Polymers for Sustained Release Drug Delivery: A Review on Recent Advances and Applications

Modern drug delivery technologies are replacing conventional dosage forms. Amongst these, the sustained or controlled release have become extremely popular in modern therapeutics. Oral route drug delivery has been recognised as the commonly used route of administration among the others, explored for systemic distribution of drugs through various products of varied dosage forms. Since targeted drug delivery is characterized by immediate release and repeated drug administration, which may increase the risk of dose variation, a formulation with regulated release that maintains a constant blood level is necessary ^[1]. The main objective of building sustained release drug delivery system is to achieve reproducibility and predictability to control drug release, drug concentration, and optimisation of therapeutic effects of the drug by controlling the release and reducing frequent doses. At peak concentration ratio declines and a slower, steady release, a sustained release dosage form will maintain a therapeutic concentration of medication in the blood throughout the dosing interval ^[2]. 1952 marks the first time when the concept of sustained release was introduced. ‘Spansules capsules’ were prepared by Smith Kline Beecham, that were coated with water soluble wax integrating various thickness of numerous micro pellets. These pellets revealed 12h controlled release kinetics of dextroamphetamine sulphate. Following that, advancements in medical research and technology led to a significant revolution in pharmaceuticals in 2010 with the introduction of Nano-technology based drug delivery ^[3]. This nano-technology based approach has been entitled as Advanced drug delivery system (ADDS) that provides improved efficacy and minimum side effects. Therefore, based on capability of controlling drug release rates, ADDS is classified into sustained and controlled release. These systems rely on advanced polymer technologies to control drug release kinetics through modified material properties. Therefore, polymers serve as the structural backbone in these formulations, enabling precise modulation of drug diffusion, erosion, and biodegradation rates. The use of polymers that act as matrix for the active for the active components, is in charge of the effectiveness of sustained release formulations. With the aim of increasing the therapeutic efficacy and reduce potential toxicity of drugs desirable release profiles can be attained that resemble zero-order kinetics by modifying the polymers composition ^[4]. 

1. Sustained Release Drug Delivery System ^[5]:

Pharmaceutical research has given sustained release a significant attention due to their potential to increase patient compliance, reduced adverse effects, improving therapeutic efficacy. Polymers adaptability, versatility and ability to modulate drug release profiles make them a integral part of sustained release systems. These systems intend to prolong therapeutic treatment effect by releasing the drug continuously over a long duration of time after administering the dose of drug.

1. 1.  Advantages
1. Improve patient compliance:

Reduced dosing frequency minimizes the requirement of multiple doses, moderating regimens.

2. Stable therapeutic drug levels:

Maintaining constant plasma drug concentration, avoiding peak valley fluctuations that come with conventional dosage forms. Therapeutic action of drugs can be prolonged for drugs with short half-life.

3. Enhance safety and efficacy:

Avoids dose dumping and overdose by lowering toxicity risks.

Minimizing drug accumulation during chronic use as it lowers systemic and local side effects.

4. Economic benefits:

Minimize healthcare burdens reducing the frequent administration and therapeutic outcomes simultaneously lowers treatment cost.

5. Optimized drug usage:

Enhance bioavailability with minimum dose that improves clinical efficiency. Drug delivery to specific targeted site reduces drug wastage and improves therapeutic impact.

1. 2.  Disadvantages:
1. Poorly designed delivery system releases the drug rapidly, causing toxicity leading to dose dumping. 
2. Drug release rates are impacted by changes in the pH of gastrointestinal tract.
3. Due to variable Gastrointestinal conditions achieving reliable invitro-in vivo correlation is complex.

3. Factors Affecting the Formulation Of SRDDS

1. Physicochemical properties of drug

Aqueous solubility: Drugs with high soluble risk rapid burst release whereas drugs with lower solubility have difficulty in attaining constant release.

Partition coefficient: high lipid solubility increases membrane permeability, but bioavailability may reduce due to low lipid solubility.

Molecular size: molecules with minute molecular size diffuses easily through polymeric matrices.

