2008 dosage-forms-final

Basic information onBasic information on pharmaceutical dosage forms pharmaceutical dosage forms

and drug delivery systemsand drug delivery systems

Martin Sterba, Martin Sterba, PharmD., PhD.PharmD., PhD.

Department of PharmacologyDepartment of Pharmacology

IntroductionIntroduction Drug ?Drug ? Active drug substanceActive drug substance (active pharmaceutical ingredient - API) (active pharmaceutical ingredient - API)

– chemical compound with pharmacological (or other chemical compound with pharmacological (or other direct effect ) intended for used in ) intended for used in diagnosis, treatment or prevention of diseasesdiagnosis, treatment or prevention of diseases

– International nonproprietary names (INN, „generic“ names)International nonproprietary names (INN, „generic“ names)

Why you should be familiar with the basic properties of pharmaceutical dosage Why you should be familiar with the basic properties of pharmaceutical dosage forms?forms?

Direct clinical use of the active drug substances „as they are“ is rare due Direct clinical use of the active drug substances „as they are“ is rare due to the number of good reasons:to the number of good reasons:

– API API handlinghandling can be difficult or impossible (e.g., low mg and can be difficult or impossible (e.g., low mg and g doses)g doses)– Accurate drug Accurate drug dosingdosing can be difficult or impossible can be difficult or impossible– API API administrationadministration can be impractical, unfeasible or not according to the can be impractical, unfeasible or not according to the

therapeutically aimstherapeutically aims– Some API can benefit from Some API can benefit from reducing the exposurereducing the exposure to the environmental factors to the environmental factors

(light, moisture…), or they need to be chemically (light, moisture…), or they need to be chemically stabilisedstabilised due to the inherent due to the inherent chemical instabilitychemical instability

– API can be API can be degradeddegraded at the site of administration (e.g., low pH in stomach) at the site of administration (e.g., low pH in stomach)– API may cause API may cause local irritations or injurylocal irritations or injury when they are present at high when they are present at high

concentrations at the site of administrationconcentrations at the site of administration– API can have unpleasant API can have unpleasant organoleptic qualitiesorganoleptic qualities (taste, smell – compliance!) (taste, smell – compliance!)– Administration of active substance would mean to have Administration of active substance would mean to have no chance for no chance for

modification (improvement) of its PK profilemodification (improvement) of its PK profile

Besides the choice of the Besides the choice of the active drug substanceactive drug substance, you need to also make a , you need to also make a responsible decision regarding responsible decision regarding the route of administrationthe route of administration and the and the DOSAGE FORMDOSAGE FORM (drug delivery system) – wrong choice can cause failure of therapy(drug delivery system) – wrong choice can cause failure of therapy

You should also be able You should also be able to handle and administerto handle and administer the drug properly or the drug properly or advise the advise the patientpatient about it – wrong use can cause failure of therapy about it – wrong use can cause failure of therapy

From drug substance to From drug substance to pharmaceutical preparationpharmaceutical preparation

Active drug substance (Active drug substance (active pharmaceutical ingredientactive pharmaceutical ingredient - API) - API)

ExcipientsExcipients (inactive pharmaceutical ingredients) (inactive pharmaceutical ingredients)– Technological, biopharmaceutical and/or stability reasonsTechnological, biopharmaceutical and/or stability reasons– Diluents/fillers, binders, lubricants, dDiluents/fillers, binders, lubricants, deesintegrants, coatings, preservants and sintegrants, coatings, preservants and

stabilizers, colorants and flavouringsstabilizers, colorants and flavourings– Should always be stated in SPC (important in the case of allergies)Should always be stated in SPC (important in the case of allergies)

Pharmaceutical dosage formPharmaceutical dosage form– determines determines the physical form of the final pharmaceutical preparation– is a drug delivery system which is formed by technological processing (drug is a drug delivery system which is formed by technological processing (drug

formulation)formulation)– must reflect therapeutic intentions, route of administrations, dosing etc.must reflect therapeutic intentions, route of administrations, dosing etc.

Pharmaceutical preparation (PP)Pharmaceutical preparation (PP)– particular pharmaceutical product containing active and inactive particular pharmaceutical product containing active and inactive

pharmaceutical ingredients formulated into the particular dosage pharmaceutical ingredients formulated into the particular dosage form.form.

– Packed and labelled appropriatelyPacked and labelled appropriately– Two major types of PP according the origin: Two major types of PP according the origin:

MManufacturedanufactured in large scales by pharmaceutical industry (original and in large scales by pharmaceutical industry (original and generic preparations)generic preparations)

CompoundedCompounded individually in compounding pharmacies individually in compounding pharmacies

Pharmaceutical preparations Pharmaceutical preparations manufactured by pharmaceutical industrymanufactured by pharmaceutical industry

Currently certainly the most frequent and favourable approachCurrently certainly the most frequent and favourable approach MUST be approved by national authority (FDA, SUKL…); in the EU - there is an MUST be approved by national authority (FDA, SUKL…); in the EU - there is an

important role of central authority (EMEA)important role of central authority (EMEA) Rigorous quality control (QC) and quality assurance (QA) during manufacturing - with Rigorous quality control (QC) and quality assurance (QA) during manufacturing - with

surveillance of national authorities to ensure the safety and effectivenesssurveillance of national authorities to ensure the safety and effectiveness

