An Overview on Implantable Drug Delivery System

Drug delivery systems that can sustain therapeutic medication doses that are pharmacologically efficacious for long time spans while also permitting "dosing-on-demand" would be immensely useful in modern medicine. Physicians can choose from a variety of precision delivery options, such as local or systemic circulation, while still ensuring appropriate dose over the duration of treatment with implantable drug delivery systems. These systems have several advantages, including focused local medication delivery at a steady and predetermined pace, which reduces the amount of medication required and the associated negative effects while boosting the efficacy of treatment. These systems are especially useful for conditions including Management of cardiovascular disease, TB, diabetes, cancer, and chronic pain, to mention a few, that require longterm medication or face issues with patient compliance. The first section of this chapter provides an overview of different implantable drug delivery devices, ranging from biomaterial-based to electromechanical. Techniques for optimizing medication delivery are also explored, including approaches to alter drug release patterns and the release kinetics process. After that, prospective therapeutic applications and biocompatibility issues will be briefly discussed. These systems' performance and related applications differ. The performance, functioning principle, fabrication procedures, and dimensional constraints of each technology are highlighted. We look at the current research on implanted drug delivery systems, with an emphasis on application and chip performance, as well as a comparison of passive and active delivery systems. Finally, this article sums up with an overview of implantable drug delivery systems' future prospects, particularly in terms of precision and customised medicine. Review Article Fulzele et al.; JPRI, 34(25A): 1-13, 2022; Article no.JPRI.83955 2


INTRODUCTION OF IMPLANTABLE DRUG DELIVERY SYSTEM
Implants are medical devices that are put inside or on the surface of the body, usually under the skin at a discreet but handy location. Implants help organs and tissues by delivering medication, monitoring physiological functioning, and providing support. Insulin, hormones, chemotherapeutics, antibiotics, analgesics, heparin, and other drugs and fluids are some of the drugs and fluids that can be delivered through implants. Implants are small sterile solid masses created by compression, moulding, or extrusion from highly pure medication. Implants are sterile drug delivery devices for subcutaneous implantation that can deliver the medication over a lengthy period of time at a controlled rate.
Drug absorption is a topic that is gaining popularity in the pharmaceutical sciences. The implantation of solid medicament pellets technology is especially important for cancer research in livestock and poultry industries where toxins or possible carcinogens are theoretical investigations involving solid drug absorption, endocrinological study, and studies related to drug metabolism and destiny, as well as numerous other areas where extended "continuous infusion" of the drug is required [1].
Pharmaceuticals have traditionally been made up of simple, fast-acting chemical components that are administered orally or as injectables. However, over the last three decades, formulations that manage the pace and duration of drug administration and target specific areas of the body for treatment have become more widespread and complicated.
Drugs can be supplied via a variety of methods and dose forms. Maintaining a consistent in vivo therapeutic concentration for an extended period of time, on the other hand, has been difficult2. Peaks and troughs in drug concentration are common when the medicine is supplied either intermittently via intravenous method or orally. A high drug concentration can be hazardous, whereas a low drug concentration can be subtherapeutic.
Continuous intravenous infusion is the most effective way to eliminate peaks and troughs during medication administration. This, however, necessitates continual monitoring and can be done by healthcare specialists [2].
To address this issue, a number of pharmaceutical delivery technologies have been explored and developed, including oral controlled release dose forms, transdermal, injectable, and implanted drug delivery systems. It is well understood that dosage form design can influence pharmacological effects. As dosage form design advances to govern the rate of drug release from its delivery system, a new, more farreaching, and positive portrayal of this concept emerges, which may contribute to the medicine's therapeutic effectiveness.
Implantable Drug Delivery Systems is one method of giving medications that are more sitespecific and require fewer dosages less frequently (IDDS).
According to USP XX [3], (The United States Pharmacopoeia, XX,1980) the implants were defined as "The pellets consisted of pure drug with no added excipients and were defined as small, rod-shaped or ovoid-shaped, sterile tablets consisting of highly purified drug usually compressed without excipients, intended for subcutaneous implantation in body tissue". The most basic implantable device in use today is delivered subcutaneously and relies exclusively on the extremely slow disintegration of a highly compressed substance to offer a very long time of drug release.
With rapid advancements in implantation therapy and excipients for controlling the release pattern, the USP XXII has redefined the implants as "Small, rod-shaped or ovoid-shaped, sterile tablets or pellets consisting of highly purified drugs compressed with recognized excipients and can be implanted in body at sites other than subcutaneous" [4]. Table 1 gives information about the advantages and disadvantages of implantable drug delivery systems.

Desirable Properties of Implantable Drug Delivery System [8]
Various ideal properties of implantable drug delivery system are given in the given below: 3) There is a possibility of intermittent release and local administration.   ICRDDSs are classified into two types. The first main class consists of polymeric ICRDDSs, to control drug release into biological systems, different polymers and polymer membranes are used. The mechanical pump-type ICRDDSs, which control drug release by an infusion pumplike action, is the second major kind.

