Respi dosage forms

uses of intranasal delivery

Topical drug delivery

Treatments of congestion, rhinitis, sinusitis etc

Systemic drug delivery (mainly to brain)

Alzheimer's disease, epilepsy, brain tumors etc

advantages of intranasal delivery

Rapid onset of drug action

Hepatic and gastrointestinal metabolism avoidance

Noninvasiveness and ease of access

No sterilization requirements (vs parenteral) -> lower costs

Non-irritative (if designed properly)

Can be used for prolonged periods

nasal mucus - properties

Thickness: 5um

Composition

95% water

2.5-3% mucin (glycoprotein)

2% of electrolytes, proteins, lipids, enzymes, antibodies, sloughed epithelial cells and bacterial products

nasal mucus - functions

Humidification and warming of the inhaled air

Physical and enzymatic protection of the nasal epithelium against several foreign compounds, including drugs

Filter out particles larger than 3–10 um --- > nanoparticles can diffuse faster through mucus

Topical drug delivery --- > broad distribution of drug on the mucosal surfaces is desirable

function of nasal airflow

Air flows superiorly into the nares, the passes through the nasopharynx, pharynx, larynx, trachea and reach the lungs

Upper airways narrowing allows for close contact b/w airstream and mucosal surfaces

Evaporation of fluid from mucosal blanket -> humification of air

Contact b/w air and blood supply in nasal membranes (esp inferior turbinate mucosa)

Nasal illnesses e.g. inflammation, allergies, sinusitis can obstruct nasal airflow

Sniffing forces air into superior nasal vault -> better contact with olfactory mucosa

factors affecting intranasal delivery

Vol: Limited drug administration (~100-150 ul) -> affects dose+ freq of administration

MCC: Drug must pervade through the mucus and cells to reach blood/brain. High permeability is desirable. Drug trapped in mucus can be cleared by MCC

Mucoadhesive agents e.g. chitosan can be employed to lower MCC rate. Increasing viscosity of mucus or drug formulation can decrease MCC rate. Drug formulations with high viscosity e.g. gels allow for longer retention time and thus increased absorption

pH: should be b/w 5.0-6.5 to prevent irritation in nasal mucosa

Drug absorption in nasal cavity: Drug molecules need to move across the mucus layer, epithelial layer, basement membrane, and capillary endothelium

what is mucociliary clearance

Inhaled particles/pathogens adhere to mucus layer

Cilia provide the driving force to move adhered particles/pathogens to nasopharynx & GIT at average speed of 6mm/min (3-25mm/min)

Mucus transit time in human nasal cavity is 15-20min

Drug deposited in posterior area of nose is cleared more rapidly than anterior. MCC is slower in ant part of nose (less cilia)

factors affecting MCC

Temp -> higher temp = faster MCC

Sulphur dioxide leads to sig reduction in MCC (unknown mechanism)

Cigarette smoke enhances mucus viscosity and/or diminishes cilia no. (decreases MCC)

how is drug absorbed in the nasal cavity

Epithelial layer: Pseudostratified columnar cells linked by tight junctions

Transcellular diffusion: Mainly for small lipophilic drug compounds

Pass through epithelial cell membrane down conc grad. Usually require a selective transport system to cross lipid bilayer of membrane

Paracellular diffusion: For large and polar drugs

Tight junctions act as barriers, large molecules with molecular radii > 11nm cannot pass through

factors affecting drug absorption in nasal cavity

Drug molecule & formulation properties

Design of delivery device

Application technique

Ideal drug candidates for topical delivery: Hydrophilic (low permeability through membrane)

Ideal drug candidates for nose-to-brain/systemic delivery: Lipophilic (high permeability through membrane)

physicochemical properties of drug molecules affecting delivery

molecular weight

lipophilicity

pKa

Aqueous solubility

physicochemical properties - molecular weight

Lower molecular weight gives better absorption

Lipophilic drugs: Molecular weight < 1 k Da --- > well absorbed

Polar drugs

Molecular weight < 300 Da --- > permeation not considerably influenced by physicochemical properties

Molecular weight > 300 Da --- > lower permeation rate for higher molecular weight

physicochemical properties - lipophilicity

Determined experimentally as partition coefficients (log P) or distribution coefficient (log D)

Log P --- > P = C octanol / C water

Log D --- > D = C octanol / C water (at specific pH)

