Nanosuspensions : A Novel Approach In Drug Delivery

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V.B. Patil

V.B. Patil

More than 40 percent of the drugs coming from High-throughoutput screening are poorly soluble in water. Obviously poorly water-soluble drugs show many problems in formulating them in conventional dosage forms.

One of the critical problems associated with poorly soluble drugs is too low bioavailability and or erratic absorption. The problem is even more complex for drugs such as itraconazole and Carbamazepine (belonging to BCS CLASS II) as classified by BCS System as they are poorly soluble in both aqueous and organic media, and for those drugs having a log P value of 2. There are number of formulation approaches to resolve the problems of low solubility and low bioavailability.

These techniques for solubility enhancement have some limitations and hence have limited utility in solubility enhancement. Nanotechnology can be used to resolve the problems associated with these conventional approaches for solubility and bioavailability enhancement. Nanotechnology is defined as the science and engineering carried out in the nanoscale that is 10-9 meters. The present article describes the details about nanosuspensions. Nanosuspensions consist of the pure poorly water-soluble drug without any matrix material suspended in dispersion. The review article includes the methods of preparation with their merits and demerits, characterization and evaluation parameters. A nanosuspension not only solve the problems of poor solubility and bioavailability but also alter the pharmacokinetics of drug and thus improves drug safety and efficacy.

Introduction:

More than 40 percent of the drugs coming from High-throughoutput screening are poorly soluble in water1. Obviously poorly water-soluble drugs show many problems in formulating them in conventional dosage forms. One of the critical problems associated with poorly soluble drugs is too low bioavailability and or erratic absorption2.

The problem is even more complex for drugs such as itraconazole and Carbamazepine (belonging to BCS CLASS II) as classified by BCS System3,4 as they are poorly soluble in both aqueous and organic media, and for those drugs having a log P value of 2.  The performance of these drugs is dissolution rate-limited (for Class II and III drugs) and is affected by the fed/fasted state of the patient. Dissolution rates of sparingly soluble drugs are related to the shape as well as the particle size. Therefore decrease in particle size results in an increase in dissolution rate5.

There are number of formulation approaches to resolve the problems of low solubility and low bioavailability. The approaches include micronization6, solublization using co-solvents, use of permeation enhancers, oily solutions, surfactant dispersions6, salt formation7 and precipitation techniques8,9. These techniques for solubility enhancement have some limitations and hence have limited utility in solubility enhancement. Micronization by colloid mills or jet mills increases the dissolution velocity of drug due to increase in surface area but does not increase the saturation solubility6.

Other techniques like liposomes10, emulsions, microemulsions11, solid-dispersions12 and inclusion complexes using Cyclodextrins13 show reasonable success but they lack in universal applicability to all drugs. These techniques are not applicable to the drugs, which are not soluble in both aqueous and organic medias. Hence there is need of some different and simple approach to tackle the formulation problems to improve their efficacy and to optimize the therapy with respect to pharmacoeconomics.

Nanotechnology can be used to resolve the problems associated with these conventional approaches for solubility and bioavailability enhancement. Nanotechnology is defined as the science and engineering carried out in the nanoscale that is 10-9 meters14. The drug microparticles/micronized drug powder is transferred to drug nanoparticles by techniques like Bottom Up Technology (precipitation) and Top Down Technology15,16 or disintegration methods. Nano is a Greek word, which means ‘dwarf’. Nano means it is the factor of 10-9 or one billionth. Some comparisons of nanoscale are given below,

0.1 nm = Diameter of one Hydrogen atom

2.5 nm = Width of a DNA molecule17.

1micron = 1000nm.

1nm = 10-9m= 10-7cm = 10-6mm.

micron = 10-6m= 10-4cm = 10-3mm.

