revision on antipsychotics

PART 1: INTRODUCTION TO PSYCHOTROPIC FORMULATIONS

Section 1: Learning Objectives (Page 2)

By the end of this lecture, students should be able to:

• Understand the challenges associated with psychiatric illness treatment.

• Recognise and appreciate innovative psychotropic drug formulations.

Section 2: The Challenges of Psychiatric Illness Treatment (Pages 3-4)

2.1. Long-Term Treatment Requirement (Page 3):

• The treatment of psychiatric illness frequently requires long-term treatment (often years or lifelong).

2.2. The Compliance Problem (Page 3):

• Poor treatment compliance is a widespread issue that significantly affects the success of treatment.

• This leads to suboptimal treatment outcomes, including relapse, hospitalisation, and reduced quality of life.

2.3. Factors Influencing Success of Psychotropic Pharmacotherapy (Page 4):
Success depends on several factors in addition to drug efficacy:

1. Treatment compliance – the patient's ability and willingness to follow the prescribed regimen.

2. Availability of optimal dosage forms – formulations that suit patient needs and preferences.

3. Reduction in side effects – minimising adverse effects that can lead to discontinuation.

Section 3: What Do Novel Formulations Offer? (Page 5)

Innovative drug delivery systems for psychotropic medications aim to provide:

• Enhanced drug delivery (more predictable and consistent).

• Improved efficacy (better clinical outcomes).

• Reduced side effects (improved tolerability).

• Simplify treatment regimens (fewer doses per day).

• Improve medication adherence (easier for patients to stick to treatment).

• Better health outcomes (overall improved prognosis and quality of life).

PART 2: INNOVATIVE DRUG DELIVERY SYSTEMS FOR PSYCHOTROPICS

Section 4: Overview of Innovations (Page 6)

A number of innovative drug delivery systems have been developed to address the challenges of psychiatric treatment:

PART 3: PARENTERAL FORMULATIONS – DEPOT INJECTIONS

Section 5: Parenteral Administration Overview (Page 7)

• Parenteral (injectable) formulations are a key strategy for improving adherence in patients with chronic psychiatric illness, particularly schizophrenia.

• They provide sustained drug levels and eliminate the need for daily oral dosing.

Section 6: Oil-Based Injections – Solutions and Suspensions (Page 8)

Section 7: Drug Release from Oily Solutions – Kinetics (Pages 9-11)

7.1. Rate-Determining Step (Page 9):

• In oily solutions, the release rate is determined by the partitioning of the drug out of the oil (formulation) into the surrounding aqueous media (absorption media).

• This is an equilibrium process described by the apparent oil/water partition coefficient (K) :

�=����K=Cw​Co​​

Where:

• ��Co​ = concentration of drug in oil phase

• ��Cw​ = concentration of drug in water phase

7.2. Fraction of Drug Available for Absorption (Pages 10-11):

• The fraction of drug (f) in the aqueous phase is the only form available for absorption.

�=1+�1+�f=1+K1+α​

Where:

• �f = fractional concentration of drug released

• �=��/(��+��)α=Vo​/(Vw​+Vo​) (volume ratio of oil to total volume)

• �K = oil/water partition coefficient

Interpretation:

• Higher K (more lipophilic drug): Lower �f → slower release, longer duration.

• Lower K (less lipophilic drug): Higher �f → faster release, shorter duration.

• This relationship allows formulators to control duration of action by modifying the drug's lipophilicity (e.g., via salt formation).

Section 8: Case Study – Fluphenazine Salts (Page 12)

Fluphenazine is available as three different salt forms, each with different lipophilicity and therefore different duration of action.

Image Description (Page 12): Shows the chemical structures of the three fluphenazine salts, highlighting the increasing carbon chain length from hydrochloride to enanthate to decanoate. The longer the fatty acid chain, the more lipophilic the molecule.

Mechanism: The longer the fatty acid chain esterified to the fluphenazine molecule, the higher its lipophilicity (logP). Higher lipophilicity means slower partitioning from the oil depot into the aqueous phase, resulting in a prolonged duration of action.

Section 9: Other Injectable Depot Formulations (Page 13)

Section 10: Oily Formulations for IM Injection – Summary (Page 14)

• Suitability: Only drugs that are appreciably oil-soluble and have the desired partition characteristics are suitable for formulation as oily injections.

