michniak 3 mucosal drug delivery I

polymer definition

- substance formed by the linkage of a large number of monomers

bioadhesive polymer

- synthetic or natural polymer which binds to biological substrates such as mucosal membranes

- aka biological glues

- incorporated into drugs to enable them to bind to target tissues

mucosal membranes

- moist membranes that line passageways and structures in body that lead to outside environment

- in mouth, vagina, respiratory tract, GI tract, and nose

what do mucosal membranes secrete

- mucus

mucus

- acts as a protective barrier and also lubricates the mucosal membrane

- contains mucin , water, and inorganic salts

mucin

- primary constituent of mucus

Orabase®

- formulation used to treat mouth ulcers

- contains polymers like gelatin, pectin, and carboxymethylcellulose [CMC]

examples of bioadhesive polymers

- acacia gum

- alginic acid

- carbomers/carbopols

- hydroxypropyl methylcellulose (HPMC)

- sodium hyaluronate

- pectin

- polyvinylalcohol [PVA]

- polyvinylpyrrolidone [PVP]

- tragacanth

acacia gum

- natural polymer is a dried gum obtained from stem and branches of Acacia Senegal tree

- use: pharmaceutical thickener

alginic acid

- natural polymer found in the cell walls of brown algae

- widely used in the manufacture of alginate salts

- sodium alginate

carbomers/carbopols

- polyacrylic acid polymers widely used in the pharmaceutical and cosmetic industries as thickening agents

advantage of carbomers on formulation science

- adhere strongly to mucosal membranes without causing irritation

- exhibit low toxicity profiles

- compatible with many drugs

Hydroxypropyl methylcellulose (HPMC)

- included in preparations used to moisten contact lenses and in oral gels

Sodium hyaluronate

- high molecular weight biological polymer made of repeating disaccharide units of glucuronic acid and N-acetyl-D-glucosamine

- used during intraocular surgery to protect the cornea

- acts as a tear substitute in the treatment of dry eyes

transdermal drug systems adhesives

- addition of additives to TDDS to the adhesive matrix causes unpredictable variations in patch adhesive properties

- pressure sensitive adhesives [PSAs] guarantee adhesion

- drug and other excipients have to be incorporated/dissolved into adhesive matrix and be stable and also release drug when placed onto skin

pressure sensitive adhesives [PSAs]

- adhesives capable of binding to skin surfaces with application of light pressure

- when removed, does not leave any visually noticeable residues or cause irreversible skin damage

- most challenging is the matrix patch [drug-in adhesive type] in which the PSA is the main constituent of the dosage form

classifications of pressure sensitive adhesives

- solvent-based

- water based

- hot melt types

different PSAs

- polyisobutylenes

- acrylic-based adhesives

- silicon based adhesives

- PVP and polymethyl methacrylate

polyisobutylene

- most common; less allergic reactions and used in scopolamine patch

Polyvinyl pyrrolidone (PVP) & polymethyl methacrylate & mixtures of the two

- good for hydrophilic APIs and proteins since more water can be present

types od TDDS rate controlling membranes

- ethylene vinyl acetate copolymer [EVA]

- silicone rubber

- polyurethane

EVA

- most commonly used since permeability can be changed by changing the vinyl acetate content of the polymer

who regulates types of in vitro drug release tests that should be used for these patches?

- USP

Drug absorption

- process by which a drug leaves site of administration and enters the general circulation

- drug has to cross several cell membranes before reaching its target tissue/organ

membrane function

- barriers

- control drug/molecule transport across cells

- general structure is a matrix of proteins surrounded by a phospholipid bilayer

ways to cross membrane

- passive diffusion

- facilitated passive diffusion

- active transport

- pinocytosis

what is drug absorption determined by

- physicochemical properties

- formulation

- route of administration

passive diffusion

- molecules moving down a concentration gradient without the expenditure of energy

- lipid soluble and small molecules do this easily

facilitated passive diffusion

- carrier proteins specific to a substrate will transport something down its concentration gradient without the use of energy

- depends on the availability of carriers, so this process can become saturated

- glucose from blood is an example

active transport

- movement of molecules against concentration gradient

- requires input of energy obtained from ATP

pinocytosis

- form of endocytosis

- cell drinking

- cell engulfs large molecules and fluid that may be present in the extracellular region

adhesion of bioadhesive drugs to mucosal membranes effect

- increase in the concentration of the drug at site of action

major outcome of using bioadhesive polymers in drug delivery system

- enhances the absorption of drugs

bioadhesion

- describes the bonding or adhesion between synthetic or natural polymer and sot tissues

mucoadhesion

- adhesion interactions between polymers and mucus or mucosal surfaces

mechanisms of bioadhesion step 1

- wetting and swelling of polymer

- intimate contact with the substrate

- surface tension and forces allow for bioadhesives to adhere to biological tissues