Stability: the drug stability must be intact in gastrointestinal fluids and during prolonged release.

2. Biological factors

Absorption window: drug absorbed only in specific GI regions are poor candidates due to variable residence times.

Permeability: low intestinal permeability limits absorption, reducing SRDDS efficacy

Half-life: drugs with short half-lives are ideal for SRDDS to extend therapeutic action

3. Pharmacokinetic and safety considerations

Therapeutic index: narrow therapeutic windows increase risks of toxicity if dose dumping occurs

Metabolism: drugs prone to extensive first pass metabolism may require alternative delivery routes.

Dose size: optimal doses range between 0.5-1.0g approximately, higher doses complicate controlled release.

4. Drug release mechanisms

Zero order kinetics: ideal for maintaining steady plasma concentrations, often achieved using matrix systems or osmotic pumps.

Polymer selection: hydrophilic/hydrophobic polymers regulate diffusion rates, impacting release duration.

5. Patient-centric factors

GI transit time: prolonged release must align with GI motility to ensure complete absorption.

Figure 1. Drug concentration profiles in plasma for zero-order controlled release, sustained release, and conventional release.

3.1. Sustained release system is classified based on the mechanisms of action and formulation strategies ^[6]:

1. Diffusion sustained system

Reservoir type: consists of a drug core encircled by a membrane that regulates then pace of drug diffusion.

Matrix type: in a polymer matrix the drug is distributed throughout, and the drug’s diffusion through the matrix regulates the release rate.

2. Dissolution sustained system

Reservoir type: this type of system is comparable to diffusion-controlled systems, except the drugs dissolution from a solid into solution controls the release rate.

Matrix type: the medication is encased in a matrix that gradually dissolves and releases the medication as it degrades.

3. Methods using ion-exchange: These methods make use of ion- exchange resins, which provide regulated release based on ionic interactions by releasing the medicine in return for ions in the GI tract.
4. Methods using osmotic pressure: These techniques guarantee a steady release rate regardless of concentration by using osmotic pressure to propel the drug’s release from a dosage form.
5. pH-independent formulation: These formulations improve dependability in various ways by releasing medications at a constant rate despite changes in the gastrointestinal tract pH.
6. Altered density formulation: Modified formulations for density, based on buoyancy and sedimentation principles, these devices alter density to regulate medication release, influencing the duration of the drug’s presence in the GI tract.

Due to increase versatility in dosage form design and patient preferences, the delivery of drug through oral route for sustained release systems has drawn a considerable attention ^[7]. The physicochemical characteristics of the medication and the kind of drug delivery, the treatment, patent health, the duration of therapy, presence of food, GI motility, and the co-administration are some of the variables affect the design of Sustained release mechanisms ^[8]. The integration of advance polymer technologies in sustained release systems marks a significant breakthrough in pharmaceutical formulation, improving patient adherence and treatment outcomes. This versatility not only improves bioavailability but also enables targeted delivery, revolutionizing treatment strategies and enhancing overall therapeutic outcomes. with potential use in personalized and innovative medication formulations, sustained release systems along with advance polymers appear to have greater potential in drug delivery ^[9].

4. Polymers Used In SRDDS:

The word ‘polymer’, which comes from the Greek word “poly” and “mer”, that means ‘many parts’, refers to macromolecules composed of repeating chemical subunits. Polymers preserve stability of encapsulated material along with transporting it to intended location. Polymers derived from both natural and synthetic sources, at right quantities, can be biocompatible and biodegradable with no potential harm. Numerous smaller molecules, referred to as monomers are polymerized to produce polymers, both natural and synthetic ^[10]. The most essential component of pharmaceutical industry today, polymers play an integral part in developing and formulating different drug delivery mechanisms. Polymer being the crucial part of pharmaceutical drug delivery, regulate the drug release form device. The responsibility of polymer is to protect drug from physiological environment and extending their release while improving their stability. Polymers need to be non-toxic, biocompatible, and have the right chemical and physical characteristics for their intended purpose.

