Pharmaceutics all topics

Oral transmucosal drug delivery

Utilizes the oral cavity for drug absorption and bypasses hepatic circulation to avoid first-pass metabolism.

Sublingual (SL) drug delivery

Uses the mucosa of the ventral surface of the tongue and the floor of the mouth under the tongue for drug absorption.

Buccal drug delivery

Uses the epithelial lining of the cheeks, gums, and upper and lower lips for drug absorption.

First pass effect

When a drug gets metabolized at a specific location in the body, resulting in a reduced concentration of the active drug upon reaching its site of action or systemic circulation, often associated with the liver.

Oral transmucosal absorption sites

Buccal and sublingual (SL).

Vascularity of the sublingual space

Highly vascularized with abundant blood vessels.

Vascularity of the buccal space

Less extensive vascular network than the sublingual space.

Permeability of the oral mucosa compared to skin

Generally more permeable than the skin.

Relative permeability of buccal vs. sublingual regions

The SL region is more permeable than the buccal region.

Thickness of the buccal epithelium

500 to 900 μm.

Thickness of the SL epithelium

100 to 200 μm.

Effect of epithelium thickness on permeability

The greater the thickness, the lower the permeability.

Keratinization of buccal and SL mucosa

Not keratinized, making them more absorbent than keratinized regions like the gingivae and hard palate.

Layer of the oral mucosa rich in blood supply

Lamina propria.

Result of drug reaching the lamina propria

Absorbed systemically, bypassing the 1st pass effect.

Blood flow in the SL space compared to the buccal space

Faster in the SL space.

Substances that lubricate the oral epithelium

Saliva and mucus.

Potential effects of saliva on drugs

Can degrade some drugs (enzymes), dissolve drugs and increase bioavailability, or wash away drugs leading to swallowing.

Enzyme levels in the oral cavity compared to the GIT

Lower than in the GIT.

Alternate administration route offered by the oral cavity

For peptides and labile molecules.

Potential effects of mucus on drug absorption

Can be a physical barrier, bind drugs, and mechanically clear drugs.

Oral transmucosal absorption route for low MW lipophilic drugs

Passive transcellular diffusion.

Oral transmucosal absorption route for low MW hydrophilic drugs

Passive paracellular diffusion.

Oral transmucosal absorption route for monosaccharides & amino acids

Carrier-mediated transcellular diffusion.

Oral transmucosal absorption route for high MW drugs

Transcellular endocytic process.

Drug absorption steps across buccal/SL mucosa

Release from dosage form, dissolve in saliva, partition into epithelial lining, diffuse across epithelial barrier, absorb into systemic circulation via lamina propria vasculature.

Where absorbed drug from oral transmucosal delivery drains

Into the internal jugular vein, avoiding first-pass metabolism.

Use of systemic SL drug delivery

For rapid onset of action.

Use of systemic buccal drug delivery

For prolonged delivery.

Saliva's role as a barrier to drug absorption

Poses a more significant barrier in the SL space due to heavy secretion and washing effect.

Ideal MW for buccal/SL drug delivery

< 500 Da, although buccal can accommodate up to 20,000 Da with penetration enhancers.

Ideal Log Ko/w for buccal/SL drug delivery

2 - 4.

Ideal solubility in saliva for buccal/SL drug delivery

High for quick dissolution.

Ideal pKa for weak acid drugs for buccal/SL absorption (saliva pH 6)

> 2, to maximize the unionized fraction.

Ideal pKa for weak base drugs for buccal/SL absorption (saliva pH 6)

< 10, to maximize the unionized fraction.

Preferred mucin binding for buccal/SL drugs

None to low.

Preferred drug dose for buccal/SL dosage forms

Low/potent drug.

Preferred size for buccal/SL dosage forms

Small to avoid spitting/swallowing.

Common excipients in buccal/SL dosage forms

Sweeteners, flavorants, colorants.

Special excipients for buccal formulations

Insoluble gum base resins, mucoadhesives, penetration enhancers for large MW drugs.

Special excipients for SL formulations

Super-disintegrants & effervescent salts.

Dosage forms for buccal delivery

Lollipops, chewing gums, lozenges/troches, tablets with mucoadhesive, patches with mucoadhesives.

Dosage forms for SL delivery

Uncoated tablets, patches/films, sprays.

Onset of action for buccal dosage forms

Immediate action or prolonged action.

Onset of action for SL dosage forms

Quick (1 - 5 min); immediate action.

Feasibility of sustained release via SL route

Not feasible due to saliva and mucus production.

Characteristic of SL tablets for rapid disintegration

Generally contain specific super-disintegrants, effervescent agents, and highly water-soluble excipients.

Coating on SL tablets for rapid release

SL tablets are typically uncoated for rapid drug release.

Characteristic of buccal formulations for sustained release

Intended for sustained release.

Desired characteristic of buccal dosage forms in the mouth

Designed to be kept in the mouth for extended periods (6 - 12 hours).

