Implantable Drug Delivery System

Implantable Drug Delivery System: In the year 1861, Lafarge introduced the concept of an implantable system for sustained release drug administration. In the very beginning, it was first introduced to produce solid implants containing steroid hormones implantable system for long-term delivery.  Implantable drug delivery systems are placed under the skin and designed to release drugs into the bloodstream without the repeat insertion of needles. 

“A sterile drug delivery device for subcutaneous implantation having the ability to deliver  the drugs at a controlled rate over a prolonged period, comprising a rod-shaped  polymeric inner matrix with an elongated body and two ends.”

Ideal Properties of an Implantable Drug Delivery System 

  • Environmentally stable.
  • Biocompatible.
  • Easy to sterilize.
  • Rate controlled release of the drug.
  • Improve patient compliance by reducing the frequency of drug administration over the entire period of treatment.
  • Easy to manufacture and relatively inexpensive.
  • Good mechanical strength.
  • Free from surgical procedure. 

Advantages of an Implantable Drug Delivery System 

Convenience: Implantation therapy permits patients to receive medication outside the hospital with minimal medical surveillance. 

Compliance: Compliance is increased greatly by allowing a reduction or complete elimination of patient-involved dosing.

Improved drug delivery: Using an implantable drug delivery system the drug is delivered locally or in systemic circulation with minimal interference by biological or metabolic barriers. 

Potential for controlled release: These deliver drugs by zero order-controlled release kinetics, so it can reduce the dosage frequency and increase patient compliance. 

Potential for intermittent release: Extremely programmable pumps can facilitate intermittent release in response to various factors such as; cardiac rhythm, metabolic needs,  etc. 

Flexibility: Various types of flexibilities like; materials, methods of manufactures, etc. are available in the case of implants. Controlled delivery of both hydrophilic and lipophilic drugs can be obtained from here.

Disadvantages of an Implantable Drug Delivery System 

Invasive: For the insertion of the implants, a patient has to face either a major or a minor surgical procedure. 

Termination: Non-biodegradable polymeric implants can be terminated from the body also with the help of a surgical method at the end of the treatment. 

The danger of device failure: If due to some reason, the device fails to operate properly during the treatment then again surgical steps should be taken for removal of the device from the patient’s body. 

Limited to potent drug: The size of the device is very small to reduce the patient’s discomfort, therefore only the potent drugs which are very small in amount can only be used in this system.

Adverse reaction: As a high concentration of a drug is delivered to the implantation site with the help of the device therefore there is always a chance of adverse reaction due to this local high concentration. 

Mechanism of Drug Release from Implantable Therapeutic System 

Fig.1: Classification of Drug Release from Implantable Therapeutic System

Classification of Drug Release from Implantable Therapeutic System

A. Polymer Membrane Permeation-Controlled Drug Delivery System: 

  • In this controlled drug delivery device, the drug reservoir is encapsulated within a  capsule-shaped or spherical compartment.
  • This total system is covered with a rate-controlling polymeric membrane.
  • The drug reservoir can be either solid particles or the dispersion of the solid particles in a liquid or solid dispersing medium.
  • The encapsulation of the drug reservoir system inside the polymeric membrane can be done by encapsulation,  microencapsulation, molding, extrusion,  etc.  
Norplant Subdermal Implant 
Fig.2: Norplant Subdermal Implant 

B. Polymer Matrix Diffusion-Controlled Drug Delivery System: 

  • In this implantable device, the reservoir is formed by the dispersion of the solid particles throughout a lipophilic or hydrophilic polymer matrix.
  • This dispersion can be obtained by dispersing the solid drug dosage form in the liquid or semisolid polymer matrix at room temperature followed by cross-linking of the polymer chains.
  • The drug-polymer dispersions are then molded or extruded to form drug delivery devices of various shapes.
  • It can also be prepared by dissolving the drug solid or the polymer in an organic solvent followed by conservation or solid evaporation at an elevated temperature under a  vacuum to form a microsphere.
Compudose Implant 
Fig.3: Compudose Implant 