Nanosuspensions consist of the pure poorly water-soluble drug without any matrix material suspended in dispersion 18. It is sub-micron colloidal dispersion of pure particles of drug stabilized by surfactants19. By formulating nanosuspensions problems associated with delivery of poorly water-soluble drugs and poorly water-soluble and lipid-soluble drugs can be solved. Nanosuspensions differ from nanoparticles20, which are polymeric colloidal carriers of drugs (Nanospheres and nanocapsules), and from solid-lipid nanoparticles21 (SLN), which are lipidic carriers of drug. The potential benefits of nanoparticles over conventional technologies are described in Table122.

When to go for nanosuspensions approach

Preparing nanosuspensions is preferred for the compounds that are insoluble in water (but are soluble in oil) with high log P value. Conventionally the drugs that are insoluble in water but soluble in oil phase system are formulated in liposome, emulsion systems but these lipidic formulation approaches are not applicable to all drugs. In these cases nanosuspensions are preferred. In case of drugs that are insoluble in both water and in organic media instead of using lipidic systems nanosuspensions are used as a formulation approach. Nanosuspension formulation approach is most suitable for the compounds with high log P value, high melting point and high dose23. Figure1 shows selection criteria for formulation approach to enhance solubility of poorly soluble drugs24.

Methods of preparation of nanosuspensions                                                                                                                       

Mainly there are two methods for preparation of nanosuspensions. The conventional methods of precipitation (Hydrosols25) are called ‘Bottom Up technology’. In Bottom Up Technology the drug is dissolved in a solvent, which is then added to non-solvent to precipitate the crystals. The basic advantage of precipitation technique is the use of simple and low cost equipments. The basic challenge of this technique is that during the precipitation procedure the growing of the drug crystals needs to be controlled by addition of surfactant to avoid formation of microparticles. The limitation of this precipitation technique is that the drug needs to be soluble in atleast one solvent and this solvent needs to be miscible with nonsolvent. Moreover precipitation technique is not applicable to drugs, which are simultaneously poorly soluble in aqueous and nonaqueous media25.

The ‘Top Down Technologies’ are the disintegration methods and are preferred over the precipitation methods. The ‘Top Down Technologies’ include Media Milling (Nanocrystals), High Pressure Homogenization in water (Dissocubes), High Pressure Homogenization in nonaqueous media (Nanopure) and combination of Precipitation and High-Pressure Homogenization (Nanoedege) 15,16. Few other techniques used for preparing nanosuspensions are emulsion as templates, microemulsion as templates etc23. Figure 2 showing the methods of preparation of nanosuspensions by various methods.

A) Media Milling (Nanocrystals or Nanosystems)

The method is first developed and reported by Liversidge et.al. (1992) The nanosuspensions are prepared by using high-shear media mills. The milling chamber charged with milling media, water, drug and stabilizer is rotated at a very high shear rate under controlled temperatures for several days (at least 2-7 days). The milling medium is composed of glass, Zirconium oxide or highly cross-linked polystyrene resin. The high energy shear forces are generated as a result of the impaction of the milling media with the drug resulting into breaking of microparticulate drug to nanosized particles23,25.

Advantages

1. Media milling is applicable to the drugs that are poorly soluble in both aqueous and organic media.

2. Very dilute as well as highly concentrated nanosuspensions can be prepared by handling 1mg/ml to 400mg/ml drug quantity.

3. Nanosize distribution of final nanosize products.

Disadvantages

1. Nanosuspensions contaminated with materials eroded from balls may be problematic when it is used for long therapy.

2. The media milling technique is time consuming.

3. Some fractions of particles are in the micrometer range.

4. Scale up is not easy due to mill size and weight.

B) Homogenization In Water (Dissocubes)

R.H.Muller developed Dissocubes technology in 1999. The instrument can be operated at pressure varying from 100 – 1500 bars (2800 –21300psi) and up to 2000 bars with volume capacity of 40ml (for laboratory scale). For preparation of nano suspension, we have to start with the micronized drug particle size less than 25µm to prevent blocking of homogenization gap hence it is essential to prepare a presuspension of the micronized drug in a surfactant solution using high speed stirrer16.

