Methods Of Formulation II Flashcards
What are the structures of the lung (include surface area)
Oxygen and carbon dioxide are exchanged between blood and inhaled air
The respiratory tract comprises of the trachea, bronchi and bronchioles, which connect with the alveoli
The lung of an adult male has approximately has a surface area of 100 – 140 m2
The conducting airways are lined with ciliated epithelial cells
Insoluble particles deposited in the airways are trapped by mucus, swept upwards by the beating cilia to the throat and swallowed
How do we use the lung for local drug delivery and what are the benefits
Treatment for asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis e.g. corticosteroidsandbronchodilators
Rapid onset of activity, lower dose administered, reduced risk of side effects and reduced cost
Which drugs do we administer to the lungs to achieve systemic drug delivery
Systemic delivery
Sodium cromoglicate (anti-allergy, anti-inflammatory; poorly absorbed orally)
Isoprenaline (bradycardia, heart block; rapidly metabolized orally)
Biopharmaceuticals e.g. insulin, vaccines and growth hormone which are suceptible to degradation by stomach acid (protein based)
What is the ideal size for aerosol particles
Will come up in the exam
Particles of1-5µmare needed to achieve good penetration into airways
Particles > 10µm are deposited in the mouth and throat
Particles < 0.5µm may be exhaled
What are the two ways which an aerosol will be prepared
An aerosol may be prepared by dispersion or condensation
Describe a dispersion aerosol
Achieved by the use of a pressurised container, with a liquefied gas used as a propellant
The solution or suspension of active ingredients is contained within the liquefied propellant, or within an additional solvent
When the container is opened or deployed, the vapour pressure of the propellant forces the liquid out of the container, producing a dispersion in the air which can be inhaled
Describe a condensation aerosol
A sample of vapour-saturated gas is subjected to rapid volume expansion (supercooling)
This lowers the temperature and causes supersaturation
The vapour condenses on any ions or particles present forming colloidal particles and is packaged for delivery
How do we administer aerosols
Aerosols are administered via inhalers or nebulisers
What is the difference between MDI and DPIs
Metered dose inhalers (MDI) generate an aerosol when deployed
Dry powder inhalers (DPI) contain capsules or blisters loaded with drug particles
A capsule is pierced and as the drug is inhaled by the patient, it passes through a mesh or screen to shear the particles into aerosol form
What types of drugs are inhalers used to administer
Inhalers are primarily used to administer corticosteroidsandbronchodilators
Other than inhalers, how can aerosols be administered
Nebuliser. Nebulisers are commonly used for the treatment ofcystic fibrosis, asthma, COPDand otherrespiratory diseases
Nebulisers can deliver corticosteroids and bronchodilators, but also antibiotics e.g. colistin for cystic fibrosis and pain medications e.g. morphine for COPD
How do nebulisers work
A nebuliser convertsliquid into aerosol droplets, which are inhaled through a face mask or mouth piece
It can be driven by compressed gas or by an ultrasonically vibrating crystal
Which conditions do we treat with locally acting drugs via the nasal pathway and which drugs do we often deliver
Treatment of allergic rhinitis, nasal congestion and nasal infection
Drugs used include antihistamines, corticosteroids, sodium cromoglicate, antiseptics/antibiotics
Which conditions do we treat with systemic drugs via the nasal pathway and which drugs do we often deliver
Sympathomimetics e.g. adrenaline, noradrenaline, dopamine
Analgesics e.g. fentanyl
Erectile dysfunction
Proposed portal for vaccine delivery e.g. influenza (and potentially TB)
Potential for drugs to cross the blood-brain barrier, leading to new treatments for Alzheimer’s disease, brain tumours, epilepsy, pain and sleep disorders
What dosage forms are used for nasal delivery
Dosage forms include mists and drops
What are the structures of the nasal cavity (include surface area)
The nasal cavity has a total surface area of ~160 cm2 (moistened environment)
The nasal vestibule is the narrowest part and contains cilia that filter out particles >10 μm
The turbinate region, filled with folded projections of tissue from the nasal septum, is composed of mucus-secreting goblet cells, ciliated and non-ciliated cells
How are drugs absorbed via the nasal pathway
Particles 5–10 μm in size deposit on the mucous lining the turbinate walls
The main drug absorption site is the epithelium of the nasal turbinates
Drugs cross the nasal epithelium by passive diffusion via transcellular (lipophilic drugs) or paracellular (hydrophilic drugs) routes
WHy is the nose a good site of drug delivery
The nose contains a rich supply of blood vessels
This allows inhaled drugs to be rapidly absorbed into the bloodstream, providing a fast onset of action
(a barrier, however, is the nasal epithelium is protected by a layer of mucus 1–10 μm thick, sitting above the cilia )
What is PecFent and when is it used
PecFent nasal spray contains the active ingredient fentanyl, an opioid analgesic
People with long-term, ongoing, severe pain, such as the pain caused by cancer, are given opioids
Occasionally the pain can become worse despite taking these strong painkillers; this is known as ‘breakthrough’ pain
