Drug Delivery Systems Chapter 1

Chapter 1: Drug Delivery System

• Drug delivery systems (DDS) are a focus of development due to several reasons
• Improved therapeutic efficacy and safety via precise spatial and temporal drug placement in the body, reducing the size and number of doses
• Potential for re-patenting existing drugs by using new techniques and concepts
• Increasing costs of new drug development encourage DDS creation
• New systems are necessary to deliver novel and genetically-engineered pharmaceuticals without significant immunogenic or biological inactivation
• Enzyme deficient disease and cancer therapy can be improved with better targeting

Introduction

• Attention focused on DDS development for therapeutic efficacy, safety, spatial, and temporal drug placement reducing dose size and number.
• Possibility of re-patenting
• Increasing costs encourage DDS development
• Delivering novel, genetically-engineered pharmaceuticals (biopharmaceuticals, peptides, and proteins) to target sites without adverse effects
• Enzyme deficient disease and cancer therapy can be enhanced by better targeting

Drug Delivery

• Drug delivery involves approaches, formulations, technologies, and systems needed (place and rate) to safely achieve a desired therapeutic outcome.
• Drug delivery encompasses quantity and duration of drug presence inside the body by various chemical formulations (prodrug)
• Medical devices and drug-device products can be a part of drug delivery mechanisms
• Drug delivery is a concept integrated with dosage form and route of administration

Drug Delivery Technologies

• Drug delivery technologies modify drug release profiles for improved efficacy, safety, and patient convenience and compliance
• Current efforts in drug delivery involve

1. Controlled release drug action: drug is released from formulation (sustained, delayed, pulsed)
2. Targeted delivery systems: drug action is confined to a specific target area of the body (important in cancer therapy)
3. Localized drug action: drug action is confined to a particular tissue or organ (spatial control), examples include intrauterine devices and ophthalmic delivery

Controlled Release Formulation

• When a drug is injected or ingested, systemic drug level may exceed therapeutic level briefly, then declines to ineffective levels.
• Fluctuations can be undesirable, especially in drugs with a low therapeutic index.
• Fluctuation magnitude depends on absorption rate, distribution rate, and elimination rate and dosing intervals
• Plasma drug concentration may not be maintained above a minimum therapeutic level for a very long period
• Administering a dose before the first dose is fully eliminated can cause drug accumulation in the body, leading to toxic levels

Controlled Release Formulation

• Each drug has a therapeutic window where drug-plasma concentration below therapeutic level is insufficient, and above it results in undesirable/toxic effects.
• Ideal profile maintains relatively constant drug concentration throughout treatment duration.
• Controlled release systems can reduce undesired fluctuations in drug levels, reducing side effects and improving therapeutic outcomes. Drug is released continually at a rate dictated by the body's needs (Kabs).

Terminology of Drug Delivery and Targeting

• Drug delivery and targeting terminology is extensive and evolving.
• Systems are described with terms like "controlled release," "sustained release,” "zero-order," "reservoir," "monolithic," "membrane-controlled," “smart,” “stealth” (RES), etc.
• Terms are not always used consistently and may be inaccurate.

Terminology of Drug Delivery and Targeting

• Common terms in drug delivery and targeting include:

1. Prolonged/Sustained Release: extended drug presence
2. Zero-Order Release: constant effective drug level over time
3. Variable Release: variable drug input rate
4. Bio-responsive Release: drug release modulated by a biological stimulus

Terminology of Drug Delivery and Targeting

• Common terms include

5. Pulsatile Release: drug release in pulses (circadian rhythms where constant release is not desired)
6. Delayed Release: release at a time other than immediately after administration (e.g., enteric coated)
7. Modulated/Self-Regulated Release: drug delivery controlled by the patient
8. Temporal Drug Delivery: controlled delivery to achieve desired time-related effects in the body
9. Spatial Drug Delivery (Targeted Delivery Systems): Drug delivery to a specific body region, both route and distribution.
10. Drug Delivery System (DDS): general term for any sophisticated delivery system incorporating various advanced technologies (rate-control, pulsatile release, bio-responsive) to target spatial and/or temporal delivery.

Commonly Used Abbreviations

• List of common abbreviations (CD, CR, DR, ER, XL, XR, XT, IR, ES, XS, MR, SA, SR, LA, LAR) and their meanings related to drug delivery.
• Note that no industry standard exists and confusion or misinterpretations have led to prescribing errors.

Targeted Drug Delivery

• Conventional dosage forms reach all parts of the body (healthy and diseased)
• Drug effect results from action on a target (receptor) site, while undesirable effects stem from action on non-target sites.
• Some drugs are specific in their action (hormones, enzymes), interacting with receptors in specific cell types.
• Many drugs are not specific and interact with both target and non-target cells.

