Mustafa - ophthalmic, nanomedicine, semisolid dosage forms

Pharmaceutical nanotechnology: the _______, _________ and ________ of pharmaceutical materials, structures and products that have one or more dimensions (diameter) between approximately ___ to ____ nm

Frequently, particles in larger size ranges are also considered as nanotechnology (sizes up to ______ nm)

design, characterization, production, 1-100, 1000

1. Colloidal particles - size range of ________ nm

2. Nano-capsules =

3. Nano-spheres =

4. Mainly developed for ________ administration

5. advantages (3)

6. commonly used materials (4)

1. 1-1000

2. core shell structure

3. matrix system

4. parenteral

5. protect from degradation, control drug release, targeted delivery

6. PLGA, polysaccharide (chitosan, alginate), solid lipid, albumin

Classification of Dispersed Systems

Molecular dispersion

1. Size

2. characteristics

3. Examples

Colloidal dispersion

4. size

5. characteristics

6. examples

Coarse dispersion

7. size

8. characteristics

9. examples

1. < 1 nm

2. pass through membrane, invisible in e- microscope

3. ions, glucose

4. 1-500 nm

5. pass through filter paper but not membrane, visible under e- microscope

6. nanoparticles, viruses, liposomes, polymers, paint

7. > 0.5 micrometer

8. do not pass through either, visible under optical microscope

9. emulsions, susp, rbcs

Nanoparticles for Paclitaxel (cancer treatment drug)

1. Abraxane → paclitaxel ________-bound nanoparticle formulation, ___ ______ ______, can be delivered into body at ____ higher dose within ___ minutes

2. Taxol → conventional paclitaxel formulation, organic solvent IS used to increase the _______ of paclitaxel, pre-medication is needed to avoid ____ _____; infusion for ____ hours

1. albumin, no organic solvent, 50%, 30

2. solubility, side effects, 3

Liposome nanoparticle example

1. small spherical vesicle composed of a _____ bilayer

2. ______ core + ______ sphere

3. ________ in diameter

4. _______ or ______ structure

5. surface can be _______

6. water soluble drug is encapsulated in the _______

7. water insoluble drug is encapsulated in the ________

1. lipid

2. aqueous, lipid

3. 20 nm - 10 micrometer

4. unilamellar, multilamellar

5. modified

6. core

7. lipid bilayer (sphere)

Preparation of Liposome

1. _________ is a technique where the liposome suspension is passed through a membrane filter of defined pore size

2. Lipid dispersion is forced through ______ with different pore sizes

3. result → _______ and _______ size

4. _______ is usually used as the membrane for liposome extrusion

1. extrusion

2. filters

3. homogenous, uniform

4. polycarbonate

Mononuclear phagocytic system MPS

1. is a part of the _____ system → a collection of ______ cells

2. mainly exists in the …. (4)

3. Rapid clearing of nanoparticles by phagocytes via ________

Surface characteristics affect the uptake of nanoparticles by MPS

4. Particles with more hydrophobic surface is preferentially taken up by the ______, ______, and ______

5. Hydrophilic nanoparticles show ___% less uptake by the _____ and ______

6. Surface modification with flexible _______ polymer ______ PREVENTS plasma protein absorption and consecutive uptake by the MPS

1. immune, phagocytic

2. liver, spleen, lungs, lymph nodes

3. phagocytosis

4. liver, spleen, lungs

5. 1%, liver, spleen

6. hydrophilic, PEG

Types of liposomes (4)

1. conventional → neutral or - charged

2. stealth → sterically stabilized, polymer coatings, prolonged circulation time

3. immunoliposome → antibody modified

4. cationic → + charged for nucleic acid delivery

What kind of liposome are PEG modifed? (conventional, stealth, immuno, or cationic?)

stealth

1. Stealth liposome → liposome coated with inert biocompatible polymers such as _____ → ______ circulation in blood can lead to higher uptake by ______ cells

2. 2 examples

3. ^

4. These improved _______ for solid tumors and decreased ____ ______

1. PEG, longer, tumor

2. Doxorubicin → 20 min circulation t1/2

3. Doxil → 55 hours circulation t1/2

4. targeting, cardiac toxicity

disadvantages of liposomes (4)

1. expensive

2. poor shelf life, lipid prods may break down in presence of H2O

3. poor encapsulation efficiency for some drugs

4. difficulty in scale up

Preparation of Liposome → Thin Film Hydration Method Steps (8)

