BIOMD202 8p1 Introduction to Pharmaceutical Formulation, Dosage Forms, and Drug Delivery

Introduction to Pharmaceutical Formulation and Dosage Forms

• Definition of Dosage Form: A dosage form is the acceptable physical form in which a medicine is produced for administration to a patient. It is a combination of the drug (API) and various excipients.

• Active Pharmaceutical Ingredient (API): This is the active part of the medicine that possesses pharmacological properties. Synonyms for API used in the industry or research include:

  • Bioactive.  

  • Therapeutic agent.

  • Drug.

• Constituents of a Medicine: Most medicines are not composed solely of the active part. For example, in an ibuprofen tablet analyzed in the lab, while the total weight might be approximately $280\,mg$ to $290\,mg$, the API (ibuprofen) may only account for $200\,mg$. The remaining weight consists of excipients.

The Role and Selection of Excipients

• Verbatim Definition of Excipient: Excipients are typically inert materials. They do not have any pharmacological property, but their function is to:     * Stabilize the drug's API.     * Transform the medicine into a shape-acceptable form (e.g., turning white ibuprofen powder into a tablet).

• Broad Range of Excipients and Functions:

  • Diluents: Examples include lactose, microcrystalline cellulose, and starch. They add bulk to the formulation.

  • Lubricants: Used for manufacturing feasibility.

  • Binders: Help hold the tablet together.

  • Disintegrants: Help the tablet break apart after administration.

  • Coating Materials: Polymers used for drugs that are not palatable. A specific example is Hydroxypropyl Methylcellulose ($HPMC$).

• Considerations for Choosing Excipients:

  • Physicochemical Properties of the Drug: Selection depends on the drug's polymorphic forms (different crystalline forms, hydrates) and sensitivity to heat or moisture.

  • Microenvironmental pH: The drug may not be stable at certain higher or lower $pH$ levels, necessitating specific excipients.

  • Hygroscopicity: Some excipients, like sugars, are hygroscopic (absorb moisture from the atmosphere), making them unsuitable for moisture-sensitive drugs.

  • Manufacturing Process: The choice of excipient is dictated by the manufacturing method, such as direct compression or granulation (wet vs. dry).

Advanced Drug Delivery Systems

• Definition of Drug Delivery System: These systems utilize certain types of "carriers" or "cargos" to deliver the API from the site of administration to a specific targeted site.

• Nanoparticles and Liposomes: These are advanced versions of drug delivery.

• Case Study: Pfizer COVID-19 Vaccine:     * API: Messenger RNA ($mRNA$).

  • Formulation Type: Nanoparticle drug delivery system.

  • Objective: The $mRNA$ is inherently unstable and degrades quickly. The nanoparticle stabilizes the $mRNA$ and carries it into the cell. Inside the cell, the $mRNA$ replicates to produce antigens, which trigger the immune reaction against the virus.

Routes of Drug Administration

• Oral Route:

  • The most common route, accounting for approximately $60\,\%$ to $70\,\%$ of all medicines.

  • It is easy to formulate and prepare.

  • Significantly cheaper than parenteral formulations.

• Parenteral Route:

  • Etymology: Derived from the Greek words "para" and "entera," meaning "outside the oral."

  • Includes intravenous (IV) (directly into veins), subcutaneous (below the skin), and intradermal injections.

  • Manufacturing Requirements: Must be prepared in specialized, highly controlled environments called $GMP\,ISO\,5$. These environments require strict control over particle size, making these formulations expensive.

• Topical Route: Includes creams, emulsions, and lotions applied to the skin.

• Inhalational Route: Used for asthmatic patients (e.g., inhalation powders).

• Intravaginal Route: Often uses intravaginal rings for steroid hormones like estradiol and estriol.

• Rectal Route: Includes rectal suppositories, often used in pediatric populations.

• Ocular and Otic Routes: Eye drops and ear drops respectively, primarily for local infections.