Log P or Log D > 0 --- > lipophilic

Log P or Log D < 0 --- > hydrophilic

Nasal membrane is lipophilic thus lipophilic drugs are absorbed well in nasal cavity. Pharmacokinetic profiles similar to intravenous administration. Bioavailability ~ 100%

Polar drugs most affected by MCC: Highly soluble in mucus and their passage through membrane is very slow

physicochemical properties - pKa

Strength of acid in solution. Lower pKa --- > stronger acid

pKa affects the ionization of drug molecule at specific pH, especially for polar drugs

Adjust pH to be 1.5 to 2 pH unit below pKa for acid to suppress ionization

Adjust pH to be 1.5 to 2 pH unit above pKa for base to suppress ionization

Non-ionized drug molecules are well absorbed

physicochemical properties - aqueous solubility

Drugs with poor aq solubility and/or requiring high doses can be problematic

Aqueous solubility enhancement by co-solvents and surfactants

Nano emulsion (NE) particles approximately the size of 100 nm or smaller remained longer in the nasal cavity

what are the types of drug absorption enhancers

surfactants

enzyme inhibitors

tight junction modulators

cationic polymers

drug absorption enhancers - surfactants

Amphiphilic molecules with lipophilic and hydrophilic residues

Improve absorption by disrupting the cell membrane through membrane protein leaching and opening tight junctions

Can prevent degradation of drugs by enzymes

e.g. phospholipids, bile salts + derivatives, fatty acids, non-ionic surfactants, alkyl glycosides

drug absorption enhancers - enzyme inhibitors

Aminopeptidases and proteases are the majority of enzymes found in the nasal pathway and lungs

Drugs that are peptides, proteins, and nucleic acids are particularly susceptible to the degradation by these enzymes

enzyme inhibitors help prevent degradation

Examples: Bacitracin, leupeptin, soybean trypsin inhibitor, bestatin and phosphoramidon

drug absorption enhancers - tight junction modulators

Open tight junctions for large molecules (>11 nm in radii) to pass through

e.g. claudin

drug absorption enhancers - cationic polymers

Interacts electrostatically with mucin chains that are negatively charged

Negatively charged molecules can interact with cationic polymer to improve absorption by prolonging the residence time of the drug in the mucosa

Examples: cationic gelatins, cationic pullulans, polyethylenamine, chitosan and poly-L- arginine

safety concerns for intranasal delivery

Excipients can reduce safety of final therapeutic product

Benzalkonium chloride - preservative

Commonly used preservation in intranasal formulations

Cilia toxicity in vitro + vivo have been reported occasionally

types of intranasal delivery preparations

Vapor: e.g. decongestants (menthol) for rhinitis

Nasal drops -> dropper/squeeze bottle

Nasal wash: saline irrigation for rhinitis

Nasal stick: menthol stick

Nasal gel (semi solid): hydration of nasal passage

Nasal spray & powder

precautions when using intranasal products

Sensitive nature of nasal mucosa

Direct contact of the tip of the spray nozzle during actuation & localized concentrated anterior drug deposition on the septum can cause mechanical irritation and injury to the mucosa, causing nosebleeds and crusting, and potentially erosions or perforation

High-speed impaction and low temperature of some pressurized devices may cause unpleasant sensations reducing patient acceptance and compliance

intranasal delivery - nasal unit/bidose system

Advantages

Avoidance of preservatives

Portable

High dose accuracy

Requires aseptic filling of device

Suitable for cost extensive and sensitive drug substance

intranasal delivery - metered dose pump

Most common in market

Dose vol: 25-200 uL

Advantages: High dosage accuracy, High reproducibility of plume geometry

Particle size + plume geometry depend on Pump properties, Formulation properties, Actuator orifice, Applied force

intranasal delivery - nebulizer

Breaks up medical solutions/suspensions into small aerosol droplets using:

Compressed gasses (air, oxygen, nitrogen)

Ultrasonic power

Mechanical power

Smaller particles and slows speed of nebulized aerosol. Improved deposition to upper narrow part of the nose (vs metered-dose spray pump)

developmental considerations - delivery device

Liquid (most cases), solid or gel

Dosing frequency -> single or multi-dose delivery system

Compatibility of formulation with delivery device -> choice of device materials

Sorption of formulation -> swelling/discoloration of device components

Immersion tests of the functional parts of the pump in the formulation

developmental considerations - formulation

Drug molecule -> concentration, stability

Co-solvent -> solubility of drug molecule

pH -> 5.0 – 6.5

Osmolality -> hypotonic nasal spray formulations improve drug permeability through the nasal mucosa; typical range: 300 – 700 mOsmol/K

