michniak 4: mucosal drug delivery II

oral route

- most popular of all routes of administration

- first pass metabolism and enzymatic/pH degradation in the GIT

- highly acceptable by patients and mucosa is relatively permeable with rich blood supply

transmucosal routes

- offer alternate routes for drug delivery

- have certain advantages over oral delivery

- non-invasive compared to parenteral

systemic mucosal drug delivery advantages

- possible avoidance of first pass effect

- no presystemic elimination within GI

- depending on the particular drug, a better enzymatic flora for drug absorption

Zicam

- example of potential irritation and irreversible damage to the ciliary action of the nasal cavity from chronic application of nasal dosage forms

- large intra- and inter-subject variability in mucus secretion in the nasal mucosa that significantly affects the drug absorption from this site

disadvantages of rectal, vaginal, and ocular mucosal drug delivery

- poor patient acceptability associated with these sites; reserved for local rather than systemic applications

what increases tolerance to potential allergens in the oral mucosa?

- lack of Langerhans cells

nasal route example meds

- Miacalcin nasal spray for osteoporosis

- Suprefact nasal spray for prostate cancer and endometriosis treatment

disadvantage of nasal route

- small dose

- solids and liquids excluded if >20 micron size and exhaled if <0.5 micron

rectal route med example

- suppository or enema

- aspirin, theophylline, chlorpromazine

- useful in children

rectal route disadvantage

- erratic and slow absorption

- low compliance

vaginal route med examples

- creams and suppositories usually to treat vaginal infections and vaginitis

- Premarin cream

- Vagifem tablets

buccal route of administration

- the tissue regenerates faster than skin

- recovers faster from irritation

- can use polymer films as well as buccal patches, SL tablets, etc

intrauterine route of administration

- contraceptive devices

- controlled release devices

types of oral mucosal delivery

- sublingual

- buccal

- dental/periodontal/gingival

- local

- palatal

oral cavity

- easy termination in case of adverse events, blood flow constant during disease, so flow is never the rate limiting step

- multiple routes available

oral mucosa structure

- epithelium --> lamina propria --> submucosa

epithelium

- similar to stratified squamous epithelia found in the rest of the body

- has a mitotically active basal cell layer, cells are shed from the surface of the epithelium

- epithelium is about 40-50 cell layers thick, while that of the sublingual epithelium contains somewhat fewer

- epithelial cells increase in size and become flatter as they travel from the basal layer upwards

mucosa

- stratified squamous epithelium

masticatory mucosa (gingiva and hard palate)

- keratinized epithelium similar to skin

- represent 25% of the total surface area of oral lining tissues

lining mucosa

- covers remaining regions but not dorsal surface of tongue

- represents 60% of total surface area, capable of stretching

- non-keratinized

specialized mucosa

- on dorsum of tongue only

- represents 15% of total surface area

- has keratinized and non-keratinized portions

saliva

- protective fluid for all tissues in the oral cavity

- protects soft tissues from abrasion by rough materials and chemicals

- allows for the continuous mineralization of the tooth enamel after eruption and helps in remineralization of the enamel in early stages of dental caries

- aqueous fluid with 1% organic and inorganic materials

- pH: 5.5-7.5 depending on flow rate

major determinants of salivary composition

- time of day

- type of stimulus

- degree of stimulation

saliva pH and flow rate

- at high flow rates, the sodium and bicarbonate concentrations increase and they also lead to a more alkaline pH

daily salivary volume

- between 0.5 to 2 liters

- amount of fluid available to hydrate oral mucosal dosage forms

- main reason behind the selection of hydrophilic polymeric matrices as vehicles for oral transmucosal drug delivery systems is this water rich environment of the oral cavity

permeation pathways for passive drug transport

- transcellular route [lipoidal pathway]

