Pharmaceutics Vertical Theme (P)

Advantages of inhalation therapy?

1)Drug delivery directly to site of action.

2)Rapid drug onset

3)Lower doses required

4)Fewer side effects

5)Less drug in systemic circulation

Aerosol

Relatively stable suspension of particles or liquid droplets in a gas, particles are very small, so have low mass and gravitational force, therefore collisions with gas particles keeps particles suspended.

Droplet vs airborne transmission

1)Droplet transmission- cough and sneezes, can spread saliva and mucus.

2)Airborne transmission- Tiny particles, can be produced by talking and supsended in air for longer and travel further.

Aerosol behaviour

Particle movement in the air is controlled by the interaction with the surrounding air molecules and gravity. Aerodynamic properties depend on- size, shape and density.

3 mechanisms of how particles can deposit

1) Inertial impaction (90%)

2)Sedimentation (9%)

3)Diffusion (1%)

Inertial impaction

Commonly occurs in: large particles, fast moving particles, change in direction or turbulence.

Gravitational sedimentation

Occurs where velocity in the respiratory tract is low, and residence time is high. Important deposition in bronchioles. Less efficient than inertial impact at delivering drugs.

2 most important factors influencing where drug deposits.

1)Speed- flow rate

2)Size

Factors controlling aerosol deposition from an inhaler

1)Aerosol Properties- Aerodynamic diameter, and particle size.

2)Mode of inhalation- Flow rate, inhaled volume, breathing holding pause.

3)Patient related factors- Anatomical and physiological variations, obstructive airway disease.

Factors controlling drug delivery to the lungs

Formulated drug and excipients, device design and whether efficiently preformed → Deagglomeration of inhaled dose → Lung deposition, particle size and impact sedimentation → Dissolution, physicochemical properties and fluid distribution → Absorption → Local effect

PMDIs

An aerosol is formed by a propellant, the propellant is what forces the aerosol out when you use it. It is compressed at 300-500kPa which is what coverts it to a liquid (Pressure converts gas to a liquid). When pressure is released the liquid propellant rapidly boils to form a gas, and this is what leaves the inhailer.

PMDI propellants

Current PMDI propellants are hydrofluroalkanes (HFAs) and chloroflurocarbons (CFCs) we once used but we banned as they depleted the ozone layer.

3 type of drug formulations for PMDIs

1)Suspension (drug crystal and propellant)

2)Solution

3)Non-volatile solution (aerosol droplets)

Suspension based formulations

Preferred, bigger dose can be given, requires drug to be milled or micronized, as drug particles need to be really small, requires drug to practically be insoluble in the propellant, drugs should be freely dispersed in propellant (why patients are told to shake inhaler before use).

Main problems with PMDIs

Physical stability- 1)Rapid flocculation- between any two particles is an attractive force, flocculation is where attractive forces pull drug particles together into loose agglomerates, shaking can break these agglomerates up. 2)Bulk separation- either all drug floats to the top or the other way around. This is controlled by density of the drug and particle size. If density of a drug is greater than propellant then it will sink to the bottom. 3)Irreversible aggregation- crystal growth, caking (particles stick to one another in an irreversible way).

WE TRY TO AVOID ALL THIS USING SURFACANTS AND DISPERSING AGENTS

Role of excipients

Ensures physical stability of suspension, must be capable of dispersing and redispersion of drug in suspension, allows homologous distribution of drug in suspension, minimal segregation, stop particles sticking together, allowing particles to stay suspended.

Solution based formulations in aerosols

Solution based formulations can only be used if solubility and stability of a drug in propellant and co solvent are adequate. Amount of emitted dose is directly related to solubility. There is a potential for drug to crystallise out during shelf-life, usually requires co-solvent ethanol.

NO NEED FOR SURFACANTS, AS THERE ARE NO SOLID PARTICLES.

Solution based problems

1)Co-solvents can cause corrosion of aluminium canisters

2)Drugs can be relatively unstable

3)modification of drugs chemical structure

Advantages of PMDIs

Many doses, compact, consistent delivery, cheap, sealed canister protects drug, lower capital cost for market entry

Disadvantages to PMDIs

Reliant on patient doing it correctly, force of aerosol spray, ‘cold freon effect’, varying deposition in lungs.

DPIs- Dry powder inhalers

These are a more environmentally friendly alternative to PMDIs, they are inspirationally flow driven, automatically breath actuated, easy to use, environmentally friendly, long term replacement for PMDIs.