Table 1. Development timeline of polymers

Timeline of Polymers in Pharmaceuticals

4.1. Ideal Properties of Polymers ^[11]:

• Non-toxicity and biocompatibility: these polymers are suitable for medical applications lime sutures and drug delivery as they do not negatively impact living. The ability of a substance to synchronize with biological systems without triggering an adverse immune response is known as biocompatibility. For example, polylactic acid is mostly used in medical implants because of non-toxic degradation products.
• Biodegradable: biodegradable polymers reduce their influence on the environment by gradually dissolving into non-toxic components through natural processes. This property is crucial in addressing plastic waste issues. Materials like polyglycolic acid and polylactic acid decompose into harmless substances that makes them simple for single use applications in the body.
• Good mechanical Properties: To ensure that the polymer can tolerate stress, characteristics such as tensile strength, flexibility, and durability are crucial. For example, the composition and manufacturing techniques of biodegradable polyesters results in varying range of tensile strengths. Despite the fact that many biodegradable alternatives have limitations to conventional plastics, improved mechanical properties enable them to be used in load bearing applications.
• Good barrier properties: Polymers with strong barrier property is crucial as they control drug dispersion and prevent the active components from deterioration. Polymers such as poly lactic-co-glycolic acid and hydroxypropyl methylcellulose, that delay releasing rates and guard drugs from moisture and gastrointestinal fluids, enhance drug stability.
• Simple to process: polymers are essential for sustained release systems as they enable accurate control of drug release. Polymers like polylactic-co-glycolic acid, hydroxypropyl methyl cellulose, and Eudragit are easily used to provide drug encapsulation and controlled release rates. They are ideal for the sustained release formulations due to their versatility that enables scalable production, reduces cost and ensures consistent therapeutic results.

4.2. Classification of Pharmaceutical Polymers:

1. Natural Polymers: 

Natural polymers obtained from sources such as plants, animals and microorganisms. Proteins, enzymes, polysaccharides, gummy extracts as natural polymers are becoming an integral part in formulating pharmaceutical products. Well-known natural polymers used are Chitosan, alginate, Gelatin, Gaur gum, agar. The plant-based polymers are widely used in the formulations of dosage forms matrix systems, microspheres, nanoparticles and additionally they possess properties of binders, stabiliser, gelling agents, bio-adhesive. Matrix system is the most widely accepted due to their ease of formulation. Several natural gums and mucilage are examined as polymers for sustained release systems ^[12].

1. Chitosan: Derived from chitin, it is a biodegradable and biocompatible polymer. Due to its cationic nature, chitosan enhances the stability and solubility of negatively charged drugs by forming polyelectrolyte complexes with them. Nanoparticles based on chitosan are being developed for sustained release of different therapeutic agents.
2. Hyaluronic acid:  A naturally occurring polysaccharide. It is known for its ability to target CD44 receptors, a property that allows targeted drug delivery improving localisation and efficacy of the therapeutic agents.
3. Alginate: a brown seaweed derived polysaccharide used in drug delivery as its gel forming ability and biocompatibility. Alginate beads on encapsulation provide sustained release through diffusion and degradation mechanisms ^[13].
4. Gelatin: it is a natural polymer extracted from collagen that can be modified to control drug release rates. Gelatin-based hydrogels can be developed for sustained release of protein and peptides.

2. Semi-Synthetic Polymers:

These are chemically modified natural polymers such as cellulose acetate, hydroxy propyl methyl cellulose. These polymers are utilized for developing matrix systems that improve stability and bioavailability of the drugs.

1. Hydroxypropyl Methylcellulose: It is used in sustained release formulation because of its capacity to form gels and control drug release. A zero-order release profile provided by HPMC is ideal for maintaining consistent drug levels in blood stream.
2. Carboxy methyl cellulose: This cellulose gum derivative with various functional properties such as binding stabilizing, emulsifying are used for designing matrix systems that provide sustained release of drug. Due to its hydrophilic nature, it can retain water to form a gel that can regulate the drug release rate. It is often combined with other polymers ^[15].
3. Sodium carboxy methyl cellulose: it is a derivative of carboxy methyl cellulose, that increases the viscosity of formulations contributing to sustained release of the drug. Its properties can be adjusted by varying the concentration, affecting the drug release rate.

