Lecture Drug Dosage Forms 2024.pdf

Branko Radojkovic [email protected]  Medicines are rarely administered in their pure chemical form - active pharmaceutical ingredients (API) APIs are combined with a number of inert substances (excipients) and transformed into a convenient dosage form t...

Branko Radojkovic [email protected]  Medicines are rarely administered in their pure chemical form - active pharmaceutical ingredients (API) APIs are combined with a number of inert substances (excipients) and transformed into a convenient dosage form that can be administered by a suitable route The therapeutic response to a medicine is function of its intrinsic pharmacological activity, dose given, route of administration, and specific dosage form Dose-response relationship obtained after drug administration by different routes are not the same Variations are also observed when the same medicine is administered in different dosage forms or similar dosage forms produced by different manufacturers Shargel L. & Yu A. B. (2016). Applied Biopharmaceutics and Pharmacokinetics (7th edition.). McGraw Hill.  Biopharmaceutics examines the interrelationship of the physical/chemical properties of the drug, the dosage form (drug product) in which the drug is given, and the route of administration on the rate and extent of systemic drug absorption Biopharmaceutics and Pharmacokinetics: Introduction; retrieved from: https://www.pharmacy180.com/article/biopharmaceutics-and-pharmacokinetics-2447/ Shargel L. & Yu A. B. (2016). Applied Biopharmaceutics and Pharmacokinetics (7th edition.). McGraw Hill.  Medicines are given in a variety of dosage forms for systemic or local therapeutic activity Dosage forms can be considered to be drug delivery systems that release and deliver drug to the site of action such that they produce the desired therapeutic effect; In addition, they are designed specifically to meet the patient’s needs including palatability, convenience, and safety Advances in pharmaceutical technology and manufacturing have focused on developing quality products that are safer, more effective, and more convenient for the patient Shargel L. & Yu A. B. (2016). Applied Biopharmaceutics and Pharmacokinetics (7th edition.). McGraw Hill. Shargel L. & Yu A. B. (2016). Applied Biopharmaceutics and Pharmacokinetics (7th edition.). McGraw Hill.  Based on physical form: ✓ solid ✓ semi-solid ✓ liquid ✓ gaseous Local vs. systemic effect Administration site (internal/external) Route of administration  Based on microscopic structure: Monophasic dosage forms - API/s and excipients are dissolved in the base/solvent (e.g. true solutions) Polyphasic dosage forms - ≥ two distinctive phases (e.g. emulsions, suspensions, colloidal systems)  Solid oral dosage forms are usually swallowed to release the active substance at one or more sites of the digestive tract Mainly systemic effect (few medicines are administered orally for local effect in GIT) Solid dosage forms can be a powder or a mixture of powders, often further processed into granules, tablets or hard capsules Soft gelatin capsules (liquid filled) Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer.  Systemic drug absorption from an oral solid consists of a succession of rate processes: disintegration of the dosage form and subsequent release of the drug dissolution of the drug in an aqueous environment absorption across cell membranes into the systemic circulation Liberation = disintegration ± dissolution Shargel L. & Yu A. B. (2016). Applied Biopharmaceutics and Pharmacokinetics (7th edition.). McGraw Hill.  Active substances are only absorbed from the gastrointestinal tract in the dissolved state! Dissolution of the active substance should occur as fast as possible after administration if an immediate effect is intended The disintegration rate depends on the quantity and type of excipients, the processing conditions, as well as on the API itself Tablets and capsules must first disintegrate in contact with fluid, for the API/s to be dissolved; in contrast – API/s in oral powders are immediately available for dissolution Modified release oral solids (e.g. delayed release, sustained release, EC) Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer. Advantages Disadvantages ✓ Patient preference ✓ Poor dose flexibility ✓ Taste masking +/- ✓ Swallowing difficulties ✓ Modified release possible ✓ Paediatric patients ✓ Chemical stability ✓ Slow onset +/-  Preparations that are injected intravascularly, administered into body tissues or into visceral cavities. The parenteral route of administration is often chosen for active substances that are poorly absorbed via the oral route or when rapid systemic availability and effects are required Almost always administered for systemic effect (notable exceptions!) Caution: Must be sterile! Isotonicity, pH, excipients, endotoxins (…) Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer.  Commonly used parenteral administration routes are: - Intravenous (IV) - Subcutaneous (SC) - Intracutaneous/Intradermal (ID) - Intramuscular (IM) Other more specific routes are employed for the administration of the active substance directly to the therapeutic site: - Intrathecal, epidural or intracisternal - Intraocular/intravitreal - Intraarticular - Intracardiac (etc…) Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer.  