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Oral drug delivery

Dr. Herman J. Woerdenbag

Department of Pharmaceu1cal Technology and Biopharmacy
University of Groningen
The Netherlands

2016 H.J.Woerdenbag

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1. General aspects oral

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Oral administra<on forms

Intake by mouth
Oromucosal prepara1ons
Mouthwash, mucoadhesive products
AQer swallowing
Absorp1on via gastrointes1nal tract
In most cases systemic eect

Solid oral dosage forms

Liquid oral dosage forms
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Biopharmacy oral
Pharmaceu1cal availability, rate of absorp1on, bioavailability
strongly depend on design and formula1on dosage form

Transit: API exposed to various condi1ons

Residence 1me
Diges1ve and metabolising enzymes

Mouth oesophagus stomach small intes1ne

(duodenum, jejunum, ileum) large intes1ne (colon) -
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Gastrointes<nal tract (1)

Transport func1on
Corroding and irrita1ng API (doxycycline, bisphosphonates) may cause
damage if they s1ck: take ample water when swallowing
Acidic, pH 1.5-3.0 (extremes: 1.0-5.0)
Diges1ve enzymes
Residence 1me depends on nutri1onal status and physical form
- Solu1on of API on empty stomach: passage within 30 min
- Large non-disintegra1ng tablet with high fat meal: several hours
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Gastrointes<nal tract (2)

Small intes<ne
In duodenum addi1on pacrea1c juice: pH 6.4-6.8
- pH maintained in jejunum and proximal ileum
- Terminal ileum: pH 7.1-7.5
Transit 1me 4.5-6 hours
Duodenum principal site of absorp1on for many API
- Large surface, rela1vely large varia1on in luminal pH: many API nonionised

- pH drops to 6.4-7.4
- Metabolic ac1vity intes1nal ora, short chain facy acids
- Residence 1me 6-12 hours
- Absorp1on of API of minor importance aQer oral administra1on
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Gastrointes<nal tract (3)

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pH prole gi tract / IntelliCaps

Maurer et al., PLoS ONE 2015;10(7):e0129076.

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Absorp<on from gastrointes<nal tract

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First-pass metabolism
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Interac<ons with food (1)

Food may delay stomach emptying
Delay absorp1on of API absorbed from small intes1ne
Food may change pH in gastrointes1nal tract
Inuence pH dependent absorp1on of API
Food components may form insoluble complexes with API
Absorp1on API hampered
Taking much uid enhances amount of liquid for dissolu1on
Larger frac1ons of poorly soluble API dissolve
Bioavailability changes
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Interac<ons with food (2)

Fat food s1mulates bile excre1on
Emulsifying eect of bile increases solubility of lipophilic API
Food increases blood ow to intes1nal tract
Absorp1on of API may increase
Higher portal API concentra1ons
First-pass eect decreases
Certain food substances and herbal prepara1on may
interfere with drug metabolising enzymes
Pharmacokine1c interac1ons
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2. Oral solid
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Solid prepara<ons for oral use

Immediate release, modied release

Powder, liquid


Orodispersible prepara1ons
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Product design (1)

Proper<es API
Solubility, par1cle size, crystal modica1on, wecability
- Par1cle size API maximal 180 micrometer
- If necessary, par1cle size reduc1on

API cannot be manufactured into tablet of capsule without

addi1onal substances
- To obtain sucient powder mass (lling agent)
- To improve owability (lubricant, glidant)
- To improve disintegra1on (disintegra1on agent)
- To obtain desired proper1es of a dosage form
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Product design (2)

Adsorp1on API to excipient(s) and vice versa
Poorly water soluble API (ethinylestradiol, dexamethasone) oQen
adsorb to poorly water soluble or water insoluble excipients
(microcrystalline cellulose)
- Colloidal anhydrous silica may adsorb to API par1cles (low dosed API!)

