Nasal and pulmonary delivery system - Nainesh patel

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Nasal and Pulmonary Delivery System

Nainesh Patel

Email :[email protected]

(M) +919158659501

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Nasal Delivery Platforms

Nasal Delivery System.

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The nasal route is commonly used

for the delivery of drugs to alleviate

a number of local disorders such as

sinus congestion and allergic

rhinitis.

It is also begging utilized as an

alternative to oral and injection

methods for the systemic delivery

of a variety of drug including

vaccines, proteins and peptides.

Advantages of Nasal delivery.

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The large surface area for absorption in the nose ,coupled with the

high density of blood vessels, enables efficient absorption into the

blood stream.

Rapid onset of action compared to oral delivery.

Avoiding enzyme degradation of the drug with in the GI tract and

first pass hepatic metabolism.

Painless delivery compared to Injection delivery.

Targeting the Nose

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Regulatory /Analytical Application for Nasal spray.

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CMC specifications for Nasal spray

Bioequivalence In vitro test

One time characterization study

CMC specifications for Nasal spray.

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Appearance

Identification

Assay

Related substance

Particulate matter

Microbial limits

Net content

Leachable and Exactable

Weight loss on stability

pH

Osmolality,

Viscosity

Pump delivery

Spray content uniformity

Spray pattern

Plume geometry

Droplet size distribution.

Particle size distribution.


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Appearance

Priming and Repriming

Spray pattern

Plume geometry

Small droplet size by Cascade Impactor

Droplet size distribution by Laser Diffraction

Microscopy for suspension.

One time characterization study.

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Appearance

Priming and repriming in various orientations

Device robustness ( Shaking, Dropping, Vibrating )

Effect of dosing orientation (60°,75°and 90°)

Profiling of sprays near container exhaustion (tail off

characteristics)

Preservative effectiveness

Photo stability

Cleaning instructions

Test and Related method/Instrument

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Appearance-

Identification-

Assay-

Related substance-

Particulate matter-

Microbial limits-

Net content-


Weight loss on stability-

By visual method

By FTIR/HPLC/TLC

By HPLC

By HPLC

By visual/By Instrument

By Micro

By Analytical balance

By HPLC/GC/GC MS

By Analytical balance

Test and Related method/Instrument

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Pump Delivery

Spray pattern

Plume geometry

Droplet size

Small droplet size by ACI

-By NSP UA actuator

-By ADSA-Spray view

-By ADSA-Spray view

-Spraytec-Malvern

-Expansion chamber with ACI

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pMetered Dose Inhaler

&

Dry Powder Inhaler Delivery Platforms.

pMDI & DPI Delivery System.

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Inhaled drug product are becoming

increasingly popular means of local

or systemic therapy via lungs.

(a) locally(directly) to treat lung

diseases such as asthma and chronic

obstructive pulmonary

diseases(COPD) and to deliver

locally-acting drugs such as

antibiotics and antiviral directly to

the lungs to curb infection.

(b) systemically, for example in

pain relief and anesthetic

applications.

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Pulmonary delivery offers a number of advantages compared to

the more traditional oral and parental routes.

Directly targets the lung.

Rapid onset of drug action.

Drug effective in relatively low doses.

Fewer side effects.

Avoids hepatic metabolism.

Injection-free administration.

Advantage of pMDI & DPI Delivery

System.

Regulatory /Analytical Application for pMDI

& DPI.

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CMC specifications for Metered Dose Inhaler


(Till date no draft/Finial guidance for In vitro study.)

One time characterization study

CMC specifications for pMDI &DPI.

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Appearance and color

Identification

Microbial limits

Water or Moisture content

Assay of Dehydrated Alcohol(if used as co solvent)

Net content

Assay (drug content)

Related substance

Dose content uniformity.

Dose content uniformity through container life.

Particle size distribution

Microscopic evaluation.

Spray pattern

Plume geometry

Leak rate

Pressure Testing

Valve delivery (shot weight)


One time characterization study.

