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What are extended-release dosage forms?
- Allows at least two fold reduction in dosing frequency compared to the conventional dosage form of the same drug.
- The controlled-release products are considered extended-release dosage forms.
- There are several monographs in USP XXIII
What are delayed-release dosage forms?
- It releases the drug in parts at a time or times other than promptly after administration.
- Frequently, they are designed to deliver one portion of the drug immediately after the administration.
- Enteric-coated tablets fall into this category.
What is a targeted-release dosage form?
- A dosage form that releases the drug at or near the site of action.
- They may have immediate or extended-release characteristics.
What are controlled-released dosage forms?
- Controlled release: denotes that the system is able to provide some actual therapeutic control, whether this be of a temporal nature, spatial nature, or both
-- although resulting in a zero-order delivery system, may also incorporate methods to promote localization of the drug at an active site.
-- not all controlled systems are sustaining, e.g.: targeted drug delivery and prodrugs.
What is a sustained-release dosage form?
- Sustained release: any dosage form that provides medication over an extended time
- timed release, prolonged release etc
What are the goals of a drug delivery system?
- To deliver adequate amounts of drug to its site of action
- To provide and maintain:
-- maximum therapeutic benefit over a desired period
-- maximum safety
-- maximum reliability
How are the goals of drug delivery systems accomplished?
- onset of drug action duration and intensity of drug action
- elimination of the drug from the body
- distribution of the drug within the body and thus deliver optimum therapeutic benefit consistent with safety and reliability
What are the benefits of controlled delivery systems?
- Continuously blood levels in the desired range
- Side effects minimized
- Facilitates drugs with short in vivo half-lives
- Enhanced Patient compliance
- Lowered overall cost of the therapy
- Health care in the remote areas made easier
What are the assumptions of controlled release products?
- Concentrations in plasma are proportional at the site of action
- Concentration at the site of action is proportional to the pharmacodynamic response
What are some examples of undesired constant level situations?
- Diabetes
- Circadian rhythms
- Hypertension – Covera
- Oral Contraceptives
- Bronchial Dyspnea, COPD
What is a prodrug?
- Are latentiated form of a drug which must undergo biotransformation in vivo to active form.
- Prodrugs should not have any inherent p.col. activity
- Potential advantages:
-- improved (or control over) bioavailability,
-- patient acceptability,
-- stability
What are the examples of prodrugs?
1. Pivampicillin → Ampicillin - Prodrug better absorbed
2. L-Dopa → Dopamine – crosses BBB
3. Dipivalyl Epinephrine → Epinephrine e.g. Propine@
Prodrug more stable, better bioavailability (10 X)
4. Testosterone Palmitate → Testosterone. Better bioavaialbility and longer duration of action
5. Chloramphenicol Palmitate: no bitterness
6. Clindamycin Phosphate: No irritation during IM injection
7. Erythromycin Estolate: More stable in GI Tract
What are the types of diffusion controlled delivery systems?
Reservoir & matrix delivery systems.
How are reservoir systems prepared?
- A core of drug (reservoir) surrounded by an inert polymeric membrane.
- Polymers used for coating include ethyl cellulose, ethylene-vinyl acetate copolymer (EVA), and others.
- Any shape or size: The product may look like a conventional tablet, fiber or a bead, large or small.
- The small beads are prepared by a process known as microencapsulation.
What is the mechanism of release for reservoir systems?
Rate of drug release is controlled by the rate of diffusion across the polymer coating
What is an example of drug design-based forms of modified released drugs?
prodrugs
What is the equation for the mechanism of action of reservior systems?
- δMt = Mass of drug released after time, t
- δMt/ δt = steady-state release rate at time, t
- A = surface area of the device
- D = Diffusion Coefficient of drug
- K = Partition Coefficient of drug (ratio of drug concentration in membrane to that in the surrounding fluid
- ΔC = Concentration difference across membrane
h = Thickness of the diffusion layer
How could a true zero order release system be possible??
A true ZERO ORDER release system would be possible if all of the variables on the right side of equation, A, D, K, ΔC and h could be kept constant. That is very difficult to do.
What are the advantages of reservoir systems?
- Zero order release is possible
- Release kinetics may be easily controlled by parameters
What are the disadvantages of reservoir systems??
- Implantable device must be removed.
- Leaks would be dangerous, potential for toxicity if the system fails
- Lag time may be observed in case of devices used soon after construction since drug molecules must get across the membrane first.
- Burst effect may be observed if the device has been stored for a long time due to saturation of the membrane with the drug
What is the difference between aged and fresh reservoir systems?
- Freshly made, lag time is a factor
- Aged, burst is a factor
What are examples of reservoir systems?