- paracellular route [aqueous pore pathway]

intracellular spaces

- major barrier to permeation of lipophilic compounds

cell membrane

- major transport barrier for hydrophilic compounds

extrernal carotid artery

- maxillary, hard palate, cheeks

- lingual, tongue, SL, gingival

- facial, soft palate, lips

blood flow in dorsal of tongue

- 100.6 ml/min per 100g tissue

blood flow in buccal mucosal

- 20.3 ml/min per 100g tissue

barriers to permeation

- transcellular barrier for lipophilic drugs

- paracellular barrier for hydrophilic drugs

- saliva

saliva as a barrier

- 0.5 to 2 liters per day forms film 0.1 mm thick

- mix of serous secretions which are high in glycosylated protein of low viscosity and mucus secretion with more carbohydrates than proteins and little enzyme activity

- pH 5.5-7.5

- mucus is negatively charged and reduced transfer of anionic compounds

Tetracycines

- complex with mucus and result in delay in permeation

drugs with more than 30 kDA molecular mass

- delay in delivery

in vitro permeation study models

- animal tissue from rabbit, hamster, murine, rat

- cell lines [Cell Culture:TR-146; EpiOral-MatTek in vitro tissue model]

in vivo permeation study models

- dogs, rabbits, monkeys, pigs, rodents, hamsters

- non-keratinized similar to human tissue

- typical study design: flux measurements, irritation, toxicity studies and bioadhesion measurements

classification of dosage form

- non-attached or mobile solid dosage form

- attached or immobilized dosage forms

- accelerated/controlled release

- topical/systemic release

attached/immobilized dosage forms

- prolonged contact [can be used for controlled release], high drug concentration at the absorptive surface, any part of mucosa [buccal, lingual, SL, gingival], system itself protects drug from environmental degradation, permits modification of membrane permeability by addition of enhancers

non-attached or mobile solid dosage form

- short residence time, reduced effectiveness due to intra and inter-individual variability in saliva secretion, tongue and cheek movements

- requires conscious efforts by the patient, fast absorbing drugs which are not easily degraded are ideal candidates

sublingual tablets, lozenges and chewing gums are examples

sublingual tablets

- nitroglycerin and fentanyl

- important factor: disintegration time, 2 min for nitroglycerin USP

lozenges

- zinc gluconate

- disadvantage: sucking/saliva secretion affects bioavailability; dosage form needs to be palatable

chewing gums

- patient acceptability, ease of termination, variability in dosing by changes in chewing behavior, and less irritation all make this form of delivery more popular

- first monograph on chewing gum published in European Pharmacopoeia in 1998

components of drug chewing gum

- gum base made of elastomers, resins, waxes, fats, and emulsifiers [glycerin and lecithin]

formulation considerations for chewing gum

- water solubility, amount left behind after chewing and by swallowing

- intra and inter-individual variability in bioavailability due to chewing rate and time

extended release chewing gums

- nicotine as a complex bound with a cation exchange resin

- encapsulation

accelerated release chewing gums

- emulsifiers, hydrophilic complexes of lipophilic drugs

nicotine chewing gums

- nicotine is released over 30 minutes of intermittent chewing from chewing gum

- nicotine mainly absorbed into the blood through buccal mucosa

- recommended starting dose is 8-12 pieces of 2 mg chewing gum per day

- max dose is 15 pieces of 4 mg gum per day

mechanism of adhesion for mucoadhesives

- covalent [1]

- electrostatic [2]

- hydrogen bonding [3]

- hydrophobic interactions [4]

stages of mucoadhesion

- first is contact stage

- second is consolidation stage [physical and chemical]

examples of mucoadhesives

- films, sprays, buccoadhesive sprays

films/patches structure

- uni/bi-directional release

- removable/biodegradable, dissolvable matrix or backing layer

- topical/systemic release

- adhesive portion could be a drug carrier or only serve retention purposes

- impermeable backing layer

- size is 1-3 cm^2

impermeable backing layer function

- protects from saliva

- usually promotes unidirectional release

systemic delivery sprays sequence

1. spray delivers a fine mist of droplets

2. solvent is either absorbed through the membrane taking some drug with it o is diluted by the saliva

3. drug in the solvent and not immediately absorbed is deposited as a thin film on the mucin layer [possible with the help of a mucoadhesive]

4. drug substance can then diffuse into the lipid layer in the membrane and enter systemic circulation