- polymers swell due to affinity for water

mechanisms of bioadhesion step 2

- interpenetration between the polymer chains and the mucosal membrane through semipermeable adhesive bonds

- surface of mucosal membranes made of glycoproteins

- strength of semipermeable adhesive bonds depends on degree of penetration between the two polymer groups

- strong bonds when one polymer group is soluble in the other, and both polymer types are a similar chemical structure

mechanisms of bioadhesion step 3

- formulation of chemical bonds between the entangled chains

- covalent bonds and VDWs/H-bonds exploited in the manufacture of bioadhesive formulations in which strong adhesions between polymers are formed

characteristics of bioadhesive polymers

- flexibility

- hydrophilicity

- hydrogen bonding

- high molecular weight

- surface tension

flexibility

- controls extent of the interpretation between the polymers and mucosal/epithelial surfaces

hydrophilicity

- polymers that are hydrophilic in nature are able to form strong adhesive bonds with mucosal membranes because the mucus layer contains large amounts of water

hydrogen bonding

- presence of H-bond forming groups [OH and COOH] are vital in large quantities

high molecular weight

- polymers with a high molecular weight are desirable because they provide more available bonding sites

surface tension

- needed to spread the bioadhesive polymer into the mucosal layer epithelial surface

targets for bioadhesive formulations

- eye

- nasal cavity

- oral cavity

- skin

- vagina

- rectum

eye bioadhesive systems

- mucoadhesive eye drops/inserts

- one of the most important and complex organs in the body, which is why it is so hard to target because of how protected it is

- system must be easy to use, comfortable, and maintain substantial concentrations of the drug in the eye to produce therapeutic effects

some conditions of the eye

- conjunctivitis, dry eye, glaucoma

conjunctivitis

- inflammation of the conjunctivae, which are mucous membranes covering the whites of the eye and the inside of the eyelids

- caused by bacteria, viruses or allergens and the signs and symptoms dependent on type of conjunctivitis

- symptoms: redness of the eye, grittiness or itchy eyes and the presence of a sticky or watery discharge

dry eye

- occurs hen people don't have enough tears or the adequate composition of tears recruited to lubricate the eyes

- Occurrence of dry eyes increases with age

- eyes become itchy, gritty, painful and have burning sensation

- ex: artificial tears

glaucoma

- pressure in eyeballs; causes excessive amounts of aqueous humor [fluid that fills the eyeballs]

- this puts pressure on the optic nerves and compresses the blood vessels in the eye

- resultant effects include abnormalities in vision and total blindness

ocular bioadhesive formulations

- Produce prolonged or sustained release of drugs into the eye

- drugs containing polymers attach to mucin on the conjunctival surface through non-covalent bonds

- polymer remains in contact with surface of the eye until mucin replaces itself, or the pressure of blinking removes drug from the eye

artificial tears

- contain the polymer PVA, which inceases tear production and protects the eye from further irritation

monomer of PVA

- vinyl alcohol

nasal cavity bioadhesive systems

- nasal drug delivery systems

- antihistamines and steroids are administered as nasal drops/sprays to treat conditions affecting the nose

- nasal mucociliary clearance affects retention and effects of the drugs in the nose

mucociliary clearance

- transports mucus from the cells lining the nose and protects the respiratory tract from damage caused by inhaled substances, including dirt particles and medicines

nasal bioadhesive formulations

- mucociliary clearance overcome when bioadhesive polymers are mixed with drugs intended to be delivered in the nose

- ex: methylcellulose exhibits the most reduction in mucociliary clearance whilst carbopol 934P shows the least reduction

- Rhinocort

- Flosane and Nasonex

- Beconase

- Nasacort

rhinocort

- powdered mixture beclomethasone dipropionate and hydroxypropylcellulose

- patients suffering from nasal allergy administer one spray twice a day into the nasal cavity

- powder sticks to and swells on the cells lining the nose and remains there until approximately six hours after administration

Beconase

- used to treat nasal inflammation and allergies associated with hayfever

- contains beclomethasone dipropionate[active ingredient] and carboxymethyl cellulose and microcrystalline cellulose [polymers]

Nasacort

- treats allergies that result in the inflammation of the nose

- triamcinolone acetonide [active] and microcrystalline cellulose [polymer]

- polymer swells in the presence of water and is able to spread across the nasal mucosa, thus helping the distribution of the drug over the mucosal surface

oral cavity bioadhesive systems

- dental gels/buccal systems

oral cavity common conditions

- mouth ulcers

- oral thrush/candida

- gingivitis

mouth ulcers

- breach or break in the mucus membrane that lines the inside of the mouth

- majority of patients suffer from mino aphthous ulcers

- ulcers are roundish, shallow, grey-white color and painful

- small and appear in small crops

oral thrush/candida

- an infection caused by Candida albicans [fungus] in the oral cavity

- also arise due to diabetes, recent antibiotic therapy and inhaled corticosteroids