Main challenge with DPIs

Patient inspiration is highly variable- intrinsic variability

Aerosolization

This is the process of turning a dry powder into an aerosol. In DPIs a patients inspiratory action provides energy required for fluidisation, and entertainment of formulation and de-aggregation of drugs for delivery to the lungs. Patients need to generate minimum inhalation (Qmin). Variation of inhalation flow rate = variation in drug delivery.

Fine particle fraction (FPF)

This is the % of drug that reaches the lungs, it is dependent on three factors. 1)Inhaler device 2) Patient inspiratory flow 3) Powder formulation. Complex interaction between these factors govern respiratory dose and therapeutic efficacy.

4 Main classes of DPIs

1)Single unit dose (disposable)

2)Single dose (reusable)- capsules are put in device with dose

3)Multi-dose devices

4)Multi-dose reservoir - Moving mechanism inside which will measure appropriate volume of powder

2 Dry powder aerosol formulation strategy

1)Carrier-based systems- when drug particles are together they dont flow and so stick together, making them hard to break up, and so they will stick to your lungs. We mix these with large excipient particles with small particles on the surface. The drug particles make bonds between the small particles on the surface, these bonds need to be strong enough to stick together, but week enough that when patient breaths in we can break them apart.

2)Agglomerate systems- alternative is to not have an excipient and instead form an agglomerate system where you treat the powder in some way to gently stick particles together so they flow, but enough to break apart when inhaled by patient.

ON THE WHOLE WE HAVE CARRIER BASED SYSTEMS

carrier formulations benefits

1) Allows accurate metering of small quantities of potent drug

2)Improves handling and processing

3)The following carrier properties are used to control FBF - particle side, particle shape, surface roughness- smoother surfaces cause great increase in therapeutic dose

DPI advantages

1) Propellant free - more environmentally friendly

2) No excipients

3) Breath actuated

4) Can deliver large doses

5) Drug is in dry solid form

DPI disadvantages

1) Dependent on patients ability to in hail

2) Exposure to ambient conditions may effect stability

3) Generally less effective at delivery than PMDIs

4) Some devices are difficult for patients to activate- DPI inhaler technique aims to overcome this

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Nebulisers

Contain a drug with a sterile aqueous solution, uses external energy supply to aerosolise the drug, which can then be inhaled through a mask. Up to 2/3 of the dose is left in device and up to 2/3 is lost during expiration, many particles are too large or too small, and many nebulisers deliver as little as 10% of target dose to the lungs.

pneumatic nebulisers

Older design, it generates and aerosol using compressed air. Pros and cons: Cheaper, smaller particle size, variable performance (between and within devices), dead volume, lower output (can take 20-30mins to give a dose), portability (larger size and has a power supply).

Turbinates’ in the nasal cavity

These are contained within the nasal cavity, 3 of them stacked above each other in the nose, these help regulate airflow. They warm and humidify air as it passes through the nasal cavity, they can swell and contract altering the volume of air which goes into the nasal cavity. They help detect pathogenicity of inhaled particles , but problems with these can impair quality of life.

Factors which make up the mucus layer

1) Pore size

2) Viscoelasticity

3) PH

4) Ionic strength

5) Charge

THESE ALTER THE WAY DRUGS PASS THROUGH THE EPITHELIUM

Transcellular vs paracellular absorption

1)Transcellular = through cells

2)Paracellular = between cells

Mucosal absorption is dependent on

1. Whether the drug is lipophilic
2. Particle size
3. Mucus is more than water
4. Temperature and humidity
5. Nasal clearance ( slower if nostril is obstructed )

Nasal sprays

1) Nasal fentanyl - used to treat breakthrough pain in adults already receiving background opioid therapy for chronic cancer pain

2) Nasal vaccinations (influenza)- no needle, so good for young children, small dose into each nostril, unfortunately has rapid clearance and insufficient uptake

3) Nicotine nasal spray - Nicotine replacement therapy, unfortunately does have irritation and side effects

Current issues with nasal drug delivery

1. Poor permeability from nasal mucosa
2. Mucociliary clearance
3. Enzyme degradation of drug
4. Low retention time
5. Nasomucosal toxicity
6. Low volume in nasal cavity

2 ways to increase permeation/ permeability of a drug

1. Transient opening of tight junctions between adjacent cells for improved paracellular diffusion
2. Perturbation of lipid bilayer and increased membrane fluidity promoting transcellular permeation of drugs - so essentially disrupting the lipid bilayer

Peptide drug delivery

Complex protein contributes to mucus layer - predominant proteolytic enzyme is aminopeptidase- this will break don the amino acids and peptides in mucus.