Principle

In piston gap homogeniser particle size reduction is based on the cavitation principle. Particles are also reduced due to high shear forces and the collision of the particles against each other. The dispersion contained in 3cm diameter cylinder; suddenly passes through a very narrow gap of 25µm. According to Bernoulli’s Law the flow volume of liquid in a closed system per cross section is constant. The reduction in diameter from 3cm to 25µm leads to increase in dynamic pressure and decrease of static pressure below the boiling point of water at room temperature. Due to this water starts boiling at room temperature and forms gas bubbles, which implode when the suspension leaves the gap (called cavitation) and normal air pressure is reached. The size of the drug nanocrystals that can be achieved mainly depends on factors like temperature, number of homogenization cycles, and power density of homogeniser and homogenization pressure.

Advantages

1. It does not cause the erosion of processed materials26.

2. Very dilute as well as highly concentrated nanosuspensions can be prepared by handling 1mg/ml to 400mg/ml drug quantity27.

3. It is applicable to the drugs that are poorly soluble in both aqueous and organic media.

4. It allows aseptic production of nanosuspensions for parentral administration28.

Disadvantages

1.  Preprocessing like micronization of drug is required.

2.  High cost instruments are required that increases the cost of dosage form.

C) Homogenisation In Nonaqueous Media (Nanopure)

The drugs that are chemically labile can be processed in such nonaqueous media or water-miscible liquids like polyethyleneglycol-400 (PEG), PEG1000 etc. The homogenization can be done at room temperature, 0o C and below freezing point (-20o C)16.

D) Combined Precipitation And Homogenization (Nanoedege)

The precipitated drug nanoparticles have tendency to continue crystal growth to the size of microcrystals. They need to be processed with high-energy forces (Homogenisation). The are in completely amorphous, partially amorphous or completely crystalline which create problems in long term stability as well as in bioavailability, so the precipitated particle suspension is subsequently homogenized which preserve the particle size obtained after the precipitation step16.

Properties of nanosuspensions

1. Physical Long-term Stability 

Dispersed systems show physical instability due to Ostwald ripening which is responsible for crystal growth to form microparticles. Ostwald ripening is defined as the tendency for a particle dispersion to grow in diameter over time; by a process in which the smaller particles dissolve because of their higher solubility, with subsequent crystallization onto larger particles to form microparticles. Ostwald ripening is caused due to the difference in dissolution velocity/ saturation solubility of small and large particles. In nanosuspensions all particles are of uniform size hence there is little difference between saturation solubility of drug particles. The difference in the concentration of the saturated solutions around a small and large particle leads to the diffusion of dissolved drug from the outer area of the large particles. As a result the solution around large particles is supersaturated leading to the drug crystallization and growth of the large crystals or microparticles. Ostwald ripening is totally absent in nanosuspensions due to uniform particle size, which is also responsible for long-term physical stability of nanosuspensions23,25.

2. Increase in Saturation Solubility and Dissolution Velocity of drug

Dissolution of drug is increased due to increase in the surface area of the drug particles from micrometers to the nanometer size. According to Noyes-Whitney equation (equation no.1) dissolution velocity increase due to increase in the surface area from micron size to particles of nanometer size.                             

Dx/dt = [( D x A/ h] [Cs-X/V] ------------------(1)

Where D is diffusion coefficient, A is surface area of particle, dx/dt is the dissolution velocity, V is volume of dissolution medium and X is the concentration in surrounding liquid.

According to the Prandtl equation, for small particles the diffusional distance h decreases with decreasing particle size. The decrease in h increases Cs (saturation solubility) and leads to an increase in gradient (Cs-Cx)/h and thus to an increase in the dissolution velocity. According to Ostwald-Freunddlich equation decrease in particle size below 1μm increases the intrinsic solubility or saturation solubility23,25.

3. Internal structure of Nanosuspensions

The high-energy input during disintegration process causes structural changes inside the drug particles. When the drug particles are exposed to high-pressure homogenisation particles are transformed from crystalline state to amorphous state. The change in state depends upon the hardness of drug, number of homogenisation cycles chemical nature of drug and power density applied by homogeniser23,25.