• Local vs. Systemic Action:

  • Local: The drug acts exactly where it is applied (e.g., eye and ear drops).

  • Systemic: The drug enters the bloodstream to act on a different part of the body (e.g., oral ibuprofen reaching the head to relieve a headache).

Classification of Dosage Forms by State of Matter

• Solid: Tablets, capsules.

• Liquid: Oral solutions (e.g., paracetamol/acetaminophen solutions with roughly $66\,\%$ sugar), suspensions (where particles are suspended rather than dissolved).

• Gas: Inhalational anesthetics or powders.

Immediate Release (IR) vs. Controlled Release (CR)

• Immediate Release (Conventional):

  • A preparation where the release of the active drug is not deliberately modified by special formulation design or manufacturing.

  • The drug releases its payload straight away, typically within a few minutes to an hour after disintegration.  

  • The dissolution profile follows the Noyes-Whitney equation and depends on the intrinsic properties of the active substance.

  • Limitations: Requires frequent dosing for drugs with a short half-life ($t_{1/2}$).

  • Case Study: Levodopa: Used for Parkinsonism. It has a very short half-life and clears the body rapidly. If given as an IR formulation, a patient might need to take it $3$ to $4$ times a day, which is inconvenient and reduces adherence.

  • Therapeutic Window: IR drugs can cause fluctuating plasma concentrations that move between the Minimum Effective Concentration ($MEC$) and the Maximum Toxic Concentration ($MTC$).

• Controlled Release (Modified, Sustained, Extended):

  • A preparation where the rate and place of release are different from conventional forms.

  • Uses special polymers to retard the immediate release of the API.

  • Goals: Increased patient adherence, improved safety, and reduced toxicity.  

  • Advantages: Reduces dosing frequency, provides a smooth/steady plasma release profile, and is more economical (one tablet per day vs. four).

Specific Mechanisms of Controlled Release

• Enteric Coated Tablets:

  • Stomach $pH$ is approximately $2$. Intestinal $pH$ is between $6.5$ and $7$.

  • Certain APIs (like peptides or enzymes such as chymotrypsin and protease) are unstable in gastric $pH$.

  • Mechanism: The tablet is coated with enteric polymers (e.g., cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate) that do not dissolve in acidic $pH$ but dissolve in the intestine.

  • Safety Warning: These tablets should never be chewed or broken; they must be swallowed whole to maintain the coating's integrity.

• Matrix (Monolithic) Systems:

  • The drug is uniformly dispersed throughout a polymer matrix.

  • Mechanism: Release occurs via diffusion, swelling, or erosion of the matrix.

  • Types: Hydrophilic matrices (water-loving) and hydrophobic/lipid systems (e.g., waxes, ethyl cellulose).

• Membrane Control (Reservoir) Systems:

  • A drug-rich core (reservoir) is separated from the environment by a rate-controlling membrane.   

  • The drug must diffuse through the membrane to be released. Dose dumping is a potential risk if the membrane is compromised.

  • Example: Estradiol patches (transdermal).

• Osmotic Pump Systems (OROS):  

  • Mechanism: The tablet is coated with a semi-permeable membrane that allows water in but does not allow drug out. As water enters, it creates osmotic pressure. The building pressure pushes the drug out through a laser-drilled orifice at a constant rate.

  • Leading Expert: The company Alza (USA) is the primary expert in this technology.

Potential Limitations of Controlled Release

• Inter-individual Variation: Differences in genetics, enzyme levels, and food habits (e.g., high meat vs. high green diets) change $pH$ and affect drug release.

• Duration Limits: Oral delivery is typically limited to a $12\,hour$ window based on gastrointestinal transit time.

• Dose Dumping: If a controlled release tablet is crushed or fails, a potentially fatal dose of drug could be released at once.

  • Example: Morphine (opioid) or Risperdal (used for schizophrenia) sustain serious risks if the release mechanism fails.

• Suitability: Not all drugs can be sustained-release; the drug must be potent and cannot have a very narrow therapeutic index.