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DRUG DELIVERY SYSTEMS

Conventional dosage forms deliver their active ingredients at rates that are highest initially and decline steadily thereafter (ie. first-order kinetics process).

Repetitive dosing with such dosage forms causes a sawtooth pattern of peaks and troughs in the concentrations of the agents in blood and tissues.

Problems With This Conventional Approach:

Hence, the development of systems designed to control the rate of drug release into the body.

Such systems would be expected to be most useful for:-

(a) Drugs used in a chronic or asymptomatic disease where compliance may be poor.

(b) Drugs with a narrow therapeutic margin.

(c) Drugs with short half-lives necessitating frequent dosing with conventional dosage forms.

Drug delivery systems can be divided into six groups:-

1. Physically - controlled.
2. Chemically - modified.
3. Osmotically - controlled.
4. Diffusion - controlled.
5. Mechanically - controlled.
6. Targeted drug delivery.

1. Physically - Controlled Drug Delivery:

Discussed previously in other lectures (modifying bioavailability by changing the physical properties of the drug or its vehicle).

Eg:

(a) Selection of dosage form:

Solution > suspension > capsule > tablet > coated tablet.

(b) Particle size control:

Eg: Griseofulvin
Nitrofurantoin

(c) Viscosity of vehicle with im injections:

Eg: Fluphenazine decanoate.

 

2. Chemically - Modified Drug Delivery:

Eg:

(a) “Pro-drugs”:

Sulindac.

(b) Use of alternate chemical forms:

Eg: 

(i) Use of salt forms:

Sodium phenobarbitone.

(ii) Use of esters:

- Erythromycin ethylsuccinate - po.
- Fluphenazine decanoate - im.

 

3. Osmotically - Controlled Drug Delivery:

Osmosis is the energy source for drug delivery.

OROS system (Alza Corporation).

Drug solution flows from the system at a constant, zero-order rate as the tablet progresses through the GIT until all of the solid drug in the core is dissolved or until the unit is eliminated.

In vivo and in vitro testing have shown that the delivery rate is independent of GI motility, pH and food in the GIT.

Release of drug is controlled by the solubility of the drug in gastric fluid, the osmotic pressure of the core formulation, and the dimensions and permeability of the membrane.

Eg: Use salt form - rate of delivery.

Eg: OSMOSSIN (MSD) Indomethacin:

- Contains 85mg Indomethacin.
- Delivers 75mg/hour Indomethacin.

Clinical trials:

(a) Once daily OSMOSSIN equally effective to 25mg capsule tds.

(b) Small reduction in GI side effects.

(c) Fewer CNS side effects.

However, problems have arisen with the product. ~ 20 reported deaths associated with the use of OSMOSSIN.

Other possible OROS system products soon to be available include Acetazolamide, Hydralazine and Metopiolol.

NB: Biopharmaceutic problems still remain with the use of the OROS system (because of oral route of administration):-

Eg:

(a) Generally require at least once-daily dosing because of GI transit time.

(b) Still incur losses before drug reaches systemic circulation:-

- Passage through GI membranes.
- “First-pass” effects.

Alternative - rectal administration:

- Avoids “first-pass” effect.
- Can use in unconscious, convulsing or vomiting patients.

Eg: OSMET rectal drug delivery system.

Results with Theophylline:

- Constant steady-state plasma levels.

- Defaecation and re-insertion of the system caused no noticeable disturbance in plasma levels.

4. Diffusion - Controlled Drug Delivery:

Drug diffuses through a membrane at a constant rate. The rate of delivery may be adjusted by varying the nature of the membrane and the concentration of the solution in contact with the membrane.

(a) Ophthalmic:

OCUSERT - pilocarpine.

Thin elliptical units comprising a pilocarpine core sandwiched between two flexible ethlene vinyl acetate membranes. Pilocarpine release rate of either 20mg/hr or 40mg/hr for one week.

 

(b) Intra-uterine:

PROGESTASERT - delivers 65mg progesterone per day into the uterus for one year (contraception).

 

(c) Transdermal:

Basic requirements:

- Drug must readily penetrate epidermis (ie.. high partition coefficient).

