Drug Formulation and Bioavailability

Prostaglandin ester prodrugs

used in the treatment of elevated intraocular pressures (IOP) are isopropyl ester prodrugs that are hydrolyzed by esterases to the biologically active acid.

An ester-linked molecular group is cleaved off after corneal penetration

Latanoprost (Xalatan®)

Travoprost (Travatan®)

Tafluprost (Zioptan®)

Retro-Metabolic Drug Design or Soft Drug Concept

A new compound is created based on an inactive metabolite of a previous compound

Goal: Retain therapeutic efficacy and minimize adverse side effects.

Loteprednol (Lotemax®)

• Designed as a “soft” steroid (turned off → inactive)

• Has a short half-life and is associated with a lower incidence of adverse effects than ketone-based steroids (prednisolone)

Active Pharmaceutical Ingredient (API)

Any component of a drug product intended to furnish pharmacological activity

The components of a drug compound which exert a pharmacological effect

The chemicals in drug products that make the medications work.

Excipients

The inactive or inert substances

They are not an active pharmaceutical ingredient (API).

Stability

Complex drug molecules will lose stability in solution form

range of API for a particular dosage form is +/- 10% of the labeled amount

range may be higher or lower depending on the therapeutic index (ratio of the toxic dose to the therapeutic dose)

Acetylcholine (Miochol-E®) : degrades in minutes in solution

Other factors which affect stability

Oxidation can break down some drugs

• (e.g., proparacaine should be stored in a refrigerator and protected from light changing colors – do not use if discolored)

Microbial contamination

Heat

pH

Osmolarity and Tonicity

Osmolarity is the measure of solute concentration

The combination of the active drug, preservative, and vehicle usually results in a hypotonic solution (< 290 mOsm).

Tonicity is a measure of the effective osmotic pressure gradient

ophthalmic vehicle

The combination of all the components of an ophthalmic preparation which are used to deliver the active pharmaceutical ingredient minus the active pharmaceutical agent (API)

Preservative

A chemical that is added to drug preparations to prevent the growth of microorganisms.

preservatives can irritate and damage the corneal epithelium and cause epithelial toxicity: superficial punctate keratitis secondary to preservatives.

The FDA uses the Preservative Effectiveness Test (PET) as a minimum standard of preservative performance.

viscosity-increasing agent

Slow drainage of the product from the eye, increasing retention time of the active drug

gels and cellulose and polys

antioxidant

Prevent or delay deterioration of products by oxygen in the air.

wetting agent

Reduce surface tension, allowing the drug solution to spread across ocular surface.

buffer

Help maintain ophthalmic products in the pH range of 6 to 8

tonicity agent

These agents help ophthalmic solutions to be isotonic

help prevent ocular irritation and tissue damage.

A range of 0.6% to 1.8% is usually comfortable for ophthalmic use.

Preservative Effectiveness Test (PET)

Bacterial and fungal organisms are used to challenge the preservative

PET then compares the number of microorganisms found on a control sample against the test sample over the course of 28 days or 4 weeks

key is to suppress/decrease contamination, not exterminate

Types of Preservatives in Ophthalmic Preparations

May be classified by their chemical class and fall into three main categories:

1. Chemical

2. Oxidizing agents

3. Ionic buffered

May also be classified by their mechanism of action

Chemical (or Chemical Detergents)

Sometimes also referred to as Chemical Detergents since the original preservative was a chemical detergent known as benzalkonium chloride (BAK or BZAK).

Also known as detergent surfactants (lower the surface tension)

known to cause bacterial cell membrane instability → cell death (= bactericidal)

Chemical Preservatives (5 categories)

1. Detergents

2. Mercurial derivatives

3. Amides or Biguanides

4. Alcohols

5. Miscellaneous

1. Detergent Chemical Preservatives

1. Benzalkonium Chloride (BAC, BAK, BZAK)

• Is a quaternary ammonium compound (“quat”)

• Quaternary surfactants are preferred by many manufacturers due to stability, excellent antimicrobial properties in acid formulation, and long shelf life.

• Facilitates increased drug penetration

• Long term accumulation due to BZAK being contained in multiple ocular preparations can contribute to toxic effects on corneal epithelium and tear film.

2. Benzethonium Chloride

3. Polyquaternium-1 (Polyquad®)

• derivative of BZAK and is also a detergent

• Less toxic to the cornea and conjunctiva than BZAK but does contribute to dry eye syndrome.