3 Main parts of the ear

1. External ear- from pinna to tympanic membrane (eardrum)
2. Middle ear- usually air filled cavity with the temporal bone of skull around it - eustachian tube connects this to the inner ear- there are two barriers in the way which aim to protect the brain- oval window and round window. Eustachian tube aims to get rid of anything which is harmful or not wanted by the exit at the back of the throat.
3. Inner ear- contains cochlear implant (auditory organ) and vestibular system (organ of balance).

THE TYMPANIC MEMBRANE IS THE FIRST LINE OF DEFENCE

Common ear infections

1. Otitis media- build up of fluid on the other side of the tympanic membrane (middle ear) and this causes inflammation- standard ear infection
2. Menieres disease (vertigo)- When things go wrong in the balance organ in the middle ear
3. Hearing loss
4. Tinnitus

Ear wax

This is another line of defence. Ear wax consists of sebum, skin cells, sweat and dirt. Function is as a protective coating and to trap particulates, moving them away from the ear drum. It is acidic so does not support bacterial growth.

Middle ear

3 Auditory ossicles- Some of the smallest bones in the body, transmit sound from air to fluid- filled part by amplifying vibrations from the tympanic membrane.


1. Malleus
2. Incus
3. Stapes

These are sites where you may start to develop bacterial infections if bacteria has made its was through.

2 Main parts to the inner ear

1)Cochlear- auditory organ

2)Vestibular system- balance organ

Why is it difficult to treat inner ear infections

You have 3 lines of defence which you have to go through- Eustachian tube, tympanic membrane and round window- after drug passes through round window distribution depends on inner ear fluids.

Ototoxicity

Adverse reaction to drugs affecting the inner ear or auditory nerve via cell degeneration. Effects cochlear or vestibular systems, or both. Over 600 drugs are considered ototoxic.

Colloids

Mixture in which one substance consisting of microscopically dispersed insoluble particles suspended throughout another substance. Examples- Emulsions, microemulsions and creams, oral suspensions, topical dosage forms, injections and aerosols.

Dispersed systems

Emulsions and suspensions are dispersed systems, the liquid or solid phase is dispersed in an external liquid phase. Disperse phase = phase that is sub-divided. Continuous phase = phase which disperse phase is distributed. Emulsions and suspensions are unstable so require stabilisers.

Colloid Stability

Water insoluble drugs in fine dispersed form. Higher surface area → higher surface energy → aggregation → thermodynamically unstable.

Suspension particles achieve lower surface area by flocculating or aggregating

Sedimentation

Factors that increase sedimentation rate: Particle diameter and particle density.

Factors that decrease sedimentation rate: Increased viscosity

Total potential energy of particles

The total potential energy of particles consists of two things- Attractive forces (van der waals) and VR ( electrostatic repulsive forces/energy)

Caking

In deflocculated systems particles are no associated, however when there is pressure on individual particles there is then close packing on the bottom of the container, which is caking. Caking is not prevented by reducing particle size or increasing viscosity. CAKING IS SOMETHING WE DO NOT WANT.

Controlled flocculation

Flocculation is controlled with non-ionic polymers (instead of surfactants) to increase viscosity -making the continuous phase more viscous, slowing how quickly they come together.

Characteristics of any acceptable suspension

1. Suspension material does not settle rapidly
2. Setting particles must form cake and easily resuspend once shaken

Surfactants

Surfactants hide one droplet from another water droplet, this causes lower interfacial tension and facilitates the dispersal of oil into smaller droplets, helps to keep particles in dispersed state.

Hydrophile-lipophile balance (HLB) system

HLB number is a measure of balance between hydrophobic and hydrophilic components of a surfactant . Hydrophilicity of a surfactant is required for enthalpic stabilising force. Surfactant hydrophobicity is need for absorption at oil-water interface. HLB is expressed on a scale of 1-20. High HLB = Hydrophilic surfactant. Low HLB= oil soluble surfacant.

Gels

Gels are viscoelastic solid like materials comprised of an elastic cross-linked network and a solvent which is a major component. The solid like appearance of a gel is a result of the entrapment and adhesion of the liquid in the large surface area of a solid 3D matrix (formulation of a solid matrix is a result of cross-linking of polymeric strands of macromolecules by physical or chemical forces).

