Nanocrystals for parenteral use

1

NANOCRYSTALS

IN PARENTERAL USE

LOGO

CREDIT SEMINAR (GE-511)

PRESENTED BY

DEVESH KUMAR JAIN

M.S. (PHARM.) 1st SEMESTER

DEPARTMENT OF PHARMACEUTICS

National Institute of Pharmaceutical Education and Research

NANOCRYSTALS IN PARENTERAL USE

3

FLOW OF PRESENTATION

Introduction

Methods of Preparation

Properties of Nanocrystals

Parenteral administration of Nanocrystals

Nanocrystalline Solid Dispersion Technology (NanoCrySP)

4

INTRODUCTION

Nanocrystals Drug nanocrystals are particles made from 100% drug

Stabilized by surfactants or polymeric steric stabilizers

Nanocrystals have size ranges from 1-1000 nm

Need of Nanocrystals At present about 40% of the drugs being in the development pipelines are poorly

soluble

70% of the potential drug candidates are discarded due to low bioavailability

They can increase the solubility of poorly soluble drugs e.g. Curcumin

Gao et al. Journal of Controlled Release, 160 (2012) 418-430

5

METHODS OF PREPARATIONMethods

Bottom-up Technique

Precipitation Technique

Top-down Techniques

Size-reduction Techniques

Combination-Techniques

Bottom-up Technique

Poorly water soluble drug

Dissolved in Organic solvent

Add non-solvent

Rapid Nucleation & Precipitation

or

or

Muller et al. European Journal of Pharmaceutics and Biopharmaceutics, 78 (2011) 1-9

6

Top-down Techniques

1. Pearl / Ball milling by Elan Nanosystems

Marketed products are Rapamune®, Emend®, Tricor®, Megace ES®

2. High Pressure Homogenization (HPH) Technique : 3 types

Microfluidizer technology Piston gap homogenization in water

Piston-gap homogenization in water reduced mixtures or non-

aqueous medium

321

Nanopure® technologyMicrofluidizer®

technologyDissocubes®

technology

METHODS OF PREPARATIONCont…

Gao et al. Journal of nanoparticle research, 10 (2008), 845-62

7

Combination-techniques

METHODS OF PREPARATION

Bottom-up

Top-down

NanoEdge® technology

Microprecipitation +

Homogenization

SmartCrystal® technology

Spray-drying+

High Pressure Homogenisation

Combinationtechniques

Cont…

Muller et al. European Journal of Pharmaceutics and Biopharmaceutics , 78 (2011) 1-9

PROPERTIES OF NANOCRYSTALS

Increasing Saturation solubility: f (Dissolution pressure)

Macro ParticleMiroparticle Nanoparticle

Highest Dp Increase dissolution velocity: f (surface area)

A= 60,000 µm2 A= * 10

A= *5000 Increase adhesiveness: f (contact area)

Increased contact area

8Muller et al. European Journal of Pharmaceutics and Biopharmaceutics , 78 (2011) 1-9

9

Particle Size is strictly controlled for parenteral purposes

Increase in drug solubility due to increased surface area

Safe Composition in terms of reduced dose and reduced solvent-related adverse

effects

Tolerance to Various Sterilizations such as gamma irradiation, filtration

sterilization, and thermal sterilization

Attenuate side effects related to transient high systemic exposure

PROPERTIES OF NANOCRYSTALSCont…


10

PARENTERAL ADMINISTRATION OF NANOCRYSTALS

Intravenous Administration

Ophthalmic Administration

Pulmonary Administration

Intramuscular Administration

Following routes are considered for administration:

11

Particle size should be less than 5 µm to avoid blockade of blood capillaries

Nanosuspension is a dosage form of nanocrystals stabilized by surface active

agents in a solvent

Engulfment of nanocrystals in relation with their size:

Intravenous administration

Gao et al. Journal of nanoparticle research, 10 (2008), 845-62

12

Consequence of Nanosuspension after

administration

Opsonin protein is adsorbed on the surface of nanocrystals, so they recognised by RES system

This should be avoided for cancer targeting since Nanocrystals is coated by albumin, dextran & PEG by physical adsorption

Recognized as foreign matter

Rapidly cleared by phagocytic cells of mononuclear phagocyte system (MPS) which abounds in special tissues and organs, such as liver, lung and spleen

Passive Targeting process Used in cancer of liver &

lungs

Intravenous administrationCont…

Muller et al. European Journal of Pharmaceutics and Biopharmaceutics, 78 (2011) 1-9