2. Mercurial Chemical Preservatives

1. Thimerosal

• mercurial compound that blocks or inhibits microbial metabolism

• Patients can develop contact sensitivity and allergies to thimerosal which may take weeks or months.

3. Biguanide Amide Chemical Preservatives

1. Polyhexamethylene Biguanide (PHMB)

• Disrupts cell membranes (bactericidal)

• Known for its activity against Acanthamoeba

• Used in multipurpose contact lens solutions.

2. Chlorhexidine

• Often combined with EDTA or thimerosal for greater effectiveness.

3. Polyaminopropyl Biguanide (PAPB)

• High molecular weight biguanide that disrupts cell membranes

• prevents absorption into contact lens matrix

4. Alcohol Chemical Preservatives

1. Chlorobutanol

• Less effective than BZAK when used alone, therefore, often combined with EDTA.

• No allergic reactions with prolonged use.

2. Benzyl Alcohol

• Should not be used to wet and insert lenses due to possible hypersensitivity reactions.

5. Miscellaneous Chemical Preservatives

1. Sorbic Acid

• An organic acid

• Produces low incidence of hypersensitivity reactions and is considered less toxic than other chemical preservatives.

2. Methylparaben and Propylparaben (Parabens)

• Referred to as paraben esters as a class.

• Often two or more parabens are included in the same product.

• Blocks microbial metabolism

• Can cause allergic reactions and can cross react with PABA esters

3. Disodium EDTA (ethylenediaminetetraacetic acid)

• Is a chelating agent

• Also has antioxidant properties

• Can cause contact dermatitis

Oxidizing Preservatives

Stabilized Oxychloro-Complex (Purite®) and Sodium Perborate (GenAqua®)

• neutralized by mammalian cells and do not accumulate, in contrast to the chemical preservatives

• Less toxic than chemical preservatives

Purite® (stabilized oxychloro-complex) dissipates into water and sodium chloride (NaCl) on exposure to light.

GenAqua® (sodium perborate) is converted to hydrogen peroxide and then into oxygen and water once in the eye.

Ionic Buffered Preservatives

SofZia®

• breaks up into innate ingredients

• The SofZia® preservative system is used in Travatan Z® (travoprost)

Viscosity-Increasing Agents

1. Polyacrylic Acids: Carbopol Gels or Carbomer

• generic name for synthetic high molecular weight polymers of acrylic acid.

• Compounds with pseudoplastic properties: where viscosity decreases with increasing shear rate (blinking) and ocular movement, allow for greater patient acceptance

• Viscoelastic agents

• Shear-thinning polymers

2. Hydroxypropyl Methylcellulose (Hypromellose)

• Is a cellulose derivative (cellulose ether) and a viscoelastic polymer.

• Prolongs tear film wetting time

3. Carboxymethylcellulose (CMC)

• similar to above

4. Poloxamer 407

• A viscosity enhancer/builder and wetting agent

5. Polyvinyl Alcohol (PVA) or Polyvinylpyrrolidone (PVP)

• vinyl derivatives

• water-soluble polymers

6. Polyethylene glycol (PEG) and Propylene glycol

• Ethylene glycol (by contrast): toxic organic compound and is best known for its use in antifreeze

Antioxidant Agents: Prevent or delay deterioration of products by oxygen in the air.

1. Disodium EDTA

2. Sodium bisulfite (“sulfites”)

3. Sodium metabisulfite (“sulfites”)

Wetting Agents: Reduce surface tension, allowing the drug solution to spread across the ocular surface.

1. Polysorbate

2. Poloxamer

Buffers: Maintain ophthalmic products in the pH range of 6 to 8

Inactive Ingredients as Drug Delivery Systems

• Solutions

• Suspensions (heterogeneous mixture; need to shake)

• Emulsions (also known as a colloid) (mixture normally unmixable)

• Ointment Bases (mixtures of white petrolatum and liquid mineral oil; lanolin)

• Gel-type systems (aqueous drop in the eye reversibly gels on contact)

Targeted Drug Delivery Systems

• Liposomes (microscopic vesicles composed of lipid bilayers)

• Nanoparticles (polymeric colloidal particles; nanotechnology)

• Cyclodextrins (cyclic oligosaccharides)

• Soft-contact lenses

• Device Inserts

• Intraocular Medication Delivery (Intravitreal Implants)