C. Membrane-Matrix Hybrid Type Drug Delivery System: 

  • This type of drug delivery system is a hybrid form of polymer membrane permeation-controlled drug delivery system and the polymer matrix permeation controlled drug delivery system.
  • It follows the constant drug release kinetics just like the polymer membrane permeation-controlled drug delivery system.
  • Therefore, it will reduce the chances of dose dumping from the reservoir compartment.
  • Just like the matrix diffusion system,  the drug reservoir is also prepared by the homogeneous dispersion of the drug solid particles throughout a  polymer matrix.
  • But in the case of this implantable drug delivery, the total reservoir is encapsulated within a rate-controlling polymeric membrane.
  • This is a sandwich-type implantable device.
Norplant II Subdermal Implant 
Fig.4: Norplant II Subdermal Implant 

D. Micro Reservoir Partition-Controlled Drug Delivery System: 

  • In this controlled release drug delivery device, the drug reservoir is a suspension of drug crystals in an aqueous solution of water-miscible polymer and it also forms a  homogeneous dispersion.
  • Micro dispersion is obtained by the high-energy dispersion technique.
  • Different sizes and shapes of drug delivery devices can be obtained with the help of extrusion and molding.
  • According to the physicochemical properties of the drug, the device can be further coated with a layer of biocompatible polymer to modify the mechanism and the rate of drug release.
Syncromate Implant
Fig.5: Syncromate Implant

E. Osmotic Pressure Activated Drug Delivery System: 

  1. From the above-mentioned definition, it can be easily assumed that the osmotic pressure is the main source of energy in this case to activate and modulate the delivery of the drug. 
  2. Here, the drug reservoir is either a solution or a semisolid state which is contained within a semipermeable compartment with controlled water permeability. 
  3. The volume of the drug solution released is determined by the equation. 
Implantable Drug Delivery System

In this type of controlled drug delivery system, the release of the drug takes place due to osmotic pressure.

  • Drug reservoir which can be either a solid or a suspension is contained in a  semipermeable housing.
  • The release is activated through a specially formed orifice and the rate of release is modulated by controlling the osmotic gradient.
  • Thus, the release rate is dependent on water permeability of the membrane, the solubility of the osmogen, effective surface area of semi-permeable housing as well as an osmotic gradient.
  • A representative example of this type of implantable controlled release drug delivery system is the alzet osmotic pump.
Alzet Osmotic Pump 
Fig.6: Alzet Osmotic Pump 

F. Higuchi Leeper Osmotic Pumps: 

The Higuchi-Leeper pump has no water chamber, and the activation of the device occurs after the imbibition of the water from the surrounding environment. This variation allows the device to be prepared loaded with drugs and can be stored for a long before use. HiguchiLeeper pumps contain a rigid housing and a semi-permeable membrane supported on a  perforated frame; a salt chamber containing a fluid solution with an excess of solid salt is usually present in this type of pump. Upon administration/implantation, surrounding biological fluid penetrates the device through a porous and semi-permeable membrane and dissolves the MgSO4, creating osmotic pressure inside the device that pushes a movable separator toward the drug chamber to remove the drug outside the device. It is widely employed for veterinary use. This type of pump is implanted in the body of an animal for the delivery of antibiotics or growth hormones to animals.

Higuchi Leeper Osmotic Pump 
Fig.7: Higuchi Leeper Osmotic Pump 

G. Higuchi-Theeuwes Osmotic Pump: 

In this device, the rigid housing consisted of a semi-permeable membrane. This membrane is strong enough to withstand the pumping pressure developed inside the device due to the imbibition of water. The drug is loaded in the device only before its application,  which extends the advantage for storage of the device for a longer duration. The release of the drug from the device is governed by the salt used in the salt chamber and the permeability characteristics of the outer membrane.