- Bayer-timed-release aspirin
- Nitrospan : microencapsulated nitroglycerine
- Nitroglycerin Extended - Release capsules, Kenwood
- Nitro-bid: marion
What is a matrix system?
- Drug is dispersed in a solid dispersion medium which is insoluble (non-erodible) or less soluble (erodible) than the drug.
- The matrix material may be a long chain fatty acid or alcohol or a high molecular weight polymer which is biologically inert.
What is a matrix system?
- Drug is dispersed in a solid dispersion medium which is insoluble (non-erodible) or less soluble (erodible) than the drug.
- The matrix material may be a long chain fatty acid or alcohol or a high molecular weight polymer which is biologically inert.
What is the mechanism of release of a matrix system?
- Drug in the exterior regions of the device is dissolved first and diffuses out of the matrix.
-- This process continues until the device is exhausted.
- System to be diffusion controlled, rate of dissolution of the drug in the bathing fluid must be much faster than the rate of diffusion of the dissolved drug leaving the matrix.
- Rate of drug diffusion from the matrix is controlled by several factors which depend upon the system design, whether the system is porous or nonporous.
What is the Higuchi equation?
- Higuchi equation describes the mechanism of drug release from inert matrix systems.
- M = amount of drug released per unit area
- K = Higuchi Rate Constant
- t = time
- A plot of amount of drug released versus the square root of time will be linear
For nonporous homogeneous matrices, what does K (the rate constant) depend upon?
- For nonporous homogeneous matrices, K, the rate constant, depends upon:
1. concentration of the drug in the matrix
2. Diffusion coefficient in the matrix
For porous homogenous matrices, what doe K (the rate constant) depend on?
- Porosity of the matrix
- Tortuosity of the matrix
- Solubility of the drug in the release medium
- Diffusion coefficient in the release medium
- In this case drug is able to pass out of the matrix via fluid-filled pores and channels
What are the advantages of matrix systems?
- Easy to make.
- Can be made to release high molecular weight compounds.
- Leaks do not create a severe problem since drug is uniformly dispersed
What are the disadvantages of matrix systems?
- If implanted, the insoluble matrix must be removed.
- The release rate is not zero order but release, if quite slow, can be indistinguishable from zero order.
What are examples of nonerodible matrix systems?
- GRADUMETS: inert, insoluble or nonerodible porous plastic disc, from Abbott
-- Desoxyn: Methamphertamine HCl
-- Ferro-Gradumet: Ferrous sulfate
What are examples of erodible matrix systems?
- Erosion Tablet: Constant-T (theophylline); Tenuate Dospan (diethylpropion HCl)
- LONTABS from Ciba-Geigy
- Forhistal: Dimethindone maleate
- Procan SR tablets Procainamide HCl Park Davis
- SLOW-K POTASSIUM Ciba-Geigy
- K-TAB POTASSIUM ABBOTT
What are pH-independent release systems?
Acidic or basic drugs are mixed with appropriate buffering agent before coating with a suitable polymer
What are dissolution-controlled devices?
- Dissolution of the drug in the medium controls the rate of drug release
- Drugs with a slow dissolution rate can be expected to demonstrate sustained-action properties.
- Rate of dissolution of a drug can also be slowed by coating the particles or by incorporating slowly dissolving carrier.
- The drug release follows Noyes-Whitney dissolution rate law.
What is the Noyes-Whitney equation?
- where,δC/δt = dissolution rate
- D = Diffusion coefficient
- S = Surface area of the dissolving particle
- h = Thickness of the diffusion layer
- V = Volume of the dissolution medium
- Cs = Saturation Solubility of the drug in the medium
- Ct = Conc. of drug in the medium at time, t
What is the Hixon-Crowell equation?
- For spherical particles, the change in the surface area can be related to the weight of the particle and the Noyes Whitney equation is modified to:
-- (W0)1/3 – (Wt)1/3 = kt , where
-- W0 and Wt are the Initial weight and weight of the drug remaining undissolved at time, t
-- A plot of (W01/3 - Wt1/3) vs time- t, is linear
What are spansules capsules?
- Beads with different coating thicknesses of the dissolving coat that surrounds the drug
- Benzedrine®
-- Amphetamine sulfate
- Ornade®
-- Phenylpropanolamine HCl and Chlorpheniramine Maleate
- Thorazine®
-- Chlorpromazine HCl
What are some other encapsulated dissolution products?
- Contac Capsules®
-- Phenylpropanolamine HCl, chlorpheniramine maleate, atropine sulfate, scopolamine HBr, Hyoscyamine sulfate
- Sequel Capsules ® : Ferro-Sequels by Lederle
- Tempules Capsules Nicobid® (Nicotinic Acid) from Armour
- Repetab ® Tablets from Schering
What are swelling-controlled dissolution products?