5. alternatively the drug dissolved in the saliva and is transported to stomach or with sloughed mucin layer

Striant

- an example of a buccoadhesive tablet

- testosterone buccal system

- June 2003 FDA approved

Periochip

- intraperiodontal pocket delivery

- composed of 2.5 mg chlorhexidine digluconate in a biodegradable matrix of hydrolyzed gelatin, cross linked with glutaraldehyde

periodontitis

- destructive bacterial infection causing breakdown of periodontal attachment

- causes loosening of tooth

- challenge is delivery of antibiotics to the periodontal pocket

BTCP (Breakthrough Cancer Pain)

- transitory flares of pain rising from moderate to severe intensity, occurring on a background of otherwise stable pain in a patient receiving chronic opioid therapy; up to 86% patients experience the pain 1 to 4 times a day with the onset of 3 min and lasting up to 30 min

- short and immediate acting medications with oral morphine and hydromorphone, transdermal fentanyl are used to control this

- fentanyl is 100x more potent than morphine and lipid soluble; 25-30% bioavailable orally

fentanyl in saliva

- 80% non-ionized, making it the only opioid suitable for transmucosal absorption

Actiq

- oral transmucosal fentanyl citrate [OTFC] consists of medicated sucrose and liquid glucose matrix attached to a radiopaque plastic handle

- analgesic effect starts within 15 minutes and lasts up to one hour

- FDA approved OFTCs for BTCP in 1998

Oravescent SL/BL tablets

- OFTC different formulation

- if system had low pH, them weak base would dissolve adequately because ionized form predominates

- if pH were to gradually increase, some of the ionized drug would slowly be converted to the unionized form and permeate more easily through mucosa because unionized form predominates

nose

- respiratory portion of the nasal cavity contains ciliated projections consisting of columnar epithelial cells

- blanket of nasal mucus is transported by the synchronized beat of the cilia

why choose nasal administration

- local effects

- mainly due to its large surface area

nasal drug delivery advantages

- avoidance of first-pass effect and destruction in GIT

- rate and extent of absorption and the plasma concentration vs time profiles are relatively comparable to that obtained by IV medication

- existence of a rich vasculature and highly permeable structure in the nasal mucosa for systemic absorption

- ease and convenience of intranasal drug administration

physiological factors that affect PK and bioavailability; nasal

- speed of mucus flow

- change in physiological state

- atmospheric conditions in the nasal cavity

dosage form factors that affect PK and bioavailability; nasal

- physiochemical properties of the active drug

- concentration of active drug

- physicochemical properties of pharmaceutical excipients used

- density, viscosity, and pH characteristics of the formulation

- toxicity of the dosage form

administration factors that affect PK and bioavailability; nasal

- size of dose

- site of deposition

nasal delivery of organic based pharmaceuticals

- drugs with extensive presystemic metabolism can be rapidly absorbed through nasal mucosa with systemic bioavailability of approximately 100% [progesterone, estradiol, testosterone, hydralazine]

- Water-soluble organic-based compounds are well absorbed and nasal absorption is likely dependent on aqueous channel diffusion [sodium cromoglycate]

nasal delivery of peptide-based pharmaceuticals

- general low oral bioavailability and normally administered parenterally

extent of systemic delivery of peptides or proteins by transnasal permeation may depend on

- structure and size of molecules

- partition coefficient

- susceptibility to proteolysis by nasal enzymes

- nasal residence time

- formulation variables [pH, viscosity, and osmolarity]

when no enhancer is used

- good systemic bioavailability can be achieved for molecules up to 1000 Daltons in MW

with the assistance of enhancers

- a good bioavailability can be extended to a molecular weight of at least 6000 Da

methods used to facilitate nasal absorption of drugs

- structural modification

- salt or ester formation

- formulation design

- surfactants

structural modification

- the chemical modification of the molecular structure of a drug has been often used to modify the physicochemical properties of a drug, and hence it could also be utilized to enhance the nasal absorption of a drug

salt or ester formation

- the drug could be converted to form a salt or an ester for achieving better transnasal permeability, such as formation of a salt with increased solubility or of an ester with better nasal a