Evaluation of nanosuspensions25,29:–

A) In-Vitro Evaluations

1. Particle size and size distribution

2. Particle charge (Zeta Potential)

3. Crystalline state and morphology

4. Saturation solubility and dissolution velocity

B) In-Vivo Evaluation

C) Evaluation for surface-modified Nanosuspensions29

             1.Surface hydrophilicity

             2. Adhesion properties

             3. Interaction with body proteins

1) Mean particle size and size distribution

The mean particle size and the width of particle size distribution (called Polydidpersity Index) are determined by Photon Correlation Spectroscopy30 (PCS). Particle size and polydispersity index (PI) governs the saturation solubility; dissolution velocity and biological performance. It is proved that change in particle size changes saturation solubility and dissolution velocity. PCS measures the particle size in the range of 3nm-   3 µm only. PI governs the physical stability of nanosuspension and should be as low as possible for long-term stability. (Should be close to zero). PCS is a versatile technique but has low measuring range. In addition to PCS analysis nanosuspensions are analyzed by Laser Diffractometry (LD). LD measures volume size distribution and measures particles ranging from 0.05- 80μm upto 2000µm. Atomic Force Microscopy31 is used for visualization of particle shape.

2) Particle charge (Zeta Potential)

article charge determines the stability of nanosuspension. For electrostatically stabilized nanosuspension a minimum zeta potential of ±30mV and for combined steric and electrostatic stabilization it should be a minimum of ±20mV.

3) Crystalline state and particle morphology

Differential Scanning Calorimetry32 (DSC) determines the crystalline structure. When nanosuspensions are prepared drug particles get converted to amorphous form hence it is essential to measure the extent of amorphous drug generated during the production of nanosuspensions. The X-Ray Diffraction33 (XRD) is also used for determining change in physical state and extent of amorphous drug.

4) Saturation solubility and dissolution velocity

The nanosuspension increase the saturation solubility as well as dissolution velocity. Saturation solubility is compound specific constant depending upon temperature and the properties of dissolution medium. Kelvin equation and the Ostwald-Freundlich equations can explain increase in saturation solubility.

Conclusion

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Drugs with poor solubility and low bioavailability are called ‘brick dust’ candidates once abandoned from formulation development work can be rescued with nanosuspensions technology. A nanosuspension not only solve the problems of poor solubility and bioavailability but also alters the pharmacokinetics of drug and thus improves drug safety and efficacy.

References

1. Lipinski C. Poor aqueous solubility- an industry wide problem in drug discovery.  Am.pharm.Rev.2002;5: 82-85.

2. Elaine Merisko-Liversidge, Gary G. Liversidge, Eugene R.Cooper. Nanosizing: a formulation approach for poorly water-soluble compounds. Eur.J.Pharm.Sci.2003; 18:113-120.

3. Guidance for industry waiver of In-Vivo Bioavailability and Bioequivalence studies  for Immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System. CDER, Aug. 2000.

4. Nehal A.Kasim, Chandrasekharan Ramachndran, Marvial  Bermejo,Hans Lennernas Ajaz S.Hussain,Hans E.Junginger,Saloman A.et.al. Molecular Properties of WHO Drugs and provisional Biopharmaceutical Classification. Molecular Pharmaceutics.

5. Mitra Mosharraf, Christer Nystrom. The effect of particle size and shape on the surface specific dissolution rate of microsized practically insoluble drugs. Int.J. Pharm.1995; 122:35-47.

6. S.M.Wong,I.W.Kellaway,S.Murdan. Enhancement of the dissolution rate and oral absorption of a poorly water soluble drug by formation of surfactant-containing microparticles. Int.J.Pharm.2006; 317:61-68.

7. Parikh R.K.,Manusun SN.S.,Gohel M.C. and Soniwala M.M. Dissolution enhancement of Nimesulide using complexation and salt formation techniques. Indian drugs. 2005;42(3):149-154.