Original pharmaceutical preparationsOriginal pharmaceutical preparations– undergo full and very extensive pharmacological/toxicological and undergo full and very extensive pharmacological/toxicological and

pharmaceutical pre-clinical and clinical development and evaluationpharmaceutical pre-clinical and clinical development and evaluation– particularly important is the proof of effectiveness and safetyparticularly important is the proof of effectiveness and safety

Generic pharmaceutical preparations („Generic pharmaceutical preparations („authorised authorised copies of original copies of original preparations“)preparations“)

– Can be released after the expiration of the patent protection of the original Can be released after the expiration of the patent protection of the original preparationpreparation

– The approval for clinical use is easier due to the prior experience with the original The approval for clinical use is easier due to the prior experience with the original preparationpreparation

– Must be Must be pharmaceutically equivalent: same API, dose, pharmaceutical pharmaceutical dosage form and the same route of administration as in original dosage form and the same route of administration as in original preparationpreparation

– Must be clinically bioequivalent:Must be clinically bioequivalent: i.e. it must be of very close PK profile as i.e. it must be of very close PK profile as original preparation. PK parameters (Cmax, tmax, AUC) are within 80-original preparation. PK parameters (Cmax, tmax, AUC) are within 80-125 % range as compared with the original preparation.125 % range as compared with the original preparation.

– The proof of therapeutic equivalence (comparing directly the clinical The proof of therapeutic equivalence (comparing directly the clinical effectiveness) is not commonly required (due to the technical, financial and effectiveness) is not commonly required (due to the technical, financial and ethical issues). Hence, it can be only assumed from the bioequivalenceethical issues). Hence, it can be only assumed from the bioequivalence

– Decrease the costs of pharmacotherapy and thus make the drugs more Decrease the costs of pharmacotherapy and thus make the drugs more availableavailable

Pharmaceutical preparations Pharmaceutical preparations compounded individuallycompounded individually

These PP are These PP are compounded compounded individuallyindividually for a for a particular patientparticular patient according according to the to the physician's prescriptionphysician's prescription in a pharmacyin a pharmacy licensed for compounding licensed for compounding

In contrast to the past, they are used rather In contrast to the past, they are used rather rarelyrarely and mostly in specific and mostly in specific situationssituations

It is highly advisable that whenever the particular suitable PP is approved It is highly advisable that whenever the particular suitable PP is approved and commercially available it should be preferred over the compoundingand commercially available it should be preferred over the compounding

The main advantageThe main advantage of compounded PP is the opportunity to individualize of compounded PP is the opportunity to individualize the pharmacotherapythe pharmacotherapy– Although the choice of commercially available PP manufactured by Although the choice of commercially available PP manufactured by

pharmaceutical industry is quite rich pharmaceutical industry is quite rich it need not cover all individual demandsit need not cover all individual demands– Hence, the individually compounded PP can be a justified choice whenHence, the individually compounded PP can be a justified choice when::

The drug in a particular dosage form The drug in a particular dosage form is not commercially availableis not commercially available on the market on the market The The extraordinary low or high dose is neededextraordinary low or high dose is needed (young children, elderly people, special (young children, elderly people, special

situations – e.g., intoxications). In this case right dosage strength need not be readily situations – e.g., intoxications). In this case right dosage strength need not be readily commercially available for every patient commercially available for every patient

The The patient suffers from the allergy on a specific excipientspatient suffers from the allergy on a specific excipients (e.g., lactose – a filler, (e.g., lactose – a filler, some colorizingsome colorizing//flavouring flavouring or antimicrobial or antimicrobial agentsagents - parabens - parabens) or another drug ) or another drug appearing in the PPappearing in the PP

Patient is unable to use a PP in its commercially available dosage form (e.g., children, Patient is unable to use a PP in its commercially available dosage form (e.g., children, elderly)elderly)

The major disadvantage is the lack of standardization (it is always a The major disadvantage is the lack of standardization (it is always a „single-patient batch“), unavailability of rigorous QC testing and the „single-patient batch“), unavailability of rigorous QC testing and the appropriate clinical evaluation. appropriate clinical evaluation.

Classification of pharmaceutical Classification of pharmaceutical dosage forms according to its dosage forms according to its physical physical

propertiesproperties

Dosage formsDosage forms– Homogenous systemsHomogenous systems– Dispersion systems – one phase (dispersed phase) is distributed Dispersion systems – one phase (dispersed phase) is distributed

throughout another one (continuous phase, dispersion medium)throughout another one (continuous phase, dispersion medium) According to the size of dispersed particles (1 nm- 0,5 mm) a According to the size of dispersed particles (1 nm- 0,5 mm) a

molecular, colloidal and coarse dispersions can be distinguishedmolecular, colloidal and coarse dispersions can be distinguished May require shaking before administrationMay require shaking before administration

According to the overall physical properties of dosage forms According to the overall physical properties of dosage forms (both homogenous and dispersion systems) one can (both homogenous and dispersion systems) one can distinguishdistinguish