Special packaging for hygroscopic medicines

Pharmaceu<cal availability can be inuenced by excipients

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Biopharmacy oral solid

1. Disintegra1on
2. Dissolu1on
3. Absorp1on
Each step can be
rate limi1ng

Pharmaceu1cal availability

Biological availability
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Prepara<on oral solid dosage forms

Step 1: prepara1on homogeneous powder mixture
Most essen1al issue for oral solid dosage forms

Step 2: even distribu1on over dose units

Capsule body, die tablelng machine, powder paper

Step 3: control
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Condi<ons for good mixing

Equal par<cle size of the substances to be mixed
Demixing, max. 180 micrometer, agglomerates

Equal mixing ra<o

Prevent loss due to dus1ng during mixing

Neutralise sta1c electricity
Prevent absorp1on to utensils
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Tablets (1)

Solid prepara1ons for oral administra1on, each containing a

single dose of one or more ac1ve substances
Obtained by compressing uniform volumes of par1cles or by
another suitable manufacturing technique, such as extrusion,
moulding, or freeze-drying
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Tablets (2)
Pa1ent friendly, easy to use
Swallowed as a whole
Swallowed aQer being chewed or aQer disintegra1on
Dissolved or dispersed in water before being administered
Retained in the mouth where ac1ve substance is liberated
Accurate dosage
Fast and large scale industrial manufacture
Stable (solid, dry)
Advanced delivery forms
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Composi<on of a tablet
Ac1ve substance
Welng agent
Colouring agent
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TableVng process

Good owability
of powder mixture
Par1cle size
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Protec1on API Film coa<ng
Tablets, mul1par1culates
Taste masking Sugar coa1ng
Compression coa1ng
Facilita1on of swallowing
Masking batch dierences
Improvement of product appearance
Facilita1on of iden1ca1on
For automa1c lling and packaging equipment
Modica1on of drug release (.)
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Modied release drug delivery

Most oral medicines are immediate release
Rapid onset
Rela1vely fast eect
Rela1vely short dura1on of eect

Modied release to deliver API at

Desired rate
Predened 1me point
Specic site of gastrointes1nal tract
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Why modied release?

Keep drug in the therapeu1c range for a longer period of 1me
Chronic diseases
Control of a cri1cal minimum level (pain)
Maintain drug levels overnight
Chronotherapy (chronopharmacology)
Arthri1s, asthma
Reduc1on of side eects
Reduc1on of Cmax
Compliance improvement (becer pharmacotherapeu1c outcome)
Administra1on once daily is most comfortable, thus op1mal
Local treatment gastrointes1nal parts, site-specic targe1ng
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Proper<es API for modied release

Therapeu1c eect is desired over longer period of 1me (t1/2 <12 h)
Elimina1on so rapid that dosing > once daily is necessary
API with long t1/2 in delayed release product is irra1onal
Side eects related to high plasma levels
Absorp1on occurs over en1re small intes1ne (+ stomach)
No irrita1on in gastrointes1nal tract
No increase in rst-pass metabolism in case of delayed absorp1on
Dose-dumping does not pose unacceptable health risks
Dose is such that a dosage form of acceptable size can be produced
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Immediate release / modied release

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Drug targe<ng with modied release

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Biopharmaceu<cs and modied release

Higher gastric pH may cause premature release and/or dose
dumping (release of dose in one bolus)
Transit 1me through gastrointes1nal tract and residence 1me in
various parts dier
Fasted or fed
Individual dierences
Short transit 1me small intes1ne may be too short for very slow
releasing dosage form; colonic absorp1on?
Free uid (available to dissolve drug or dosage form)
Stomach around 100 mL, small intes1ne 50-100 mL, colon 10 mL
Composi1on may inuence swelling matrix system
Ions, fats, enzymes, salts
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Modied release formula<on design (1)

Single en<ty or mul<ple unit system
Monolithic (one part, tablet)
- Remains intact or erodes during residency in gastrointes1nal tract
- Can be trapped (with food) and prevented from reaching small intes1ne
(major absorp1on site)
Mul<-par<culate (pellets, granules in capsule or tablet)
- More reproducible gastric emptying (independent of stomach lling)
- Less risk of dose dumping (dose released at once)
- Large surface area, and higher dissolu1on rate require larger delay
- More dicult to manufacture and to scale up

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Modied release formula<on design (2)

Matrix formula<on or coated formula<on
Matrix formula1on
- API in matrix with release modifying proper1es
- Matrix encompassing en1re dosage form
Coated formula1on
- API in core
- Surrounded by modied release coa1ng
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Modied release formula<on design (3)

Release rate
Determined by dissololu1on rate API and diusion dissolved API
- Release zero order, pseudozero order, rst order