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Determination of Appropriate storage conditions.

Stability of primary(unprotected)package.

Temperature cycling.

Effect of resting time.

Priming and repriming in various orientations.

Effect of storage on the particle size distribution.

Drug deposition on mouth piece and/or Accessories.

Cleaning instructions.

Profiling of sprays near container exhaustion (tail off characteristics).

Plume geometry.

Microbial challenge.

In vitro Dose Proportionality.

Effect of varying flow rate.

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Instrument and various technique used for Nasal

Spray, Metered Dose Inhaler, Dry Powder Inhaler.

Basic set up for determination of

Aerodynamic particle size.

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Aerodynamic particle size by Anderson

Cascade Impactor.

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Anderson cascade impactor is mimic of the pulmonary track and

Lungs.

Cascade impactor testing is the principal technique and key parameters

for determining metrics that describe Aerodynamic particle size

distribution of Orally Inhaled Products. Like MDI,DPI and Nasal

spray.

Based on Aerodynamic particle size distribution data, we can

predicted and optimized of drug deposition characteristic in the human

respiratory tract.

Cascade impactor operates on the principle of internal impaction.

i.e separation is provided on the basis of difference in inertia –a function

of particle size and velocity.

Aerodynamic particle size by Anderson Cascade Impactor.

Aerodynamic particle size by NGI

Next generation Impactor.

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Aerodynamic particle size by NGI

Next generation Impactor.

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Next Generation Impactor (NGI) is mimic of the pulmonary track

and Lungs.

Next Generation Impactor (NGI) testing is advanced technique and key

parameters for determining metrics that describe Aerodynamic

particle size distribution of Orally Inhaled Products. Like MDI,DPI

and Nasal spray.

Based on Aerodynamic particle size distribution data, we can

predicted and optimized of drug deposition characteristic in the human

respiratory tract.

Cascade impactor operates on the principle of internal impaction.

i.e separation is provided on the basis of difference in inertia –a function

of particle size and velocity.

Moisture content by coulometer with

Automated actuation.

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Basic Actuation system for Nasal

spray and pMDI.

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• Reduce operators induced subjectivity.

•Actuation parameters relevant to patient use.

Droplet size Distribution by Spraytec-

Malvern UK.

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Droplet size Distribution by Spraytec-

Malvern UK.

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Droplet size Distribution by Spraytec.

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A typical nasal spray formulation consists of a bottle with a metered spray pump, containing the drug suspended or dissolved in a aqueous medium.

Pump actuation by the patient delivers drug laden droplets in to the nasal cavity.

Most nasal spray pumps produces droplets in the size range from 20 µm to 120 µm. It is critically important that the droplets are of a size that enables their deposition within the nasal passages.

If droplet are too small (< 10µm), particle/droplet may pass through the nasal passages and deposit in the lungs. Potentially allowing deposition of drug and Excipients not approved for pulmonary absorption. If droplet are too large, particle/droplet may trapped in nostril.

Spray pattern and Plume geometry by

ADSA-Innova system-US

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Spray pattern and Plume geometry by

ADSA-Innova system-US

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Spray pattern Plume geometry

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Automated testing of nasal spray pumps yields test data that are more reliable than the data that result from manual methods. That is because spray patterns depend so heavily on actuation velocity and acceleration. For example:

• High actuation velocity and acceleration produce smaller droplets in a more atomized cloud.

• Low actuation velocity and acceleration levels produce larger droplets in more stream-like sprays.

The FDA requires these two tests spray pattern and plume geometry in submissions for approval of drugs.

Spray pattern and Plume geometry -Theory

Spray pattern and Plume geometry -Theory

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The FDA recommends that test labs use automated actuation

systems to reduce variability in these measurements due to

operator factors. Automated actuation also increases measurement

sensitivity, in order to detect differences among products.

During product development, analysts can use these

measurements to design a delivery system that accounts for the

properties of the fluid that carries the drug. Automated testing also

helps to find acceptable tolerances for variables of interest during

stability testing. Lastly, quality control of release grade products

requires highly consistent test methods and sensitive measurement

technologies.

