A mini review on nanosuspension drug delivery system : An innovative approach for poorly aqueous soluble drugs

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About Authors
Praveen Kumar. K*1, Sudhir KK1, Akshay KA1, Sachin KK1, Shripathy. D2, Shabaraya AR3.
1M Pharm, Department of Pharmaceutics, Srinivas College of pharmacy, Mangalore- 574143)
2Associate professor, Department of Pharmaceutics, Srinivas college of Pharmacy)
3Principal and HOD of Pharmaceutics, Srinivas college of pharmacy, Mangalore)
* kodavanjipraveen@gmail.com

ABSTRACT
Pharmaceutical nanosuspensions is an emerging techniques for insoluble drugs to make it as soluble. More than 40% of the new drugs are being produced through drug discovery programs are poorly water-soluble compound. Formulating a poorly water soluble drug has always been a challenging problem to pharma industry. The techniques like bottom up and top down methods. Solvent, stabilizers and preservatives are very essential for the formulation of nanosuspensions. The particle size in the range of 100-600nm, Percentage drug encapsulation efficiency (%EE) and zeta potential in the range of -25 to +25mV. The other evaluation parameters like X-ray diffraction study, kinetic release, were also performed based on the type of formulations.

INTRODUCTION
Generally the active pharmaceutical ingredient are very important in the preparation of pharmaceutical formulations. But more than 40% of the active pharmaceutical ingredients are synthesised through drug discovery programmes that are water insoluble or lipophilic drugs. The formulation of a poorly aqueous soluble form can be converted into soluble form is a challenging problem by the pharmaceutical scientist. The innovated formulation contained nano-sized particles can be manufactured to all drug compounds belonging to BCS classes II and IV. To enhance their solubility and hence penetration of drug from gut to the systemic circulation by the gastrointestinal barrier.1
Basically, the rate-limiting step for absorption of the drugs in the above classes is the dissolution velocity arising from low solubility. Although the drugs are high permeability, the poor solubility results in a low concentration gradient between gut and blood vessel consequent to a problem of drug transport and oral absorption. Now a days, there are a large percentage of drug compounds in drug development represents as poor aqueous solubility. Therefore, one of the most challenging tasks in drug development is to improve the drug solubility in order to enhance the bioavailability of these drugs.2

There are many existing methods for enhancing the solubility of poorly aqueous drugs, which include micronization, co-solvency, salt form, using surfactants, precipitation technique. Other techniques such as liposomes, emulsions, micro-emulsion, solid dispersion, and inclusion cyclodextrin complex can enhance the drug solubility markedly, but they could not possible to all drugs. However, these methods have their own drawbacks such as a large amount of additives that may induce stability and toxicity issues. Therefore, they are frequently not ideal for clinical treatment.3since, nanosuspension drug delivery system was firstly developed in 1994, and nanosuspension has attracted more attention as a formulation for the poorly aqueous soluble drugs.4 

Pharmaceutically developed nanosuspension can be defined as a very finely colloidal or biphasic, dispersed or solid drug particles in aqueous vehicle dosage form, particle size of range less than 1µm, without any matrix material, stabilised by using suitable surface active agents &stabilizers, prepared by suitable methods for the drug delivery applications based on the site of application like oral, topical, parenteral, ocular & pulmonary routes. This type of formulations not only solves the problem of poor aqueous solubility & drug availability in the body and also alters the pharmacokinetics of drug & that improves safety & efficacy. This advanced approach is most suitable for the compounds with more log P value, great melting point & more initial dose. More drug availability in the body when comparing to the existing methods of drug delivery. The decreased in particle size leads to an enhanced in the surface area & absolutely increased in the rate of dissolution as described by Nernst-Brunner & Levich modification or Noyes-Whitney equation. In addition, slightly increased in saturation solubility is depended by particle size reduction due to an increase dissolution pressure. This can be explained by the Ostwald-Freundlich equation. Depending on the production technique applied changes in crystalline structure of the drug particles may also occur. An increasing amount of amorphous drug fraction could produce higher saturation solubility. Furthermore, a general adhesiveness to the tissue has been described for nano-sized particles.5

These types of innovations, the drug is to be maintained as a crystalline state with reduced particle size, leading to increase dissolution rate & therefore improved bioavailability. The encapsulated form of drug within nanosuspension can exist in pharmaceutically accepted crystalline or amorphous state. In this novel technique can successfully formulate the brick dust molecules for improved dissolution & good absorption.6

Criteria for selection of host molecule as a nanosuspension : 7
In this method the API that is having either of the following characteristics like,
a) Non aqueous drug molecule having good solubility in the oils.
b) Non aqueous active pharma ingredient have insoluble in both water and oils.
c) Drug molecules having the tendency of the lesser crystals to dissolve the solvent.
d) Large initial dose molecules.