Polymeric ICRDDS
There are numerous polymeric systems10 available for regulating medication release in a variety of drug delivery methods based on their controlled release mechanisms, as shown below:

Diffusion controlled systems
Reservoir System: A drug core wrapped in a polymer membrane that regulates the rate at which the drug is released into the biological environment11. Because diffusion through the polymer membrane is the rate-limiting phase in these systems, it is an important element of these systems in 3rd Fig.

a) Biodegradable polymeric fibre system
Biodegradable hollow polymer fibres (with an outside diameter of 700 -800 microns and an internal diameter of 445 -600 microns) were utilised to regulate hormone release, addressing the restrictions associated with reservoir type systems' non-biodegradability (Fig. 4).

b) Matrix Systems
The active medication is uniformly dispersed throughout a solid non-bio erodible polymer in this system. Diffusion of drugs via the polymer matrix, like in reservoir systems, is the ratelimiting step (  The medicine is dispersed in a polymer that is progressively biologically degraded at a predetermined rate in this system. The medication is equally spread throughout the polymer, as in matrix systems, and is synthesized in essentially the same way. In contrast to matrix systems, which rely on solution-diffusion mechanisms for regulated release, bioerodible systems release at the rate of polymer bioerosion. It should be noted, however, that some drug diffusion from the polymer matrix does occur in practice. The bioerodible polymer is eventually absorbed by the body, which is a basic advantage of bioerodible systems. This decreases the need for surgical removal, resulting in patients having a more favorable attitude toward therapy.

Magnetically controlled systems
Throughout the system, the drug, and small magnetic beads are placed uniformly within a polymer. When exposed to aqueous fluids, the drug is released via diffusion-controlled matrix systems. When exposed to an oscillating external magnetic field, however, the medication is released at a much faster pace. This is most likely due to polymer compression caused by the scattered magnets' movement [11] (Fig. 8).

2.1Mechanical IDDSS
The mechanical IDDSs, which release medicine via mechanical pump mechanisms, is the second most common form of IDDS. The following section discusses some of the clinically investigated mechanical IDDSs.

Infusion pumps
The Infusaid infusion pump (Infusaid Corp., Sharon MA) was one of the earliest mechanical controlled release drug delivery systems to be developed and commercially sold [12].

Peristaltic pumps
Peristaltic pumps are predominantly rotating solenoid-driven pumps [13]. The pump, electronics, and batteries are housed in laserwelded titanium chambers. For improved biocompatibility, the chambers must be coated with silicone polymers.

Swelling control systems
The medication is dissolved or disseminated within a polymer matrix in these prepared systems and is unable to diffuse through that matrix. The medication enclosed in that area of the polymer is then ingested at a controlled rate into the matrix, causing it to swell and release the drug encased in that section of the polymer." Thus, the rate of diffusion of biological fluid into the polymer determines the release rate ( Fig. 9). Several dosage forms have been devised that control the flow of medication from a reservoir using an osmotic pressure differential. (Fig.10).

Controlled release micropumps
It utilises diffusion over a rate-controlling membrane to provide accurate baseline delivery, while a fast-oscillating piston working on a compressible disc of foam boosts supply. The concentration differential between the drug reservoir and the delivery site is sufficient to encourage drug diffusion to the delivery site in the absence of an external power source; this is known as basal delivery. By compressing the foam disc with a coated mild steel piston on a regular basis, increased supply is provided without the usage of valves. When a current is given to the solenoid coil, the driving piston becomes contained within the solenoid and the foam disc compresses.

DRUG RELEASE FROM IMPLANTABLE DRUG DELIVERY SYSTEM [14,15]
Osmotic pumping and diffusion are basically very effective methods for delivering pharmaceuticals in a sequential manner, where the drug dosage released is proportional to the square root of release duration. Swelling control and solvent penetration into the drugdevice matrix are often much slower than drug diffusion, leading to a reduced release rate. Drug solubility and diffusion coefficient in the polymer, drug load, and polymer are in vivo degradation rate all influence drug release kinetics in systems regulated by osmotic pressure, swelling, and passive diffusion.

Reservoir systems
Drug is released at a constant rate, does not depend on concentration gradient. The ratecontrolling polymer membrane's thickness and permeability limit this, and zero-order release kinetics can be obtained.

Matrix systems
Diffusion lengths, as well as the degree of swelling, regulated solute transport, which is directly driven by the concentration gradient via Fickian diffusion.
Non-erodible, diffusion-controlled drug delivery systems are most effective for medicines having a molecular weight of 1000 Dalton or less.