Emitted dose by Glass Twin Impinger.

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Emitted dose by Glass Twin Impinger.

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Glass Twin impinger developed at GSK lab.UK and it is recognized

as apparatus A in Ph.Eur.2.9.18.

It is designed such that at a flow rate 60.0 L/min through the

impinger.

The particle cut off diameter is 6.4 microns. Particle smaller than

6.4 microns pass in to the lower impingement chamber.

The value of the Glass Twin impinger, particularly with respect to

routine quality control application.

Glass Twin impinger used for routine QC applications.

Delivered Dose by DUSA.

(Dose Unit Sampling Apparatus)

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For pMDI/ DPI For Nasal spray

Delivered Dose by DUSA.

(Dose Unit Sampling Apparatus)

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The Delivered dose is the total amount of drug emitted from the

medical device and hence available to the patient/user.

It is used to perform those tests specified in the pharmacopoeia

relating to Delivered or emitted dose namely “Delivered Dose

Uniformity and Delivered Dose Uniformity over the Entire

contents.

It is designed such that at a flow rate 28.3 L/min including filter

and inhaler..

Small Droplet size by Anderson

cascade Impactor.

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Small Droplet size by ACI.

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A two-liter or larger induction port (expansion

chamber) is preferred to this test.

The total mass of drug below the top stage is of primary

interest.

The total mass of drug collected on all stages and

accessories is recommended to be between 85 and 115

percent of label claim on a per actuation basis.

Brief Summary of Sophisticated

Instrument.

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Instrument/Make Application

Anderson Cascade Impactor-Westech Scientific Instruments-

UK/Copley Scientific ,UK

Aerodynamic particle size Distribution

for MDI,DPI and Nasal spray.

Next Generation Impactor-

Copley Scientific ,UK

Aerodynamic particle size Distribution

for MDI,DPI and Nasal spray.

Aerosol Drug Spray

Analyser(ADSA)

Innova system ,USA,

Determination of Spray pattern and

Plume geometry for MDI and Nasal

spray.

SPRAY VIEW® -Image Therm,Proveris Scientific,USA.

Determination of Spray pattern and

Plume geometry for MDI and Nasal

spray

Spraytec-Malvern, UK. Droplet size distribution by laser

diffraction for MDI and Nasal spray

Brief Summary of sophisticated

Instrument.

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Instrument/Make Application

Glass Expansion chamber-Westech Scientific Instruments-UK/Copley

Scientific ,UK

Determination of Small droplet size

for Nasal spray.

Delivered Dose Uniformity Apparatus.(DUSA)-

Westech Scientific Instruments-UK/Copley

Scientific ,UK

Determination of Uniformity of

Delivery

Glass Twin Impinger.-

Copley Scientific ,UK./Westtech Instrument.

Determination of Emitted dose

Delivery

New High Capacity Pump Model HCP5.

Westech Scientific Instruments-UK/Copley

Scientific ,UK.

Common Utilities for Testing.

Copley Inhaler Testing Data Analysis Software.

(CITDAS –V-3.00)

To calculate MMAD and GSD.

Regulatory bodies.

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ANVISA (Brazil) : Pharmaceutical Equivalence and Bioequivalence of

Nasal Spray and Aerosol Drug.

EMEA (Europe) -Nasal spray-inhalation-suspension 2006.

Health Canada (Canadian guidelines)-Nasal spray-inhalation

November 2003.

CDER (US): Nasal Spray and Inhalation Solution, Suspension, and Spray

Drug Products - Chemistry, Manufacturing, and Controls Documentation.

CDER (US): Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI)

Drug Products Chemistry, Manufacturing, and Controls Documentation.

US Pharmacopeia :601-Aerosole, Nasal sprays, Metered Dose Inhalers

and Dry powder inhalers.

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Thank You!

Nasal and pulmonary delivery system - Nainesh patel

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