1. lipids + hydrophobic drugs in organic solvent

2. rotary evaporation

3. dry lipid film

4. hydration

5. stirring

6. downsizing (extrusion)

7. purification

8. final liposome

Similarities of Liposome & cell membrane (3)

1. similar lipid bilayer

2. high biocompatibility

3. no toxicity (immunogenicity)

Liposome vs micelle

micelle = single chain amphiphile, liposome = double chain amphiphile

Applications of Liposome (3)

1. cosmetics

2. diagnostic imaging of tumors

3. drug delivery

advantages of liposomes

1. ________ and ________

2. can _______ drugs w diverse properties

3. __________

4. _______ drug release

5. surface can be _______ w targeting ______ for targeted drug delivery

1. biocompatible, biodegradable

2. encapsulate

3. protection

4. prolong

5. modified, ligands

1. __________ ________ ____ ________ effect when molecules (liposomes/nanoparticles) with certain size ______ in tumor tissue much more than they do in normal tissues → tumor cells grow quickly

2. the newly formed tumor vessels are usually _______

3. the neovasculature is ….

4. and the endothelial cells are ….

1. enhanced permeability and retention EPR, accumulate

2. abnormal

3. irregular, dilated, leaky, defective,

4. poorly aligned, large fenestrations

cellular uptake of liposomes (6 steps)

1. specific absorption

2. nonspecific absorption

3. fusion w membrane

4. destabilize and release

5. exchange of lipid components w cell memb

6. endocytosis

Name the configurations of lysosomes

1. multilamellar

2. large unilamellar

3. small unilamellar

4. multivesicular

1. Most anterior part of eye → target membrane

2. Posterior inner layer of eye

3. Liquid that fills anterior and posterior chambers

1. Cornea

2. Neural retina

3. Aqueous humor

Highly efficient _____ ______ system that contribute to LOW ocular drug bioavailability via the topical route

Lacrimal drainage

1. The ______ route of drug delivery is the most common way of treating the anterior segment

2. More than ____% of the ophthalmic medicines on the market are in the form of ____ _____

3. Topical ophthalmic preparations can be classified into ….

1. Topical

2. 90%, eye drops

3. Solutions, suspensions, ointments, gels

3 Factors affecting ocular drug delivery

Physiological, drug properties, formulation

The ocular bioavailability of aqueous ophthalmic solutions is usually LOW owing to the barrier properties of the _____ and ______

conjunctiva, cornea

Loss of drug can happen due to several processes such as

1. ________ loss of drug due to tear turnover

2. _______ by the naso-lacrimal apparatus

3. In situ _______

4. Systemic _______ (conjunctival and nasal mucosae)

1. Pre corneal

2. Drainage

3. Metabolism

4. Absorption

Max volume at one time that the eye can accommodate

30 microliters

Cornea

1. Outer epithelial and endothelial layer is _______

2. Middle stromal layer is ________

3. Log P of _____ is optimal (more lipophilic or hydrophilic?)

4. T or F: hydrophilic molecules can pass lipophilic layers

1. Lipophilic

2. hydrophilic

3. 2-3, lipophilic

4. F

Ophthalmic ______ generally produce GREATER ocular bioavailability bc of the greater contact time, drug absorption is increased

Ointments

enhancing ocular drug bioavailability by 2 strategies:

1. Sustained drug del systems (3)

2. Enhancing drug absorption (2)

1. implants, inserts, colloids

2. viscosity enhancing agents, penetration enhancers

Ophthalmic preparations require special considerations regarding … (5)

1. Sterility

2. Preservation

3. Isotonicity

4. Buffering

5. Viscosity

Methods of sterilization (4)

1. Autoclave

2. Filtration → for heat sensitive

3. Gas sterilization → ethylene oxide

4. Gamma irradiation → $$, for heat sensitive

Microbial preservatives used in ophthalmic formulations (4)

Benzalkonium cl, benzethonium cl, chlorobutanol, phenyl mercuric acetate

1. Ophthalmic preparations must be formulated at a pH equivalent to tear fluid pH = ____

2. Eye can tolerate a range of tonicities _______% NaCl solution

3. Tonicity agents (6)

4. Hypotonic causes _______

5. Hypertonic causes ______ and is more or less severe than hypo?

1. 7.4

2. 0.6-1.8%

3. NaCl, KCl, buffering salts, dextrose, mannitol, glycerol

4. oedema

5. Dryness, less

1. Viscosity enhancers enables the formulation to remain in the eye ________ and gives ________ ______ for the drug to exert its therapeutic activity

2. Acceptable viscosity of ophthalmic preparations is up to ____ mPa

3. Commonly used viscosity enhancers (4)

1. longer, more time

2. 15

3. MCC, HPMC, HEC, PVA

Routes of Ocular Drug Administration

1. Topical administration - may deliver drugs to ______ segment of eye (______ and _____), high patient compliance

2. Intravitreal and periocular injections - deliver drug to the ______ segment (______)

3. ^ Which injection is more invasive, intravitreal or periocular?