Processes involed
- Hydrata1on of device
- Diusion of water into device
- Dissolu1on of API
- Diusion of dissolved API out of device
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Control of drug release

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Types of modied release dosage forms

Extended release
Prolonged, sustained, controlled release
Delayed release
Lag 1me (intake-ac1on)
Release API at higher pH
- Gastroprotec1on
Site-specic targe1ng
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Hydrophilic matrix
Slow/sustained release by diusion API through swollen polymer
API trapped in slowly dissolving matrix
Swelling polymers
Polyethylene oxide
Eroding system
For drugs requiring extended release ac1on
Once daily, reduc1on side eects
Enhanced compliance
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Insoluble polymer matrix

Slow / sustained release by diusion API through non-
dissolving polymer scaold
Insoluble polymers
Non-eroding system
For drugs requiring extended release ac1on
Once daily, reduc1on side eects
Enhanced compliance
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Membrane controlled extended release

Slow/sustained release by diusion API through polymer coat
Modied by lm thickness and/or pore formers
Water insoluble polymers
Ethylcellulose, acrylic copolymers
Pore formers
Polyethylene glycol
Non-eroding system
Drugs requiring extended release ac1on
Once daily, reduc1on side eects
Enhanced compliance
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Osmo<c pump system

Water diusion through semi-permeable coat increases
osmo1c pressure in device forcing drug out through hole
Osmo1cally ac1ve ller
Semi-permeable membrane
Cellulose acetate
Non-eroding system
Drugs requiring extended release ac1on
Once daily, reduc1on side eects
Enhanced compliance
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Gastroreten<ve system
Extended release
S1cking to stomach wall (mucoadhesion)
Avoiding gastric emptying by large size
Floa1ng on stomach contents
Mucoadesive polymers, swelling polymers
Gas genera1on bicarbonates
Eroding system, but slowly
For drugs with poor colonic absorp1on
For local delivery to the stomach
Mainly experimental
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pH controlled delayed release

Delayed release
Coa1ng pH sensi1ve
Dissolu1on in desired part of tract
pH responsive polymers
Acrylic co-polymers, phtalate polymers
Eroding system
For acid sensi1ve drugs, stomach irritants, colonic delivery,
small intes1nal delivery
Enteric coa1ng Polymers: one type of monomer
Co-polymers: two types of monomers
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ColoPulse technology (RUG)

pH sensi1ve coa1ng:
Eudragit S100

Super disintegrant:

Small increase (0.5 unit)

of pH in ileocecal region:
pulsed release
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GISS: gastrointes<nal simula<on system

pH 7.5

pH 1.2 pH 6.8 pH 6.0

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Bacterially triggered delayed release

Delayed release
Coa1ng digested by colonic bacteria
Polysaccharides only digested by colonic bacetria
Some starches, pec1n
Eroding system
For colonic delivery of drugs
Usually local ac1on
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Mul1ple unit pellet system
Losec (omeprazole), Nexium (esomeprazole)
Tablet built up from small pellets, each pellet enteric coated

Swallowing problems: MUPS can be taken as drink

Disintegrate tablet in water, fruit juice, apple sauce
Suitable for feeding tubes
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Release proles in vitro (l) and in vivo (r)

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Capsules (1)

Solid prepara1ons for oral use with hard or soQ shells of

various shapes and capaci1es, usually containing single dose
of ac1ve substance(s)
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Capsules (2)
Hard capsules (dry solids, semi-solids, non-aqueous liquids)
SoQ capsules (oily liquid)

Immediate release
Modied release
Filled with granules or par1cles with coa1ng
Capsules shell with coa1ng
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Hard capsules
Industrially manufactured
Suited for (small scale) extemporaneous prepara1ons
API itself or tablet (dose adapta1on)
Hard capsule shell
Capsule body (upper) and cap (lower)
Gela1n, HPMC (hydroxypropyl methylcellulose)
Closure of body and cap with glue (USA)
Capsule masks bad taste and odour
Capsule shell swells and opens, and content is released
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Capsule lling: machine, hand

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Capsules tailor-made
Most suitable form for individual prepara1on
(Required dose) unavailable as marketed product
Required dose cannot be obtained by simply splilng a tablet
Pa1ent has swallowing problems
Can be easily prepared in the pharmacy on a small scale
Pa1ents with swallowing problems