Advantages : 8
1. Nanosuspensions were more stable than lipoidal carriers.
2. Provide ease of manufacture and scale up for large scale production.
3. Tissue inconvenience can be reduced by formulating as a nanosuspension.
4. Enhanced bioavailability in ocular and inhalation route.
5. Parenteral (IV) route can be achieved rapid onset of action. & tissue targeting.
6. Solid dosage form containing nanosuspension to produce improved bioavailability.
7. Duration of action can be increased, due to submicronic level of particle size.
8. Drug with higher penetrability value can be formulated as nanosuspension to increase the bioavailability as well as the duration of action.
9. High dissolution rate can be achieved due to improved tissue performance & saturation solubility of the drug molecules.
10. It can be converted in to suitable dosage forms like, tablets, capsules, pellets, hydrogel & suppositories based on the requirement of formulator.
11. The amorphous fraction of the particles increases leading to a surface charge in the crystalline structure leads to higher solubility.
12. Surface-modification of nanosuspension is one of the possibility to target site specific.

Disadvantages for Nanosuspension Drug delivery system :
1. Physical instability is one of the main drawback in this type of formulation.
2. The care must be taken during handling & transport, because the preparation could be bulk.
3. Dose fixation could be difficult.

Methods for the preparation of nanosuspension: 9, 11, 16, 24, 26, 27
The techniques for the preparation of nanosuspension can be broadly classified in to four methods like,
I. Bottom up techniques
II. Top down techniques
III. Combined techniques
IV. Other techniques

Fig no: 01 Methods for nanosuspension preparation

I Bottom-up technology:
It is the oldest method. In this method, drug or host molecule can be dissolved in the organic solvent and could be injected through the aqueous solvent. The entire solution can be stabilized by suitable stabilizers.
Advantage :
1) Use of simplest and common methods.
2) Higher saturation solubility is one of the advantage for precipitation compared to other method of preparation.

Disadvantages :
1) Drug solubility is the main criteria.
2) The solvent miscibility with at least one non-solvent is to be required.
3) Complete removal of solvent residues is another one of the challenging step, thus increasing production costs.
4) The preservation of particle character is little bit difficult (i.e. size, in case of amorphous fraction). It can be done by using spray dryer as a second step process for the particle size preservation.

Eg: Precipitation ultrasonication method

Fig no : 02 Precipitation ultrasonication methd

II  Top-Down Technology:
The top down technologies include,
a)  Media milling method :

Fig no: 03 Media milling method

b) High pressure homogenization method :

Fig no : 04 High Pressure Homogenization (HPH)

III Combination methods:

1.0 Emulsion Diffusion Method :

Fig no: 05 Emulsion diffusion method

2.0 Micro-emulsion Template;

Fig no: 06 Micro emulsion template method

IV Newer methods:
i. Supercritical Fluid Method;
Supercritical fluid technology is the advanced method to prepare nanoparticles from drug solutions. The Rapid Expansion of Supercritical Solution Process (RESS). It involves the passage of supercritical fluid containing drugs through a nozzle, which leads to the precipitation of the nano sized fine particles by evaporation of solvents.

Fig no: 07 Super critical fluid method

ii Dry Co-Grinding;
It is the modified techniques of conventional milling method. This method is applicable in case of poorly soluble drugs with soluble polymers and Copolymers can be dispersing in a liquid or a suitable media. Polymers like PVP, Polyethylene glycol (PEG), Hydroxypropyl methylcellulose (HPMC) and Cyclodextrin derivatives have been used in the preparation of nanosuspensions.

Components of nanosuspension formulation:  Nanosuspension formulation requires basically stabilizer or surfactant, proper solvent system and others ingredients for its preparation7.

Table no : 01 Ingredients required for nanosuspension formulation



 

SL NO:

 


 

Ingredients

 


 

Role of the ingredients in the formulation

 


 

Examples

 


 

01

 


 

Stabilizers

 


 

It can be used to reduce the surface free energy or aggregation or Surface tension that can be essential for the physical stability of pharmaceutical nanosuspension.

 


 

Polysorbates, Povidone, Poloxamer and lecithin

 


 

02

 


 

Solvents

 


 

Organic solvent are more common, but they are less hazardous in nature.

 

Must solubilize the active pharmaceutical ingredient.

 


 

Methanol, Ethanol, DMSO, Chloroform.

 


 

03

 


 

Preservatives

 


 

The entire formulation can be protected from the microbial attack.

 


 

Benzoic acid, Methyl or Propyl parabens.

 


 

04

 


 

Co-surfactants

 


 

They are influence phase behaviour. Therefore the effect of co-surfactant on uptake of the internal phase or drug loading should be investigated

 


 

Transcutol, Bile salts, Isopropanol.

 


 

05

 


 

Other additives

 


 

Uses of other ingredients mainly depends upon either the route of administration or physicochemical properties of drug.

 


 

Buffers, Salts, Polyols, Osmogenes and Cryoprotectant

 

 

Characterisation of nanosuspension formulations:
Nanosuspensions are characterized for physical appearance, Drug excipient interactions studied by FTIR, particle size, zeta potential, crystalline status, dissolution studies and in vivo studies. Among this, the most important characterization techniques were discussed.