PecFent is used to relieve breakthrough pain in people already receiving opioids on a regular basis
Which conditions do we treat with locally acting drugs via the rectal pathway and which drugs do we often deliver
Treatment of haemorrhoids, constipation or colitis
Drugs used include antiseptics, local anaesthetics, vasoconstrictors, anti-inflammatory compounds, soothing and protective agents, laxatives
Which conditions do we treat with systemic drugs via the rectal pathway and which drugs do we often deliver
All drugs which are orally administered can be given rectally
anti-asthmatic drugs
anti-inflammatory drugs
analgesic drugs
Which dosage forms are avalible for the rectal route
suppositories, rectal capsules
rectal solutions, emulsions and suspensions
powders and tablets that form rectal solutions and suspensions
semi-solid preparations, foams and rectal tampons
What are the advantages of the rectal delivery route
The avoids the oral route (patient vomiting, unconscious, GI problem)
Very young, very old or mentally ill patients may more easily be treated
Avoids adverse GI effects, problems with instability at low pH, high first-pass metabolism, unacceptable taste
Small and large doses can be administered
No protease activity is present in the rectum (protein based drugs can be administered this way)
Skilled health practitioner not needed
What are the disadvantages of the rectal delivery route
Route is generally disliked by patients – UK/USA versus Europe
- Slow and sometimes incomplete drug absorption, variability between patients
- Development of proctitis with long-term rectal delivery
- Problems with leakage and insertion
- Short shelf life
- Market size of rectal and vaginal formulations is less than 1% of the total pharmaceuticals market
What are the structures of the rectum (include surface area)
- The rectum is the final 15-20cm of the colon prior to the anus, a circular muscle
- It has a flat surface without any villi and with only 3 major folds – the rectal valves
- The rectal wall is composed of a single layer epithelium, composed of cylindrical cells and goblet cells that secrete mucus
- The total volume of mucus is estimated at 3ml spread over a total surface area of 300 cm2
What is the pH of the rectum and why is this important
The pH~7.5 in adults and slightly more alkaline in most children
There is little buffering capacity
Which veins supply rectal blood flow
The rectum is served by 3 separate veins
-the inferior and middle haemorrhoidal veins drain into the inferior vena cava (bypass first pass metabolism)
-the superior haemorrhoidal vein drains into the portal vein (doesn’t bypass first pass metabolism)
Drug absorption occurs via passive diffusion
What differs between the rate and extent of drug absorption between rectal and oral drug delivery
Drug absorption occurs via passive diffusion
Because of inter-individual variations and the venous drainage of the rectum, the bioavailability is very unpredictable
In general, the rate and extent of drug absorption is lower than the oral route, mainly due to
the limited surface area for absorption
the low fluid volume, which affects drug dissolution
What impact does the presence of surfactants have on rectal drug delivery
All types of surfactants seem to be effective in improving drug delivery, but may cause irritation of the rectal mucosa longer term
How do drugs get into systemic circulation via rectal delivery
Depending on the vehicle, a suppository will either dissolve in the rectal fluid or melt on the mucous layer
Drugs will
diffuse out of the suppository towards the rectal membranes
penetrate the mucous layer
penetrate and cross the rectal epithelium
The rectal wall may exert pressure on a suppository:
Abdominal organs may press on to the rectum, stimulating spreading and absorption (beneficical)
Motility of the muscles of the rectal wall, originating from normally occurring colonic motor complexes, may stimulate spreading and absorption
What are suppositories and how big are they
Suppositories - single-dose preparations varying in shape, volume and consistency
Rectal suppositories are usually 1 - 4g in weight
Their drug content varies from <0.1% to 40%
The suppository bases are either glyceride-type fatty bases or water-soluble bases
What properties should a suppository base have (7)
The suppository base should
have a melting range small enough to give rapid solidification after preparation, preventing sedimentation of suspended drug particles
exhibit enough volume contraction to permit removal from the mould following solidification
melt, dissolve or disperse at body temperature
dissolve in the available volume of rectal fluid
be chemically and physically stable during storage
be non-irritant
have an appropriate viscosity to minimise leakage
What are the different types of suppository bases
Fatty bases used are mixtures of natural or synthetic vegetable oils e.g. Cotmar, Dehydag,
They consist of mixed triglycerides, saturated fatty acids, waxes and fatty alcohols
Water-soluble vehicles are used much less frequently
Glycerinated gelatin bases are mostly used for laxative purposes
Polyethylene glycol bases have a melting point well above body temperature
What are the characteristics of PEG bases
Polyethylene glycol bases have a melting point well above body temperature
They must dissolve in rectal fluid to release the drug, but they are miscible with water
Drugs may remain in the base, and drug release may be slow