Viscosity/surface tension -> drop particle size, spray angles, residence time in the nasal cavity

Penetration enhancers -> co-solvents, ionic and some non-ionic surfactants, selected fatty acids and cyclodextrin

Preservative

nanocarriers for intranasal delivery

Topical delivery

Topical steroids are poorly distributed in the sinuses and nose, limiting therapeutic outcomes

Use nanocarrier technology can enhance bioavailability and patience compliance

Examples of nanocarriers: Lipid nanoparticle, Nanoemulsion, Polymeric nanoparticle

Nose-to-brain delivery

Target olfactory region, the only site in the human body that allows direct contact of CNS with external environment

Allows bypass of BBB

formulation considerations - priming

Fill the dosing chambers before use and to assure full dosing of the product

Re-priming -> some pumps do not retain the dose in the metering chamber when stored for longer periods (7 days, 1 month etc)

formulation considerations - spray pattern

Ovality of emitted spray -> plume shape + spray angle

Depending on particle size distribution, actuator design

orifice diameter, actuation velocity, actuation acceleration, stroke length etc

Drag force on droplets

formulation considerations - particle size distributions

Viscosity, surface tension

High surfactant conc, lower surface tension

Ideally > 10 μm, when < 10 μm, droplets can travel further down the respiratory tract past nasopharynx (bitter aftertaste)

Most nasal spray pumps produce droplets in the range from 20μm to around 120μm

Dv10, Dv50, Dv90 (particle size at 10%, 50% and 90% of the cumulative size graph)

Dv10, Dv50, Dv90 determination

what is pulmonary delivery?

Drug delivery where medication is inhaled through the lungs and enters bloodstream through alveolar epithelium

Advantages: similar to intranasal delivery

Topical delivery: Airway diseases (e.g. asthma, bronchitis, cystic fibrosis, COPD

Systemic delivery: DM etc

what are the conducting airways?

Nasal cavity, pharynx, larynx, trachea, bronchi, terminal bronchioles

Function: filter, warm and humidify the inspired air

No gas exchange takes place

No. of airways multiply in a dichotomous branching pattern

Airway dimensions reduced with each bifurcation

Progressive increase in SA, Progressive decrease in air velocity

Epithelium generally contains ciliated cells, mucus secreting goblet cells and mucus secreting glands

what are the respiratory airways?

Respiratory bronchioles, alveolar ducts, alveolar sacs

Function: gas exchange with blood stream

respiratory airways - alveoli

~ 300mil alveoli in each lung

Tiny structures to achieve a large SA (~100m2 in total)

Surface is lined with phospholipids (lung surfactant)

Devoid of mucus -> macrophages play an impt role in clearance

respiratory airways - lung surfactant

A lipoprotein complex consisting of 90% lipid and 10% protein

Secreted by epithelial cells in alveoli

Functions

Reduce surface tension at the air-liquid interface, stabilize the alveoli against collapse

Act as host defense against inhaled pathogens and particles

Facilitates oxygen penetration through the lung surface lining and into the blood

Provide anti-inflammatory and antioxidant effects

respiratory airways - pulmonary blood circulation

Branches of the right and left bronchial arteries provide blood to the lung bronchi and smaller air passages

Venous return is mostly through bronchial veins

Alveolar region and respiratory bronchioles receive most of the pulmonary circulation

Blood flow in the larger airways (i.e. trachea to terminal bronchioles) is through systemic circulation

aerosol deposition - definition

Aerosol: solid particles or liquid droplets suspended in a gas

Particles are generally categorized based on diameter sizes

Coarse particle: ≥ 5 μm

Fine particle: 0.1 to 5 μm

Ultrafine particle: ≤ 0.1 μm -> more likely to deposit

aerosol deposition - targeted delivery

Alveolar region is premier target for drug delivery, has largest SA + thinnest diffusion pathway for dissolved material

Many diseases e.g. asthma and chronic bronchitis show effects in bronchioles or trachea

Due to poor drug absorption, not primary targets

aerosol deposition - mechanisms

Deposition mechanism depends on:

Particle size + shape, Breathing rate, Lung volume, Respiration volume, Health condition of the individual

Mechanisms of aerosol deposition:

Impaction

Sedimentation

Brownian diffusion

Interception

aerosol deposition - impaction

Large particles (>= 5um) with high velocity do not follow the trajectory of the air stream due to inertia. They impact the wall of the airways and deposit there