- Active in small doses (for practical purposes, drug delivery is subject to a limit of ~ 10mg/day).

- Non-irritant to skin.

Eg:

(i) Scopolamine (Hyoscine) - (SCOP):

For prevention of motion sickness - releases Hyoscine over a 72 hour period. Avoids sharp dose-related peaks in plasma levels that are associated with undesirable CNS and anti-cholinergic effects.

(ii) Nitroglycerin - (NITRADISC, TRANSDERM-NITRO):

Prophylaxis of angina over 24 hour period. Conventional Nitroglycerin ointments or Sorbide nitrate tablets require multiple daily doses.

Also, the ointments are messy and difficult to apply uniformly dosage can be variable.

(iii) Clonidine (CATAPRES):

Once weekly dosage regimen (8.8mg/hr) for hypertension.

Aims to reduce the dose-dependent side effects of dry mouth, drowsiness, dizziness and sexual dysfunction. Also, avoidance of rebound hypertensive crisis with missed oral doses.

(iv) Oestradiol (ESTRADERM):

Twice weekly dosage regimen (either 0.05mg or 0.10mg/day) for menopausal symptoms.

Avoids the large “first-pass” effect with Oestradiol and reduces the risk of systemic side effects (eg. hypertension, thromboembolism).

TRANSDERMAL DRUG DELIVERY SYSTEMS

Advantages	Disadvantages
- Avoids chemically hostile GI environment.	- Drugs that require high blood levels (low potency) cannot be administered.
- Avoids GI adverse effects.	- Adhesive may not adhere well to all types of skin.
- Avoids first-pass effect.	- Drug or formulation may cause skin irritation or allergy.
- Overcomes GI contraindications to oral therapy (eg. bowel obstruction).	- May be uncomfortable to wear.
- Increases patient compliance.	- System may not be economical.
- Allows effective use of drugs with short half-lives (eg. Nitroglycerin).
- Provides controlled plasma levels.
- Interrupts drug input in toxicity.

5. Mechanically - Controlled Drug Delivery:

Eg:

(i) Continuous intravenous infusion:

Infusion pump systems (eg. IVAC) providing constant and continuous drug input:-

- Morphine in terminal cancer.

- ICU: Morphine, Midazolam, Inotropes (eg. Dopamine, Dobutamine), fluid and electrolytes.

- Subcutaneously implanted intravenous insulin pump - risks of thrombosis, infection.

(ii) Epidural infusion:

- Bupivacaine (MARCAIN) post surgery or in ICU.

- Morphine in terminal cancer.

(iii) Subcutaneous infusion:

- Portable insulin infusion pump systems: Basal delivery of soluble insulin (~ 1 unit/hr) with manually set boluses prior to meals.

NB: Patient education and motivation are crucial.

(iv) Elastomers:

Natural or synthetic polymer membranes with elastic qualities, that are capable of storing mechanical energy..

The elastomeric balloon deflates, exerting a nearly constant pressure on the reservoir solution. This enables the unit to provide constant administration of solution for up to 14 days.

Eg: AR/MED portable intravenous infusor units.

Perspectives on Rate - Controlled Drug Delivery Systems:

The application of rate - controlled drug delivery systems is now a routine facet of hospital, in particular intensive care, medicine, eg. administration of Dopamine, Morphine and Midazolam, using IVAC intravenous infusion pumps.

The next step is the application of this technology to non-hospitalised patients. The impact of this technology will be most profound in the following circumstances:-

(a) In chronic therapy with drugs that cause troublesome side effects (narrow therapeutic margins) and/or require multiple daily doses.

(b) Among paediatric, geriatric or seriously ill patients who are incapable of self-administering medication.

(c) In developing countries, where drug delivery systems that require minimal medical supervision and provide prolonged therapy from one dose or application would be particularly advantageous, eg. contraception, treatment/prevention of tropical infections.

Overall, such technology will:-

(a) Enhance the safety and efficacy of drug therapy.

(b) Improve patient compliance.

(c) Permit the utilisation in the general community of drugs previously considered too difficult to administer outside the hospital environment (eg. Morphine infusions).