4. Systemic administration - delivers drug into ______ segment, still not a successful route due to limited _____ into ocular tissues

1. anterior, cornea, conjunctiva

2. posterior, retina

3. intravitreal

4. posterior, absorption

2 types of ophthalmic preparations + examples

1. conventional systems → soln, susp, gel, ointments

2. non-conventional → implants, collagen shields

Conventional delivery systems

1. Drugs are commonly applied to the eye for the _____ effect of the medication on the surface of the eye or on its interior

2. ________ solutions are most frequently employed

1. localized

2. aqueous

Ophthalmic solutions

1. Ophthalmic solutions are most often administered in the form of ________.

2. Ophthalmic solutions must be ______ and contain adequate preservatives.

3. Disadvantage of ophthalmic solutions is the short _________ of drug with the absorbing tissues of the external eye mainly cornea (_____ ocular bioavailability).

1. eye drops

2. sterile

3. contact time, low

Ophthalmic suspensions

1. employed to a much ______ extent than are ophthalmic solutions

2. may be prepared when the API is _______ in the desired vehicle OR _____ in solution form

3. drug particle size is ________ (reduced) to prevent ________ of the cornea

4. particles in suspension should be _______ μm which will not cause irritation to the eyes

5. the suspended particles can NOT agglomerate into larger particles upon storage, _______ agents are added to prevent agglomeration

6. may also be desired to provide a ______ release of drug from the vehicle

1. lesser

2. insoluble, unstable

3. micronized, scratching

4. <10

5. flocculating

6. slower

Ophthalmic ointments

1. ointments are cleared from the eye more _______ than solution

2. ophthalmic ointments, in contrast to dermatological ointments, MUST be _______

3. ointment base for an ophthalmic ointment must be nonirritating to the eye, with melting/softening point close to _______ temperature

4. Primary advantage of ointment over solution → increased drug ocular _______ _____

5. Disadvantage → ______ vision which occurs as ointment base melts and is spread across the lens

1. slowly

2. sterile

3. body

4. contact time

5. blurred

Ophthalmic Gels

1. divided into 2 categories →

2. gelling agents are polymers such as _____ and ______

3. can provide improved __________ by increasing the corneal contact time

1. gel/gel eye drops → gel before application, in situ gels → form gel upon application

2. MC, CMC

3. bioavailability

Ophthalmic preparations are mostly packaged in soft ______ containers holding 2, 2.5, 5, 10, 15, and 30 mL of product with a fixed built-in _______

Ophthalmic solutions used as eyewashes are generally packaged with an ____ ____, which should be cleaned and dried thoroughly before and after each use

plastic, dropper, eye cup

Ocular Implants

1. implants made from ______________ polymers which are _________, can result in drug release over ______ months period

2. mainly treat ______ segment eye disorders

3. __________ _______ delivers the drug over a 6 month period (manage Cytomegalovirus retinitis, a complication of ____)

4. use associated with _________ (inflammation of the intraocular fluids)

1. poly lactide/glycolide, biodegradable, 5-6

2. posterior

3. ganciclovir GCV implant, AIDs

4. endophthalmitis

1. ________ _______ are designed to be a __________, _______-term therapeutic bandage lens for cornea

2. these shields can be used in patients who underwent ______ surgery for delivery of ______ agents without disturbing the eye

3. utility of collagen shields for _______ segment drug delivery is still under investigation

1. collagen shields, disposable, short

2. corneal, therapeutic

3. posterior

Disadvantages of ocular drug delivery

1. intraocular implants →

2. systemic admin →

3. intravitreal injections →

4. topical application →

1. risk of retinal detachment and intravitreal hemorrhage, invasive

2. limited penetration, systemic toxicity

3. risk of retinal detachment, intravitreal hemorrhage, endophthalmitis, cataracts, rapidly diluted, need to repeat