3. Synthetic Polymers ^[16]:

Chemical synthesis is used to produce synthetic polymers. Examples poly lactic co-glycolic acid, polyethylene glycol, polycaprolactone.

1. Poly lactic co-glycolic acid (PLGA): PLGA is commonly used polymer in drug delivery. The rate of degradation of PLGA can be altered by modulating the ratio of lactic acid to glycolic acid enabling controlled release. Nanoparticles and microspheres are studied for sustained release of various drugs, such as vaccines and anticancer agents ^[17].
2. Polyethylene glycol (PEG): it is widely utilized polymer in SRDDS due to its versatility & specific applications. Its properties enable control drug release making it ideal for hydrogel and nanoparticles. For example, a study published demonstrated the use of PEGylated improved the solubility and circulation time of nanoparticles for sustained release of the nanoparticles in the bloodstream, leading to improved therapeutic efficacy and reduced adverse effects. By adjusting the molecular weight of PEG, modulation of release profiles meets specific therapeutic needs, making it valuable for modern drug delivery strategies. This versatility and effectiveness of PEG plays important role in advancing the formulations ^[18].
3. Polycaprolactone (PCL): Biodegradable polyester with a hydrophilic polymer that increase   the stability and solubility of drugs. PEGylation of therapeutic agents can prolong the circulation time in the blood stream, leading to sustained release and reduce immunogenicity. Low rate of degradation compared to PLGA. It is used in long term drug delivery applications.

4.3. MECHANISM OF DRUG RELEASE ^[19]:

Several mechanisms involved in controlling drug release using polymers

1. Diffusion: The primary mechanism where drug diffuses through the polymer matrix. The rate of drug diffusion depends on drugs solubility and polymer permeability.

Figure 2. Reservoir and matrix diffusion systems

2. Degradation: Biodegradable polymers break down over time, releasing the encapsulated drug. The degradation rate can be controlled by integrating the polymer’s chemical structure.

Figure 3. Degradation mechanism of drug release

3. Swelling: Hydrophilic polymers absorb water, leading to swelling and subsequent drug release.

Figure 4. Swelling mechanism of drug release

5. Recent Advances in Polymer Based SRDDS

Recent breakthroughs in pharmaceuticals have made it possible for researchers to create certain enzyme-sensitive polymers that release the integrated therapeutic substance specifically at targeted site. Recent advances in polymer chemistry and processing techniques have led to ingenious delivery systems of the drug that can respond to physiological conditions and target specific tissues. The selection of polymers plays a significant part in development of sustained release formulations. The choice of biodegradable or non-biodegradable, their molecular weight and composition impact drug release kinetics and bioavailability ^[20].

Various Advancements in Polymers Used In SRDDS

1. Nanotechnology Integration:

Polymeric nanoparticles, micelles, and dendrimers are developed to enhance drug bioavailability and targeting capabilities. Nanotechnology has significantly advanced the development of stimuli responsive modern drug delivery systems enabling controlled therapeutic interventions. These systems utilize nanomaterials that respond to specific internal or external stimuli, like pH changes, temperature variations, or magnetic fields, to release drugs at targeted sites enhancing efficacy and minimizing side effects ^[21].

Key integrations of nanotechnology:

1. Metal organic frameworks:

Metal organic frameworks are porous crystalline solids that consists of metal ions and organic ligands. Properties such as larger surface area, adjustable porosity and structural versatility make them ideal for drug loading and control release rates. Recent research has brought to attention MOF based sustained release drug delivery in cancer treatment, where these MOFs release drug to specific tumor location in response to stimuli ^[22].

2. Polymeric nanocarriers:

Figure 5. Nano carriers used in SRDDS

3. Carbon Nanotubes:

 Due to the unique structural and electrical properties CNTs are used as DRUG delivery nanocarriers. Functionalised CNTs can be used in cancer therapy as they pass through the cellular membrane in response to stimuli ^[24].

Figure 6. Carbon Nanotubes