PEG-based formulations are especially suited for application in tropical climates
PEG bases can oxidise forming peroxides on storage, therefore airtight packaging is recommended
How big should suppository drug particles be
To prevent sedimentation during manufacture the drug particle size must be <150µm
Particles < 50 μm will not cause irritation to the patient
The smaller the particles, the higher the dissolution rate
How do we make suppositories
Suppositories are formed by: Hand rolling (small scale, 6-50 at a time) Compression moulding (semi-automated, 20,000/hour) Fusion moulding (semi-automated, 20,000/hour)
What additives do we include in suppositories
Inclusion of viscosity enhancers (e.g. colloidal silicon oxide, aluminium monostearate) slows drug release
Surfactants are added to act as wetting agents and to prevent particle aggregation
What are the other rectacl dosage forms
Lipid-based ointments (local delivery), rectal capsules (systemic delivery), rectal tablets (used for constipation), rectal solutions, emulsions and suspensions (enemas) (used to evacuate, cleanse or treat lower GI tract)
What are the specifics surrounding enemas
Enemas may have a relatively large volume e.g. treatments for rectocolitis are ~100 mL
This enables the drug to reach the upper part of the rectum and the sigmoid colon
The container design is adapted for delivery or comes with an applicator
Which conditions do we treat with local drugs via the vaginal pathway and which drugs do we often deliver
Anti-fungal or anti-bacterial drugs e.g. clotrimazole
Spermicides e.g. nonoxynol-9
Microbicides to prevent transmission of HIV, chlamydia and trichomonas e.g. tenofovir (advanced stages of clinical development)
Which conditions do we treat with systemic drugs via the vaginal pathway and which drugs do we often deliver
Drugs which are administered vaginally to achieve systemic effects (HRTs)
oestrogens, progesterone and prostaglandin analogues
Progesterone administered vaginally has a higher bioavailability compared to the oral route and bypasses hepatic metabolism
What dosage forms are avalible for the vaginal route
Pessaries, tablets, films, capsules, rings and medicated tampons
Solutions, emulsions and suspensions
Creams, gels, ointments, sprays and foams
There are variations in preference for different dosage forms: USA - creams and foams; France - pessaries; India - tablets
What are the structures of the vagina, what is the average pH and why
The vagina is a fibro-muscular tube 4-6 inches long
Its wall is coated with cervico-vaginal fluids containing mucin, salts, acids, proteins and water
In healthy adult women vaginal pH is 3.5-4.5
This is due to the conversion of glycogen from the mucosal epithelium to lactic acid by lactobacillus
What makes the vagina’s environment so variable
Vaginal ecology is dynamic and responds to changes in hormone levels, contraceptives, topical drugs, age, infection and the presence of semen
The composition and volume of fluids and environment varies significantly with age, stage of menstrual cycle, pregnancy, sexual activity and infections
Which blood vessels supply the vagina with blood
The vaginal wall contains a vast network of blood vessels - blood drainage is via the vaginal vein into the vena cava, bypassing first pass metabolism
What should the ideal vaginal dosage form be
Ideal vaginal dosage forms should
be long acting, reducing the frequency of administration
be stable in a range of climatic conditions
be of appropriate viscosity to minimise leakage
not lead to any irritation
be easy to insert and/or apply
What are vaginal pessaries and what characteristics should they have.
Pessaries (vaginal suppositories) are solid, single-dose preparations for vaginal insertion. They should be made:
of a shape, volume and consistency suitable for insertion (weight ~1g)
containing drug particles < 50 μm in size, to avoid irritation and sedimentation during manufacture
of a base that is soluble or dispersible in water, or melts at body temperature
of a base with melting range that gives rapid solidification after preparation, preventing sedimentation of suspended drug particles
from glycerol-gelatin bases, which are well tolerated
What are vaginal tablets and what characteristics should they have.
Vaginal tablets are solid, single-dose preparations similar to oral tablets
They may be coated or uncoated, and are usually ovoid in shape
Tablets are easy to store, use and manufacture
They should rapidly disintegrate in a small volume of vaginal fluids - excipients can improve disintegration
Lactose is often used as a filler as it is a natural substrate for the vaginal microflora
Tablets and films may include excipients to increase viscosity and improve retention (reduce leakage)
What other vaginal preparations are available
Semi-solid vaginal preparations include ointments, creams and gels (inclusion of tube is more expensive)
Vaginal capsules (shell pessaries) - antibiotics and antifungals
Vaginal solutions, emulsions and suspensions (local effect or irrigation)
Medicated vaginal tampons
What are the key conciderations when formulating for the lung, rectum and vagina respectively
- Drugs administered to the nose or lung must be delivered by aerosol via particles of a defined size
- Drugs administered rectally must be formulated to overcome the lack of fluid present and be viscous enough to prevent leakage
- Formulations administered vaginally must withstand local changes in microflora, pH and fluid volume