• Oils that may be used for IM injection:

  • Sesame oil

  • Olive oil

  • Arachis (peanut) oil

  • Maize oil

  • Almond oil

  • Cotton seed oil

  • Castor oil

  • Fractionated coconut oil

Section 11: Aqueous-Based Long-Acting Injection – Risperdal Consta® (Page 15)

• Drug: Risperidone (atypical antipsychotic).

• Formulation Type: Long-acting, water-based injection (unlike oil-based depots).

• Technology: Extended-release microspheres composed of a biodegradable polymer.

• Mechanism: After IM injection, the PLGA microspheres reside in the muscle tissue and slowly degrade by hydrolysis, releasing risperidone over a period of 2 weeks.

PART 4: ORAL FORMULATIONS

Section 12: Controlled-Release Paroxetine (Pages 17-19)

12.1. Rationale for Development (Page 17):

• A controlled-release (CR) formulation of the SSRI paroxetine was developed to:

  1. Improve general tolerability.

  2. Decrease the GI side effects (nausea, diarrhoea) of the immediate-release (IR) dosage form.

  3. Improve patients' compliance.

12.2. Formulation Design (Pages 17-18):

Image Description (Page 17-18): Likely shows a diagram of the two-layer tablet design and a graph comparing nausea rates between IR and CR paroxetine, demonstrating reduced GI side effects with the CR formulation.

12.3. Dosing Consideration (Page 19):

• Question: Why does the individual dose of paroxetine CR need to be about 25% higher than that of the IR formulation to achieve equivalent dosing?

• Answer: About 80% of the paroxetine content of the tablets is released, and the remaining 20% is retained within each tablet (due to the matrix and coating design). Therefore, a higher nominal dose is needed to deliver the same amount of bioavailable drug.

Image Description (Page 19): Likely shows a graph illustrating the difference in bioavailability between IR and CR paroxetine formulations.

Section 13: Weekly Fluoxetine Capsules (Prozac Weekly®) (Pages 20-21)

13.1. Formulation Design (Page 20):

• Drug: Fluoxetine hydrochloride (SSRI).

• Dose: 90 mg (equivalent to fluoxetine).

• Formulation Type: Delayed-release capsules containing enteric-coated pellets.

• Release Mechanism: The enteric-coated pellets do not dissolve until they reach a portion of the gastrointestinal tract where the pH exceeds 5.5 (i.e., the small intestine).

13.2. Rationale for Weekly Dosing (Page 20):

• Both fluoxetine and its major active metabolite, norfluoxetine, have exceptionally long half-lives:

  • Fluoxetine: 2 to 7 days

  • Norfluoxetine: 4 to 16 days

• This long half-life allows for once-weekly dosing once steady state is achieved.

13.3. Advantages of Weekly Formulation (Page 21):

• Improved compliance: Patients only need to remember to take medication once a week.

• Decreased cost of medication: Fewer doses = lower cost? (Debatable, as dose is higher).

• Minimise potential for adverse drug-drug interactions: Less frequent dosing may reduce the window for interactions.

• Variable compliance but less side effects: Even if a dose is missed, the long half-life provides a buffer.

• Overall improved outcome.

Image Description (Page 21): Likely shows graphs comparing patient compliance rates between once-daily and once-weekly fluoxetine, demonstrating higher adherence with the weekly regimen.

Section 14: OROS® (Osmotic-controlled Release Oral delivery System) for Methylphenidate (Pages 22-26)

14.1. Technology Overview (Page 22):

• OROS® is an advanced drug delivery technology based on the osmotic pump as the driving force for highly predictable and reliable controlled drug release.

• It has been applied to methylphenidate (for ADHD) using an advanced trilayer formulation (Concerta®).

14.2. Tablet Design – Trilayer OROS® (Pages 23, 26):

The tablet consists of three core compartments surrounded by a semi-permeable membrane with a laser-drilled delivery orifice. The membrane is overcoated with an immediate-release drug layer.

14.3. Mechanism of Action (Page 23):

1. Initial Release: The drug overcoat dissolves quickly, providing an initial immediate-release dose.

2. Water Influx: Water is absorbed through the exposed semi-permeable membrane into the tablet core.

3. Push Compartment Expansion: The push compartment expands, creating pressure.

4. Controlled Release from Compartment 1: Drug from the first compartment is pushed out through the orifice at a controlled rate.