Disintegration of buccal dosage forms

Do not disintegrate but dissolve slowly over an extended period.

Role of mucoadhesives in buccal tablets

Crucial for keeping the dosage form attached to the buccal pouch for prolonged drug release.

Mechanism of mucoadhesives

Swell upon contact with saliva, forming a 3D matrix to attach to the buccal pouch.

Buccal dosage forms that allow for sustained release

Lozenges, Tablets, Patches.

Region of the mouth utilized by lollipops and chewing gum dosage forms

Whole mouth.

Major advantage of using the transmucosal space for drug delivery

Bypasses first-pass metabolism.

Main issue with CNS drug therapy

Getting the drug into the CNS system is challenging.

Barrier layers limiting molecule exchange between blood and neural tissue/fluid

Blood-Brain Barrier (BBB), Arachnoid epithelium, Choroid plexus epithelium.

Barrier layer exerting the most significant control over the brain's microenvironment

The Blood-Brain Barrier (BBB).

Location and formation of the Blood-Brain Barrier

Located in the cerebrum and formed by cerebrovascular endothelial cells between blood and interstitial fluid (ISF).

Location of the Arachnoid epithelium barrier

Between blood and subarachnoid cerebrospinal fluid (CSF).

Location of the Choroid plexus epithelium barrier

Between blood and ventricular CSF.

Pathway that transports nutrition to the brain and can be utilized for drug transport

Carrier-mediated transport.

Intracarotid infusion

The introduction of fluids and drugs directly into the carotid artery, the main artery in the neck that carries blood from the heart to the brain.

Capsules

Solid dosage forms in which medicinal agents and inert substances are enclosed in a small gelatin shell or synthetic polymer.

Categorization of capsule dosage forms

Hard Gelatin Capsules (HGC) or Soft Gelatin Capsules (SGC).

Structure of Hard Gelatin Capsules (HGC)

Comprise two pieces, a cap and a body, fitted and locked together after filling.

Importance of locking HGCs

To prevent tampering of contents.

Composition of HGC shell

Gelatin, sugar, and water.

Typical moisture content of HGCs

13 - 16 %.

Range of HGC capsule sizes

000 (the largest) to 5 (the smallest).

Effect of increasing HGC capsule size number on loaded volume

As HGC capsule sizes increase, the amount or volume that can be loaded decreases (as size numbers go from 000 to 5).

Contents that can be delivered in HGCs

Powders, granules, tablets, and non-aqueous liquids.

Manufacturing of HGCs

Can be manufactured or compounded.

Routes of administration for HGCs

Oral use only.

Structure of Soft Gelatin Capsules (SGC)

One-piece, hermetically sealed dosage forms.

Composition of SGC shell

Gelatin with glycerin/sorbitol as a plasticizer, water, and methyl or propyl paraben as a preservative.

Role of plasticizer in SGCs

Makes the gelatin capsules pliable and soft, preventing cracking and allowing them to be molded into different shapes.

Typical moisture content of SGCs

20 - 30%.

Additive often found in SGCs for identification

Titanium dioxide as an opacifier.

Contents that can be incorporated into SGCs

Only non-aqueous liquids (solutions, suspensions, self-emulsifying systems).

Why aqueous liquids cannot fill capsules

Water will dissolve the capsule shell.

Manufacturing of SGCs

Can only be manufactured.

Routes of administration for SGCs

Oral, ophthalmic, dental, vaginal, and rectal routes of administration.

Counseling point for non-oral capsules

Specify the route of administration.

Drugs that can be incorporated into a capsule dosage form

Any drug or excipient, except hygroscopic molecules; also used for drugs with poor compressibility or requiring high doses.

Excipients in capsules that maintain a dry state

Desiccants.

Excipients in SGCs that make them more pliable

Plasticizer.

Physical stability issues with capsules

Changes in moisture content (swelling, dissolving, sticking from excess water; cracking, loss of contents from water loss).

Chemical stability issues with capsules

Minimal issues due to minimal drug exposure to the environment, enhanced by opacifiers and antioxidants.

Microbiological stability issues with capsules

More significant with SGCs than HGCs due to higher water content, requiring preservatives in the shell.

Effect of improper storage on gelatin capsules

Sticking together, becoming brittle, cracking.

Swallowing vaginal capsules

Vaginal capsules should not be swallowed, but inserted vaginally.

Rate-limiting step (RLS) for drug absorption from capsules

Depends on the contents present inside the capsule.

RLS for non-aqueous solutions in capsules

Diffusion or partition coefficient.

RLS for suspensions, powders, granules, or tablets inside capsules

Dissolution.

Process required for a drug in a solid dosage form (like powder or granules in a capsule) before absorption

Dissolution.

New Molecular Entities (NME)

A key term related to FDA approval.

New Biologic Entities (NBE)

A key term related to FDA approval.

Investigational New Drug (IND)

A key term related to FDA approval.