- The drug may be suspended and/or dissolved in the polymer matrix which swells and facilitates release
- Drug is released by a combination of dissolution and diffusion mechanism.
-- Initially - dissolution controlled but may gradually shift to diffusion control due to increased swelling of the polymer.
What is an example of swelling-controlled dissolution products?
- Levoxyl (Thyroxin 3 or 4)
What are the advantages of swelling controlled systems?
- No burst effect
- Reformulation of the vehicle not necessary for different drugs
What are bioerodible systems?
- Polymer may gradually dissolve or degrade.
- The mechanism of drug release is quite complex.
- It may be a combination of diffusion and dissolution mechanisms.
What are the advantages and disadvantages of bioerodible systems?
- Zero order release is possible only if surface erosion occurs and surface area does not change with time. True zero order is impossible- only apparent zero order.
- Such systems do not require removal when implanted.
- Release kinetics are hard to control.
What is mechanism I of bioerosion?
Entrap the drug in a water-soluble polymer.
What is mechanism II of bioerosion?
The drug is entrapped in a polymer which is insoluble initially but gradually becomes soluble. Partially esterified copolymers of methyl vinyl ether and maleic anhydride.

Polymer-CH2 - CH(OCH3) - CH(COOR) - CHCOOH

Polymer-CH2 - CH(OCH3) - CH(COOR) - CHCOO - + H+
What is mechanism III of bioerosion?
- Drug is entrapped in a polymer which undergoes hydrolytic or enzymatic cleavage
- Example: Polylactic acid, polyphosphoric acid, polyglycolic acid or copolymers of these
What is mechanism IV of bioerosion?
- The drug is chemically bonded directly to the polymer and is released by hydrolytic or enzymatic cleavage.
- The cleavage of the drug from the polymer backbone must be rate limiting in order to be useful.
-Very high drug loadings are possible.
What are osmotically controlled systems?
- Osmotic pressure provides the driving force for drug release.
- The key element is the semipermeable membrane that is permeable to water but not to the drug.
How are osmotically controlled systems constructed?
- The simplest device may consist of a core of drug surrounded by a semipermeable membrane with a laser-drilled hole.
- When the device is exposed to water, water will flow into it across semipermeable membrane due to osmotic pressure difference.
- Solution of the drug escapes through the hole.
What are the types of osmotically controlled systems?
- Type I: Drug and Electrolyte in the same compartment
- Type II: Drug and Electrolyte in Separate Compartments
What are type I osmotically controlled systems?
- Drug and the electrolyte form a solid core surrounded by a semipermeable membrane.
- Incoming water dissolves them both, the ectrolyte providing the high osmotic pressure difference.
What are type II osmotically controlled systems?
- A bag, made of an impermeable membrane and containing a solution of the drug, is surrounded by an osmotic compartment (semipermeable wall) containing the electrolyte.
What are the equations related to the mechanism of drug release of osmotically controlled systems?
δV/δt = Ak / h (Δπ - ΔP ) and
δM/δt = (δV/δt ) Cs where
δV/δt = rate of flow of water into device
δM/δt = rate of drug leaving the orifice
k = membrane permeability
A = membrane area
h = membrane thickness
Δπ = Osmotiic pressure difference
ΔP = hydrostatic pressure difference
Cs = solution conc. of drug
How is the rate changed in osmotically controlled systems?
- Both systems have single or multiple holes bored through them to allow release.
- The size and the number of holes control the rate.
What are the advantages of osmotically controlled systems?
- Both systems have single or multiple holes bored through them to allow release.
- The size and the number of holes control the rate.
What are examples of osmotically controlled systems?
- Procardia XL - Nifedipine
- Glucotrol XL - Glipizide
- Acutrim -Phenylpropanolamine HCl
What are systems based on ion-exhange principle?
- Ion exchange systems utilize water-insoluble cross-linked polymer resins.
- These polymers contain numerous salt-foming functional groups.
- The drug is bound to the resin and is released by exchanging with appropriately charged ions present in the bathing fluid.
-- POLYMER - DRUG+ + Na+ = POLYMER - Na+ + DRUG +
-- POLYMER + DRUG- + Cl- = POLYMER + Cl- + DRUG-
What are examples of systems based on the ion-exchange principle?
- IONAMINE capsules from Pennwalt contain 15 or 30 mg of phentermine as cationic exchange resin complex.
- BIPHETAMINE capsules contain d, dl amphetamine
- Pennkinetic @ DDS:
- A second generation ion-exchange based system:
- TUSSIONEX SUSPENSION: Hydrocodone and Chlorpheniramine as ion-exchange complex with polystyrene resin.