Targeted Drug Delivery

• Drug molecule availability to a cell is governed by pharmacokinetics (release, absorption, distribution, elimination).
• High drug doses can lead to high drug levels in non-target sites, creating local/systemic side effects.
• Conventional dosage forms often have excess drug compared to needs.

Targeted Drug Delivery

• New controlled drug delivery systems are available to restrict drug action to target sites.
• Therapeutic effects can be improved by increasing the amount of drug in target cells while reducing it in non-target tissues.
• Targeting is crucial in cancer chemo, intracellular parasitic disease treatments, and gene/enzyme therapies.
• Combining targeting and controlled release technologies in dosage forms is potential.

Targeted Drug Delivery

• Definition: use of carriers to deliver drugs only to target cells (albumin, antibodies, liposomes, micro/nanoparticle carriers, cyclodextrins, viruses, RBCs) linked through covalent or non-covalent binding
• Drug-carrier complexes' in vivo distribution is dictated by carrier properties and not by the drug properties
• Carriers can be specific or non-specific in their distribution

Targeted Drug Delivery

• Specific distribution relies on chemical recognition between the carrier and target site
• Non-specific distribution relies on carrier properties (size, distribution, lipophilicity/hydrophilicity, surface charge)
• Carriers offer advantages: protect drugs from degradation, avoid immunogenicity and antigenicity, and improve drug solubility

Drug Carriers

• Examples of drug carriers are shown (Antibodies, liposomes, and micelles). Different methods/ types exist and are categorized..

Localized Drug Action

• Site of application is the site of action.
• Localized drug action involves placing a DDS directly into the affected tissue or organ.
• Combine localized action with controlled release for rate-controlled drug delivery.
• Important in cases of anticancer and anti-fertility drugs, ophthalmic delivery, dermal therapy, local GIT problems, and lower respiratory tract.

The Rational of CDDS

• An ideal drug delivery system should deliver drug at a rate determined by the body's needs for the treatment period and direct the drug to the precise treatment site or localized to diseased tissue/organs.
• CDDS aim to alter drug pharmacokinetics, either through novel delivery systems or by modifying the drug's molecular structure or physiological parameters.
• Goals of CDDS are to enhance drug delivery control, safety, and efficacy, promoting patient compliance

Available Drug Delivery System

• Current DDS systems cannot fully meet goals of precise rate/site control for drug delivery.
• Conventional and prolonged release systems are unable to fully control rate/site and cannot maintain constant drug level in plasma/target tissue through these forms.
• IV infusion can maintain constant plasma levels but is inconvenient.
• Oral and transdermal routes are preferred for DDS because of their non-invasive nature

Types of Therapeutic Systems

• Three types of therapeutic systems are available:

1. Passive pre-programmed: predetermined release rates, no response to external cues.
2. Active pre-programmed: release rate altered by external cues (e.g., insulin pumps);
3. Active self-programmed: release rates are modulated in response to biological cues (e.g., blood sugar levels).

Advantages of Controlled Drug Delivery System

• Reduced dosing frequency
• Reduced fluctuation in circulating drug levels
• Avoidance of night-time dosing
• Therapeutic action enhancement via consistent drug exposure
• Reduction in undesirable local/systemic side effects
• Improved patient adherence and treatment success (especially for long-term therapies)
• Crucial for patient compliance to drug regimens.

Patient Compliance

• Patient compliance significantly impacts treatment success.
• Factors affecting compliance include disease awareness, faith in treatment, understanding treatment schedules, complexities of regimen, cost, and adverse effects.
• The use of CDDS can address patient non-compliance by minimizing the frequency and complexity of drug intake, and minimizing local/systemic side effects.

Economic Advantages

• Lower cost of introducing new DDS of successful existing drugs compared to the costs of introducing new drugs overall.
• FDA requirements for new DDS are less restrictive than for new drugs.
• Repatenting existing successful drugs with new DDS is an economic option

Limitations of Controlled Drug Delivery System

• Possible dose dumping from faulty formulations
• Limited ability to precisely adjust medication dosage
• Potential for increased first-pass metabolism
• Unpredictable and poor in-vivo-in-vitro correlation
• Slow drug absorption
• Toxicity risk from polymer additives
• High cost to develop and maintain these systems relative to conventional forms
• Not suitable to all drugs and needs.