– Gaseous dosage formsGaseous dosage forms– Liquid dosage formsLiquid dosage forms– Semisolid dosage formsSemisolid dosage forms– Solid dosage formsSolid dosage forms

GasesGases– GasesGases – medicinal gases, inhalation/volatile anaesthetics – medicinal gases, inhalation/volatile anaesthetics

(vaporised before administration by inhalation)(vaporised before administration by inhalation)– AerodispersionsAerodispersions of solid particles (e.g., inhalation of solid particles (e.g., inhalation

antiasthmatics) or liquid particles (inhalation antiasthmatics or antiasthmatics) or liquid particles (inhalation antiasthmatics or sprays)sprays)

LiquidsLiquids– SolutionsSolutions – one homogenous phase – one homogenous phase,, prepared by dissolving one prepared by dissolving one

or more solutes in a solventor more solutes in a solvent– Emulsions Emulsions

a dispersion system consisting of two immiscible liquidsa dispersion system consisting of two immiscible liquids o/w or w/oo/w or w/o cloudy appearancecloudy appearance

– SuspensionsSuspensions A dispersion system where solid particles are dispersed in liquid A dispersion system where solid particles are dispersed in liquid

phasephase Not intended for systemic administration of drugs with high potencyNot intended for systemic administration of drugs with high potency

Classification of pharmaceutical Classification of pharmaceutical dosage forms according to its physical dosage forms according to its physical

propertiesproperties

ow

Volume/weight for estimation of dose Volume/weight for estimation of dose of liquid dosage formsof liquid dosage forms

Dosing measureAprox. volume

(ml)

Aprox. weight

(g)

1 drop 0,05 0,05

1 teaspoonful 5 5

1 tablespoonful 15 15

20 drops of aqueous solution 1 1

60 drops of ethanolic solution 1,25 1

Classification of pharmaceutical Classification of pharmaceutical dosage forms according to its physical dosage forms according to its physical

propertiesproperties Semisolid dosage formsSemisolid dosage forms– Unshaped (without specific physical shape)Unshaped (without specific physical shape)

Gels Gels --A semisolid systems in which a liquid phase is constrained within a 3D cross-linked matrix.

CreamsCreams – semisolid emulsion systems (o/w, w/o) containing more than 10% – semisolid emulsion systems (o/w, w/o) containing more than 10% of water.of water.

– o/w creams - more comfortable and cosmetically acceptable as they are less o/w creams - more comfortable and cosmetically acceptable as they are less greasy and more easily water washable greasy and more easily water washable

– w/o creams – accommodate and release better lipophilic API, moisturizing, Cold w/o creams – accommodate and release better lipophilic API, moisturizing, Cold creamscreams

Ointments Ointments – semisolid dosage forms with the oleaginous (hydrocarbon), – semisolid dosage forms with the oleaginous (hydrocarbon), water-soluble or emulsifying basewater-soluble or emulsifying base

– Oleaginous (hydrocabon) base: Petrolatum (Vaseline – white, yellow)Oleaginous (hydrocabon) base: Petrolatum (Vaseline – white, yellow)– Water-soluble base: Polyethylenglycol (PEG)- ointment – syn. macrogol ointmentsWater-soluble base: Polyethylenglycol (PEG)- ointment – syn. macrogol ointments

Pastes Pastes – semisolid dispersion system, where a solid particles (> 25%, e.g. – semisolid dispersion system, where a solid particles (> 25%, e.g. ZnO) are dispersed in ointments – mostly oleaginous (Petrolatum)ZnO) are dispersed in ointments – mostly oleaginous (Petrolatum)

– ShapedShaped SuppositoriesSuppositories (for rectal administration) (for rectal administration)

– different shapesdifferent shapes– Melting/dissolving at body temperatureMelting/dissolving at body temperature– Oleaginous (cacao butter, adeps neutralis) or aqueous (PEGs, Oleaginous (cacao butter, adeps neutralis) or aqueous (PEGs, glycerinated

gelatine)

Pessaries Pessaries (vaginal suppositories)(vaginal suppositories)– Similar as above, PEGs or Similar as above, PEGs or glycerinated gelatine are often used as base. are often used as base.

Solid Solid dosage formsdosage forms– Unshaped (without specific shape)Unshaped (without specific shape)

- - powders for external/internal usepowders for external/internal use

– ShapedShaped- TabletsTablets- CapsulesCapsules- ImplantatesImplantates

- Transdermal patchesTransdermal patches……

Classification of pharmaceutical Classification of pharmaceutical dosage forms according to its physical dosage forms according to its physical

propertiesproperties

Dosage formsDosage forms– for systemic administrationfor systemic administration

pp.o..o. s.l. and buc.s.l. and buc. rectalrectal pparenteralarenteral transdermaltransdermal inhalationinhalation

– for local administrationfor local administration TopicalTopical (on the skin or mucosa) (on the skin or mucosa)

– Into/onto - the eye, nose, earInto/onto - the eye, nose, ear - the oral cavity- the oral cavity

- the vagina, rectum- the vagina, rectum - the brochi- the brochi - the skin- the skin

Local parenteral (viz Parenteral above)Local parenteral (viz Parenteral above)