Viscous cross-linked systems

Gels

Characteristic features of gels

1. Large increase in viscosity above gel point
2. Appearance of rubber like elasticity
3. Gel retains shape under low stress, but deforms under higher stress

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Physical gels and Supra molecular gels

New gels which are derived from low molecular mass compounds- There applications are very diverse due to there polymeric counter parts.

How are gels classified

Classified based on their origin and constitution, the type of cross-linking that creates a 3D network, and the medium they encompass.

Hydrogels

Retain a significant amount of water, but retain water insoluble, and because of this property they are used in topical drug delivery and wound healing. Often used in soft contact lenses to keep eye moist.

Diffusion rate of drug through hydrogels

Diffusion of drug through hydrogel depends on the physical structure of the polymer network and its chemical nature. If a gel is highly hydrated then diffusion occurs through the pores, if gel hydration is low then the drug dissolves in the polymer and is transported between chains.

Swelling of hydrogels and drug release

Swelling characteristics of a polymeric gel can be changed by heat, PH, or application of electric current. Results in responsive drug delivery. Swollen state → Drug release on. Shrunken state → Drug release off.

Type 1 vs Type 2 Gels

1. Type 1 Gels : Irreversible systems (chemical gels)- 3D network formed by covalent bonds between macromolecules. Formed by polymerization of monomers of water soluble polymers in the presence of X-Linking.
2. Type 2 Gels : Heat reversible systems, held together by intermolecular bonds eg- hydrogen bonds. They form gels upon cooling below the temperature (gel point temperature).

Applications of supramolecular gels

1. Cosmetic formulations
2. Biomedical applications- media for tissue engineering
3. Use in controlled release of molecules- therapeutic drug delivery, used of stimuli sensitive gels for site specific and programmed drug delivery, model antigen for immunogenicity studies, and wound dressing.

Amphiphile

A chemical compound possessing both hydrophilic and lipophilic properties

Micellization

At very low amphiphile concentration molecules will disperse randomly without any ordering. At slightly higher, but still low conc, amphiphilic molecules will spontaneously assemble into micelles or vesicles, this is done to hide the hydrophobic tail inside micelle core- and so inside the micelle drugs can be carried. At higher concentrations the assembly will be more ordered.

Liposomes

Vesicular structures based on one or more lipid bilayers encapsulating an aqueous core. Are considered as a liquid crystal. The lipid molecules are usually phospholipids with hydrophilic head group and two hydrophobic chains. Liposomes can either be multilamellar- several vesicles have engulfed each other or uni-lamellar.

Stability of liposomes depends on…

1. Lipid composition
2. Storage conditions: Light, oxygen, temperature
3. Stabilisers: Cholesterol alpha-tocopherol, inert atmosphere

Why are liposomes good drug carriers

1. Due to lipid composition- bio-compatible, biodegradable.
2. Liposomes are composed of natural phospholipids, meaning they are biologically inert, weakly immunogenic, and so low intrinsic toxicity
3. Lipid bilayer is biocompatible in large amounts

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Classification of liposomes

1. Conventional Liposomes- Neutral or negatively charged, are generally used for passive targeting to cells of the mps (mononuclear phagocyte systems).
2. Sterically stable- Liposomes with hydrophilic coatings are used to obtain prolonged circulation times.
3. Immunoliposomes (antibody targeted)- can either be conventional or sterically stabilized, are used for active targeting purposes.
4. Cationic liposomes- Positively charged, are used for the delivery of genetic material.

Conventional Liposomes

Typically composed of phospholipid and cholesterol. They protect encapsulated molecules from degradation, and can passively target tissues or organs, that have discontinuous epithelium. They have been approved for parenteral drug delivery of anti-fungal drug amphotericin B

Immunoliposomes

Have specific antibodies or antibody fragments on the surface to enhance target binding, there primary focus is targeting the delivery of anti-cancer agents.

Cationic Liposomes

Relatively new development of liposome therapeutics, which demonstrates considerable potential for improving delivery of genetic material.

Toxicity of liposomes

1. Most liposomes are well tolerated
2. Cationic liposomes may activate complements and induce adverse side effects via IV route
3. PEGlayted liposomes may induce transient reactions upon injection in a sub set of patients.

Nanomedicine

Application of technologies on the scale of 1-500nm to diagnose and treat disease.

Increase drug penetration and stability, to small to be detected by the immune system. Delivery of the drug in the target organ using lower doses so as to reduce side effects.