Higuchi-Theeuwes Osmotic Pump
Fig.8: Higuchi-Theeuwes Osmotic Pump

H. Elementary Osmotic Pump (EOP): 

It is fabricated as a tablet coated with a semi-permeable membrane, usually cellulose acetate. A small orifice is drilled through the membrane coating. When this coated tablet is exposed to an aqueous environment, the osmotic pressure of the soluble drug inside the tablet draws water through the semi-permeable coating and a saturated aqueous solution of the drug is formed inside the device. The membrane is non-extensible and the increase in volume due to imbibition of water raises the hydrostatic pressure inside the tablet, eventually leading to the flow of saturated solution of active agent out of the device through a small orifice.

Elementary Osmotic Pump 
Fig.9: Elementary Osmotic Pump 

I. Push-Pull Osmotic Pump (PPOP): 

The push-pull osmotic pump is delivered both poorly water-soluble and highly water-soluble drugs at a constant rate. This system resembles a standard bilayer-coated tablet. One layer  (the upper layer) contains the drug in a formulation of a polymeric, osmotic agent, and other tablet excipients. This polymeric osmotic agent can form a suspension of the drug in situ.  When this tablet later imbibes water, the other layer contains osmotic and coloring agents,  polymer, and tablet excipients. These layers are formed and bonded together by tablet compression to form a single bilayer core. The tablet core is then coated with a semipermeable membrane. After the coating has been applied, a small hole is drilled through the membrane by a laser or mechanical drill on the drug layer side of the tablet.  When the system is placed in an aqueous environment, water is attracted into the tablet by an osmotic agent in both layers. The osmotic attraction in the drug layer pulls water into the compartment to form in situ a suspension of the drug. The osmotic agent in the nondrug layer simultaneously attracts water into that compartment, causing it to expand volumetrically, and the expansion of the non-drug layer pushes the drug suspension out of the delivery orifice.

Push-Pull Osmotic Pump 
Fig.10: Push-Pull Osmotic Pump 

J. Controlled Porosity Osmotic Pump (CPOP): 

It is an osmotic tablet wherein the delivery orifices (holes) are formed in situ through the leaching of water-soluble pore-forming agents incorporated in a semi-permeable membrane  (SPM) (e.g., urea, nicotinamide, sorbitol, etc.). The drug release rate from CPOP depends on various factors like; coating thickness, the solubility of the drug in tablet core, level of leachable pore-forming agent(s), and the osmotic pressure difference across the membrane. 

Controlled Porosity Osmotic Pump 
Fig.11: Controlled Porosity Osmotic Pump 

K. Liquid-Oral Osmotic (L-OROS) System: 

Various L-OROS systems available to provide controlled delivery of liquid drug formulations include; L-OROS hard cap, L-OROS soft cap, and a delayed liquid bolus delivery system. Each of these systems includes; a liquid drug layer, an osmotic engine or push layer,  and a semi-permeable membrane coating. When the system is in contact with the aqueous environment, water permeates across the rate-controlling membrane and activates the osmotic layer.

Liquid Oral Osmotic System 
Fig.12: Liquid Oral Osmotic System 

The delayed liquid bolus delivery system comprises three layers: a placebo delay layer,  a liquid drug layer, and an osmotic engine, all surrounded by a rate-controlling semipermeable membrane (SPM). The delivery orifice is drilled on the placebo layer end of the capsule-shaped device. When the osmotic engine expands, the placebo is released first,  delaying the release of the drug layer. Drug release can be delayed from 1 to 10 hours,  depending on the permeability of the rate-controlling membrane and the size of the placebo

L. Sandwiched Osmotic Tablet (SOT): 

The sandwiched osmotic tablet is composed of a polymeric push layer sandwiched between two drug layers with two delivery orifices. When placed in the aqueous environment, the middle push layer containing the swelling agents swells, and the drug is released from the two orifices situated on opposite sides of the tablet; thus, sandwiched osmotic tablets (SOTS) can be suitable for drugs prone to cause local irritation of the gastric mucosa.

Sandwiched Osmotic Tablet
Fig.13: Sandwiched Osmotic Tablet
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