4. limited penetration, rapid tear washout, poor patient compliance

Pharmacologic categories of ophthalmic drugs

1. ___________: tetracaine, cocaine, proparacaine

2. ____________ agents: steroidal and nonsteroidal

3. ________ and _______ agents: gentamicin, ciprofloxacin, ofloxacin

4. ________ agents: amphoterecin B, natamycin

5. ________ agents: trifluridine, idoxuridine, vidarabine

6. ___________: cause cell contraction → zinc sulfate

1. anesthetics

2. anti-inflammatory

3. antibiotic, antimicrobial

4. antifungal

5. antiviral

6. astringents

Pilocarpine ocusert system is advantageous over pilocarpine eye drops because ….

a. it is more invasive

b. increased drug eye contact time and bioavailability

c. decreased patient compliance

d. less expensive

b

A ________ dermatological product is designed to deliver drug into the skin for treating dermal disorders, with the skin as the target organ (LOCAL DELIVERY)

topical

A ________ product is designed to deliver drugs through the skin (percutaneous absorption) to the general circulation for systemic effects, with the skin not being the target organ (SYSTEMIC DELIVERY)

transdermal

1. Example of products that interact with stratum corneum

2. Example of products that remain on skin surface

3. Example of products that reach the dermis or epidermis layers

1. moisturizers

2. sunscreens, barrier creams

3. antimicrobial agents, local anesthetics

Properties of Topical Formulations

Topical semisolid preparations may or may not contain a drug substance dissolved and/or dispersed in a simple or multi-component base (main component)

1. The base may consist of _______ or ________ substances

2. preparation may have _______ or ________ properties

3. Topical semisolid preparations may contain excipients such as …. (6)

4. Topical dermatological semisolid preparations for use on broken or severely injured skin must be _________

1. natural, synthetic

2. hydrophilic, hydrophobic

3. antimicrobial preservatives, antioxidants, stabilizers, emulsifiers, thickeners, penetration enhancers

4. sterile

Topical formulations

1. Emollients form a _______ on the skin surface and fill in any _____

2. Occlusives form a _________ ______ and prevent transepidermal ______ ______

3. Humectants attract _____ from the dermis and the environment into the ______

1. film, gaps

2. protective barrier, water loss

3. water, epidermis

4 categories of semisolid preparations

creams, ointments, pastes, gels

4 main groups of ointment bases

hydrocarbon, absorption, emulsion, water soluble

Hydrophilic petrolatum USP is an example of an _________ base

absorption

Hydrophilic ointment USP is an example of an _______ base

emulsion

1. ________ are in the emulsion class of ointments

2. Vanishing creams are ________ _______ containing large percentages of water and stearic acid or other oleaginous components

3. Many patients and physicians prefer creams to ointments because they are easier to ______ and _____

4. Example of W/O cream

5. Example of O/W cream

6. Creams are generally described as either ___________ or _________

1. creams

2. O/W emulsions

3. spread, remove

4. cold cream

5. hydrophilic ointment

6. nonwashable, washable

Emulsions are two-phase systems in which one liquid is dispersed throughout another liquid in the form of small ______, the two phases are ________ → two types: oil in water O/W and water in oil W/O

droplets, immiscible

Pharmaceutical gels are semisolid preparations where macromolecules (_______ _____) at low concentration are uniformly distributed throughout a liquid

If the liquid is in water, aqueous gels are formed which are also called ________

gelling agents, hydrogels

________ contain a large amount (20-50%) of finely powdered solids dispersed in a _______ base

They are more ________ in consistency and ____ greasy than ointments

pastes, hydrophobic , stiff, less

Ointments and other semisolid preparations are packaged either in large-mouth ________ _____ or in ________/________ ______

ointment jars, metal/plastic tubes

Which topical dermatological dosage form is used for example in the treatment of nappy rash or for skin lesions where there is oozing or crusting?

paste

Which drug involves nanoparticle albumin-bound paclitaxel?

Abraxane or Taxol?

abraxane

T or F:

Ointments are more greasy than pastes

T

Which ophthalmic preparation has to be micronized + add flocculating agents (to prevent agglomeration) ?

suspension

Summary: Name the materials used for …

1. Colloidal particles

2. Viscosity enhancers

3. Liposome extrusion membrane

4. Tonicity agents

5. Gelling agents

6. Ocular implants

7. Microbial preservatives

1. PLGA, polysaccharides (chitosan, alginate), solid lipids, albumin

2. MCC, HPMC, HEC, PVA

3. polycarbonate

4. NaCl, KCl, buffering salts, dextrose, mannitol, glycerol

5. MC, CMC

6. poly lactide/glycolides

7. Benzalkonium cl, benzethonium cl, chlorobutanol, phenyl mercuric acetate