From API, from tablets (adapta1on dose) (with excipients)

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Pa<ents with swallowing problems

Open capsule
Separate cap from body
Mix content with semi-liquid food
Apple sauce, custard

Powder content suitable for feeding tube

Mix with water
Not for coated capsules

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Eect of hydrophilic excipients

Excipients in capsules
Lubricant (owability)
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So] capsules
SoQ gela1n capsules = soQgels
Poorly water-soluble drugs
Liquid or semi-solid formula1on converted into solid dosage
Drug compound in solu1on or in matrix
Industrially manufactured
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Dierent so]gel formula<ons

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Progesterone in so]gel
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Self-emulsifying drug delivery systems (SMEDDS, SNEDDS)
Focus on bioavailability improvement API of (mainly) BCS class II
API solubilised in core of oil droplets
Very small emulsied par1cles (submicron) good stability
Contains API, oil, emulsier, co-solvent and/or co-emulsier
In soQgel capsules
In gastrointes1nal tact spontaneous forma1on of micro- or nano-
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Solid, loose, dry par1cles of varying degree of neness

One or more ac1ve substances, may contain excipients
Generally administered with in or with water or another
stable liquid
May also be swallowed directly
Single-dose or mul1dose

Eervescent powders: acid subtance plus carbonate

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Oromucosal prepara<ons (1)


Solid, semi-solid or liquid prepara1ons, containing one or

more ac1ve substances intended for administra1on to the
oral cavity and/or the throat to obtain a local or systemic
Local: designed for applica1on site within oral cavity or throat (gingival,
Systemic: designed for absorp1on via oral mucosa (e.g., sublingual)
(Some of) the ac1ve substance(s) will be swallowed and absorbed via
the gastrointes1nal tract
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Oromucosal prepara<ons (2)

Gingival solu1ons
Oromucosal solu1ons and oromucosal suspensions
Semi-solid oromucosal prepara1ons (gingival gel, gingival paste, oromucosal gel,
oromucosal paste)
Oromucosal drops, oromucosal sprays, sublingual sprays, oropharyngeal sprays
Lozenges and pas1lles
Compressed lozenges
Sublingual tablets and buccal tablets
Oromucosal capsules
Mucoadhesive prepara1ons
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Oral mucosa
Good blood circula1on

Absorp1on of drugs

Venous ouylow
Not via liver portal system
Less rst-pass eect
Becer bioavailability
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Oromucosal administra<on
Pain (malignancies)
Fentanyl (lolly, lozenge)

Pallia1ve seda1on
Midazolam (solu1on in cheek pouch)

Angina pectoris acack

Nitroglycerin (spray)

Pa1ent friendly
Rapid ac1on
Lipolic API
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Transmucosal dosage forms

Fentanyl lollypop
Pa1ent friendly
Rapid ac1on
Lipophilic drugs
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Orodispersible lms
Mucoadhesive prepara1ons
Retained in oral cavity by adhesion to mucosal epithelium
Single- or mul1layer sheets of suitable material that disperse
rapidly in the mouth
Release of API, absorp1on via mucosa possible
Swallowing, gastrointes1nal absorp1on
Cannot be spit out (children)
No water required for intake (pa1ents with swallowing problems,
pa1ents with water intake restric1ons, ease)
Elderly, small children, psychiatric pa1ents, travelers, sporters
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Characteris<cs ODF
Thin lm, polymer basis
S1cks to oral mucosa (tongue, palate, cheek)
Thickness max. 1 mm
Size 210 cm2
Fast disintegra1on
Ph. Eur. <180 s; USP < 30 s
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ODF on the market

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Composi<on ODF
Solvent(s) (plus co-solvents)
Other excipients
Taste corrector (sweetener)
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Prepara<on of ODF
Solvent cas1ng method
Industrial, extemporaneous
Hot-melt extrusion
Good perspec1ve
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Solvent cas<ng


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Hot-melt extrusion (HME)

No solvent needed
No release liner
Higher temperature
Enhanced solubility API
Thermostability API required
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Droplets on plain lm
Adjustable dose
Only small amounts of API
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Quality by design: op<misa<on