Common mechanism in upper respiratory tree of the lung (oropharyngeal and trachea-bronchial region where there is high air velocity and turbulent airflow

Particles with a size >10um deposit in upper airways, are rapidly removed by MCC + coughing (trachea), subsequently swallowed

Stokes number (Stk): ratio of the particle's momentum response time to the flow-field time scale

Stk >> 1, particle's movement dominated by its inertia and continues along its initial trajectory, ends in compaction on airway wall

To estimate fraction of deposited aerosol due to inertial impaction

aerosol deposition - sedimentation

Settling of particles under the action of gravity. Occurs in the lower bronchial airways and alveolar region

Particles 0.5-5 um: May avoid impaction in the upper airways, deposit by sedimentation and impaction in the lower tracheobronchial and alveolar regions

Particles (3 – 5 μm): Deposition mainly in the trachea-bronchial region

Particles (< 3 μm): Deposition mainly in the alveolar region

Rate of sedimentation increases with an increase in particle size and a decrease in air flow rate

sedimentation - gravitational force

pulls particle down

sedimentation - buoyancy force

opposes gravitational force

sedimentation - drag force

like air resistant

fraction of deposited aerosol due to gravitational sedimentation (fs)

aerosol deposition - Brownian diffusion

Main deposition mechanisms for particles < 0.5 um in alveolar region

Brownian motion -> random motions of the particles caused by their collisions with gas molecules

Brownian motion increases with decreasing particle size and airflow rate

Particles move from high conc to low conc across the streamline and deposit upon contact with airway wall

aerosol deposition - interception

Particles having extreme shapes e.g. rods, tubes (fiber) are caught on airway walls

Usually deposit within the lower (smaller diameter) airways

physiological factors affecting therapeutic effectiveness of drugs

airway geometry

inhalation mode

airflow rate

disease states

mechanism of particle clearance

therapeutic effectiveness - airway geometry

Each bifurcation, branching, and decrease in the lumen diameter of the airways in the respiratory tract increases the possibility of deposition of particles by impaction and decreases the fraction of aerosol available for therapeutic effect

Shape of the pharynx and larynx influence the airflow in trachea and bronchi

Sudden decrease in the downstream diameter at the bifurcations in the upper respiratory tree leads to the generation of turbulent airflow which increases particle deposition in the upper airways

Decreases velocity of particles

therapeutic effectiveness - inhalation mode

Nose breathing enhances possibility of deposition of fine particles in the peripheral alveolar region of the lung. Larger particles are retained in the nose and pharynx

Mouth breathing increases the chances of deposition of coarse particles (>= 10 um) in the upper tracheobronchial region

Holding the breath increases the time between inspiration and exhalation, which facilitates sedimentation of aerosol in the lung periphery

therapeutic effectiveness - airflow rate

Pts advised to breathe slowly and deeply and hold their breath when inhaling a medication

Fast and turbulent airflow reduces the residence time of the particles in the airways by enhancing the deposition of aerosol in the oropharynx region and upper airways. Lower deposition proportion of fine particles

Slow inhalation leads to deposition in the lower peripheral airways. Lower possibility of particle/droplet impaction

Increasing tidal vol (vol of air displaced b/w normal inspiration and expiration when extra effort is not applied) enhances deposition of aerosol particles into lower bronchial and alveolar regions

therapeutic effectiveness - disease state

Bronchial obstruction and narrowing of airways occur due to mucus accumulation and inflammation in respiratory diseases

Asthma is a chronic inflammatory disease characterized by airflow obstruction due to constriction of the bronchial airways in response to a stimulus (pollutants, allergens, or exercise)

This constriction may also in turn result in a thickened mucus layer and sub epithelial fibrosis

In such conditions, the aerosolized drug is deposited more in the upper airways by the inertial impaction mechanism instead of there being a uniform distribution in the lungs --- > loss of drug efficacy

Accumulation of thick mucus in the airways can impair the MCC --- > patient being more susceptible to airways infections

therapeutic effectiveness - mechanisms of pathway clearance

MCC

mechanical clearance

enzymatic degradation

alveolar macrophages

mechanisms of pathway mechanism - MCC

Removes insoluble inhaled particles from the upper respiratory tract and acts as a potential physical barrier for drug penetration

Majority of the deposited particles in the trachea-bronchial region of the respiratory tract are cleared within 24 h of inhalation in healthy subjects