5. Controlled Release from Compartment 2: Drug release then begins from the second compartment at a different, pre-programmed rate.

• Result: Provides a rapid onset (from the overcoat) followed by a controlled, ascending release profile that matches the child's school day.

Image Description (Page 23): A diagram showing the trilayer OROS tablet before and during operation, illustrating the expansion of the push layer and drug extrusion through the laser-drilled orifice. Page 25 likely shows the chemical structure of methylphenidate and a graph of its plasma concentration over time.

14.4. Advantages (Page 25):

• Less side effects (smoother plasma profile avoids peaks and troughs).

• Improved compliance (once-daily dosing).

Image Description (Page 26): A detailed diagram showing different OROS configurations: Push-Pull™, L-OROS™ (for liquids), and the Tri-Layer system used for methylphenidate.

Section 15: Rapidly Dissolving Tablets (Pages 27-29)

15.1. Overview (Page 27):

• Purpose: Represent the latest advance in drug delivery technology for managing acute psychosis.

• Target Population: Widely used in patients who have difficulty swallowing tablets, such as children and the elderly.

• Available For: Atypical antipsychotics:

  • Olanzapine (Zydis®)

  • Risperidone (M-Tab®)

Image Description (Page 27): Likely shows a person placing a rapidly dissolving tablet on their tongue, illustrating the ease of administration without water.

15.2. Rationale (Page 28):

• Traditional tablets and capsules administered with water may be inconvenient or impractical for some patients.

• Example: A very elderly patient may not be able to swallow a daily dose of antidepressant.

15.3. Types of Fast-Dissolving Tablets (Page 29):

PART 5: TRANSDERMAL DELIVERY

Section 16: Transdermal Drug Delivery Overview (Page 31)

• Definition: Transdermal drug delivery systems are designed to support the passage of drug substances from the surface of the skin, through its various layers, and into the systemic circulation.

• First Approved Transdermal System: Transderm Scop® (scopolamine) was approved by the FDA in 1979 for prevention of nausea and vomiting associated with travel (sea sickness).

Image Description (Page 31): A diagram showing the layers of the skin (stratum corneum, epidermis, dermis) and a transdermal patch applied to the surface, with arrows indicating drug diffusion into the capillaries.

Section 17: Types of Transdermal Systems (Pages 32-36)

There are two major types of transdermal therapeutic systems (TTS):

Image Description (Pages 32-34): Diagrams illustrating the layered structure of matrix and reservoir patches.

Section 18: Examples of Transdermal Psychotropic Patches

18.1. EMSAM® (Selegiline Transdermal System) – Page 37:

• Drug: Selegiline (MAOI antidepressant).

• Design: Transdermal system designed to continuously deliver selegiline over a 24-hour period.

• Dosing: Contains 1 mg selegiline per cm²; delivers approximately 0.3 mg/cm² over 24 hours.

• Available Sizes/Doses:

  • 20 mg/20 cm² → delivers ~6 mg/24h

  • 30 mg/30 cm² → delivers ~9 mg/24h

  • 40 mg/40 cm² → delivers ~12 mg/24h

• UK Status: EMSAM does not have a UK licence, so neither a GP nor a psychiatrist will prescribe it, unless it's part of a clinical trial.

18.2. Rivastigmine Patches (Page 38):

• Drug: Rivastigmine (cholinesterase inhibitor for Alzheimer's/dementia).

• Key Instruction: The patch should not be cut into pieces. Cutting can damage the rate-controlling mechanism and lead to dose dumping.

Image Description (Page 38): Shows a rivastigmine patch and a BNF entry, with a clear warning not to cut the patch.

PART 6: CONCLUSIONS AND SUMMARY

Section 19: Key Takeaways (Page 39)

• New formulations of psychotropic drugs can offer advantages over older formulations in terms of:

  • Convenience

  • Side effect profiles (improved tolerability)

  • Efficacy

  • Faster onset and prolonged duration of action

• Use of these new formulations can help to enhance patient satisfaction and compliance, thereby improving patient prognosis, both in acute and outpatient treatment.

• Novel formulations, including rapid-dissolving tablets and transdermal patches, are useful and effective alternatives to the traditional tablet form, providing more acceptable forms of medication for patients requiring long-term treatment.

• Conventional depot oil formulations are still widely used for chronic schizophrenia management.

SUMMARY TABLE: KEY PSYCHOTROPIC FORMULATIONS