UCL Formulation of Small Molecules Course

UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
Formulation of small molecules
Prof Abdul Basit

BRUNSWICK SQUARE
Course outline
• Lectures/workshops
• Overview, oral drug delivery, oro-mucosal delivery,

skin delivery, inhalation, ocular delivery, rectal
delivery, vaginal delivery
• Assessment
• 2 x 1000 words essays (67%)
• Exam – 1 hour (33%)
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Recommended reading
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Big business….
BRUNSWICK SQUAREDeveloping a medicine
100,000 100 10 3 1
Successful
Medicines
Research Create
it
Make
Technical it
Safety Test it
(pre-clinical)
Medical
Test it
Regulatory (man)
Register
it
Commercial Sell
it
Years 1 2 3 4 5 6 7
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Pharmacognosy & Pharmacology & Physiology

Phytotherapy • Actions - analgesic, antipyretic,
• Natural products anti-inflammatory, anti-platelet
Pharmaceutics & Biochemistry

Formulation ASPIRIN • Mechanism
• Preparation of medicine COOH • Metabolism
• Side effects
O C CH3
O
(Acetylsalicylic acid)
Pharmaceutical
Chemistry Pharmacokinetics &
•Structure and analysis Drug Delivery
• Synthesis, properties
Therapeutics
Pharmacy Practice
• Uses, side effects, drug
Law & Ethics
interactions, doses
• Preparations and uses
• OTC limitations on sale
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Effectiveness of medicines
[Spear et al., 2001]

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What is pharmaceutics?
• Conversion of a drug into a medicinal product
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Pharmaceutics
• Pharmaceutics is the study of drug formulations and
the processes by which they are designed,
manufactured and delivered to the body.
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Formulation
• Formulation involves the presentation of a therapeutic
substance in a manner in which it can be suitably
administered to a patient to achieve a predictable
therapeutic response
• This may require the inclusion in the product of

pharmacologically inert ingredients (excipients)
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Paracetamol
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Paracetamol products
Suspension contains: maltitol, glycerol, sorbitol solution, dispersible

cellulose, xanthan gum, methyl parahydroxybenzoate (E218), propyl
parahydroxybenzoate (E216), acesulfame potassium, strawberry
flavouring and purified water.
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Main routes of drug administration

1. Buccal (inside mouth)
2. Oral (swallow)
3. Sublingual (under tongue)
4. Nasal
5. Rectal
6. Vaginal
7. Inhalation (to lungs)
8. Eye
9. Ear
10. Parenteral
a) Intravenous
b) Subcutaneous
c) Intramuscular
d) Intraspinal
Topical – skin (any site)

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Pathways a drug may take following

administration by different routes
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Plasma concentration-time plot for equivalent doses of

same drug given by intravenous bolus injection and as
an oral solution
Simplistically, bioavailability
indicates the proportion of drug
that enters systemic circulation
following administration
Here, same dosage form,

different route, bioavailability
<100%
F = AUC (oral)
AUC (IV)
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Variation in time of onset of action for

different dosage forms
Time of onset of action Dosage Forms
Seconds i.v. injections
Seconds/minutes i.m. and s.c. injections, buccal

tablets, aerosols, gases
Minutes to hours Short-term depot injections,
solutions, suspensions, powders,
granules, capsules, tablets,
modified-release tablets
Several hours Enteric-coated formulations
Days to months to years Depot injections, implants
Varies Topical preparations

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Pharmaceutical products
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Factors to be considered in formulation
Biopharmaceutical factors
a) Drugs must be in solution to be absorbed via absorbing
membranes
b) Absorption is generally by passive diffusion
c) Site of action may be distant from site of absorption
d) Onset and duration of activity may depend on site of
administration
e) Rate and extent of absorption may be affected by food,
disease state, age of patient, co-administration of other
drugs, physicochemical properties of the drug, type of dosage
form
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Challenges to formulators and

manufacturers
Products must be:
• Safe
• Effective
• Appropriate quality
Requirements of regulatory bodies, e.g. MHRA, EMA,

FDA who approve all marketed medicinal products
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Variability Saliva volume

pH and β
Liver enzymes (CYP3A4) Age Saliva enzymes
Hepatic blood flow Ionic compositions
Pregnancy
Bile secretion and MMC Weight
Pancreatic enzymes
Bile salts
Bicarbonate secretion Gastric pH and acid output
Gut Hormones Fluid Volume and
Composition
pH and β
Disease Height
Gastric Enzymes
Ionic composition and Gastric Emptying Time
bicarbonate secretion
Fluid volume and composition
Blood flow Microbiota

Race Gender
Ionic composition Microbial enzymes and
Transit and motility
Fluid volume and metabolites
Genetics
composition Mucus thickness
Mucosal enzymes
pH and β Transit and motility
Mucus thickness
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Gastrointestinal tract
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Stomach
•Reservoir for food
•Production of chyme
•Capacity ≈ 1.5 L
•Gastric secretions include:
hydrochloric acid
gastrin
pepsins
mucus
•Little drug absorption here; small
surface area
•Rate of gastric emptying controls
onset of absorption
•Normal gastric residence time:
5 min-2 h
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Small intestine: villus

•4-5 m long, 25-30 mm diameter
•Main functions: digestion and absorption
•Divided into:
duodenum (20-30 cm)
jejunum (2 m)
ileum (3 m)
•Walls richly supplied by blood
•Potential for hepatic presystemic clearance
•Fats are absorbed into the lymphatic system
•Surface area enhanced by:
Folds of Kerckring
villi
microvilli
•Secretions: bicarbonate, enzymes, bile salts
•Normal transit time: 3-4 h
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Colon
•≈ 1.5 m
•No villi
•Surface area increased by:
folded mucosa
microvilli
•Main functions:
absorption of Na+ and Cl-
storage/compaction of faeces
•≈ 1012 bacteria/g contents
•Transit time: 2-48 h
•Normal total GI transit time: 12-36 h
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Barriers to drug absorption

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Respiratory tract
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Pulmonary epithelium
Bronchi Bronchioles
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Factors affecting particle deposition

• Drug
• Dosage form
• Lung morphology
• Oral vs nasal breathing
• Inspiratory flow rate
• Co-ordination of aerosol generation with inspiration
• Tidal volume
• Breath holding
• Disease states
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Inhaled insulin for

treatment of diabetes
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Human skin
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Pathways across the skin barrier
1: across stratum corneum

2: via hair follicles
3: via sweat glands
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Needleless injection

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UCL SCHOOL OF PHARMACY

Formulation of small molecules

Prof Abdul Basit

• Overview, oral drug delivery, oro-mucosal delivery,

Pharmacognosy & Pharmacology & Physiology

Pharmaceutics & Biochemistry

[Spear et al., 2001]

• This may require the inclusion in the product of

Suspension contains: maltitol, glycerol, sorbitol solution, dispersible

Main routes of drug administration

Topical – skin (any site)

Pathways a drug may take following

Plasma concentration-time plot for equivalent doses of

Here, same dosage form,

Variation in time of onset of action for

Seconds i.v. injections

Seconds/minutes i.m. and s.c. injections, buccal

Days to months to years Depot injections, implants

Varies Topical preparations

Factors to be considered in formulation

Challenges to formulators and

Requirements of regulatory bodies, e.g. MHRA, EMA,

Variability Saliva volume

Blood flow Microbiota

Small intestine: villus

Barriers to drug absorption

Factors affecting particle deposition

Inhaled insulin for

Pathways across the skin barrier

1: across stratum corneum

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