MCC is prevalent in the upper airways as compared to the lower airways

mechanisms of pathway mechanism - mechanical clearance

Includes coughing, sneezing or swallowing of inhaled particles in the upper region of the respiratory tract

Occurs instantly after the deposition of particles in the larger airways

Coughing is spontaneously provoked when a particle of size ≥10 μm is inhale

Cough turns into the major mechanism of clearance in respiratory disease conditions (e.g. bronchitis, asthma or pneumonia) --- > MCC becomes impaired

mechanisms of pathway mechanism - enzymatic clearance

Many inhaled drugs are substrates for the CYP450 enzymes present in the lung epithelia

Phase II metabolic enzymes (e.g. esterase and peptidases) are expressed in the lung

mechanisms of pathway mechanism - alveolar macrophages

If the inhaled drug has poor solubility and particles remain in the alveoli for sufficient time, they can be cleared by macrophages --- > reduced therapeutic effect

Clearance by alveolar macrophages is still the main obstacle to achieve controlled drug release in the alveoli

Most of the materials used to prepare particles that can sustain the release of a drug for the extended period are rigid and have all the physicochemical characteristics that make them an ideal target for macrophage uptake

what are the receptors in the lungs

Most important receptor classes are:

𝛽𝛽-adrenergic receptors

muscarinic receptors (M3)

histaminic receptors (H1 and H2)

glucocorticoid receptors (GR)

leukotriene 1 receptors

prostacyclin receptors (PR)

Not uniformly distributed throughout the lung

For instance, the alveolar walls, endothelium, and smooth muscle cells of bronchial vessels have high concentrations of GR --- > potential targets for steroidal anti-inflammatory drugs and glucocorticosteroids (e.g. betamethasone)

how is the drug absorbed in the lungs

Epithelium of the lung is the major barrier to the absorption of inhaled drugs. Thick (50-60 um) in trachea, decreases to 0.2 um in alveoli

Pulmonary membrane is naturally permeable to small molecule drugs and many therapeutic peptides and proteins

The lungs are more permeable to macromolecules than any other portal of entry into the body. A number of peptides have demonstrated a very high bioavailability through the pulmonary route. Highly cationic small molecules can exhibit prolonged absorption

Absorption of the inhaled drugs can be paracellular or transcellular

drug absorption - diffusion control

Follows Fick's law across biological lipid cell membranes

Greater the lipophilicity and the smaller the molecular weight -> faster and greater the lung absorption

For small molecule drugs (molecular weight ≤ 781 Da)

Lipophilic drugs (log P > 0) cluster around a half-life of ~1 min

Hydrophilic drugs (log P < 0) cluster around a half-life of ~1 h

Half-life is increased with increasing molecular weight at 1,000 Da or greater

drug absorption - transporter control

TP-Binding Cassette (ABC) transporters

Serve for efflux in the lung --- > defensive functions against certain exogenous substances

Examples: lung resistance-related protein (LRP) and P-glycoprotein (PgP)

Studies showed increased uptake of the PgP substrate drugs (e.g. rhodamine 6G and idarubicin) from the perfusate to the lung in the presence of PgP inhibitors (e.g. GF120918)

Receptor-mediated endocytosis

Receptors: gp60, FcRn, pIgR for albumin, IgG and IgA respectively

Albumin, IgG and IgA --- > serum proteins that can be found in the lung epithelial cells despite their large molecular sizes

what are the major aerolization systems

Dry powder inhaler (DPI)

Propellant-based system e.g. pressurized metered dose inhalers (pMDIs)

Nebulizer

DPI devices - single-unit dose device

Most widely utilized type of DPI

Patients load the device with a hard capsule containing micronized powder formulation prior to inhalation

Capsule must be ruptured before the inhalation maneuver and is removed prior to loading the next dose into the device

Examples: Rotahaler® (GlaxoSmithKline, UK)

DPI devices - multiple dose

Multiple dose device

Premetered doses stored in individually sealed protective packaging (e.g. blisters, disks, cartridges, or dimpled tapes)

Example: Diskhaler (GlaxoSmithKline, UK)

Multidose reservoir device

Contains the bulk powder formulation in a multidose reservoir. Individual doses are metered under gravity and dispensed by a built-in mechanism or by scrapping the metered dose of drug from a compacted powder block just before inhalation

Example: Turbuhaler® (AstraZeneca, UK)

DPI devices - power dispersion mechanism

Passive

Relies solely on the energy generated by patient inspiratory flow rates to fluidize and disperse the powder

Example: Novolizer® (Meda AB, Sweden)

