Drug delivery approaches, routes of administration, prolonged release preparations. Ondřej Zendulka Farmakologický ústav 1 Drug dosage forms (DDF) •final form in which is the drug administered to patients •consists of active drugs and vehicles •enables the drug to be administered by the selected route •helps to administered accurate dose of the drug 2 DDF •protection of active substance (AS) against environmental influences (light, humidity) •protection of AS in human body (↓ pH in stomach) •adjustment of organoleptic properties (smell, taste) •influence of the PK properties: •release adjustment •targeted distribution of AS 3 Pharmacological differences between administration routes §Pharmacodynamic •change in the character of the drug‘s effect § §Pharmacokinetic •local vs. systemic effect => local vs systemic administration •the change of the latence of the effect onset/duration. or toxicity 4 Administration/effect of drug 5 Local • drug absorption is limited • effect aimed on target tissue/organ • low risk of AE • effect depends upon final concentration Systemic • drug is absorbed to systemic circulation • possible influence on whole body • higher risk of AE • effect depends on dose, bioavailability and DDF Klasifikace aplikačních způsobů 6 § local type of effect systemic •parenteral •enteral •enteral •transdermal, intranasal, i.v., i.m., s.c., i.a., inhalations, i.o…. • •on skin, mucosas, vaginal, intraocular, •intraarticular, intrathecal… •orally, rectally •orally, rectally •parenteral Classification of administration routes 7 Non-invasive • vaginal, (intrauterine?) • sublingval • epicutaneous • oral • intranasal • inhalational • rectal Invasive • intravenous • intraartrerial • intraoseal • intramuscular • subcutaneous • intradermal • implants •with regerd to the disrupotion of natural protective barriers Systemic drug administration CSF Systemic circulation liver •skin muscle placent lungs brain intestine foetus bone milk and sweat glands kidney joint •enteral •transdermal •intravascular •intraosseal •intrathecal •intramuscular •intraarticular •inhalational bile •milk, sweat •faeces •urine •exhaled air •upraveno dle Rang &Dále‘s Pharmacology 2011 •Administration •Excretion Types of administration with regard to the drug‘s profile of plasma levels 9 Repeated drug administration • for the chronic therapy • following dose is administered before the previous is fully eliminated = drug cummulation Single (bolus) drug administration • all DDF and routes of administrations • drugs are not cumulated in the body or in case of vaccination Typy aplikací léčiv vzhledem k plazmatickému profilu léčiva 10 Opakované • pro chronickou terapii • následující dávka léčiva podána před plnou eliminací dávky předchozí = kumulace Jednorázové (bolusové) podání léčiva • jakákoliv léková forma a cesta aplikace • nedochází ke kumulaci léčiva, často u akutních stavů nebo vakcinace t [min] c [mg/ml] 20 0 15 10 5 30 0 25 40 35 45 5 15 20 10 30 25 35 i.v./ i.a. other Typy aplikací léčiv vzhledem k plazmatickému profilu léčiva 11 Opakované • pro chronickou terapii • následující dávka léčiva podána před plnou eliminací dávky předchozí = kumulace Jednorázové (bolusové) podání léčiva • jakákoliv léková forma a cesta aplikace • nedochází ke kumulaci léčiva, často u akutních stavů nebo vakcinace t [min] c [mg/ml] 20 0 15 10 5 30 0 25 40 35 45 5 15 20 10 30 25 35 i.v./ i.a. ostatní t [h] c [mg/l] 48 0 36 24 12 72 0 60 96 84 108 5 15 20 10 30 25 35 min. toxic min. therapeutic therapeutic window Typy aplikací léčiv vzhledem k plazmatickému profilu léčiva 12 Kontinuální • léčivo podáváno/uvolňováno z lékové formy konstantní rychlostí • ustálení plazmatických koncentrací • i.v. infuze, pumpy, náplasti, implantáty, depotní injekce, vag. kroužky a intrauterinní tělíska t [h] c [mg/ml] 8 0 6 4 2 12 0 10 16 14 18 5 15 20 10 30 25 35 min. toxic min. therapeutic therapeutic window Administration routes for local effect •intraurethral, intravesical, intracavernal •dental, gingival, oral •endotracheopulmonal •intraaural •intraamniotic •intracoronar •conjunctival, intrathecal, intraocular, intraarticular • 13 Conjunctival administration •usually eye drops and ointments •local effect •risk of systemic AE •specific quality requirements - sterility 14 [USEMAP] Intrathecal/intracerebral/intracerebroventricular administration 15 •to the subarachnoideal space/ brain/ brain vetricles [USEMAP] [USEMAP] [USEMAP] Intraarticular administration 16 •analgesics/antiphlogistics •hyaluronic acid •for local effect § § •intravitreal implants in macular degeneration [USEMAP] •Intraocular administration [USEMAP] [USEMAP] [USEMAP] Vaginal, endocervical, intrauterinal 17 §1. local effect • minimum of AE • specific adjuvants ↓ pH • antibiotics, antimycotics, antiparasitics • §2. systemic effect • vaginal rings intrauterine devices • controlled drug release • contraceptives § The Liletta hormonal IUD (credit: Medicines360 ) Epicutaneous/transdermal administration 18 •Local effect •ointments, creams, solutions, patches •minimal AE •dermatology •Systemic effect •transdermal administration •mainly patches •continuous release •local+systemic AE •high compliance •easy discontinuation 19 Margetts, Contin Educ Anaesth Crit Care Pain, 2007, 7, 171-176 Intranasal administration 20 •drops, sprays, ointments •local effect - antiseptics, ATB • - antihistamines, decongestants • - antiphlogistics •systemic effect - analgesics, antivirotics • - hormones (ADH, gonadotropin, insulin) Inhalation 21 •gases, aerosols •systemic effect – general anesthetics •local effect – antiasthmatics •fast onset of effect •minimal presystemic elimination •administration from spray cans or other instruments (turbohaler, dischaler, nebuliser) [USEMAP] Rectal administration 22 •suppositories, capsules, tablets, foams, tampones •alternative for peroral administration in case of nausea/vomitting or unconciousness •variable drug absorption Sublingual administration 23 •fast onset of effect •oinly for small and lipiphilic molecules •sprays, tablets, dispergable films •analgesics – fentanyl, buprenorfin •hypnotics – zolpidem •vazodilators – nitroglycerine •antiemetics – ondansetrone •homeopatics, alergens, cannabis…. Oral administration 24 §1. for local effect • minimal AE • risk of interaction with coadministered drugs •antacids, laxatives, antibiotics §2. for systemic effect • drug absorbed from different parts of GIT •can be influenced by DDF • „slow“ effect onset • the effect depends on patients „compliance“ § Salvador et al. 2017 Perorální lékové formy s řízením uvolňováním 25 • systems of controlled release: matrix § reservoirs § particles § nanoparticles • controlled release: continuous § pulsatile § [USEMAP] 26 § •Lobenberg et al, Eur J Pharmaceut Biopharmaceut , 60 2005 Injections 27 •intravenous, intraarterial •injection/infusion •100% bioavailability, „immediate“ effect •true solutions + emulsions •intramuscular •max. volume 5 ml •to m. glu. maximus •absorption: solution> emulsion> suspension •subcutaneous •to 2 ml •variable absorption with regard to adipose tissue Injections 28 •intradermal •minimal volume •diagnostic purposes •intraosseal •alternative to i.v. •injection/infusion • §Eg. Atropine onset of the effect §i.v. 30-90 s; s.c. 15-30 min; i.m. 30-45 min [USEMAP] [USEMAP] Implants 29 • degradable/nondegradable • usually s.c. or intraocular • systemic/local effect • continuous/pulsatile release = continuous/repeated drug administration • increased patient‘s compliance • complicated discontinuation Factors influencing the drug delivery approach 30 • • drug physicochemical properties • therapeutic indication + disease severity • benefit:risk ratio • co-morbidities, co-medications Innovations in drug administration •new posssibilities of administration routes are probably depleted => modification of DDF •the goals are: § 1. increase of drug safety/decrease of drug toxicity § 2. increase the efficacy of administered dose § 3. increase the patient‘s compliance 31 for more see Current Opinion in Pharmacology, vol 36, 2017