 

6. Targeted Drug Delivery Systems:

All of the controlled drug delivery systems described so far have one notable shortcoming: They do not affect drug distribution, ie. while they ensure delivery of drug to the body within a desired time frame, they do not restrict delivery to specific location(s) within the body.

Drug targeting is the delivery of a drug to a specific site in the body where desirable effects can be achieved without exposing other sites to possible drug toxicity.

One of the main reasons for the relative lack of success in the development of drug targeting has been the difficulties in producing reliable, stable and effective biological carrier - drug complexes.

Approaches to drug targeting:-

(a) Liposomes:

Hydrated liquid crystals formed when phospholipids (eg. Lecithin) are allowed to swell in aqueous media.

When suitably dispersed they consist of a series of concentric alternating layers of lipid and aqueous compartments within which water - or lipid - soluble drugs can be entrapped.

Since liposomes are only taken up from the blood stream by certain tissues (eg. liver, spleen, cancer cells), they can provide a means for selective delivery of drugs to tissues.

Eg: 

- Chemotherapy: Adriamycin liposomes ( cardiac toxicity).

- Radio-opaque dyes for CAT scanning of liver and spleen.

- Acetylcysteine liposome for paracetamol toxicity.

 

(b) DNA binding:

Eg: DNA-bound adriamycin:-

- Increased uptake of the DNA - drug complex by tumour cells.

- Reduced toxicity of bound drug.

 

(c) Magnetised targets:

Drug and magnetic material (eg. Ferrous oxide) are incorporated into microspheres which can be introduced into the arterial system by catheter and localised at specific sites by external high intensity magnetic fields directed at target sites.

Eg: Adriamycin complex with Albumin and Ferrous oxide matrix:-

- Still investigational.

- Difficulties generating magnetic targets within the body.

 

(d) Monoclonal antibodies:

Antibodies with single specificity, will bind to only one unique target site on an antigen.

Produced immunologically in mice, isolated and screened, and then grown in large quantities in cell culture media or the peritoneum of mice.

Uses of monoclonal antibodies:

(i) Diagnosis - (rapid, accurate):

- Pregnancy:

Antibodies specific for human chronic gonadotrophin (HCG).

Also an assay to detect onset of ovulation.

- Infections:

Eg: AIDS

Monoclonal antibody based assay for the detection of antibodies in the serum of patients who may have been exposed to the human immunodeficiency virus (HIV).

Others: 

- Chlamydia
- Legionnaires disease
- Herpes
- Hepatitis non-A, non-B.

- Cancer:

Patients with specific types of tumours shed into their blood stream different antigens characteristic of the tumour. Early detection of these antigens could lead to effective treatment before the cancer becomes widespread.

Eg: 

Ovarian cancer
GI cancers (colorectal, liver, pancreas, stomach).

(ii) Drug assays:

Eg: 

Digoxin
Theophylline
Phenobarbitone

Very specific and highly sensitive.

(iii) Tissue imaging:

Eg: Cardiac imaging - antibodies specific for myosin (which can be readily detected after cardiac injury and cellular death) determination of infarct size post - AMI.

(iv) Cancer therapy:

- Monoclonal antibodies alone:

Eg: Leukaemia, Lymphoma.

Problems:-

- Antibody response to foreign mouse immunoglobulins after several treatments.

- Antigenic modulation occurs - antigen disappears temporarily from tumour cell surface.

- Difficult to find truly specific tumour antigens.

- Monoclonal antibodies combined with antineoplastic drugs (drug delivery):

Eg: 

Methotrexate conjugate for lung cancer.
Vinblastine conjugate for adenocarcinoma.

(v) Drug toxicity:

Eg: Digoxin.

Antibodies bind to drug and complex is removed from the body.

(vi) Miscellaneous:

Eg: Contraception.

Monoclonal antibody to HCG.

? Future potential:

By 1995, a $10 billion monoclonal antibody market is predicted.

Conclusions - the future in drug delivery systems:

- Technology is continually improving.

- Systems being developed at ever-increasing rate.

- Smaller quantities of drugs, better directed to target organ(s).

- Patient education and counselling of paramount importance.