Active

Usually has an integral power source dispersion unit to aerosolize the powder using compressed air

Example: Aspirair (Vectura, UK)

DPI - particle dispersion

Turbulence inducement

Use turbulent air flows to de-agglomerate/disperse powder, provides sufficient shear stress on the particle surface

Turbulence can be generated in spiraling channels

E.g. turbuhaler

Mechanical forces

Impellers or low density beads contained within the dispersion chamber to provide mechanical forces

Pneumatic forces

Use compressed gas, vacuum or synthetic jets to disperse particles

DPI characterization methods

Delivered-dose uniformity

United State Pharmacopeia (USP) dictates that at least 9 out of the 10 actuated doses should fall between 75% and 125% of the specific targeted dose

Apparatus for testing at an airflow rate that generates a pressure drop inside the device of 4 kPa. Test flow duration, in seconds, is determined by T = 240/Qout (Qout is vol of air passing through airflow mete)

Test should be performed for sufficient time so that 4 l of air is withdrawn through the device at the test flow rate Qout

Aerodynamic particle-size distribution (APSD) (most impt)

APSD - equivalent aerodynamic diameter (d_aer

Diameter of a sphere having the same speed of fall as the particle and an equal density of 1g/cm3

USP recommends the use of a cascade impactor (CI) to assess the APSD of the emitted dose of inhalation formulations

CI fractionates and collects drug particles by aerodynamic diameter through a series of collection plates (stages) enabling the formulator to measure the APSD of the drug and to quantify the mass of drug deposited in each stage

Each stage has its own design specifications and different nominal stage cut- off diameters --- > difficult to have direct comparison of APSD data from different impactors

Factors that affect accuracy and robustness of CI:

Particle bounce, Re-entrainment, Wall loss

Coating the collection plates with a greasy material can reduce variability of CI measurements

Consist of layers of stacked up sieves/filters

APSD - Mass median aerodynamic diameter (MMAD)

d_aer below which the cumulative mass of particles is equal to 50% of the total mass of particles

APSD - fine particle fraction

Percentage of particles that have d_aer < 5um (optimal particle size for lung deposition) over delivered dose (DD) that represents the total mass of drug administered

DPI - particle engineering

Enhance particle de-aggregation through:

Reduction of particle size and/or density

Modification of particle shape and surface characteristics

Alterations in crystalline morphology

Particle processing techniques: milling, spray drying, nanoparticle, etc

particle engineering - milling

Mechanical process of reducing large particles to a powder of micro- or nano-size

Jet milling and ball milling (wet or dry basis) to produce particles <= 5um

Dry milling -> can create partially amorphous materials with surface charge, but has possible particle agglomeration

Wet milling -> some drugs might be water and heat sensitive

particle engineering - spray drying

Spraying of dissolved drug and excipient solution through an atomization nozzle. Drying of sprayed droplets at elevated temp, separation of dried product from the air

Particle size of the dried particles is directly affected by the atomizer performance

Various types of atomizers: Rotary atomizer, ultrasonic atomizer, pressure nozzle, 2-fluid nozzle

Drying air temp can be relatively high (>100*C), but actual temp of the evaporating droplets is considerably lower due to cooling by the latent heat of vaporization

For proteins and peptides, vacuum can be applied to the drying chamber to lower the inlet air temp

Spray drying used for the fabrication of low-density particles with relatively large vol diameter for better dispersibility and more efficient deep lung deposition

Pulmosphere process: Spraying an emulsion of fluorocarbon in water stabilized by phospholipid, where the drug is dissolved or dispersed in the external aqueous phase containing excipients, fluorocarbon acts as a blowing agent at high temp to produce foam-like porous or hollow structures

particle engineering - nanoparticle

Microparticle-nanoparticle composite particles

Nanoparticles are synthesized by precipitation/wet milling

After purification, nanoparticles are mixed into an aqueous solution containing dissolved lactose (or other appropriate matrix material), which is then spray dried to produce nanoparticle-containing lactose particles

After inhalation and deposition into alveolar region of the lungs, the lactose will dissolve, leaving behind their therapeutically active nanoparticles

Nanoparticle cluster

Pure nanoparticle suspensions of hydrophobic drugs naturally agglomerate via water exclusion or hydrophobic interactions if stabilizers e.g. surfactants are not included

More stable nanoparticle suspensions may be flocculated by disrupting the colloidal stability of the nanoparticles

E.g. by salting out using an a.a. or NaCl