- PENNTUSS SUSPENSION: Codeine polistirex and Chlorpheniramine and polistirex.
What are targeted delivery systems?
- Refers to drug delivery at or near the receptor site.
the conventional products deliver the drug into the body and some of the drug eventually finds its way to the right receptors.
- Targeted systems seek to improve upon this random approach to drug delivery.
What are some general considerations of targeted delivery systems?
- Target Site: accessibility e.g. brain
- Site Specific Carrier
- Drug: reactivity, size
What are antibody-targeted systems?
- The drugs are covalently linked to the antibody allowing targeting of drug but no sustained action.
- In some cases drug may be entrapped in a liposome to which antibodies are attached.
- The compounds administered by these methods have been targeted to specific antigens on tumor cells.
What are monoclonal antibodies?
- Formation of monoclonal antibodies is a very powerful technique for site-specific drug delivery.
- MABs are highly specific and recognize only one antigen or receptor site.
- Natural antobodies are not as specific.
- The obvious advantage is that through the use of monoclonal antibodies which only recognize tumor antigen, side effects of the drug on the rest of the body are reduced.
- Yet, MABs as DDS not as successful as once thought. No “Magic Bullets”
-- MABs have immunologic potential.
-- MABs are large molecular weight proteins therefore, they can carry only a few molecules of drug per unit mass, thus reducing the amount of active drug that can be easily dosed.
What is herceptin (trastuzumab)?
-Humanized Anti-HER2 Antibody
-Targets HER2 protein
- High affinity (Kd = 0.1 nM) and specificity 95% human, 5% murine
- Decreases potential for immunogenicity
- Increases potential for recruiting immune effector mechanisms
What are the indications of herceptin in metastatic breast cancer?
- First-line therapy (combination therapy)
-- Herceptin in combination with Taxol®
-- Tumors overexpressing the HER2 protein
-- No previous chemotherapy for metastatic disease
- Second-line therapy (monotherapy)
-- Herceptin single agent
-- Tumors overexpressing the HER2 protein
-- 1 or more prior chemotherapy regimens for metastatic disease
What are some other targeted therapies at genentech?
- Tarceva (Erlotinib HCL) - A potent and selective small molecule inhibitor designed to block HER1/EGFR receptor signaling (under PIII investigation)
- Omnitarg (Pertuzumab) - A HER dimerization inhibitor, a MAb that blocks HER2 heterodimerization with other HER family members (under Phase II investigation)
- Rituxan (rituximab) – first MAb approved in the US for the treatment of Cancer (CD20+, B-cell Non-Hodgkins lymphoma)
- Avastin (Bevacizumab) – A VEGF antagonist to disrupt tumor vascularization (under FDA review for CRC)
What are liposomes?
- Normally composed of phospholipids that spontaneously form multilamellar concentric bilayer vesicles with layers of aqueous media separating lipid layers.
- Commonly called MLVs (multilamellar vesicles), diameter, 0.5-10 µm.
- Sonication of MLVs leads to production of SUVs (small unilamellar vesicles), diameter, 0.02 - 0.05 µm. SUVs have a single lipid layer with an aqueous inner core.
- LUVs or Large Unilamellar Vesicles: Diameter,0.2 to 1.0 µm.
How do liposomes work as targeted delivery systems?
- Drug is added during the formation process.
- The drug resides in the aqueous or lipid layer depending upon its hydrophilic/lipophilic character.
- In general lipids demonstrate low permeability to ionic and polar compounds.
- The permeability of
liposomes can be altered by heat, pH, ionic strength, additives (cholesterol).
How do liposomes interact with cells?
- Liposomes that remain impermeable to their contents release the entrapped drug by interaction with cells.
- Liposomes interact with cells by three different mechanisms:
-- Endocytosis
-- Fusion of the vesicle by the cell
-- Adsorption to the cell wall
What are the potential advantages of liposomes as dds?
- protection of drug from metabolic enzymes
- prolonged release
- Targeting to specific cells
What are nanoparticles?
- These are small particles (200-500 nm or 0.2 to 0.5 µm ) containing dispersed drug in a suitable matrix such as gelatin or albumin.
- These are colloidal systems like liposomes.
- The small size allows intravenous administration.
- Rapidly taken up by the liver and by tumor cells suggesting the possibility of using these for targeting drugs to liver or malignant tissue.
How do resealed erythrocytes work as targeted delivery systems?
- When red blood cells are placed in hypotonic media, they swell, which causes rupturing of the membrane and formation of pores (200-500 A0).
- These pores allow free exchange of intra- and extracellular contents.
- Readjustment of the tonicity to an isotonic media allows resealing of the membrane.