8.   Marazban Sarkari, Judith Brown, Xiaoxia Chen, Steve Swinnea, Robert O.   Williams III , Keith P. Johnston. Enhanced drug dissolution using evaporative      precipitation into aqueous solution. Int.J.Pharm.2002; 243:17-31. 

9.  True L.Rogers, Ian B. Gillespie, James E. Hitt, Kevin L.Fransen,Clindy A. Crowl,Chritoper J.Tucker, et.al. Development and characterization of a scalable controlled precipitation process to enhance the dissolution of poorly soluble drugs.  Pharm.Res.2004;21(11):

10.   Riaz M., Stability and uses of liposomes. Pak.Pharm.Sci.1995;8(2): 69-79.

11.  Jadhav KR,Shaikh IM,Ambade KW, Kadam VJ. Applications of microemulsion  based drug delivery system. Cur. Dr. del.2006; 3(3): 267-273.

12   Leuner C.Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur.J.Pharm.Biopharm.2000;50(1): 47-60.

13.Challa R.,Ahuja A., Ali J., Khar RK. Cyclodextrins in drug delivery: an updated      Review. AAPS Pharm.Sci.Tech. 2005;6(2): E329-357.

14. Kostas Kostarelos The emergence of    Nanomedicine. 2006;1(1):1-3.

15. Chowdary K.P.R. and Madhavi B.L.R., Novel drug delivery technologies for      insoluble drugs. Ind.Drugs.2005;42(9): 557-563.

16. Cornelia M. Keck,, Rainer H. Muller. Drug nanocrystals of poorly soluble drugs     produced by high-pressure homogenisation. Eur. J. Pharm.Biopharm.2006;62: 3–16.

17. Rao G.C.S., Satish Kumar M., Mathivnan N.and Rao .E.B. Advances in     nanoparticulate drug delivery systems. Ind.Drugs.2004;41(7):389-395.

18. R.H.Muller, S.Gohla.A.Dingler, T.Schneppe. Large-scale production of solid-lipid nanoparticles (SLN) and nanosuspension(Dissocubes). In D.Wise (Ed.) Handbook of pharmaceutical controlled release technology.2000;359-375.

19. Barret E.Rabinow. Nanosuspensions in drug delivery. Nat. rev.2004;(3): 785-796.

20.Shobha Rani, R.Hiremath and Hota A. Nanoparticles as drug delivery systems. Ind.J.Pharm.Sci.1999; 61(2): 69-75.

21.Mehnertw, Mader K. Solid lipid nanoparticles: Production, characterization and      applications. Adv.Drug Deliv. Rev. 2000; 47(2-3): 165-96.

22.Mahesh V.Chaubal. Application of formulation technologies in lead candidate     selection and optimization. Drug Dis.Today.2004; 9(14):603-609.

23.V.B.Patravale, Abhijit A.Date and R.M.Kulkarni. Nanosuspensions: a promising drug delivery strategy. J.Pharm.Pharcol.2004; 56: 827-840.

24. Kirpukar B.K. Nanosuspensions in drug delivery : Technology and applications. Express Pharma Pulse. 2005;34-35.

25. R.H.Muller, B.H.L.Bohm and .J.Grau. Nanosuspensions : a formulation approach for poorly soluble and poorly bioavailable drugs. In D.Wise (Ed.) Handbook of pharmaceutical controlled release technology.2000;345-357.

26.K.P. Krause, O. Kayser, K. Mader, R. Gust, R.H. Muller. Heavy metal intamination of nanosuspensions produced by high-pressure homogenisation. Int J. Pharm.2000;196:169–172.

27. K.P.Krause,R.H.Muller. Production and characterization of highly concentrated nanosuspensions by high pressure homogenisation. Int.J.Pharm.2001;214:21-24.

28.Jan Moschwitzer,Georgr Achleitner, Herberk Pomper, Rainer H.Muller. Development of an intraveneously injectable chemically stable aqueous omeprazole formulation using nanosuspension. Eur. J. Pharm. Biopharm.2004;58:615-619.

29. R.H.Muller, C.Jacobs, O. Kayser. Nanosuspensions as particulate drug formulations in therapy Rationale for development and what we can expect for the future. Ad.Drug Del.Rev.2001;47:3-19.