- soft creamy-white patches which can be wiped off

- lesions are painful and can occur anywhere in the oral cavity

gingivitis

- inflammation of the gums

- caused by build-up of plaque on the teeth

- gums become reddened, swollen, and bleed easily with slight trauma such as brushing teeth

buccal mucosa

- refers to the inner lining of the lips and cheeks

- epithelium of buccal mucosa is about 40-50 cells thick and the epithelial cells become flatter as they move from basal to superficial layers

- less permeable

- unable to retain dosage forms at the site of absorption easily

- use of bioadhesive polymers allows better retention of a dosage form by spreading it over the absorption site

sublingual mucosa

- surrounds the sublingual gland, which is a mucin-producing salivary gland located underneath the tongue

- mucosa is relatively permeable and gives a rapid absorption of drugs due to excellent blood supply

- convenient, accessible and well accepted by patients

drugs administered via sublingual route

- tablets, powders, solutions, or aerosol sprays

- appropriate for many drugs as long as the drug is able to go into solution with the saliva in the mouth

- nitroglycerin SL tablets, which are administered under the tongue for prophylactic treatment of angina

skin bioadhesive systems

- patches, tapes, dressings

- liquids, powders, ointments, transdermal patches

skin functions

- protect body from injury/invasion of pathogens

- prevent dehydration

- regulate body temperature

- produce vitamin D

transdermal patches

- sustained-release devies that release a specific amount of drug whilst firmly attached to the skin

- must provide a firm, soft contact with the skin but also allow the patch to be easily removed with minor effort

drug delivery systems skin purposes

- collecting body fluids

- protecting the skin

- providing local or systemic drug delivery

Adhesion in skin

- formation of a new mechanical bond between the skin and the adhesive agent

vaginal bioadhesive systems

- local vaginal delivery systems

epithelium of vagina

- contains glycogen, which is broken down by enzymes and bacteria into acids, like lactic acid

- maintains low vaginal pH, which is normally between 4 and 5

acidic pH in vagina

- desirable because it makes vagina inhospitable to pathogens

- decreased levels of glycogen in the vagina leads to increase in vaginal pH and makes the vagina more susceptible to infection

common conditions affecting the vagina

- vaginitis

- bacterial vaginosis

- candidiasis [thrush]

- trichomoniasis

vaginitis

- vaginitis means inflammation of the vagina and it creates discharge, odour, irritation, or itching

- has many causes which include infections with trichomonas vaginalis, dietary deficiency or poor hygiene

bacterial vaginosis

- the casual organism often implicated in this infection is Gardenerella vaginalis, although other bacteria present in the vagina also contribute to the cause

- the infection arises due to the overgrowth of these bacteria

- about 50% of patients will have a thin white discharge with a strong fishy odor

candidiasis (thrush)

- is a common yeast infection caused by the organism Candida albicans

- signs and symptoms of thrush are white cheesy discharge tat itches and irritates the vagina

trichomoniases

- STI caused by Trichomonas vaginialis

- Symptoms in women include vaginal itching as well as a froth, foul-smelling, greenish-yellow discharge

vaginal bioadhesive formulations

- intravaginal route has been used to deliver contraceptives as well as anti-infective agents such as antifungal drugs to exert local effect

- agents targeted for vaginal route have been formulated into various dosage forms including creams, gels and vaginal tablets

- localized application of vaginal formulations enables the spread of these formulations over the target area, which allows an effective therapy

- Bioadhesive polymers are incorporated into vaginal formulations to aid adhering of the dosage form to its target site

- polymers also increase the retention of the active drug in the vagina and also optimizes the spread of the formulation over the vaginal epithelium

rectum bioadhesive systems

- local/systemic rectal delivery systems

- suitable for patients who cannot take medicines through oral route, like unconscious people or infants

- drugs absorbed from rectum can escape breakdown by hepatic enzymes

- mucoadhesive suppositories have been developed for the local treatment of diseases such as hemorrhoids and rectal cancer

- preparation H

preparation H

- can help shrink the hemorrhoidal tissue which is swollen by irritation

- contains PEG

summary

- bioadhesive drug delivery systems available since 1940s

- earlier applications mainly oral and GI tract

- nowadays, mucosal and epithelial surfaces including vagina, skin, and nasal cavity

bioadhesion allows retention of active drug over mucosal surface and prolongs contact time, which is why these are preferred over conventional methods of drug delivery

- bioadhesive drug delivery offers controlled release of drugs and improved patient compliance due to reduction of dosing frequency