- Technique allows entrapment of up to 40% of the drug from the extracellular media.
What are the potential advantages of having resealed erythrocytes as dds?
- They are biodegradable and nonimmunogenic. The entrapped drug is protected from immunological detection.
- The entrapped drug is protected from degradation enzymes.
- They can be modified to change their resident circulation times. The normal lifetime of a circulating erythrocyte is 120 days.
What are some examples of linking high MW protiens with drug?
- Albumin: Protein , MW 69,000 widely distributed in body. Methotrexate, and other drugs have been conjugated with albumin.
- Glycoproteins: not site specific but may be modified to have site specificity.
- Lipoproteins: involved in distribution of lipids in body
-- HDL, MW 300,000 to 600,000; LDL, MW 2.3 x 10^6; VLDL, MW 10 x 10^6; Chylomicrons, MW 10^9
- Polysaccharides : Daunomycin linked to dextran.
- DNA: Adriamycin has been conjugated to DNA
What is the goal of ocular systems?
- The Goal of most ocular systems is to maintain the drug in the precorneal region and thereby allow its diffusion across cornea over a period of time.
- Vision must not be hampered and rapid drug loss due to efficient tear drainage mechanisms must be overcome.
What are some examples of ocular systems?
- OCUSERT develeped by Alza and marketed by CIBA offers choice of two release rates, 20 and 40 microgram per hr. A reservoir system.
- Fig.: The Ocusert System
- Fig.:Conventional delivey of pilocarpine
- Fig.:Delivery from Ocusert
- Biodegradable matrices based on hydrophilic polymers such as hydroxypropyl cellulose have been successfully tried for one-day delivery.
What are the advantages of intravaginal and intrauterine systems?
Used to deliver contraceptive hormones. The advantages offered include better bioavailability, smaller dose and avoidance of first-pass effect.
What are some examples of intravaginal/intrauterine systems?
- A ring-shaped, intraveginal matrix device (silicone) delivers steroids over three days. successfully tested.
- PROGESTASERT (Alza),(reservoir) delivers progesterone to the intrauterine region at the rate of 65 micrograms per day for one year.
- Tatum-T and CU-7 : Copper wire is wrapped around a polypropylene base. Copper is released by a combination of chelation and ionization over 40 months.
What are the properties of pumps?
- Release drug independently of the drug’s properties
Can release drug directly in blood
- Can be refillable
- Need implantation
- Next: INFUSAID: a metallic pumping device.
What are some advantages of TDS over oral/iv?
- Avoids the vagaries of GI milieu
- No hepatic clearance
- No needles
- Steady maintenance of blood levels
- Increased patient compliance due to reduced frequency of administration
- Long residence time (6 - 168h)
What are some selection criteria for tds?
- Pharmacokinetic and pharmacodynamic information about the drug
- Effective blood level
- Necessity for steady-state delivery
- Skin permeability
- Diffusional and solubility properties of the drug
- Skin toxicity
- Aesthetic properties
What are the layers of the skin barrier?
- Avascular epidermis, consists of four morphologically distinct regions
-- Basal layer
-- Spinous layer
-- Granular layer
-- Horny layer
- Stratum corneum is a stratified squamous epithelium
- Designed to protect the underlying tissue
- Tortuous pathway along the intercellular lipid matrix
What are the factors affecting skin permeability?
- Crystallinity - higher Tm = lower permeability
- Solubility and Polarity - low oil solubility and low K = lower permeability
- Molecular weight - larger size = lower permeability
What are the ideal properties of a transdermal system?
-Dose: Should be low (< 20 mg/day)
- Half-life: 10 hours or less
- Molecular weight: < 400
- Melting point: < 2000C
- Partition coefficient: Log P (octanol/water) –1.0 to 4
- Skin P: > 0.5 x 10-3 cm/hr
- Skin reactions: Nonirritating and nonsensitizing
- Oral bioavailability: low
- Therapeutic index: low
What are type I tds systems?
- Type I - Semi-solid amorphous ointment, cream lotion, or viscous dispersions applied directly on the skin (Nitrobid, Progestagel, and Estragel)
- Nitrobid- is an ointment containing 2% nitroglycerine in a lanolin and white petrolatum base. Each inch, as squeezed from the tube, contains approximately 15 mg of nitroglycerin)
- NO CONTROL
What are type II tds systems?
- Type II: Reservoir (Liquid form, fill and seal laminate structure, Transderm-Nitro and Estraderm).
- Transderm-Nitro – is a transdermal system that delivers 0.1-0.6 mg of nitroglycerine per hour. The required dose can be delivered by choosing systems of different surface areas.
- ZERO ORDER DELIVERY is POSSIBLE
What are type III tds systems?