Pre formulation studies:
• Physio chemical properties of drug and excipients can be evaluated. Pre formulation studies like Colour, Melting point determination, Solubility studies in different solvents, FTIR study.
• Melting point determination:
Melting point can determined by capillary method. The sample was inserted in capillary tube having one end closed. Then the capillary was inserted in Thiele’s tube which was heated in controlled manner. The temperature at which drug sample started melting was noted as melting point temperature.
• Solubility studies:
Solubility is based on the type of drug used in the preparation. Nanosuspensions have an important advantage over other techniques, that it can increase the dissolution velocity as well as the saturation solubility. The saturation solubility of the drug in different physiological buffers as well as at different temperatures should be assessed using methods described in the literature.

Post formulation study:
1. Viscosity determination:
It can be studied by using Brookfield rotary viscometer at room temperature

2. Particle size analysis and zeta potential:
It can be studied by using Malvern zeta sizer. This parameter is very important. The average particle size range is 200-600nm

3. Percentage drug entrapment efficiency:
Methanol is used as a standard solvent used to break the nanoparticles, after centrifugation to get the entrapped and free drug. Remove the unentrapped/free drug. The % EE is calculated by using the formula,
% Entrapment efficiency=Drug added - Free drug / Total drug *100

4. X-ray diffraction study:
It is used to study the nature of the crystals of nanoparticles

5. In vitro drug release:
Nanosuspension is placed on one side of the cellophane membrane in a vertical Franz diffusion cell. Other side of the membrane was in contact with the dissolution medium. Entire dissolution assembly was placed on a magnetic stirrer at temperature of 37°C. The dissolution medium was withdrawn at different time intervals- 1hr, 2hr, 3hr, 4hr, 5hr, 6hr ,. Whenever sample was withdrawn equal volume of fresh dissolution medium was added to the cell to maintain a constant volume. Drug concentrations in the dissolution medium were determined by UV spectrophotometric method

6. Stability of Nanosuspension:
The high surface energy of nanosized particles induces agglomeration of the drug crystals. The main function of the stabilizer is to wet the drug particles thoroughly to prevent Ostwald ripening and agglomeration of the Nanosuspension and form a physically stable formulation by providing a steric or an ionic barrier.
The evaluation parameters can be changed based on the type of formulations.

Therapeutic application of nanosuspensions

Table no: 02 Applications of nanosuspension

 

SL NO:

Route of administration

Drugs

Advantages


01


Oral


Atovaquone, Bupravaquone, NSAIDs.


·         Improved oral bioavailability and solubility in case of insoluble drugs.

·         Reduce the dosing frequency.

·         Large surface area leads to enhance the onset of action.

·         Minimize the peak plasma concentration (Cmax) in case of irritant drugs.


02


Parenteral


Anti-cancers


·         Reduce the toxicity.

·         Enhancing the permeability

·         Particle size of 100-300nm can be effectively targeting the tumor cells.


03


Dermal


Anti-oxidants like Resveratrol


·         Increasing the physical stability.


04


Ocular


Flurbiprofen and Ibuprofen


·         Rapid dissolution and bioavailability.

·         Sustained release if the proper surface modification can be done by using suitable bio adhesive hydrophilic polymer.

·         Eye irritation and blurred vision can be reduced


05


Pulmonary


Corticosteroids, Antiasthmatic agents


·         An aqueous nebulizer, could achieve pulmonary drug administration by producing a suitable droplet size.

·         It is easy to achieve the droplet size in range of 01-05 can spread them rapidly on the lung surface to enable better absorption.

·         If the particle size could be  <0.5μm can easily exhale

 

Marketed Products

Table no: 03 Current marketed products of nanosuspension formulations


Sl no


Drugs


Product


Method


Company name


Indication


1


Fenofibrate


Triglide


Media milling


Abbott pharma


Hypercholesterolemia


2


Fenofibrate


Tricor


HPH


First Horizon Pharma


Hypercholesterolemia


3


Megestrol acetate


Megace


Media milling


PAR Pharma


Appetite stimulant


4


Sirolimus


Rapamune


Media milling


Wyeth


Immunosuppressant


5


Griseofulvin


Gris-PEG


Co-precipitation


Novartis


Antifungal


6


Cyclosporine


      -


HPH


              -


Immunosuppressant


7


Spironolactone


      -


HPH


              -


Diuretic


8


Itraconazole


      -


Precipitation


              -


Antifungal


9


Nabilone


Cesamet


Co-precipitation


 Lilly


Anti-emetic


10


Aprepitant


Emend


Media milling


Merck Pharma


Anti-emetic

Conclusion :  Nanosuspensions appear to be unique & yet commercially viable approach to combating problems such as poor bioavailability that are associated with the delivery of hydrophobic drugs, including those that are poorly soluble in aqueous as well as organic media. The dissolution problems of poorly water soluble drugs have been largely solved to improve drug absorption & bioavailability. Nanosuspension technology can be combined with traditional dosage forms: tablets, capsules, pellets, & can be used for parenteral products. To take advantages of nanosuspension drug delivery, simple formulation technologies & variety applications, nanosuspensions will continue to be interest as oral formulations & non-oral administration develop in the future.

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