Classification of pharmaceutical dosage Classification of pharmaceutical dosage forms according toforms according to the route of the route of

administrationadministration

Pharmaceutical dosage forms Pharmaceutical dosage forms for systemic administration for systemic administration

Generations of dosage formsGenerations of dosage forms– 11stst gen. – conventional (unmodified) release of API gen. – conventional (unmodified) release of API– 22ndnd gen. – controlled release of API (CR) gen. – controlled release of API (CR)– 33rdrd gen. – targeted distribution drug delivery systems gen. – targeted distribution drug delivery systems

Conventional vs. controlled release Conventional vs. controlled release dosage formsdosage forms

I. Gen.I. Gen. – disintegration ( – disintegration ( desegregation)desegregation) of the dosage form and of the dosage form and dissolution of API is dissolution of API is spontaneous spontaneous process; process; – drug absorption and distribution is based only on physico-chemical drug absorption and distribution is based only on physico-chemical

properties of APIproperties of API

II. Gen.II. Gen. The release of API is The release of API is under control of the drug delivery systemunder control of the drug delivery system (temporal control)(temporal control)– Advantages:Advantages:

Avoids fluctuations of plasma drug concentration Avoids fluctuations of plasma drug concentration better safety and better safety and efficacyefficacy

Decreased frequency of drug administration (often once daily admin) Decreased frequency of drug administration (often once daily admin) better compliancebetter compliance

May overcome some problems with BAVMay overcome some problems with BAV Can be much more economical (better cost-effectiveness)Can be much more economical (better cost-effectiveness)

– Sustained releaseSustained release (SR) – release of the initial API dose & further (SR) – release of the initial API dose & further prolonged releaseprolonged release

– Controlled releaseControlled release (CR) – properly controlled (0. order) release of (CR) – properly controlled (0. order) release of APIAPI

– Pulsatile release Pulsatile release

Targeted drug deliveryTargeted drug delivery The The PK PK of the drug is not of the drug is not primarly primarly determined by the physico-chemical properties of determined by the physico-chemical properties of

the APIthe API Drug delivery system provides altered PK profile - namely the targeted distribution Drug delivery system provides altered PK profile - namely the targeted distribution

of the drug to the particular organ/tissue (spatial control of the drug delivery)of the drug to the particular organ/tissue (spatial control of the drug delivery)– Improved selectivity of action (especially important where pharmacodynamic selectivityImproved selectivity of action (especially important where pharmacodynamic selectivity is is

poor)poor)– Can overcome unfavourable PK properties (rapid metabolic biotransformation or Can overcome unfavourable PK properties (rapid metabolic biotransformation or

elimination)elimination)– Improved efficacyImproved efficacy– Improved tolerability/decreased toxicityImproved tolerability/decreased toxicity

Passive targetingPassive targeting- The enhanced permeability and retention (EPR) concept

Passive accumulation of the drug at the site of pathology due to the leaky vasculature and poor venous/lymphatic drainage – solid tumours (fenestrations as large as 800nm while in most of normal tissues they are 60 nm) !!! (potentially also tissues suffering from inflammation or ischemia)

Drug delivery systems within nanometre range (Drug delivery systems within nanometre range ( 100 nm) 100 nm)– A need to prevent opsonization and RES clearence (surface of hydrophilic nature) otherwise once can have A need to prevent opsonization and RES clearence (surface of hydrophilic nature) otherwise once can have

monocyte-phagocyte targeted drug deliverymonocyte-phagocyte targeted drug delivery

– How to exploit the concept of passive targetingHow to exploit the concept of passive targeting?? Conjugation of the API with a macromolecule (a drug is bound to biomacromolecules Conjugation of the API with a macromolecule (a drug is bound to biomacromolecules

or synthetic polymers via biodegradable linker)or synthetic polymers via biodegradable linker) Liposomal encapsulation – PEGylated (stealth liposomes)Liposomal encapsulation – PEGylated (stealth liposomes) Other nanoparticlesOther nanoparticles

Active targetingActive targeting– Drug delivery system (liposomes, drug-polymer conjugates) with a Drug delivery system (liposomes, drug-polymer conjugates) with a specific ligandspecific ligand (Ab, (Ab,

Fab, peptide, protein, hormone) with high affinity to the receptor exposed selectively on Fab, peptide, protein, hormone) with high affinity to the receptor exposed selectively on the target cells (e.g., cancer cells)the target cells (e.g., cancer cells)

Dosage forms for systemic Dosage forms for systemic administrationadministration

Dosage forms for systemic administrationDosage forms for systemic administration – – ORAL (p.o.)ORAL (p.o.) solid dosage forms solid dosage forms

TabletsTablets - - Compressed product Compressed product (API+ excipients – e.g., fillers, desintegrants)(API+ excipients – e.g., fillers, desintegrants) – ConventionalConventional – Desintegration/Desagregation/Dissolution, can be divided – Desintegration/Desagregation/Dissolution, can be divided

(half/quarters)(half/quarters)– CoatedCoated (not to be divided) (not to be divided)

To mask unpleasant taste or smellTo mask unpleasant taste or smell of APIof API To avoid of adhesionTo avoid of adhesion in oesophagusin oesophagus (to facilitate swallowing and/or avoid (to facilitate swallowing and/or avoid

release of API and local adverse reactions)release of API and local adverse reactions) To ensure drug stabilityTo ensure drug stability To provide enterosolvent coatingTo provide enterosolvent coating

– To overcomeTo overcome – possible degradation of API in the stomach and possible – possible degradation of API in the stomach and possible local irritation/adverse reactions in the stomachlocal irritation/adverse reactions in the stomach

Effervescent tabletsEffervescent tablets – not a final dosage form (drug is administered as the – not a final dosage form (drug is administered as the solution), COsolution), CO2 2 produced by chemical reaction of acid and NaHCOproduced by chemical reaction of acid and NaHCO33.. Hygroscopic!!!Hygroscopic!!!