- Type III – Matrix (Peripheral adhesive laminate structure, Nitro-Disc, NitroDur I).
- In this design, the adhesive layer is separated from drug containing semisolid (as opposed to liquid in reservoir type) matrix layer by a barrier membrane. The adhesive layer exposed on the periphery of the transdermal system keeps it in place.
- ZERO ORDER DELIVERY is POSSIBLE
What are type IV transdermal systems?
-Type IV: Drug in Adhesive (Solid-state laminate structure, Nitro Dur, Transderm Scop, Catapres, Deponit, Nicotrol)
- In this design, the drug is uniformly dispersed in the adhesive. An example for this design is Nitro-Dur from Key Pharmaceuticals. This design yields a thin transdermal system with controlled release of nitroglycerine. The delivered dose in this design can be adjusted by selecting systems of different surface areas.
- NOT ZERO ORDER but MATRIX RELEASE
What are the selection criteria
- Skin permeation is governed by the diffusion equation:
J = K x Dsc x Cs/hsc
i) increasing the drug solubility in skin (KCS),
ii) increasing the diffusivity of the drug across skin (DSC), or
iii) by decreasing the diffusion path length (hSC). This could be accomplished by either chemical or physical means.
How are transdermal systems chemically enhanced?
(a) increasing the solubility of drug in the vehicle
(b) increasing drug solubility in the stratum corneum -partitioning
(c) reducing the diffusional barrier of the stratum corneum by either perturbing the intercellular lipid domains, or to a lesser degree perturbing the intracellular keratin networks,
(d) promoting drug partitioning at the stratum corneum/viable tissue interface.
- Classes : sulfoxides, alcohols, polyols, alkanes, fatty acids, esters, amines and amides, terpenes, surfactants, cyclodextrins.
What is electroporation?
Applying an electric field to a living cell for short periods of time leads to formation of transient pores in the plasma membrane resulting in increased permeability. When the electric field is discontinued, the pores close in approximately one to 30 minutes without damaging the exposed cells significantly.
What is sonophoresis?
- Sonophoresis is the ultrasound "cousin" of iontophoresis. Sonophoresis –Employes ultrasound to enhance drug transport across skin.
- Permeability increase at Ultrasound frequencies (from KHz to MHz)
- Some spectacular results have been reported (e.g., delivery of insulin and larger proteins)
- Mechanism of enhancement is unclear cavitation is believed to play a role?
What is iontophoresis?
- Controlled delivery
- Programmable - continuous versus pulsatile
- Large peptides
- Feedback control
What are transdermal drug candidates?
1. Clonidine
- low dose
- medium permeability
2. Nitroglycerin
- low dose
- high permeability
3. Nicotine
- low dose
- high permeability
4. Tetracycline
- very high dose
- very low permeability
5. Penicillin
- high dose
- high permeability
6. Aspirin
- very high dose
- medium permeability
What are limitations of transdermal systems?
- Long lag times
- Small permeability coefficient
- Low drug solubility in skin
- practical limitations on patch size
- adhesion of patch to skin surface
-- for the full duration of prescribed wear
-- while bathing, sweating
-- ease of patch removal
- patch induced irritation, allergy - contact hypersensitivity
What are some mucosal delivery systems?
- Oral
-- intestinal
-- buccal, sublingual, gingival, palatal
- Nasal
- Deep lung - inhalation
- Rectal
- Vaginal
- Simple absorptive epithelium (intestinal, nasal, deep lung) versus stratified epithelia (oral cavity,rectal, vaginal)
What are some advantages of oral mucosal delivery?
- Bypass degradation in the stomach and intestine
- Bypass hepatic first-pass metabolism
- Excellent accessibility
- Oral mucosa more permeable than skin
- Less prone to damage or irritation than nasal mucosa
- Less prone to sensitization than skin and more permeable than skin
What are the limitations of oral mucosal delivery?
- Available area for drug delivery is small (total area < 100 cm2)
- Thickness of delivery system and drug loading are limited
- Residence time is limited due to a dynamic environment
- Less permeable than the intestinal, rectal, and vaginal mucosa
What is the structure of oral mucosa?
- Mucous layer
- Keratinized/non-keratinized epithelium
- Viable layers of the epithelium
-- Turnover time – 5-6 days
- Basement membrane
- Connective tissue
- Capillary bed (buccal/sublingual, rapid onset)
What is mucoadhesion?
- Adhesive bond between polymer and biomembrane
- Mucous is a glycoprotein, carrying negative charge at physiological pH (slightly acidic)
- Many water-soluble and insoluble hydrocolloid are currently used as bioadhesives
-- PVP, PEO, Carbopol, HPC and other cellulose derivatives
- Bioadhesion occurs through entanglement of bioadhesive material and extended mucin chains
What is rapid onset versus controlled delivery?