Drug release from Biodegradable Polymeric Matrices
Medication release from biodegradable polymeric systems is governed by diffusion, degradation, or a combination of the two. When a drug's diffusion rate is less than a polymer carrier's degradation or erosion rate, a degradation regulated mechanism occurs. The medicine is released at the same time that the polymer degrades. Based on the degradation-controlled mechanism, surface degrading and bulk degrading techniques can be employed to control drug release.

Surface degradation
The surface-to-volume ratio as well as the shape of implants affects drug release, and deterioration is limited to the device's outer surface.

Bulk degradation
In a bulk deteriorating polymer, the degradation is uniform across the material. IDDS [15,16,17,18,19]  It's employed in the production of implants that contain heat or solvent-sensitive components like proteins or peptides. It has a more rapid release profile than other manufacturing procedures. Additional treatments, such as covering the implant, may be required to extend drug release. The irregular surface of a compressed implant, which has many pores and channels, might cause irregular release.

1) Solvent Casting:
-After dissolving the polymer in a suitable solvent, it is cast into a mould and then the solvent is evaporated. Films or laminar implants are frequently the product of this approach. This approach has the problem of requiring significant volumes of organic solvent, which might affect drug stability and toxicity, as well as raise environmental concerns.

2) Hot Melt Extrusion: -A die process
involves melting, mixing, and forcing a polymer through a small aperture. Thermoplastic polymers, utilized, must be aliphatic polyesters like PLA, PGA, and PLGA. It has the advantage of not requiring any solvents, but it can lead to the degradation of thermolabile drugs. Melt extrusion is used to make products like Zoladex®, Depot Profact®, and Implanon®. Extrusion is a continuous operation that allows for high throughput.

3) Injection Moulding: -Injection moulding can
be used to make implants out of thermoplastic polymers like PLGA or PLA. The polymers were heated before being put into a mould and allowed to harden. The polymers' molecular weights have decreased as a result of the high heat used. Implants made by extrusion degraded faster than those made by injection moulding.

4) 3-Dimensional (3D) Printing:
Dental implants, prosthetics, and orthopedic implants are all made with it. It's a low-cost, repeatable, and extremely customizable approach. 3D printing was utilized to create the biodegradable implant structure and then be filled along with the drug. The biodegradable implant structure was created via 3D printing, and the drug would be filled into it. Drug release would be controlled by the implant structure's disintegration or a rate-controlling membrane covering orifices in the implant.

TECHNIQUES OF IMPLANTING
Subcutaneous tissue, a layer of areolar tissue lies right beneath the skin which consists of a high-fat content but a weak nerve network and hemoperfusion. Due to easy access to implantation, sluggish drug absorption, and low drug reactivity to the insertion of foreign materials, the subcutaneous tissue is a perfect place for implantation as well as extended drug administration [15].
Depending on their shape, whether they are microspherical beads, pellets or capsules, or miniatured devices, implantable drug delivery is implanted in vivo using a variety of procedures. Microspherical beads with a particle size of 600 microns are suspended in an inert liquid vehicle and injected under the skin with 16 gauge or larger needles near the targeted area. Microsphere does not require a local anesthetic in most circumstances, also the method is very simple.
Pellet or capsules are delivered subcutaneously via a tiny incision in the skin. The skin near the targeted location of the implant is coated using iodine or another suitable antiseptic solution before implantation, and the area is anesthetized with a local anesthetic. After that, a transverse operative incision of not more than 1.5 cm is made. Then a pellet or capsule is inserted beneath the skin and pushed away from the wound. After that, the incision is stitched and coated with iodine or similar collodion.
Mechanical or pump type IDDSs are implanted under local or general anesthetic depending on their size. They are usually little more than 5 cm in diameter [6].

STERILIZATION TECHNIQUES AND ASEPTIC PROCESS FOR BIODEGRADABLE DRUG DELIVERY SYSTEMS
Sterilization is the method of removing or destroying all germs from an object or preparation, as well as ensuring that it is free of contagious dangers [21]. The aseptic process is a method of preventing bacteria from entering the production process. Before being used to deliver pharmaceuticals into the body, injectables and implanted drug delivery systems must be infection-free.
The two main ways for ensuring the sterility of drug delivery systems are terminal sterilization and aseptic processing. Drug delivery systems made using biodegradable polymers cannot be sterilized by steam sterilization because they are hydrolytically unstable in the presence of moisture and heat. E.g., at least one material property of poly (L-lactide) was changed by 7 distinct steam sterilization techniques [22]. 60-Co g-irradiation and ethylene oxide gas exposure are two typical methods for terminal sterilization.
If the biodegradable polymer is soluble in organic solvents required in manufacturing drug delivery systems or devices, the polymer solution can be sterilized using the filtration procedure in a clean environment. If filtration and terminal sterilization are not possible, aseptic processing is the last option [9].