– Rapid absorption Rapid absorption rapid on-set of action rapid on-set of action– Avoids potential tablet adhesion to mucosa and local irritation Avoids potential tablet adhesion to mucosa and local irritation

!!! Besides tablets for p.o. there are also !!! Besides tablets for p.o. there are also special tablets for s.l. a buccspecial tablets for s.l. a bucc.; .; however, these are different and presents different route of administration!!!however, these are different and presents different route of administration!!!

Capsules Capsules (not to be divided(not to be divided,, can also be compounded individually) can also be compounded individually)

- API + excipients - enclosed in the hard/soft water soluble container made of gelatin.- API + excipients - enclosed in the hard/soft water soluble container made of gelatin. - Consist of cap and body – filled with powders, pellets, granules (paste, oil)- Consist of cap and body – filled with powders, pellets, granules (paste, oil) - In the GIT gelatin shell softens, swells and dissolve – particles are dispersed - In the GIT gelatin shell softens, swells and dissolve – particles are dispersed

disintegration disintegration API dissolution API dissolution absorption absorption - Hygroscopic- Hygroscopic - Enteric coating available- Enteric coating available

CR (SR) CR (SR) tablets and capsulestablets and capsules

Reservoir Reservoir type type (not to be divided)(not to be divided)

– Core consisting of API and excipients is encapsulated by Core consisting of API and excipients is encapsulated by wall/membrane determining the rate of releasewall/membrane determining the rate of release

– Mechanisms of release Mechanisms of release Dissolution of the outer/inner layerDissolution of the outer/inner layer Diffusion (permeation) throughout membrane poresDiffusion (permeation) throughout membrane pores Osmosis (OROS system)Osmosis (OROS system)

Matrix type Matrix type (tablets)(tablets)

– Drug Drug is dispersed within the polymeris dispersed within the polymer Polymer matrix can be biodegradable – drug is Polymer matrix can be biodegradable – drug is

released continuouslyreleased continuously Polymer matrix can form pore – drug can gradually Polymer matrix can form pore – drug can gradually

diffusediffuse

Dosage forms for systemic administrationDosage forms for systemic administration

– – ORAL (p.o.)ORAL (p.o.) liquid dosage forms liquid dosage forms SolutionsSolutions (drops) – aqueous (drops) – aqueous, , oilsoils

– Syrups Syrups – aqueous sol. with sugar (or sugar substitute) with/without – aqueous sol. with sugar (or sugar substitute) with/without flavouring agentsflavouring agents

– ElixirsElixirs – sweetened hydroalcoholic sol., can accomodate less watter sol. API – sweetened hydroalcoholic sol., can accomodate less watter sol. API– TincturesTinctures – alcoholic or hydroalcoholic sol. – herbal extracts… – alcoholic or hydroalcoholic sol. – herbal extracts…

EmulsionsEmulsions SuspensionSuspension – should not be used for drugs with high potency (dosing!)– should not be used for drugs with high potency (dosing!)

• Advantages:Advantages: easier for administration (children, elderly people), good easier for administration (children, elderly people), good compliance (can be flavoured), rapid absorption, flexible dosingcompliance (can be flavoured), rapid absorption, flexible dosing

• Disadvantages:Disadvantages: stability (chemical, microbial… - a need for stability (chemical, microbial… - a need for preservatives), accurate dosing???preservatives), accurate dosing???

A note: Two liquid drug preparations need not be automatically bioequivalentA note: Two liquid drug preparations need not be automatically bioequivalent

Common API classes: antibiotics, analgesics (spasmoangesics), NSAIDs, antipyretics, antitussive agents, expectorants, vitamins…

Rectal suppositoriesRectal suppositories– Solid dosage form under r.t., which are melted at the body temperatureSolid dosage form under r.t., which are melted at the body temperature– DDifferent size – children and adultifferent size – children and adult supp. !!! supp. !!!– Suppository basis (i.e., basic excipients) – oleum cacao, adeps neutralis, Suppository basis (i.e., basic excipients) – oleum cacao, adeps neutralis,

glycerogelatine – melting point, non-irritating, chem. stable and inertglycerogelatine – melting point, non-irritating, chem. stable and inert– Different shape – mostly „torpedo“-like, formed by mould castingDifferent shape – mostly „torpedo“-like, formed by mould casting– Both manufactured and compoundedBoth manufactured and compounded– Solid suppository is melted within the ampula recti, API is dissolved and is Solid suppository is melted within the ampula recti, API is dissolved and is

absorbed absorbed It can gets into the systemic circulationIt can gets into the systemic circulation ((Middle & inferior haemorrhoidal veins Iliac

vein inferior vena cava – bypassing liver there is no first pass effect) It can pass through portal circulation: via Superior haemorrhoidal veins

Inferior mesenteric vein Hepatic portal Liver (First Pass effect can take place). It becomes to be more important when supp. is position too high in rectum.