- Rapid delivery
-- Nitroglycerin, Nifedipine
- Controlled (sustained) delivery
-- Protein and peptide delivery
What are different oral delivery systems?
1. Conventional
- buccal tablet
- lozenge
- gel
- lollypop
- chewing gum
2. Bioadhesive dosage forms
- Adhesive tablets
- Adhesive gels/ointments
- Adhesive patches
What are the types of local delivery in the oral cavity?
- Local anesthetic
-- dyclonine, benzocaine, lidocaine
- Anti-inflammatory
-- triamcinolone acetonide, hydrocortisone
- Anti-fungals, anti-bacterials
-- metronidazole, cetylpyridinium chloride
- Fluoride
- Flavors peppermint/spearmint
What are some examples of systemic delivery across the oral mucosa?
- Glyceryl trinitrate
- Nifedipine
- Nicotine
- Oxytocin
What are the properties of the skin?
- Low permeability
-- P = 5.2 x 10-3 cm/h
- Irritation/Sensitization
- Sustained delivery
- Pressure sensitive adhesives
- Removable
- MW < 400
- Active delivery such as iontophoresis/sonophoresis
What are the properties of the oral mucosa?
- Higher permeability
-- P = 2.4 x 10-2 cm/h
- Less irritation/sensitization
- Rapid onset
- Mucoadhesives
- Soluble/removable
- MW ~ few thousands
- Only passive delivery
What are some delivery issues with protein/polypeptides.
- Stability
-- Physical Instability
-- Chemical Instability
- How to Solve Stability Problems
- Handling Issues in Medical Setup
- Examples of FDA Approved Products
- Pharmacokinetics
What is protein denaturation?
- Disruption of secondary or tertiary structure
- Reversible or irreversible
- Causes include thermal stress, extremes of pH and denaturing chemicals
- Normally involves protein unfolding
- Native protein makes a sharp transition to unfolded state, possibly through intermediate states
- When the unfolded protein does not recover its native state, denaturation is irreversible
How are proteins adsorbed?
- An intravenous infusion line offers huge surface area for adsorption
- Adsorption can affect therapeutic outcome as these drugs are very potent
- In-line filter in an infusion set can also adsorb proteins
- Addition of 0.1-1% albumin minimizes adsorption
- Exposure to air/water interface can expose hydrophobic regions of protein, which can adhere to hydrophobic surfaces
- Also, the polyelectrolyte nature of proteins controls the adsorption tendency
- Adsorption is limited by the available surface.
- Following the adsorption of a closely packed monolayer of the protein, the adsorption can be saturated
- The process is often irreversible
What are some marketed formulations that contain albumin?
- Epogen is for anemic patients, followed by surgical blood loss
- Roferon A, for Chronic Myeo- Leukemia
- Intron A is for bladder cancer, CML
- Alferon N is for HIV and Heptatis C
What is protein aggregation?
- Protein molecules can undergo self-association to form dimers, trimers, tetramers or higher oligomers
- Aggregation is a common problem during formulation development and processing
What can protein aggregation lead to?
- Reduced activity
- Increased immunogenicity
- Blockage of tubing, membranes or pumps in an infusion set
- Altered physical appearance. Frosting, proceeds to precipitation
What are aggregation inducers?
- Shaking
- Passage through a needle
- Contact with hydrophobic surfaces
- Moisture in solid state
- Long-term storage
- Lyophilization
What are mechanisms of aggregation?
- With energy transfer in the form of high temperature, radiation, ultrasound or environmental changes including pH, salt concentration, and solvent composition can unfold proteins (surfactants, polysorbates- prevent this)
- Upon protein unfolding, exposed hydrophobic regions interact with those of the neighboring molecule resulting in aggregates.
How does insulin aggregate?
- At concentrations above 0.6 mg/ml insulin exists as a dimer. In the presence of zinc, insulin further associates to form hexamers
- Use of EDTA to chelate zinc ions can de-aggregate insulin to dimers
- Normally self-associated forms of insulin are non-covalent. Long-term storage, however, can induce covalent transformations.
How does aggregation in the solid state occur?
- Moisture can induce aggregation of lyophilized proteins. This process is accelerated at high temperatures
- An optimal (small) level of residual moisture is needed for the stability of a protein formulation
- Covalent bonds may be involved
How does chemical instability occur in proteins?
- Involves covalent modifications of proteins
- Is an outcome of reactions such as oxidation, hydrolysis, deamidation, beta-elimination, disulfide exchange, and racemization
- Can involve multiple reaction sites
Which proteins can be oxidized?