Formulation design to enhance nasal absorption

- proper selection of formulation excipients could improve the stability and/or enhance the nasal absorption of drugs

surfactants

- incorporation of surfactants into nasal formulations could modify the permeability of nasal mucosa, which may facilitate the nasal absorption of drugs

dosage forms for nasal drug delivery

- aerosol

- gel

- liquid

- ointment

- suspension

- sustained release

sprays and drops: nasal dosage form

- a metered-dose inhaler is a device, when manually compressed, delivers accurate and reproducible dose of the nasal or bronchial medication

- particles less than 0.5 mcm in each diameter may pass through the nose and reach terminal bronchi abd alveoli of the lungs

- nasal spray requires that the particles have a diameter larger than 4 mcm to be retained in the nose and to minimize passage into the lungs

examples of nasal dosage forms

- Nasal salmon calcitonin (Novartis & others)- postmenopausal osteoporosis, slows bone loss

- Nasal desmopressin (Ferring & partners)- replaces low levels of vasopressin for diabetes, etc.

- Nasal buserelin (Aventis)- for hormone-responsive cancers & endometriosis, etc.

- Nasal nafarelin (Searle)-hormone to treat endometriosis, menstrual cramps, etc.

- Nasal parathyroid hormone, leuprolide, insulin, interferon, etc.

nasal gel

- Zicam

sustained release nasal dosage forms

- micro- and nanoencapsulated spheres or particles

micro- and nanoencapsulated spheres or particles

- spray based-spray drying

- solvent-free-co-extrusion [specific applications in peptide and protein delivery]

- emulsion based-solvent evaporation, interfacial polymerization, polymerization in dispersed media

- melt emulsification

- liposomes

advantages of nasal drug delivery

- avoidance of hepatic first-pass elimination and destruction in the GIT

- rapid absorption of drug molecules across the nasal membrane

- may be used for local and systemic drug delivery

- relative ease and convenience

limitations of nasal drug delivery

- possible local tissue irritation

- rapid removal of the therapeutic agent from the site of absorption

- pathologic conditions such as cold or allergies that may alter the nasal bioavailability significantly

intrauterine, rectal, and vaginal administration

- tablets, minitablets, pessaries

- characterized by prolonged vaginal residency, sustained API release, suitable efficacy, and convenience for the patients

- due to the usage of natural products and synthetic polymers with high mucoadhesive properties

natural polymers

- polysaccharides and protein

polysaccharide polymers

- plant: starch, pectin, and guar gum

- microbial: pullilan, xanthan gum

- marine: chitin, alginate

protein polymers

- animal: collagen, gelatin, albumin, elastin

- plant: zein, gluten protein

vaginal drug delivery semi-solid

- geis

vaginal drug delivery solid

- suppositories

- tablets

- pessaries

- vaginal rings

- films

vaginal drug delivery particulate systems

- microspheres

- nanoparticles

- pellets

advantages of vaginal administration of drugs and hormones

- self-insertion and removal

- continuous drug administration at effective dose level

- better patient compliance

continuous drug administration at effective dose level

- the continuous release and local absorption of a drug minimizes systemic toxicity that may result from oral peak and valley drug administration

NuvaRing (Organon)

- nonbiodegradable vaginal ring as contraception

different vaginal rings

- donut-shaped [homogenous dispersion]

- sandwich dispersion

- homogenous dispersion

- disk-shaped

- core-dispersion

- sandwich dispersion

donut-shaped dispersion

- rate controlling polymeric membrane: thin line which lines the inside and outside of the ring

- drug reservoir: between the 2 outer layers of the rate-controlling

sandwich dispersion

- rate controlling polymeric membrane: 2 thick lines that line the outside and inside of the ring

- drug reservoir: in between the 2 layers of rate controlling

homogenous dispersion

- rate controlling polymeric membrane: thin ring surrounding an opaque circle

- drug reservoir: the entirety of the middle of the circle

disk-shaped

- rate controlling polymeric membrane: thick outside border around a ring

- drug reservoir: lines the inside of the ring