Fourier transform-infrared spectroscopy (FTIR)
Percent porosity is given by equation
Bulk volume – True volume
% Porosity (E) = ------------------------------------------ x 100
Bulk volume
Zeta potential of any system under investigation is a measure of the surface charge.
These tools are employed to evaluate the particle shape and size and to get morphological
information related to the drug delivery system
It serves as a major tool to determine the presence of functional groups.

24. 9. Powder X-ray diffraction (P-XRD):
10. Thermo gravimetric analysis (TGA):
Diffraction peaks for a mixture of compounds are useful in determining chemical decomposition and
complex formation. Complex formation of the drug with nanosponges alters the diffraction patterns
and also changes the crystalline nature of the drug.
These studies are carried out to understand the melting point, thermo stability and crystalline
behaviour of the particle.

25. 11. Swelling and water uptake
12. Solubility studies
The most widely used approach to study inclusion complexation is the phase solubility
method described by Higuchi and Connors model, which examines the effect of a
nanosponge, on the solubility of drug.
Phase solubility diagram Indicate the degree of complexation.

26. • In vitro diffusion model
• In vitro release kinetics experiments are performed using a multicompartment
rotating cell; an aqueous dispersion of nanosponges (1 mL) containing the drug is
placed in the donor compartment, while the receptor compartment, separated
by a hydrophilic dialysis membrane, is filled with phosphate buffer at pH 7.4 or
pH 1.2.
• Each experiment is carried out for 24 hr.
• At fixed times, the receptor buffer is completely withdrawn and replaced with
fresh buffer. The amount of drug in the medium is determined by a suitable
analytical method and drug release is calculated to determine the release
pattern.
13. Drug release kinetics:

27. 1) Nanosponges as chemical sensors:
• Nanosponges which are the type of “ metal oxides” act as a chemical sensors which is
used in highly sensitive detection of hydrogen using nanosponge titania.
• Nanosponge structure initially have no point of contact so there is less hinderance to
electron transport and it results in higher 3D interconnect nanosponges titania which is
sensitive to H2 gas.
2) Oxygen Delivery System :
• Characterized by using α, β and ϒ cyclodextrins and this are suspended in water and get
saturated with water. A silicone form of membrane can also be used for oxygen
permeation with the help of nanosponge/ hydrogel system. They can also applied it to
hypoxic tissues caused in various type of diseases.
3) Biomedical applications
• Nanosponge can be used for contaminated water. Nanosponge have been used for the
removal of organic impurities in water
Application of nanosponges

28. 4) Nanosponges as a carrier for biocatalysts and release of enzymes, proteins,
vaccines and antibodies :
• It includes the process applied in industry which correlate with operational
condition. Reactions which are not specific give rise to low yields and require
high temperatures and pressures which consume large amount of energy and
cooling water in down-stream process. This are the drawbacks can be removed
by using enzymes as biocatalysts as this operate under high reaction speed,
mild condition.
5) Solubility enhancement:
• β-cyclodextrin based nanosponges of itraconazole have enhance solubility of
poorly soluble drug. The solubility increased by 50 folds compared to ternary
dispersion system.
• Eg- copolyvidonum.
Application of nanosponges

29. 6)Topical agents
• Nanosponge delivery system is a unique technology for the controlled
release of topical agents of prolonged drug release and retention of drug
form on skin.
7) Antiviral application:
• Nanosponges used in nasal, pulmonary route of administration. It
provide specificity to deliver antiviral drug on RNA to lungs or nasal route
through nanocarriers for targeting virus which may cause infection to RTI
such as influenza virus, rhinovirus.
• Drugs used as nanocarrriers are- Zidovudine, Saquinavir.
Application of nanosponges