- Methionine, cysteine, histidine, tryptophan and tyrosine may undergo oxidation.
- Occurs in solution as well as lyophilized formulations.
What are the characteristics of methionine?
- Easily oxidized even by atmospheric oxygen to methionine sulfoxide and to methionine sulfone under extreme oxidative conditions
- Can undergo autooxidation, chemical oxidation, and photooxidation
- Peroxides, metal ions, light, and pH can catalyze oxidation
- Polysorbates as well as rubber stoppers have peroxides as impurities
- hGH undergoes oxidation at Met 14 and Met 125 but not at Met 170
-- protection by tertiary structure
* Oxidation of methionine does not change conformation in general
What are the characteristics of cystiene?
- Oxidized to cystine disulfide
- Long-term storage can induce inter-chain or intra-chain disulfide linkages
- Tertiary structure of protein can protect some Cysteine residues – such as those residues in rhIL-1b are inaccessible to oxidation
*** Oxidation may lead to partial loss of activity and may not affect antigenicity
*** Cysteine oxidation changes conformation
How can oxidation be minimized??
- Adjust pH
- Use antioxidants such as Butylated HydroxyToluene, BHA, propyl gallate, and Vit E
- Use reducing agents such as methionine, ascorbic acid, sodium sulfite, thioglycerol, and thioglycolic acid
- Use chelating agents such as EDTA, citric acid, and thioglycolic acid
- Pack the product under N2 atmosphere
- Refrigerate and protect from light
What are some preservatives in marketed formulations?
Photo
What is hydrolysis of proteins?
- Asp-Pro bonds highly susceptible to hydrolysis
- rhM-CSF - Asp169-Pro170, Asp213-Pro214 are hydrolyzed in acidic solutions
- rhM-CSF - Asp45-Pro46 is not hydrolyzed in acidic solutions
- A hydrolytically labile Asp-Pro bond can limit peptide shelf-life to 0.4 years
- rhM-CSF recombinant human macrophage colony stimulating factor
- Asp45-Pro46 is not hydrolyzed possibly because of the protein confirmation or the neighboring amino acid residues.
What is deamidation of proteins?
- Deamidation of Asn and Gln residues is a common non-enzymatic hydrolysis reaction
- Can affect protein bioactivity, half-life, conformation, aggregation, and immunogenicity
- Reaction rate is pH dependent
- At room temperature, the shelf-life of peptides undergoing only deamidation reaction is 2 years or less
- deamidation is usually minimum at pH 6
- Adrenocorticotropic hormone (ACTH) has a single Asn residue that is susceptible to deamidation under alkaline pH conditions
- Even residual moisture in solid state will allow deamidation reaction
- Asn can be replaced by other residues (such as serine) that retain the bioactivity of the peptide/protein
- Asn can be replaced by Ser as Ser has similar size and potential hydrogen donor functional group
What is beta-elimination and disulfide exchange?
- Occurs during thermal stress
- Destruction of disulfide bonds produces thiols which in turn can result in disulfide interchange
- Unpaired Cysteine residues can also result in disulfide exchange
How can disulfide exchange be minimized?
- Thiol Scavangers
-- N-ethylmaleimide
-- P-(chloromercuri)benzoate
-- Copper ion
- Accelerates in presence of
-- Thiols such as with the addition of Cysteine
What is racemization of proteins?
- Except Gly, all amino acids have a chiral carbon that may undergo base catalyzed racemization
- Racemization results in D-enantiomers which may alter bioactivity
- D-Enantiomers are often more resistant to proteolytic enzymatic degradation
-- PADRE – in our lab shown t ½ of 30 min when compared to 15 sec with l-enatiomer (change in end amino acids only- while retaining antigenicity)
What role does thermal stability play in protein degredation?
- Refrigeration may not be enough to prevent physical and chemical degradation of peptides/proteins
- Bovine insulin needs to be stored at -20oC to prevent deamidation and polymerization
- Thermal stress can induce a variety of reactions including denaturation, aggregation, and deamidation
What are the pharmacokinetics of peptides and proteins?
- Sensitive and specific assay are not always available. Such assays are essential for accurate determination of pharmacokinetics.
- Multi-exponential disposition (multi-compartment models)
- Immunogenicity alters pharmacokinetics. Proteins are more immunogenic.
- Rapid elimination (short elimination half-life). - by proteases.
- Conjugation to hydrophilic polymers (e.g., dextran, polyethylene glycol) increases the elimination half-life of the proteins.
- They also reduces immunogenecity.
- Pharmacokinetics of these molecules exhibit wide variations between species.
- Also, the same macromolecule obtained from different sources can exhibit different pharmacokinetics.