• Advantages: offers an alternative to p.o. – especially useful when patient can not swallow the drug (unconsciousness, vomiting patents, serious GIT disturbances. Children) or when we need to avoid local adverse reactions (e.g., NSAIDs).

• Disadvantages: poor compliance, some API can cause local irritation of rectal mucosa, stability of the dosage form during high temp., the melted supp. matter may come out

– Storage: cool place! Other rectal dosage forms for systemic administration: rectal tablets,

capsules Common API classes: opioid analgesics, NSAIDS, antipyretics (paracetamol),

antiemetics (thiethylperazine)

Dosage forms for systemic administrationDosage forms for systemic administrationrectal route dosage formsrectal route dosage forms

How to use suppositories?How to use suppositories?

1. Wash your hands.2. Remove a suppository from the packet (foil or plastic foil or plastic

wrapping wrapping )).3. Moisten the suppository with water or water-based

lubricating gelly.4. Lie on your side with one leg bent and the other straight.with one leg bent and the other straight.5. With your finger, gently insert the suppository into the

rectum pointed end firstpointed end first6. Lower your legs and lie (or sit) still for a few minutes.7. Wash your hands again.Wash your hands again.8. 8. Try not to empty your bowels for at least an hour, unless Try not to empty your bowels for at least an hour, unless

the suppository is a laxative.the suppository is a laxative.

Dosage forms for systemic administrationDosage forms for systemic administrationParenteral route dosage formsParenteral route dosage forms

InjectablesInjectables – – dosage forms which are intended to for administration using adosage forms which are intended to for administration using a hypodermic (hollow pointed) needlehypodermic (hollow pointed) needle (1853 by Dr. A wood) (1853 by Dr. A wood). . Can be formulated as liquids or Can be formulated as liquids or powders/lyophilisate for preparation of the solution (stability issues, follow the instructions powders/lyophilisate for preparation of the solution (stability issues, follow the instructions given by manufacturergiven by manufacturer!!!!!!) )

– InjectionsInjections ((available as ampoules, vials with rubber head)available as ampoules, vials with rubber head) Solutions, emulsions or suspensions which MUST BESolutions, emulsions or suspensions which MUST BE

–STERILESTERILE – free of microorganisms (microbiological tests) – free of microorganisms (microbiological tests)–PYROGEN-FREEPYROGEN-FREE (test for pyrogens) (test for pyrogens)–ISOTONICISOTONIC (NaCl usually as the additive) (NaCl usually as the additive)

I.V. injectionsI.V. injections–Must be PARTICLE-FREEMust be PARTICLE-FREE (visual inspection prior administration!) (visual inspection prior administration!)–Not intended for API inducing clotting or haemolysisNot intended for API inducing clotting or haemolysis–Isoacidity is desirableIsoacidity is desirable – but different pH often needed to assure solubility of API – but different pH often needed to assure solubility of API or chemical stability (may cause local reaction – phlebitis or pain at the site of or chemical stability (may cause local reaction – phlebitis or pain at the site of injection)injection)

–Moderately irritating compounds Moderately irritating compounds cancan be administered (e.g., anticancer drugs) be administered (e.g., anticancer drugs)–Vehicle – sterile water for injections, co-solvents may be added (ethanol, PEG Vehicle – sterile water for injections, co-solvents may be added (ethanol, PEG 300/400, propylenglycol, Cremophor) to solubilize poorly soluble API300/400, propylenglycol, Cremophor) to solubilize poorly soluble API

–Slow administration to avoid problems with „concentration Slow administration to avoid problems with „concentration wwaavve“e“ I.M. and S.C.I.M. and S.C.

–Isoacidity should be guaranteedIsoacidity should be guaranteed (to avoid risk of inflammation/necrosis of the (to avoid risk of inflammation/necrosis of the tissues)tissues)

–API and excipients should be non-irritatingAPI and excipients should be non-irritating–Suspension/emulsion injectables can be administered (depot forms)Suspension/emulsion injectables can be administered (depot forms), oil-based , oil-based vehicles may be usedvehicles may be used

–The volume administered depends on site of administration (e.g., up to 5 ml The volume administered depends on site of administration (e.g., up to 5 ml i.m.)i.m.)

– Infusions Infusions (avialable in plastic bags)(avialable in plastic bags) I.v. and s.c. route (the demands are as above)I.v. and s.c. route (the demands are as above) Higher volumes over much larger times (from min to days)Higher volumes over much larger times (from min to days) Infusion pump, tubing and flexible canule is needed!Infusion pump, tubing and flexible canule is needed!