2 Type of carrier based topic drug delivery systems

1. Lipid based delivery systems
2. Surfactant based systems

Vesicle based liposomes

1. Lipid bilayer structures made of phospholipids (and cholesterol)
2. Hydrophilic drugs are entrapped in the aqueous layer of liposomes, whilst hydrophobic drugs are incorporated into the lipid bilayer.

Transferosomes

Ultra-deformable liposomes composed of phospholipids and additional surfactant, emulsifier ‘edge activators’. Edge activators destabilize the lipid bilayer of the stratum cornea and increase in deformability by lowering interfacial tension of lipid bilayer.

Pros and cons of transferosomes

Advantages:


1. Elastic vesicles are capable of permeating intact skin, by squeezing themselves along the intracellular sealing lipid of the stratum cornea, the drug penetrating ability increases.
2. Localized at higher concentration and deep layers of the skin.

Disadvantages:


1. ‘Edge activators’ must be highly pure to avoid skin irritation and toxicity.

Ethosomes

Essentially liposomes which contain ethanol in there structure. Advantages: More effective at transdermal delivery than classical liposomes, smaller and have higher entrapment efficacy than liposomes, better skin permeation and stability than liposomes, alcohol enhances deformability of vesicles. MW of drug entrapped.

Disadvantage: Skin irritation due to high concentration of alcohol.

Transethasomes

New generation of ethasomal systems, combination of transferosomes and ethasomes.

Solid Lipid Nanoparticles (SLN)

1. Homologous matrix- Release from one day to a couple of weeks.
2. Fast compound delivery
3. Slow and controlled release of active compound

Disadvantages of SLN : Decreased loading capacity, expulsion of drug during storage.

Advantages of lipid nanoparticle carriers

1. Low toxicity
2. Small particle size
3. Increase skin hydration
4. Enhance stability
5. Physical sunscreen on there own
6. Reduce skin irritation

Rheology

Describes the flow of a liquid and deformation of a solid

Rate of sheer

= Distance/ Time

Rate of sheer is defined as the gradient in velocity, that is the difference in the velocity between two surfaces containing the fluid, divided by distance between them.

Layers to the skin

Epidermis → Stratum Cornea (Bricks and mortar) → Dermis → Appendoges

3 Major constituents of intracellular lipid bilayer

1. Ceramides
2. Cholesterol
3. Fatty acids

These are the breakdown products of phospholipid bilayers

Ceramides

Long chained and stiff, so do a good job within the mortar at creating a good solid barrier against water loss. But by doing this they also create a good solid barrier against things penetrating/ trying to get into the skin

Percutaneous absorption

AMOUNT OF DRUG WHICH PASSES THROUGH THE STRATUM CORNEUM, COMPARED TO THE AMOUNT APPLIED

Drug penetrates into the skin- drug cannot be removed by washing once in stratum cornea. Drug is taken up by microcirculation, drug enters systemic circulation or is carried deeper into the tissue of the skin. Percutaneous absorption is dependent on- Physicochemical properties of the drug, interactions of drug with the skin, condition of the skin.

Topical drug delivery potency

Dilution is greater than 10^4 so topical drug delivery needs to be very potent as not much is absorbed and is not very fast.

Flux in relation to lipophilicity

A increase in lipophilicity increases flux, as lipophilic drugs get into the stratum cornea easily but dont get out easily

Flux in relation to vehicle

Flux is independent of the vehicle as long as its saturated, this means the vehicle properties does not effect the stratum cornea or drug solubility in any way. This is under ideal circumstances.

Flux in relation to MW

Flux decreases with MW

Introduction of Co-Solvents

Co-Solvents such as propylene glycol in a formulation can significantly increase Cv sat

Accessing skin bioavailability in vivo in man

1. Pharmodynamic measurement (vasoconstriction assay)- Used for corticoid steroids- you apply to skin then wrap with cling film, and after steroids will cause vasoconstriction, which will lead to whitening of skin. You can look and measure that whitening.
2. Micro dialysis- Place a micro dialysis tube in the epidermis, through you can then diffuse a solution from the skin, and you can try and capture drug in the micro dialysis tube, so you can see the profile of drug moving into the dermis as a function of time.
3. Blood levels- due to micro circulation in the dermis

2 Broad Classifications of Wounds

1. Wounds without tissue loss
2. Wounds with tissue loss

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Classification of accidental wounds

1. Mechanical
2. Chemical
3. Thermal
4. Special
5. Radiation

Classification of types of wounds

1. Open Wounds
2. Depth
3. Burns
4. Closed wounds

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