Principals and Dosage Forms in the Therapy Modified Drug Release Institute of Pharmaceutical Technology and Biopharmacy
Dosage forms Definition: Dosage forms are the means by which drug molecules are delivered to sites of action within the body. Dosage form API Excipients 2
Dosage forms Manufacturing/compounding - pharmaceutical products - Pharmaceutical products, which are suitable for direct administration are called as DOSAGE FORM. Medication (medical product) = Active pharmaceutical ingredient (API)+ excipient(s) + packaging material Packaging material Dosage form 3
Dosage forms They are classified according to: Route of administration 1. Oral 2. Topical 3. Rectal 4. Parenteral 5. Vaginal 6. Inhaled 7. Ophthalmic 8. Otic Physical form 1. Solid 2. Semisolid 3. Liquid 4. Gaseous 4
Summary Dosage forms the physico-chemical appearance of the API Liquid dosage forms Solutions drops Disperse systems containing two or more phase emulsions, suspensions Injectable products injections, infusions Semisolid dosage forms ointments, suppositories Solid dosage forms powders, dusting powders, granules, tablets, capsules
Solutions Solutions -as a dosage forms- are externally or internally used preparations containing active substance(s) and solvents. Solutions have to be: free from sediments, clear, liquid preparations. Homogeneous disperse system 6
Emulsions Emulsions - as dosage forms - are liquid preparations intended for internal or external use, containing immiscible liquid phases. One liquid phase is dispersed in the form of small droplets throughout another liquid phase. The emulsions may show evidence of phase separation but are readily redispersed on shaking.
SUSPENSIONS Suspensions are liquid preparations intended for internal or external use, in which the solid dispersed phase is suspended in a liquid vehicle, the solid phase is not soluble in the liquid phase (generally: distilled water). The suspended solid may slowly separate out on standing, but it is easily redispersed. d
SUSPENSIONS flocculated and deflocculated sediment deflocculated sediment flocculated sediment compact fitting, difficult to shake until even distribution d loose fitting, easy to shake until even distribution
Parenteral preparations Injections, infusions ~ are sterile preparations intended for administration by injection, infusion or implantation into the human body. Groups: Injections Infusions Concentrates for injections and infusions Powders for injections and infusions Implants Volume Isotoncity Isohydration Injections Infusions 10
Semi-solid preparationfor cutanaous application (Ointments) CLASSIFICATION OF SEMI-SOLID PREPARATIONFOR CUTANAOUS APPLICATION: Ointments Creams Gels Pastes Medicated plasters, patches 11
Preparation of ointments Machines in pharmacy
Rectal preparations Ph. Hg. VIII. Rectal preparations are intended for rectal use in order to obtain a systemic or local effect, or they may be intended for diagnostic purposes. Several categories of rectal preparations may be distinguished: suppositories, rectal capsules, rectal solutions, emulsions and suspensions, powders and tablets for rectal solutions and suspensions, semi-solid rectal preparations, rectal foams, rectal tampons.
SOLID DOSAGE FORMS Granules Small particles that can be formed by disintegration or by integration routes through which the powder forms aggregates. Granulation is the process of collecting particles together by creating bonds between them.
Capsules Hard gelatin capsule shells can be used at a pharmacy too. They have to be transparant.
Tablets Tablets are manufactured by compression. They have different shape and color.
Tablets Direct compression Wet or dry granulation tabletting
Tablets Tablet press machine(s) eccentric ~ rotary ~
Tablets Categories of tablets: Uncoated tablets Coated tablets Effervescent tablets Soluble tablets Dispesible tablets Orodispesible tablets Gastro-resistant tablets Modified-release tablets
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LADME system liberation absorption distribution disposition metabolism excretion elimination 31/10/2017 21
Conventional drug release Modified drug release Rapid drug release Delayed drug release Slow drug release Pulsatile drug release Local drug release Self-regulating drug release Targeted drug release
Conventional drug release There is no technological modification during the manufacture to change the dissolution rate Drug release is determined by physicochemical characters
Factors affecting drug dissolution Physico-chemical properties of the API Polimorphism Chemical structure Particle size Complexation Wettability Impurities
Aspirin 500 mg tbl. Acetyl salicilyc acid Maize starch Microcrystalline cellulose
Modified drug release Aims: Optimizing the therapeutic effect by slowing, accelerating ordelaying the drugrelease Decrease toxic adverse effects Increase patient compliance
Rapid drug release Aim: Accelerating the liberation in order to reach a quick absorption
Nitromint 0.5 mg sublingual tablet Nitroglycerin In case of heart attack
Calcium 500 mg Pharmavit effervescent tablet Calcium carbonate Sodium bicarbonate Anhydrous citric acid
Nurofen Non-Aqua 200 mg tbl. Ibuprophen Croscarmellose sodium Lemon flavouor
3D printing (THERIFORM tech.) MJ Cima, JS Haggerty, EM Sachs, PA Williams. Three-dimensional printing techniques. US patent 5,204,055, 1993. Disintegrates in less than 1 s! SPRITAM 750 mg tbl.
THERIFORM technology
Delayed drug release Liberation of the API is delayed by a lag time Intestinosolvent preparations (gastric juice resistant preparations) HCl can damage the API API can damage the gastric mucosa
Delayed drug release 34
Pharmaceutical Excipients used to create delayed release preparations ph sensitive coating Intestinosolvent/gastroresistant coating Celluloseacetate phtalate (CAP) Eudragit L,S (metactylic acid copolimers)
Pancreas powder Kreon 10000 cps.
Diffucaps - delayed release Chronotherapeutic system (2003)
Diffucaps - delayed release Chronotherapeutic system (2003)
Slow/sustained drug release Release of API is slow, thus the step of the liberation is determinant for the absorption It is reasonable at APIs with short half-life and to avoid plasm fluctuations
Slow/sustained release Special case Drug dissolution at constant rate, Zero Order Kinetics (ZOK)
Pharmaceutical Excipients to create slow/sustainedrelease preparations Biodegradable and/or coated preparations Eudragit RL, RS, NE (metacrylesther copolimers)
Kaldyum Potassium-chloride 30%-os polyacrylate aqeousdispersion
Slow/sustained release Multiple unit pellet system (MUPS)
MUPS (1991)
Slow/sustained release Matrix systems ph sensitive Biodegradable. Hidrophilic(alginic acid and derivatives) Hidrophobic(ethyl-cellulose)
Slow/sustainedrelease preparations Osmotic systems (OROS): Water-soluble APIs: Elementary Osmotic Pump (EOP) Water-insoluble /less soluble APIs: Gastrointestinal Therapeutic System (GITS)
Osmotic technologies ALZA Corp. 1970 Dr. Alejandro Zaffaroni
Gastrointestinal Therapeutic System
Gastrointestinal Therapeutic System
Glargin analog insulin (Lantus SoloStar )
Glargin analog insulin
Pulsatile drug release Drug release shows a pulsatile pattern Reaseonable at circadiandiseases
Pulsatile drug release
Pulsatile drug release c p c pmax n=1 n=2 n=3 n=4 n=5 n=6 n=7 adás t
Local drug release Reasonable: If the API absorbs from a definite section of the GI tract Stability is adequate at low ph Colon-specific drug delivery
Local drug release (Gastroretentive tablets)
Targeted drug release Significant at cancer diseases API Injected to the target organ Transferred to the blood vessel of the cancerous tissue Targeting is realised by magnetic field Sonic waves, ultrasound, heat trigger the drug release Appliedby targeting molecule
Visudyne - liposome containing targeted drug release
Thank you for your attention! 59