L05 Ocular & Parenteral PDF

The most common problems with the eyes are in the morning; they are dry; they don’t produce tears during the night; we don’t blink! L05: OPHTALMIC PREPAARATIONS (Ocularia, Ophthalmica) Optalmic preparations are sterile....

The most common problems with the eyes are in the morning; they are dry; they don’t produce tears during the night; we don’t blink! L05: OPHTALMIC PREPAARATIONS (Ocularia, Ophthalmica) Optalmic preparations are sterile. Ocular barriers → Protection We apply them directly since there is low perfusion in eye and precorneal–tears; very specific; have limited volume of tears we can’t administer the drug - 7–10 µl [very low] systemically and cornea don’t - conjunctival sac 20-30 µl: storage [if we increase the volume, we can only have vessel → so it is necessary keep a small amount; overlook the capacity; crying] to overcome ocular barriers. Biopharmaceutical aspects of - 3 layers –lipophilic [helps to not evaporate], aqueous, mucin: contact with ocular administration cornea anterior segments: surface, intraocular disease (glaucoma) drainage of tears - systemic administration-low efficiency poor diffusion into eye: - 0.5-2.2 µl/min (the rate depends on blinking) → cleans the eye very difficult to have a systemic adm that works - regeneration within each 14 min lack of vascularity in the cornea cornea(500-700 m) low permeability of capillaries in the retina and iris 3 layers: both hydrophilic and lipophilic because of mentioned 3 layers → posterior segments (retina, aqueous humour) Balanced properties: so when we are making a topical drug we have to think - systemic administration(SE) about the fq properties of the eye; the drug can’t be fully hydrophilic neither - injections (intraocular, periocular) hydrophobic. - modern preparations: specific targeting, intravitreal implants - lipid-rich epithelium: top - hydrophilic stroma: mid lipid-rich endotel : below Enzymatic activity Aqueous eye drops [solutions → the objective is to pass through cornea] - lost of drug 95%of dose within few minutes by dilution with tears metabolism [very small portion] non-corneal absorption: conjunctiva, sclera drainage of tears→ nasolacrimal duct: nose, GIT  ➔ Systemic absorption → Toxicity [Important for those with CVS problem and Sterile collapsible tubes (Al = Aluminium) fitted with an applicator. We do not use children plastic tubes because the air from the environment gets sucked so the preparation is no longer sterile and not usuable; however aluminium doesn’t let air in]. aqueous humour < 10% of dose properties of drops: influence time of contact; tonicity and pH, concentration of Ophthalmic inserts (Oculoinserta; lamellae) drug, surface tension, viscosity Suspensions Sterile solid or semi-solid preparations conjunctival sac local effect only Prolonged effect therapeutic systems. Distributed individually in sterile containers depot → particle size –surface, stability Particles remain in sac drug content & dose/time Semisolid preparations prolonged contact thickness, viscosity, adhesivity More efficient Used in combination with dro General requirements: Ophthalmic preparations PhEur [both have limited stability] - tamper-evident containers - test for sterility Eye drops (Oculoguttae; collyria) - antimicrobial preservatives - decision based on the use! Sterile aqueous or oily solutions, suspensions, (emulsions) - solutions – clear, free from visible particles - suspensions - readily dispersed on shaking Sterility – all preparation at time of the first use Dropper bottle, dropper tip → instillation in drops [small portion] 50ties all preparations at time of the first use; contaminated preparations & Eye lotions (Aquae ophthalmicae; lotiones): mostly used for cleaning serious infections Sterile aqueous solutions washing, bathing of eye impregnation of eye dressings isotonic, buffered Pseudomonas aeruginosa [main reason for the need to sterilise eye products] [usually the solution tries to be as close to tear properties as possible] - aerobic G- MIO Powders for eye drops and eye lotions Pulveres pro oculoguttis et aquis - widely distributed (environment, water) ophthalmicis sterile powders => prepared immediatly before use for API with low - optimal growth at 37°C stability like some antibiotics - high ocular pathogenicity: enzyme – corneal collagen → corneal ulceration, blindness within 48h [particular if the patient has a barrier problem - Semi-solid eye preparations (Ocularia semisolida; oculenta) infection] Sterile ointments, creams or gels [Gels are very opular because their expicients are a high resistance [ very limited time to resolve the situation] to