IN VITRO RELEASE METHOD FOR IMPLANTS
As such, there is no official method to carry out the in-vitro release test for implants and implantable drug delivery systems. Below are some of the methods reported in various research journals to carry out the in vitro release test by different investigators.

Rotating Flask Technique [23,24,25]
A number of researchers have used this strategy. In this method, the keep the implant in a screwcapped flask containing a buffer with a physiological pH and ionic strength. This is then put in a 37°C water bath with a low-speed oscillator to create gentle agitation. Samples are taken from the flask on a regular basis, and the buffer is replaced. By examining the aliquots, the overall quantity of the drug can be determined. One of the key drawbacks of this method is that it requires frequent replenishment of the whole medium in order to sustain sink conditions for poorly soluble medicines. Another issue is that considerable drug activity might be lost before sampling with chemically unstable medicines. Incorporating surfactants and alcohol into the dissolving media to boost the solubility of insoluble medicines and decrease the duration of drug release in vitro are examples of modifications to this approach.

Flow-through cell [26]
This method offers a substitute to the shakingflask method thus avoiding the drawbacks listed above. The implant is put in a flow-through cell that is kept at 37 degrees Celsius in this system. The dissolution medium is slightly diffused through the flow cell, with the perfusate being collected by a fraction collector for subsequent analysis or passing through online detectors for drug detection in real-time. Hollenback has successfully used the aforesaid approach to determine the release rate of 1,3-bis(2chlorethyl)-1-nitrosourea (BCNU), a water unstable medication, from polyanhydride implants.
The detailed release profile characterization and the possibility for total release explore automation are further benefits.

Vial method [27,28,29,30]
Several researchers have employed this strategy as well. In vitro, drug release investigations are carried out in screw-capped glass vials with a capacity of 10 or 14 ml. The implants are put in vials and submerged in phosphate buffer containing an antibacterial agent and, if necessary, surfactant. Samples are incubated at 37°C without agitation for a set amount of time and then agitated for 5 minutes at sampling time. At predefined time intervals, 8.0 or 10.0 ml of the release medium is withdrawn and replaced with a fresh buffer. Using the proper analytical process, the amount of drug liberated from the removed medium is determined.

Intrinsic dissolution studies [31]
Intrinsic dissolution measurement is a useful method for determining the functioning and excipients and bulk pharmaceutical substances are characterized. Under a constant surface area situation, the intrinsic dissolution rate has been termed as the rate at which a pure pharmaceutical constituent dissolves. The bioavailability and dissolution rate of a pharmaceutical ingredient is concluded by its solid-state properties, such as crystallinity, polymorphism, amorphism, solvation, hydration, particle size, and particle surface area. The intrinsic disintegration rate is influenced by these solid-state characteristics. Hydrodynamics (e.g., test apparatus, disc rotation speed, or fluid flow) and test conditions have an influence on the dissolution rate (e.g., temperature, fluid viscosity, pH, and buffer strength in the case of ionizable compounds). Bringing in contact a material's surface area to an acceptable dissolving liquid while keeping a constant temperature, stirring speed, and pH can be used to determine its intrinsic dissolution rate. The intrinsic dissolution rate per square meter is commonly expressed in milligrams per minute.

Apparatus
A die and punch made of hardened steel are standard components of the apparatus. 3 threaded holes in the die's base allow for the attachment of a polished steel surface plate, which offers a mirror-smooth platform for compressed pellets. A known quantity of the material whose intrinsic dissolution rate is to be evaluated is put into a die cavity of 0.1cm to 1.0cm in diameter. The punch is then introduced into the die cavity, and the material is weighed and crushed using a tabletop tablet press. A compressed pellet is molded in the cavity, with a single face of a specific area revealed on the die's lowermost side. The upper surface of the die has a threaded shoulder that permits it to be connected to the holder. The holder is then connected to a laboratory stirring device, and the whole die is submerged in the dissolving fluid while the stirring device rotates.

CONCLUSION
The advancement of new medications is both costly and inefficient. It has been attempting to enhance the safety-efficacy ratio of traditional pharmaceuticals using diverse tactics such as drug individualization, dosage titration, and therapeutic drug monitorin]. Drug distribution at a specific degree, progressive delivery, and targeted delivery are other ways that have been vigorously researched. IDDSs have achieved some clinical and commercial achievements as a technique of improving pharmaceutical treatment. It is, nonetheless, critical for improving performance characteristics such as enduring biocompatibility and drug release kinetics. However, as seen above, a number of commercial approaches are capable of achieving near-ideal zero-order release. A review of longterm in vivo kinetic characteristics for IDDSs is a feasible, profitable, and clinically suitable alternative method of continuous drug administration for chronically ill patients.

DISCLAIMER
The products used for this research are commonly and predominantly used products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by the personal efforts of the authors.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.