AdvantagesAdvantages– It can be a approach of choice in the case ofIt can be a approach of choice in the case of

Problems with oral absorption (poor/erratic)Problems with oral absorption (poor/erratic) Problems with stability of API in GIT (pH, enzymes)Problems with stability of API in GIT (pH, enzymes) Uncooperative patients (unconsciousness, vomitingUncooperative patients (unconsciousness, vomiting…)…) Urgent need for rapid onset of action (emergencies)Urgent need for rapid onset of action (emergencies)

DisadvantagesDisadvantages Non-compliance (phobias, children..)Non-compliance (phobias, children..) Pain/irritation at the site of injectionPain/irritation at the site of injection

– accidental extravasation of some drugs (number of anticancer drugs) accidental extravasation of some drugs (number of anticancer drugs) may cause serious problems – tissue inflammation, necrosis…may cause serious problems – tissue inflammation, necrosis…

Certain degree of heamolysis may occurCertain degree of heamolysis may occur Need for trained personnel using aseptic procedures (problems with chronic Need for trained personnel using aseptic procedures (problems with chronic

treatment of outpatientstreatment of outpatients – s.c. route may be usable – s.c. route may be usable)) Higher risk of adverse severe adverse reactions (inc. hypersensitivity on Higher risk of adverse severe adverse reactions (inc. hypersensitivity on

excipients)excipients)

ParenteralParenteralss for local use – similar demands as given above) for local use – similar demands as given above)

Dosage forms for systemic administrationDosage forms for systemic administrationParenteral route dosage formsParenteral route dosage forms

ImplantsImplants– Controlled drug delivery for over a long time Controlled drug delivery for over a long time

(months/years)(months/years)– PrinciplePrinciple

Reservoir (Osmotic/diffusion) systemsReservoir (Osmotic/diffusion) systems Matrix systemsMatrix systems

– Non-biodegradableNon-biodegradable– Biodegrable polymeric materials with dispersed drug Biodegrable polymeric materials with dispersed drug

• AdvantagesAdvantages – largely overcomes problems with individual – largely overcomes problems with individual compliancecompliance

• DisadvantagesDisadvantages – mini-surgery is needed, uneasy to – mini-surgery is needed, uneasy to simply discontsimply discontininue the therapy, local reactionsue the therapy, local reactions

– Examples:Examples: hormones/contraception hormones/contraception

Dosage forms for systemic Dosage forms for systemic administrationadministration

Parenteral route dosage formsParenteral route dosage forms

Dosage forms for systemic administrationDosage forms for systemic administration Transdermal drug delivery sytems (TDDS)Transdermal drug delivery sytems (TDDS)

TDDS (transdermal patches) are designed for affixing on TDDS (transdermal patches) are designed for affixing on healthily and clean skin in order to assure controlled drug healthily and clean skin in order to assure controlled drug delivery into the systemic circulationdelivery into the systemic circulation

Barrier function of the skin (particularly stratum Barrier function of the skin (particularly stratum corneum)!!!corneum)!!!

TDDSTDDS– Reservoir/membrane systemsReservoir/membrane systems– Matrix systemsMatrix systems– New „micro-invasive“ systems – microneedle arraysNew „micro-invasive“ systems – microneedle arrays

Dosage forms for systemic administrationDosage forms for systemic administration Transdermal drug delivery sytems (TDDS)Transdermal drug delivery sytems (TDDS)

AdvantagesAdvantages– Elegant alternative to injectablesElegant alternative to injectables

Pain and stress-freePain and stress-free No need for trained specialistNo need for trained specialist Long-term drug delivery with minimal fluctuations of drug Long-term drug delivery with minimal fluctuations of drug

concentrationsconcentrations– Good complianceGood compliance– Unlike other controlled drug delivery systems, the delivery of the API can Unlike other controlled drug delivery systems, the delivery of the API can

be immediately discontinued (e.g., upon occurrence of adverse reactions…)be immediately discontinued (e.g., upon occurrence of adverse reactions…)

DisadvantagesDisadvantages– Not feasible for all APINot feasible for all API ! !

Mr < 500Mr < 500 Well balanced lipohilicityWell balanced lipohilicity High potency (high doses can not be accommodated and delivered)High potency (high doses can not be accommodated and delivered) Penetration enhancers can help!Penetration enhancers can help!

– Local relations (irritation, disruption of barrier skin function)Local relations (irritation, disruption of barrier skin function)– Need not be practical/comfortableNeed not be practical/comfortable– Need not be cost-effectiveNeed not be cost-effective

Examples of clinical useExamples of clinical use: hormones (HRT, contraceptives), opioid : hormones (HRT, contraceptives), opioid analgesics (e.g., fentanyl)analgesics (e.g., fentanyl), nitroglycerine, nicotine (RT), clonidine or , nitroglycerine, nicotine (RT), clonidine or scopolaminescopolamine

Dosage forms for Dosage forms for local druglocal drug administrationadministration

Into/ontoInto/onto – the eye, nose, earthe eye, nose, ear– the oral cavitthe oral cavityy– the vagina, rectumthe vagina, rectum– the brochthe brochii– the skinthe skin/hairs/hairs

Dosage forms for Dosage forms for local druglocal drug administration administrationinto the eyeinto the eye Eye liquid dosage formsEye liquid dosage forms

– Drops Drops (smaller volumes, 10-20 ml) and (smaller volumes, 10-20 ml) and LotionsLotions (up to 100 ml) (up to 100 ml) Can be both manufactured and compounded (however, higher tech. demands!) Can be both manufactured and compounded (however, higher tech. demands!) Must be Must be