Quality Target Product Prole (QTPP)
Cri1cal Quality Acributes (CQA)
- Material characteris1cs, disintegra1on 1me (measurable)
Cri1cal Process Parameters (CPP)
- Concentra1on lm forming agent, amount of plas1cizer
CQA + CPP design space
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Herbal ODF (RUG + Ubaya)

Plant name Dose of extract in ODF (mg)
5 10 15 20 25 30 40 50
Lagerstroemia speciosa (L.) Pers. -
Phyllanthus niruri L. - -
Cinnamomum burmanii Blume - -
Phaleria macrocarpa (Sche.) Boerl. - - -
Zingiber ocinale Roscoe - -

ODF suitable dosage form for herbal extracts

Each extract type and dose requires formula<on adjustment
Limited drug load
MSc thesis Gabriela Eugresya (2015) / Visser JC, Eugresya G, et al. J Herbal Med (in press)
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3. Oral liquid
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Pros and cons for oral liquids

Good alterna1ve for tablet or capsule if pa1ent has
swallowing problems
Dose easily adjustable (volume adapta1on)
Children, elderly
Suitable for administra1on through feeding tube

Physically, chemically and microbiologically less stable than

oral solid
Proper1es API important for choice pharmaceu1cal form
Dosing mistakes occur rela1vely easily
Taste can be a problem
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Target groups for oral liquid

<2 y: unable to swallow solid dosage forms
>7-8 y: tablet swallowing becomes possible
Pa1ents in care home, elderly
Swallowing problems
Pa1ents with a feeding tube
Normal pa1ents in hospital that are being adjusted to the
proper dose (1tra1ng)
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Liquid prepara<ons for oral use


Solu1ons, emulsions or suspensions containing one or more

ac1ve substances in a suitable vehicle

Oral solu1ons, emulsions, suspensions (powders and

granules for.)
Oral drops (powders for.)
Syrups (powders and granules for.)
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Oral liquids
(Aqueous) solu1on
Dispersion of par1cles in aqueous liquid (vehicle)
o/w: dispersion of fat drops in aqueous liquid
Solubilisa1on: microemulsion (micelles)

Mostly used: solu1ons and suspensions

Convenient for adap1ng a dose (children)
Shake well suspensions and emulsions
Spoon, cup, oral syringe
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Ingredients oral liquids

An1microbial preserva1ves Welng agents
An1oxidants Solubilising agents
Dispersing agents Stabilising agents
Suspending agents Flavouring agents
Thickening agents Sweetening agents
Emulsifying agents Colouring macer
Buering agents
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Choice of oral liquid (1)

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Choice of oral liquid (2)

First choice: aqueous solu1on
Advantages: homogenous, good dosing accuracy
Disadvantages: bad taste, stability, risk of crystallisa1on
API insuciently water soluble and solu1on is preferred
Adapt pH
Use co-solvents
Use becer soluble salt
Aqueous solu1on is impossible
Make suspension (solid API)
Dissolve API in lipid solvent
Make (micro)emulsion (liquid API)
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Choice of oral liquid (3)

For bad tas1ng API
For in water unstable API
Sedimenta1on occurs
- Less accurate in dosing
- Not for strongly ac1ng API and API that should be dosed very precisely
Risk of par1cle growth (Oswald ripening)
Water insoluble or water immiscible
Dissolve in oil
Emulsion (o/w) Stability oral liquids
Microemulsion (solubilisa1on) Physical shelf-life
Crystallisa1on, sedimenta1on, creaming
Chemical shelf-life
Hydrolysis, oxida1on
Microbiological shelf-life
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Mixture of two substances, one is nally dispersed in the
other, but not (or only very licle) soluble therein
Suspensions, emulsions
Physically (thermodynamically) unstable

Dispersed substance
Disperse phase, inner phase
Medium in which the inner phase is dispersed
Con1nuous phase, outer phase, vehicle
Matrix, solvent, liquid

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Suspensions for oral use

Fine distribu1on of a API in a viscous aqueous liquid
May show sedimenta1on (cacking) or oa1ng, which is
readily redispersed on shaking
Suspension should remain suciently stable to deliver correct dose

Stability enhancement
Small par1cles
Enhanced viscosity
- (Partly) occulated system
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Emulsions for oral use (1)

Liquid prepara1on of two immiscible (or partly miscible)
liquids, using a viscosity enhancer that reduces the surface
Oil in water (o/w) emulsions for oral use
Milky appearance
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Emulsions for oral use (2)