heating familiar to the eye compositioin, and there’s not lots of product loss = AP) (sterilisation), antibiotics (therapy) or many preservatives in tolerated concentrations. conjunctiva, eye lid dissolved or dispersed drugs Microbial quality - after opening [all the preservative used must be labelled] preparations in single-dose container - without preservatives (toxicity!) – can damage the cornea - single use application preparations in multi-dose containers Difference from USP: no countries putside of EU have more options for the eye, - must contain a suitable preservative because the effect only happens after larger periods of time and Europe doesn’t - to prevent secondary contamination (during the time of use)- all common believe that they are affective: restrict preparations! Depends on many factors: concentration, pH + T [if you put t in the fridge you have otherwise, the container must protect from contamination, e.g. to be sure the excipient can stay effective in cold temp], other additives [surfactants, polymers] and adsorption on container surface (plastic, glass). Ex// COMOD [Continuous MOnoDose-System] HyloComod: the preparation passes thorught a silver ball that has antiMO properties. Air can’t enter the preparation Test for efficacy for final composition: shall be demonstrated within shelf-life due to the presence of the valve. period. Preservative must work during the whole shelf-life. EX// ABAK Hyabak: presence of membrane filtration ⇑ in the activity against PA [pseudomonas aeruginosa] - the combination of preservatives - the combination with edetic acid (EDTA): common anti-oxidant and preservatives. Preservatives for ophthalmics quats - benzalkonium-chloride 0.01% (BAC) (max. allowable concentration 0.02%!), if it’s more; irritation. However it’s active in very large range oh pH - benzethonium chloride - Polyquad 0.001 – 0.1% → most safe: polyquaternium ammonium chloride (Polyquaternium 1): longer chain Efficiency of preservatives used preservatives comply with the Test for efficacy - cetrimid (trimethyltetradecyl ammonium bromid) of preservation (5.1.3) → reduction of MIO number/time the effect after 1-3 hr (kinetic of MIO inactivation)!  organic mercurial Eye drops - thiomersal 0.002%: 3rd choice Most frequent (>90%) easy to administer, develop and manufacture chlorhexidine (CHXacetate, HCl) Solutions: Aqueous (majority) – short contact and poor bioavailability alcohols Emulsions (O/V) – nanoemulsions - benzylalcohol, phenyl ethyl alcohol, chlorobutanol (CLB) Suspensions: depot in the cul-de-sac, particle size influences Purite: based on cloride stability (sedimentation) - stabilized oxychloro complex 0.005% irritation: optimum size approx. 10 μm, limit of particles >25μm: space between lid and cornea PARABENS ARE NOT RECOMMENDED (LOW EFFICENCY): never for the eye: effect of duration dissolution rate – surface Composition of eye drops - Vehicles water for injection oil for injection (castor, olive, sezame, aj.) - Tonicity adjusting agents: we try to get as near as possible to tonicity of tear (electrolytes) healthy eye can tolerate large range: 0.5 –1.7% NaCl solution non-healthy eye is more sensitive Properties → Irritation → Isotonicity Adjustment of tonicity for hypotonic (see seminar): Sodium chloride, potassium nitrate, (mannitol) - Buffers Multi-dose preparations The no irritation pH is not viable for all the drugs. Tears possess some buffer capacity: phosphate, Period of use does not exceed: 4 weeks after opening → demonstrated by the carbonate and protein buffer systems manufacturer Buffering – must be in accordance with tonicity adjustment Limit in content volume/mass [protection from longer use] - izoacidic (eye lotions) – pH 7.4: limited stability of drugs and excipients - eye drops – not more than 10 mL - euacidic (= suitable) - pH 5.0 – 6.85. Compromise level physiology - eye lotions – not more than 200 mL (irritation) stability (sterilisation) solubility & efficiency - semisolid preparations – not more than 10 g Most common :isotonic boric acid vehicle, phosphate vehicle, citrate buffers Modern suspension drops - Adjustment of viscosity : for prolonging contact time principle ex// BETOPIC GOOD: increases the stability (suspension) - polystyren sulfonic acid modern carrien: ion-exchange resin – negative prolongs the residence time charge - betaxolol (BHCl) –positive. Can control the amount that is released; BAD: sterilisation dose : if we use cellulose contorling the toxicity. Replacement of BHCl with Na+ from tears: drugs derivatives and heating we have sterisilisation problems. gets release by exchange with sodium. Requirements Excipients: Carbomer 