– SterileSterile (sterile ingredients/preparation) – proper handling, storage and (sterile ingredients/preparation) – proper handling, storage and administration to avoid contaminationadministration to avoid contamination

Often deserves to employ antimicrobial agent (may be a source of Often deserves to employ antimicrobial agent (may be a source of allergy)allergy)

– Isotonic with tearsIsotonic with tears (to avoid eye irritation due to the hypotonic (to avoid eye irritation due to the hypotonic preparations)preparations)

– Vehicle – sterile water (oil)Vehicle – sterile water (oil) Advantages:Advantages: high local concentration, lower systemic adverse reactions, minor high local concentration, lower systemic adverse reactions, minor

effects on visioneffects on vision DisadvantagesDisadvantages: local hypersensitivity,: local hypersensitivity, rapid tear eash-out rapid tear eash-out!!

Eye semisolid drug formulationEye semisolid drug formulation– Gels, creams and ointmentsGels, creams and ointments

MUST also be sterileMUST also be sterile and clear (partuculate free) and clear (partuculate free) Direct application into tDirect application into thhe conjuctiva to avoid contamination (do not e conjuctiva to avoid contamination (do not

use fingers)use fingers) AdvantagesAdvantages: API exposure is longer!: API exposure is longer! DisadvantagesDisadvantages: can hinder vision : can hinder vision (useful for overnight treatment)(useful for overnight treatment), dosage , dosage

accuracyaccuracy Eye solid drug formulationsEye solid drug formulations

– Eye insertsEye inserts (soluble, insoluble, biodegradable) – slow release of API (soluble, insoluble, biodegradable) – slow release of API ExamplesExamples: antiglaucoma drugs (pilocarpin, timolol), antimicrobial agents, : antiglaucoma drugs (pilocarpin, timolol), antimicrobial agents,

vasoconstriction agents and antihistamines, mydriatics/myoticsvasoconstriction agents and antihistamines, mydriatics/myotics

Nasal/ear Nasal/ear drops and praysdrops and prays– Usually isotonicUsually isotonic– Vehicles and API must be non-irritatingVehicles and API must be non-irritating– Vehicle – isotonic aqueous solutions/oilsVehicle – isotonic aqueous solutions/oils– Technique of (self)-administrationTechnique of (self)-administration

May require special dropping deviceMay require special dropping device When kept under lower temp. It should be warmed in hands (ear)When kept under lower temp. It should be warmed in hands (ear)

Nasal/ear semisolid dosage forms - Nasal/ear semisolid dosage forms - gels, creams and ointmentsgels, creams and ointments– More complicated administration into the earMore complicated administration into the ear

ExampleExample– Nose – decongestants, antihistamines, antiinflamatory, Nose – decongestants, antihistamines, antiinflamatory,

antiseptic agents and ATBantiseptic agents and ATB– Ear: atbEar: atb

Dosage forms for Dosage forms for local druglocal drug administration administrationinto the nose/earinto the nose/ear

Dosage forms for local drug administrationDosage forms for local drug administrationinto the vagina/rectuminto the vagina/rectum

Vaginal dosage formsVaginal dosage forms– Tablets Tablets

CCompressed products disintegrating in vagina (may also form foam)ompressed products disintegrating in vagina (may also form foam) Markedly different appearance to oral onesMarkedly different appearance to oral ones Application devicesApplication devices

– CapsulesCapsules– PessarsPessars (vaginal suppositories) – hydrophilic bases are more frequent (vaginal suppositories) – hydrophilic bases are more frequent

(more comfortable)(more comfortable) Both manufactured and compoundedBoth manufactured and compounded

– Vaginal foamsVaginal foamsExamplesExamples: namely antimicrobial agents (antibacterial, antimycotic, : namely antimicrobial agents (antibacterial, antimycotic,

antiprotozoal)antiprotozoal) Rectal dosage formsRectal dosage forms

– SuppositoriesSuppositories (as given previously for systemic admin (as given previously for systemic administrationistration))– Gels and creamsGels and creams– EnemasEnemas

Examples:Examples: antihemeroidal drugs (also inc. antihemeroidal drugs (also inc. llocal anaesthetics), ocal anaesthetics), antiseptics and laxativesantiseptics and laxatives

Dosage forms for local drug Dosage forms for local drug administrationadministration

onto the skin/hairsonto the skin/hairs Aerodispersion (macro) - Aerodispersion (macro) - sprayssprays Aquous dosage formsAquous dosage forms – – lotionslotions, , medicated shampoo, foammedicated shampoo, foam Semisolid dosage formsSemisolid dosage forms

– GelsGels– CreamsCreams– OintmentsOintments

Used asUsed as:: emollientsemollients for skin hydrationfor skin hydration to form a protective barrierto form a protective barrier as a vehicle for incorporation of APIas a vehicle for incorporation of API

Solid dosage formsSolid dosage forms– Dusting powderDusting powder (starch and talc (starch and talc as a vehicle as a vehicle))Example: atb (e.g., neomycine + bacitracine)Example: atb (e.g., neomycine + bacitracine)