May show phase separa1on but should be readily
redispersed upon shaking

Stability enhancement
Small droplets
Enhanced viscosity outer phase

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Emulsions for oral use (3)

Medicinal oils for local treatment of obs1pa1on
Mineral oil, castor oil
Oral food supplements
Fish liver oil, vegetable oil
Make it more palatable and acceptable
Unpleasant taste and odour of oil masked by aqueous outer phase

Drug delivery of oral emulsions is unpredictable

Emulsions unstable at low gastric pH
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Microemulsions (1)
Are not emulsions!
Form spontaneously when components are mixed in
appropriate ra1os
Contain large quan1ty of emulsier: 15-25% of weight oil
Forma1on of micelles of surfactants with API (or API
dissolved in oil)
Micelles dissolve in outer phase (water)
Mix oil (with API) and emulsier, pour into water and s1r

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Microemulsions (2)
Thermodynamically stable
In contrast to macroemulsions and nanoemulsions
Transparant or translucent
Low viscosity
Droplets in range 10-200 nm
Dilu1on yields emulsion
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Biopharmacy oral liquid

Mixture (solu1on)
Fast absorp1on (ac1ve substance is and remains dissolved)
Precipita1on in stomach: small par1cles, rapid passage pyloris, rapid
Absorp1on rate depends on solubility, dissolu1on rate (crystal
modica1on, par1cle size) ac1ve substance and viscosity suspension
Absorp1on rate depends on par11on coecient o/w, bile salts,
composi1on bowel content
Upon intake very ne emulsion formed, rapidly absorbed
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Conversion of oral solid to oral liquid

In case of swallowing problems
Children, elderly
Only immediate release tablets and unlocked hard capsules
can be used
Let tablet disintegrate in (warm) water (spoon, cup)
Let tablet disintegrate in (warm) water in syringe
Pulverise tablet using tablet mill and mix powder with water or semi-
solid food
Open capsule and mix powder with water or semi-solid food
Formula1on of a solid oral dosage form into a suspension is
unlikely to yield a good product

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Tablet pulverisa<on
Think carefully and always check the product characteris1cs
of a solid dosage form before considering pulverisa1on or
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Drinking straw lled with pellets containing exact dose of API
Taste masking: pa1ent does not taste or feel small pellets
when sipping favorite drink: medicine taken at same 1me
Swallowing problems in pedriatrics and geriatrics
Jeopardy of therapy compliance
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Medica<on via feeding tube

Around 70% of all medica1on is given orally
Oral administra1on impossible: consider feeding tube
Other alterna1ves: parenteral, rectal
Prerequisite: func1onal gastrointes1nal tract
Enteral administra1on: advanges compared to parenteral
Costs, safety, most natural way
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Types of feeding tube

Dependent on expected residence 1me and pa1ent condi1on
< 4 wk: nasogastric, nasoduodenal, nasojejunal tube
> 4 wk or pa1ent very young or confused: PEG tube
- Percutaneous Endoscopic Gastrostomy (small opera1on!)
Opera1on of stomach, oesophagus, pancreas: via jejunostomy
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Feeding tubes
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How to handle for tube feeding?

Disintegrate in lukewarm water: granulate, tablet
Disintegrate in warm water: dragee, capsule, lmcoated
tablet Only immediate release tablets!
Pulverise with tablet grinder: dragee, hard capsule,
lmcoated tablet, tablet
Make suspension (MUPS tablet)
Open hard capsule and use powder content
Dilute liquid oral form (mixture, suspension)
Dissolve eerverscent tablet
Use injec1on uid or powder for injec1on
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Precau<ons and warnings

Modied release products are unsuitable
Enteric coated products only in duodenum or jejunum
Biopharmaceu1cs may be inuenced
Part of gastrointes1nal skipped
Interac1on with food components
Stop food administra1on before giving medicine via tube
Adsorp1on to tube material
Clogging of the tube
Large par1cles, lumps, high viscosity
Flush tube with ample clean water before and aQer medica1on
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Pulverising modied release tablets

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Drs. Carolina Visser, pharmacist, Pharmaceu1cal Technology
and Biopharmacy, University of Groningen
Drs. Annece Schmidt, pharmacist, Apotheek De Sprong