934P: contact, stability from tears BAC (preservative) - no insoluble particles (mechanical irritation) mannitol (tonicity) NaOH (pH) - suitable clarity and rheological properties PVA or PVP Carrier (-) and Drug (+) → slow release → less systemic side effects cellulose derivatives → MC, HPC, HPMC, CMC, HEC Prolonged effect, better avaibaility of the drug, increase in stability after shaken. dextran carbomers (Carbopol 934P) → mucoadhesivity cationic nanoemulsion - electrostatic attraction - Novasorb® hyaluronic acid (artificial tears) → mucoadhesivity [Therapy of the dry eye; it helps on the moist of the eye] - positively-charged emulsion increase in solubility of lipophilic drugs - negatively charged mucine increase in absorption - Surfactans Excipients: surfactants (nonionic , cationic) pH tonicity adjustment mucin-protein layer: tear film is spread over the cornea surface → 46mN/m ideal [ limited surface tension 30 mN/m; never below this Manufacturing primary emulsion nanoemulsion - changed (high-pressure otherwise we destroy the mucin and don’t have contact cornea-tear ] homogenizer) autoclaving: as a terminal sterilization process → can be used in Mucin is in contact between cornea and tear; if we change it doesn’t work prolonged therapy and we take out the contact. preservative-free nanoemulsion single-dose therapy of DES suspensions - wetting, stability Ex// Cationorm®. Retaine MGDTM or Ikervis® → this last one: solubility of drug - oil phase: triglycerides quats [preservative with surface activity]→ benzalkonium-chlorid, - nonionicpolymer surfactant(tyloxapol) cetrimide - ionic surfactant(cetalkonium chloride ) nonionic surfactants → Polysorbate 80 (Tween 80), sorbitan-stearate (Span 60) anti-inflammatory effect: cyclosporine and keratitis, DES The simplest method is using benzalkonium chloride as a preservative, also as a surfactant.  triggered by (ions, T and pH) with their in situ gelling polymers (1X/day) Preparation is liquid until the application, often it becomes a gel after beigin in contact with the next polymers. IONS gellan gum: Na+, timolol (Timoptic XE®) sodium alginate , Ca2+ (Carteol LP) → (calcium alginate due to exchange with tear --->insoluble) T methylcellulose xyloglucane ; (Visine)→ it’s solid at normal room temp (25) and when we applied in the eye (36) it gellifies. pH carbomer polycarbophil; polyacrylic acid derivative and very senesitve to PH chitosan Semi-solid eye preparations We have the Polycarbophil → cross-linked polyacrylate. It is a very excellent pH Eye ointments and gels sensitive polymer that has mucoadhesive and prolonged time of drug administration. ointments Technologie DuraSite® : gells by pH; bioadhesion; H-bonds with mucine Simple eye ointment (Unguentum ophthalmicum simplex) - emulsifying base ➔ Azithromycin 1% Azithromycin/DEX Bromfenac 0.075% DEX - white petrolatum [vaselin] + anhydrous wool fat [emulsifying] + liquid paraffin [softening] [8:1:1] Manufacturing of ophthalmic preparations similar to parenterals. The main hydrogels – conventional viscous preparations [can be problematic if it heats] rules are protection from contamination & ensure sterility. - carbomers to keep the moisture in the eye Solutions (similar to Suspensions (similar to Ointments - HPMC (MC) aqueous injections) parenteral suspensions) dissolution of a drug in Mixing of a sterile sterilisation of an BAD: sterilisation, drainage blockage, blurred vision (THAT WHY IS USED IN THE a solvent solvent and a sterile ointment base NIGHT) and variability of dose membrane filtration micronized drug mixing with a sterile filling in the sterile under aseptic drug under aseptic containers (class A) conditions (class A) conditions (class A) In situ gelation - Benefits terminal sterilisation aseptic filling in a filling in tubes (class A) reversible phase change sol →gel viscosity increase after instillation sterile container (class A) terminal sterilisation Ls without terminal → liophilic for gels is a easier to develop, apply andadministrat sterilisation problem Quality control Gels for injections (Gelata pro iniectionibus): sterile gels for direct application. They produce the prolong release of drug at site of administration test for sterility Implants(Implantata): sterile, single dose solid preparations of a size and shape particle size (suspension preparations). scanning under a microscope. Quantity suitable for parenteral implantation; in a single-dose container → they release the corresponding to 10 μg of the solid phase active ingredient over an extended period of time (therapeutical systems) - no more than 20 particles >25 m Intravitreal preparations; sterile, non-pyrogenic. Administration