Parenteral medicines are usually formulated as liquids (solutions, emulsions or suspensions) or solids (implants) Only aqueous solutions and microemulsions (O/W, particles < 1µm) may be administered intravascularly! Suspensions and oily solutions may be only administered via select routes (IM, SC)! Large volumes may be administered as infusions, other routes are volume limited Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer. Advantages Disadvantages ✓ Rapid action +/- ✓ Higher cost ✓ Bioavailability ✓ Infection risk ✓ Precise dosing/plasma ✓ Side effects/allergies concentration ✓ Patient preference ✓ Suitable when PO route not ✓ Administration requires available skills/knowledge  Large-volume preparations intended to be used for irrigation of body cavities, wounds and surfaces, for example during surgical procedures Aqueous solutions Local effect only Irrigations come in contact with blood vessels, wounds or damaged mucosa or enter body cavities that normally have a low microbial count or are sterile. Must be sterile! Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer.  Gasses, vapours, fine droplets or particles Mainly local effect (except medical gasses and inhalant anaesthetics) Gasses and volatile substances are readily absorbed into systemic circulation Pulmonary administration of medicines primarily used to achieve local effects in the respiratory tract diseases Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer.  Particle deposition in the airways Affected by particle size and velocity Aerosol Generation Devices: I. Metered-dose inhalers (MDIs) II. Dry powder inhalers (DPIs) III. Nebulisers IV. Liquid inhalers Costa, A., Pinheiro, M., Magalhães, J., Ribeiro, R., Seabra, V., Reis, S., & Sarmento, B. (2016). The formulation of nanomedicines for treating tuberculosis. Advanced Drug Delivery Reviews, 102, 102–115. https://doi.org/10.1016/j.addr.2016.04.012 Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer.  Oromucosal preparations liquids (mouthwashes, gargles, sprays) semi-solid preparations (pastes, gels) solid dosage forms (lozenges, pastilles, troches, tablets) Mainly local effect Some medicines are administered buccally or sublingually for systemic effect Flavour and texture are important factors Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer.  Nasal preparations liquids (nasal rinses, drops, sprays) semi-solid preparations (ointments, creams, gels) solid dosage forms (nasal powders, sticks) Mainly local effect (nasal disorders) Increasing interest in the nasal route for systemically acting substances and direct nose to brain delivery. Retention of the product within the nasal cavity - particle/droplets >10 μm. The deposition site is influenced by the container/dosing device and the way of administration Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer.  Otic preparations liquids (rinses, drops) semi-solid preparations (ointments, creams) solid dosage forms (otic powders, tampons) Application to the external auditory canal and middle ear Local effect only! Some excipients and APIs are ototoxic Caution: application to middle ear (e.g. perforated eardrum, tympanostomy tubes)! Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer.  Ophthalmic preparations liquids (eye lotions, drops) semi-solid preparations (ointments, creams, gels) solid (inserts, drug eluting CL) External application to the eye (conjunctival sac, lid margin) Local effect only! (systemic side effects possible) Caution: Must be sterile! Isotonicity, pH, viscosity Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer.  Rectal preparations liquids (enemas) semi-solid preparations (ointments, creams, foams) solid (suppositories, tampons) Rectal dosage forms may be applied for systemic or local effect Local treatment of GIT/anorectal disorders, constipation, diagnostic contrast. Systemic absorption affected by choice of dosage form, excipients, properties and form of API, particle size Suppositories must melt or dissolve to release API Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer. Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer. Advantages Disadvantages ✓ Alternative to PO ✓ Poor patient acceptability administration ✓ Unpredictable absorption +/- ✓ Less invasive than injectables ✓ Avoid 1st pass effect +/-  Vaginal dosage forms: liquids (vaginal solutions, irrigations) semi-solid preparations (ointments, creams, gels) solid (vaginal tablets, pessaries, medicated tampons) Application – intravaginal, external genitalia Vaginal dosage forms are almost exclusively used for local action (e.g. vulvo-vaginal disorders) Few drugs are administered intravaginally for systemic effect Applicator/dosing device may be needed Pessaries melt or dissolve to release API Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer.  Preparations for cutaneous (or dermal) application may be used for local treatment as well as for transdermal administration with a systemic effect liquids (lotions) semi-solid preparations (ointments, creams, foams, gels) solid (powders, sticks) transdermal delivery systems Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer.  Most dermal preparations are used for local treatment of dermal or soft tissue disorders Selection of dosage form depends on location, skin condition, and the desired effect of the API/s Preparations intended for administration to wounds or damaged skin must be sterile! Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer.  Only select APIs have appropriate physico- chemical and pharmacological properties needed for transdermal delivery: Small molecules (MW ≤ 500 Da) Moderately lipophilic, the partition coefficient (log P(octanol/water)) between 1.0 and 4.0 Effective at low doses (≤ 20 mg/day) Bouwman-Boer, Y., Fenton-May, V., & Le Brun, P. (2015). Practical Pharmaceutics : An International Guideline for the Preparation, Care and Use of Medicinal Products. Springer International Publishing : Imprint: Springer.