13

Intracellular delivery of Nanocrystalsin MPS cells

Within 5 min after injection, up to 90% of the injected dose is taken up by the

liver macrophages (Kupffer cells) and about up to 5% by the spleen macrophages

High concentration of drug nanocrystals in the macrophages can lead to cytotoxic

effects, especially when delivering anti-cancer drugs

After accumulation of the drug in the liver, the liver acts as depot slowly releasing

the drug into the blood

A nanosuspension injection could replace a longer lasting infusion of a drug

solution



14

Interaction with the endothelialcells of the BBB

To direct nanocrystals to other cells in the body than the MPS, firstly they need to

avoid recognition by the immune system to enable them to circulate in the blood.

Secondly a homing device needs to be attached

For Brain specific Nanocrystals, the design & size of Nanocrystal should be such

that Apolipoprotein E adsorbed on its surface called Differential Protein

adsorption

This is observed by Kreuter et al by stabilising Nanocrystals by Tween 80 for

delivering drug Dalargin to the brain



15



16

Ophthalmic Administration

Problems in Ocular Delivery

Extensive drug loss

Frequent application

Low bioavaila

bility Low MRT

Minimal irritation

Bio-adhesion to eye tissue

Longer drug effect

Minimal drug loss

Advantages with Nanocrystals

Bansal et al. International Journal of Reasearch in Pharmaceutical and Biomedical Sciences , 3 (2012) 406-419

17

Pulmonary and IM administration

Pulmonary administration

Nanocrystal dissolves rapidly in lung

linings leading high conc.

Diameter of droplets should be 1-5

µm for delivery in bronchioles

Beneficial for local respiratory

diseases

Have higher lung-serum ratio of drug

So reduce systemic side effects

Intramuscular Administration

For longer action of drug

Better than conventional oily micro

suspension given in table belowFor a drug curcumin

Parameters IM Nanocrystals Oily micro- suspension

Plasma level conc. >10ng/ml 2-6 ng/ml

MRT Atleast 10 days 4-5 days

Bansal et al. International Journal of Reasearch in Pharmaceutical and Biomedical Sciences 3 (2012) 406-419

18

NANOCRYSTALLINE SOLID DISPERSION (NanoCrySP)

NanoCrySP is a novel spray drying based technology to generate solid particles

containing API nanocrystals dispersed in small-molecule excipients

A solution of API and excipients in a solvent or solvent mixture is spray dried to

obtain discrete particles of 2 to 10 micron size

Each particle consist of API nanocrystals in the range of 10-1000 nm

Indian Patent Application No. is 674/DEL/2012 and PCT Application no. is

PCT/IB2013/051807

Indian Patent Application no. 674/DEL/2012 PCT Application no. is PCT/IB2013/051807

Developed in NIPER S.A.S. Nagar (Mohali)

19

Process of NSD FormationDrug and excipient in solution

Solution spray through nozzle

Annealing of amorphous bed

Evaporation of solvent

Solvent

Excipient

Drug

A drop of drug excipients and solvent

Amorphous drug in metrix of excipient

Nanocrystals of drug in matrix of excipients

Indian Patent Application no. 674/DEL/2012 PCT Application no. is PCT/IB2013/051807

20

Aspirin NSD:Developed by NanoCrySP Technology

Each year cardiovascular disease (CVD) causes an estimated 17 million deaths

worldwide

In developed countries heart disease and stroke are the first and second leading

cause of death among adult men and women

Aspirin (ASP) as a inhibitor of cyclooxygenase is very beneficial in patients with

acute coronary syndrome and acute myocardial infarction

Marketed aspirin tablets takes 7.5-10 min to reach in blood but this lag time may

be fatal for a MI suffering patient

So NIPER is working on ASP-NSD for faster onset of action, as a life saving drug-

technology

21

Aspirin NSD: Developed by NanoCrySP Technology

Preparation of ASP-NSDs

Prepared by using laboratory scale Spray dryer

Generated by co-spraying mixture of ASP and crystallization inducing excipients

viz. mannitol, sucrose, sorbitol, and dextrose

Solution is spray dried at inlet and outlet temperature 40⁰C and 30⁰C respectively

Characterization of generated ASP-NSDs

SEM images with sucrose & TEM images with mannitol are

dextrose excipients are

Cont…

Kataria et al. International Journal of Pharmacy, 3 (2012) 5-10

22THANK YOU !

Nanocrystals for parenteral use

Health & Medicine

Transcript of Nanocrystals for parenteral use