or implantation - no more than 2 particles > 50 m into the vitreous humour. - None of the particles > 90 m Requirements: visible particles → new test should not contain visible partciles MICORBIAL QUALITY sub-visible particles (2.9.53): limits for sub-visible particles → surgery, 1st aid Microbial quality -sterility Can compromise the non-toxicity for the eye Category 1= sterile (no MIO) – comply with test stability. Materials and methods dissolution test – inserts designed to ensure sterility, to avoid the introduction of contaminants, to avoid the growth of MIO Test for sterility (2.6.1) → no evidence of microbial growth (no colony forming). L05: PROPERTIES OF PARENTERAL PREPARATIONS 2 different culture media is the minimum number. Under aseptic conditions (grade A) to avoid accidental contamination. Satisfactorily eliminated: anything what Sterile preparations intended for administration into the human or animal body by possesses antimicrobial activity → preservatives, antibiotics! injection, infusion or implantation. - Incubation of the filter (preferred technique) Injections(Iniectiones): sterile, non-pyrogenic solutions, emulsions or Filter -a nominal pore size ≤ 0.45 μm → cellulose nitrate, cellulose acetate suspensions, colloidal dispersions. Administered by injection needle filters Infusions(Infusiones): sterile, non-pyrogenic aqueous solutions or parenteral - Liquid preparations: aqueous, emulsions o/w, colloidal dispersions. Administered IV in large volume by ethanolic, solutions, oily administration set. preparations, soluble solids → Concentrates for injections or infusions (Concentrata pro iniectionibus et (ointment bases after melting or infusionibus): after dilution with Water for injection. Injections or infusions dissolving in isopropylmyristate) Powders for injections or infusions (Pulveres pro iniectionibus et infusionibus). Inoculation of the culture media: directly Solid, sterile substances in final container which form : solution (infusions, or after dilution - oily solutions. injections), uniform suspension (injections) :when shaken with WFI. Usually freeze- dried products. They are immediately before use. Microbial quality -pyrogens BENEFITS: Injections and infusions must be free of pyrogens: test for pyrogensor bacterial a semi-quantitative test [because you compare it with standard] endotoxins (BET) not more than the endotoxin limit concentration eg. WFU max. 0,25 IU Test for pyrogens (2.6.8): fever response test in rabbits (qualitative) BET/ml 3 animals → slow i.v. application of heated preparation (38.5°C) 0.5 –10 ml/kg of weight in vitro; simple test, rapid, a good sensitivity We can directly see what happens; we observe the respond ( + or -). However is not CONTRAS: quantified, it is expensive, time consuming, cannot be used if drug has a many interferingfactors physiological (toxic) effect on the test animal. easy to invalid: proteins, enzymes, divalent ions →false positive or negative Not required wherever a test for bacterial endotoxin is prescribed. results validation necessary! Test for bacterial endotoxins (BET, 2.6.14) :lipo-polysaccharidesproduced by gram- Monocyte-activation test (2.6.30) : to detect or quantify substances () that activate negative bacteria. Limit concentration; depends on the product volume to be human monocyte or monocytic cells to produce mediators (cytokines) administered to human in PYROGENS. It is a comparison with a standard: semi-quant. maximum dose (mg/kg). We us the estimation of standard BET BENEFITS: Detect also other pyrogenic substances (pathogen-associated molecular concentration (if we achieve lower patterns –G+ , G-MIO, viruses, fungi...) → It’s very sensitive so it could be a source than standard; we comply). It is a of pyrogen method. semi-quantitative. CONTRAS: expensive!!! very complicated test human donors! (no infection, no - The Limulus amoebocyte lysate (LAL) test NSAID, no SAID) BET+ lysate of the amoebocytes of the horseshoe crab (Limulus polyphemus or Recombinant factor C (2.6.32) –new : RFC -gen sequence of horseshoe crab: Tachypleus tridentatus) → in vitro biochemicaltest Limulus polyphenus, Tachypleus tridentatus,Tachypleus gigas, Carcinoscorpius rotundicauda fluorometry. The principle is the same as a LAL expect that here we - 6 methods results in: do not use the "animal"; so it is better because we're protecting the animal. precipitation or gelation(gel-clot method)-referrence development of turbidity after cleavage of an endogenous substrate Pyrogen testig –actual situation (turbidimetric method) development of colourafter cleavage of a synthetic peptide chromogen Pyrogenicity → suitable test for pyrogenicity. In accordance with the revised complex (chromogenic method) general monograph, a parenteral preparation complies with the test for bacterial endotoxins described in general chapter 2.6.14 or 2.6.32 if it is labelled as free from To avoid of endotoxin contamination: pyrogen-free glassware and apparatus bacterial endotoxins [LAL, recombinant factor]. With the monocyte-activation ≥ 250°C, ≥ 30 min testdescribed in general chapter 2.6.30 if it is labelled as apyrogenic. Recommendations in Chapter 5.1.10 (endotoxins) or 2.6.30 (monocyte activation) Particulate contamination the absence of particulate matter is required limits in monographs limits per eye –intravitreal preparations extraneous, mobile, insoluble particles to avoid biological hazards and embolate. Antimicrobial preservation Preservation protects against the secondary contamination! Els convservants quan s'introdueixne directament al cos: poder ser toxics, crear ram. Injections: - Single dose containers (terminal sterilisation) never contain any preservative - A suitable preservative is required in multidose aqueous injections → 1/3 (hormons, vaccines, peptides) single dose injections prepared by aseptic processing without terminal sterilisation - preservative is prohibited in a single dose exceeding15 ml routes where a preservative is not acceptable: intracisternally, to the cerebrospinal fluid or intra-or retro-ocularly Infusions: do not contain any added preservative single dose without terminal sterlization==> with preservative single dose with terminal sterlization==> without preservative Efficacy of antimicrobial preservation How to test non-aqueous preparations: - based on water activity [MONOGRAPH 2.9.57]→ a water activity below 0.60. Low-moisture foods have an extended shelf life, even without refrigeration Integrity of the container Sterile, airtight, tamper-evident containers : melting of ampoules, rubber stopper → allows withdrawing without removing determination a passageway (holes or breaks): a leak test - Dye bath test: ampoule is submerged in a coloured dye solution (methylene blue) → negative pressure → normal pressure → entering colour is visible washing necessary (limited use) - High voltage detection (preferred): measurement of the resistance across the surface. Due to high voltage significantly lower resistance → cracks or holes (0.2 μm) high resistant surface complies Vials and bottles are not subjected since rubber stopper is not rigid Properties of parenterals Osmolality (Osmol/kg, 2.2.35) BUFFERING Injections - IV application - euacidic pH in a range of 3 – 10 compromise: slight irritation at administration place and stable at sterilisation by heating and storage –> BUFFERS other application (i.m., s.c.) - isoacidic pH. Close to the physiological conditions. → ACID OR BASE Infusions: additives in large-volume parenterals directly relate metabolic acidosis or alkalosis (see seminar) OSMOTIC PROPERTIES Concentration of dissolved solutes in parenterals must be considered in osmotic Osmolarity (Osmol/l) Important for practitioners: liquid preparation – volume. relationships. Each particle dissolved in solution exerts an osmotic effect equivalent The theoretical osmolarity (USP) relates to molarity c (mol/l) & number of particles to its concentration. To be acceptable physiologically: parenteral preparations have n physiological osmolarity 306 mOsmol/l  1% (blood, plasma) 0.9% solution of to be compatible with tissues (the erythrocytes). NaCl → cos = 154 x 2 = 308 mOsmol/l [ ideal ] OSMOTIC PRESSURE OF INJECTIONS the precise interconversion between osmotic concentrations (USP) requires aqueous solutions osmotic pressure relates to administration route - experimentally determined solution density - IV isotonic slightly hypertonic - experimentally determined osmolality - SC, IM isotonic (deviations should be avoided) In isotonic solutions, the deviations between cos a mos can be neglected OSMOTIC CONCENTRATION OF INFUSIONS Other sterile preparations IV application: osmotic pressure directly relates delicate dynamic balance of ECT - Solutions for organ preservation and ICT fluid. Limited expression in kPa. - Preparations for irrigation sterile, isotonic single dose, washing of The osmotic effect of particles of a dissolved substance is expressed in osmotic cavities and surfaces (surgery, injury) concentration which does not penetrate through a membrane regardless of the - Intravesicular preparations sterile, pyrogen free instillation into the size or charge. The effect of 1 mole: 1 Osmol. urinary bladder NOT INTENDED FOR PARENTERAL ADMINISTRATION!! SHOULD BE CLEARLY DECLARED!