30. B.W.Muller, R.H.Muller. Particle size analysis of latex suspensions and microemulsions by Photon Correlation Specroscopy.J.Pharm.Sci.1984; 73: 915-918.

31. Montasser, H. Fessi, A.W. Coleman. Atomic force microscopy imaging of novel type of polymeric colloidal nanostructures. Eur. J.Pharm.Biopharm.2002;54:281–284.

32. Laura Bond, Stephanie Allen, Martyn C. Davies, Clive J. Roberts, Arif P. Shivji,Saul J.B. Tendler , Phillip M. Williams, Jianxin Zhang. Differential scanning calorimetry and scanning thermal microscopy analysis of pharmaceutical materials.Int.J.Pharm.2002;243:71–82.

33.  Scholer,N.,Krause,K.,Kayser,O.,Muller,R.H.,Borner,K.,Hahn,H.,Liesenfeld,O. Atovaquone nanosuspensions show excellent therapeutic effect in a new murine model of reactivated toxoplasmosis. Antimicrob.Agents Chemother.2001;45:1771 –1779.

34.  Gary G. L i v e r s i d g e, Kenneth C. Cundy Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral  bioavailability of nanocrystalline danazol in beagle dogs.Int.J. Pharm.1995;125:91-97

35.  Liversidge G.G.and Conzentino P. Drug particle size reduction for decreasing gastric irritancy and enhancing absorption of naproxen in rats.Int.J.Pharm.1995;125:309-313.   

36.Yajun chen, Jie Liu, Xiang Yang,Xiaoling Zhaw and Huibixu. Oleonolic acid nanosuspensions: preparation, optimization and enhanced hepatoprotective effect. J.Pharm.Pharmacol.2005;57: 259-264.

Table 1

Potential benefits of nanosuspension technology over other conventional formulations technologies for poorly soluble drugs22.

Route of administration

Potential benefits

Oral

Rapid onset

Reduced fed/fasted ratio

Improved bioavailability

Intravenous

Rapid dissolution

Tissue targeting

Ocular

Higher bioavailability

More consistent dosing

Inhalation

Higher bioavailability

More consistent dosing

Subcutaneous/ intramuscular

Higher bioavailability

Rapid onset

Reduced tissue irritation

Table 2

Drug

Indications

Route

Status

Paclitaxel

Anticancer

i.v.

Phase IV

Rapamuane

Immunosupperesant

Oral

Marketed

Emend

Antiemetic

Oral

Marketed

Budesonide

Antiasthamatic

Pulmonary

Phase I

Busulfan

Anticancer

Intrathecal

Phase I

Fenofibrate

Hypolidemic

Oral

Phase I

Thymectacin

Anticancer

I.V.

Phase I/II

Insulin

Antidiabetic

Oral

Phase I

Calcium Phosphate

Mucosal vaccine adjuvant for Herpes

Oral

------

Silver

Eczema, atopic dermatitis

Topical

Phase I

Cytokine Inhibitor

Crohn’s disease

Oral

Phase II

Figure 1

The criteria for selection of various technologies to enhance solubility of poorly soluble drugs24.

The criteria for selection of various technologies to enhance solubility of poorly soluble drugs

Nanosuspensions formulation approach is used for drugs with high log P value, high melting point and high dose.

Figure 2

Methods of Preperation of Nanosuspensions by various methods.

Methods of Preperation of Nanosuspensions by various methods

Dr.A.V.Yadav

Dr.A.V.Yadav
M.Pharm.,Phd.,AIC,LLB,   HOD Pharmaceutics,   Govt.College of Pharmacy,KArad 415124,   Dist:Satara, Maharashtra,India.

Mr.Shripawan G.Kalaskar

Mr.Shripawan G.Kalaskar
M.Pharm.(Biopharmaceutics)

Mr.Vijay B.Patil

Mr.Vijay B.Patil (Author)
M.Pharm.(Biopharmaceutics)

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