Some advantages of new drug delivery systems:

- Increased patient compliance through easier, more accurate, and less frequent dosing.

- Increased drug safety through lower dosages, decreased exposure to drug, and decreased distribution of drug to non-target tissues.

- Decreased inter and intra-patient variability in systemic drug concentrations.

- Absorption that is more consistent with the site and mechanism of action.

- Reduction in plasma levels of potentially toxic metabolites.

- Elimination of problems associated with the GIT.

- Delivery of drug through physiological barriers such as the skin and blood-brain barrier.

- Ability to deliver new biotechnology derived drugs.

Controlled Release Systems Benefits:

However, they do not obviate another fundamental limitation of traditional drug therapy, ie. inter-patient and intra-patient variations in dosage requirements.

Eg: ICU patients - abrupt physiological changes can result in swiftly changing dosage requirements of drugs, ie. patients do not remain static - they are dynamically changing.

Hence, the development of SAFCAD’s (Systems for Automated Feedback Controlled Administration of Drugs). These systems automatically administer drugs on the basis of assessment of the patient’s requirement for medication.

Although it is often possible to administer drugs under feedback control, the costs involved are justifiable only when there is good indication that control will result in a significant therapeutic improvement. Feedback control is particularly valuable for:-

- Potent drugs with a narrow therapeutic margin and a large variability of response.

- Drugs used to treat serious illness that have short durations of action - can readily alter blood levels and effect.

- Intensive care/surgery - patient’s physiological parameters and drug dosage requirements are continuously changing.

Principles of SAFCAD Operation:

Akin to thermostatically controlled heaters. Eg. in simplest form, we have a system where drug is infused at a preset rate until the patient’s measured condition is in the desired range and then the infusion is temporarily stopped. When the patient’s condition enters or approaches the undesirable region (ie. crosses a predetermined threshold), the infusion is recommenced.

The major obstacle to SAFCAD development has often been, and will continue to be, the availability of a reliable measure of drug effect. Pharmacological response is generally a more suitable measurement variable for a SAFCAD than is drug concentration (chemical analyses in physiological fluids are usually difficult and time-consuming).

Clinical Applications of SAFCAD’s:

SAFCAD’s are potentially applicable to many drugs for which individualised control is desirable. Certain areas of drug use provide the best opportunity for the development of rational and valuable SAFCAD’s:-

- Surgical agents, eg. Anaesthetics, Neuromuscular blockers, Hypotensives.

- Intensive care/emergency therapy, et. Inotropes, Hypotensives, Morphine infusion, fluids and electrolytes, anti-arrhythmics.

- Physiological supplement and replacement therapy, eg. insulin.

Examples:

1. Insulin delivery:

“Biostator”:

- Glucose analyser (Glucose oxidase).

- 2 microprocessor based digital computers.

- 2 pumping systems (one for analyser and one for infusion system).

Has warning alarms if pumps fail or if glucose level exceeds a chosen limit.

Especially useful for short term strict control of blood glucose levels, eg. surgery, pregnancy, diabetic coma.

 

2. Anaesthesia:

Eg: Thiopentone, Fentanyl.

Use of EEG activity level to control drug delivery.

The use of SAFCAD’s will become the preferred practice in surgery and intensive care during the next two or three decades.

The development of wearable SAFCAD’s will revive interest in many drugs previously discarded in research stages because administration regimes were impractical (eg. very short duration of action or difficulty of control).

The SAFCAD technology has already produced significant gains in intensive care/surgery and diabetes control, and will extend into many other areas in the next decade.

Non-automated Feedback Control:

Eg: Patient - controlled analgesia for post operative pain:

Device with the ability to administer a pre-determined amount of opiate to an intravenous line or an indwelling SC or im cannula. The timing of drug administration is controlled by the patient who pushes a button to activate the apparatus.

Drug administration is followed by a “lock out” period when the patient cannot obtain another bolus of drug.

Advantages:

- Provides flexibility for different patients’ analgesic requirements.

- Superior pain relief.

- Lower potential for over-dosage.

Disadvantages:

- Cost of apparatus.

- Some patients are unable to master the technique.