Drugs That May Be Difficult to Formulate in CDDS

• Drugs with short biological half-lives (t1/2 < 2 hr)
• Drugs with long biological half-lives (t1/2 > 8 hr)
• Potent drugs with narrow therapeutic indices
• Drugs given in large doses
• Poorly absorbed drugs
• Poorly or slightly soluble drugs

Drugs That May Be Difficult to Formulate in CDDS

• Drugs needing extensive first-pass metabolism
• Poorly/low bioavailability
• Absorption windows

Example of CDDS

• Many drugs are now formulated as controlled delivery systems.
• Examples of substances/drugs available in controlled release dosage forms (vitamins, minerals, hormones, diuretics/CV drugs, CNS drugs, respiratory drugs). Specific examples of drugs include potassium, pyridoxine, methyltestosterone, nitroglycerin, procainamide, acetazolamide, isosorbide dinitrate, diazepam, phenobarbital, amphetamine sulfate, aminophylline, and phenylpropanolamine HCI

Some Applications of CDDS

• Cancer therapy: control pharmacokinetic behavior of anti-tumor drugs, reduce adverse effects
• Fertility control: using synthetic polymers in contraception e.g., intra-uterine and intra-vaginal devices for sustained release of progestins or estrogens
• Treatment of glaucoma: overcome poor ocular penetration and loss from ocular cavity in conventional preparations. Employ synthetic polymers, and prodrugs
• Enzyme replacement therapy: improve stability and cellular uptake by using carrier complexes.

Factors Influencing the Design and Performance of CDDS

• Drug Properties: influence on drug release characteristics, availability, and target site accessibility.
• Route of Drug Delivery: limits to suitable controlled release mechanisms/devices at different administration sites.
• Physiological constraints: first-pass metabolism, gastrointestinal motility, and blood supply, negatively impact delivery/efficiency at some routes
• Target Site: maximizing the fraction of the drug reaching the target site to reduce unwanted side effects (localized delivery versus systemic
• Disease state: Pathological changes during disease course (e.g., time course of ocular changes, protein content).
• Patient characteristics: ambulatory vs. bedridden status will factor into the design considerations

Physicochemical Properties of Drugs

• Drug release characteristics reflect drug availability, controlled by drug release.
• Development of CDDS requires complete knowledge of the intrinsic properties of the drug and how they influence system design.
• Drug properties (aqueous solubility, partition coefficient, molecular size, stability, protein binding) influence drug release patterns from dosage forms and impact delivery properties, potentially necessitating changes to the desired outcome, administration route and/or efficacy

Physicochemical Properties of Drugs

• Aqueous solubility: to be absorbed, drugs must be in solution, limited GI transit time and solubility at absorption site.
• Partition coefficient and molecular size: impact drug permeability, membrane diffusion and delivery system constraints.
• Drug stability: in-vitro vs. in-vivo stability impacting chemical/physical and microbiological properties during and post release. Potential degradation or metabolism in target regions will alter the intended use/outcome
• Protein binding: impact on duration, absorption, and candidacy for CDDS.

Biological Properties of Drugs

• Comprehensive picture of drug disposition (absorption, distribution, metabolism, excretion).
• Proper pharmacological parameters (drug half-life, duration of action, drug absorption) are needed in the design for a CDDS.
• Key properties (absorption, distribution, metabolism, and excretion) and how they affect the CDDS design
• Absorption, Distribution, metabolism
• Duration and action: Biological half-life of a drug, duration of action, margin of safety. Drugs that have short and inconsistent half-lives are a poor candidate for CDDS systems
• Side effects: Minimize local and systemic side effects through the use of CDDS
• Disease state and circadian rhythm: Important factor in CDDS design; should be aligned (e.g., disease onset and drug release rate; circadian rhythm)

Selected Routes of Drug Administration

• Route of administration has a vital role in drug efficacy.
• Dosage forms are designed for different routes of administration and DDS should be appropriate for the chosen route.
• Oral delivery is the preferred route, but other non-injectable routes are gaining interest (buccal, sublingual, transdermal, nasal, pulmonary).

Route of Drug Administration

• Large surface area: enhances absorption, e.g., villi in the small intestine, lung surfaces enhance drug absorption
• Low metabolic activity: reduced enzyme activity minimizes drug metabolism, e.g., nasal cavity and buccal routes have lower metabolic activity
• Contact time: the time of contact between drug and the absorbing tissue influences drug absorption rate
• Blood supply: absorption site's blood flow delivers drug to action sites
• Accessibility: Certain absorption sites such as alveolar regions require complex devices to ensure drug delivery
• Lack/variability: essential for consistent and highly-potent drug delivery; conditions such as extremes of pH and food presence might affect drug outcomes negatively. Variations such as female menstrual cycle are further considerations
• Permeability: Some tissues/membrane surfaces (e.g., skin) impede drug absorption

This quiz explores the fundamentals of drug delivery systems (DDS) and their significance in improving therapeutic efficacy and safety. It discusses innovations in DDS, including techniques for delivering novel pharmaceuticals, the need for precise dosing, and the implications for drug development costs. Ideal for students studying pharmacology and drug design.