Applications of Polymers in Drug Delivery 

Polymer is a macromolecule, they have complex structure and  different properties. Polymer have wider application in either conventional and controlled drug delivery stystem. Polymer plays a major role in drug release by various mechanism and successful drug delivery. Polymer have wider role in design of drug delivery system. Polymer are having different functions to their application of route. In below we discuss about application of polymer in drug delivery.

Tablets

Tablets are the most commonly used dosage form for pharmaceutical preparations meant to be taken orally. Release of drug from the tablet can be controlled by altering the design and content of the formulations. In tablet the polymer are used as a Disintegrants and Binder. E.g. Starch, cellulose, Alginates, polyvinylpyrrolidine (PVP), sodium carboxy methyl cellulose (SCMC) etc are used as disintegrants. Polymers used as binders are Glucose, Starch, Hydroxyl propyl methyl cellulose (HPMC), Gelatin, Alginic acid, polyvinylpyrrolidine, Sucrose, Ethyl cellulose (EC). Polymers are also used to mask the unpleasant taste of the drug and also for enteric coating of tablets e.g. Shellac and zein. MCC enhances compressibility of tablet. ^[4]

Capsules

 Capsule are generally composed of gelatin. The composition of gelatin get varied so gelatin re of two types that is hard gelatin and soft gelatin. Fillers such as MCC and starches are used to fill up the volume in capsule. To overcome problem of aggregation various polymers such as starch and sodium starch glycolate are mixed with capsule container.^[8-10]

Polymers in Parenteral

In Parenteral the various polymer like Methacrylic acid act as an Interferon inductor which induce to the interferon in cancer like disease. Methacrylic acid alkyl amide is act as plasma expander that increase the plasma level in body when admixture of drug with polymer present in body. Some Vaccines are transpired by using polymer because that disintegrate in GIT tract, example Methyl methacrylate.^[4]

Polymers in Disperse systems

Various synthetic and natural hydrophilic polymers are extensively used to enhance the physical stability of pharmaceutical disperse systems (e.g: emulsion, suspension, etc). Examples of these include alginates, acacia, carrageenan and xanthan gum, whereas a wide range of synthetic polymers has also been used for this purpose, e.g., cellulose ethers, poly(acrylic acid), PVP and PVA. ^[4]

Polymers in Gels

Gel system consist of physical or chemical cross-linked between adjust polymer chain restrict chain mobility. Gel has rheological properties. Cross-linked gels are most commonly known as hydrogels. They are also known a  s smart polymers because they shows different gelling properties in different environment of water. Most commonly used hydrogels are poly (hydroxyethyl methacrylate), poly (methacry1ic acid) and poly (acrylamide). In pharmaceutical industries cross-linked gels are primarily use for local drug delivery of drugs to skin, oral cavity, vagina and rectum.^[5]

Swelling Controlled Release Systems

 In many drug delivery systems, the dimensions of the dosage form will change during the course of drug release due to swelling of the polymer matrix. Although the mechanism for drug release is diffusion, Examples of systemsb  that exhibit swelling controlled release are physically crosslinked and chemically crosslinked gels. In terms of controlled drug release, chemically Crosslinked hydrogels e.g., poly(hydroxyethylmethacrylate), have been used to provide controlled drug release from medical devices, whereas swelling controlled physical hydrogels may be easily manufactured by directly compression of drug with a hydrophilic polymer, e.g., HPMC. ^[4]

Temperature Responsive Drug Release

Several reports have been published on the design and application of controlled systems for the administration of drugs that use the temperature as an external stimulus. The polymers used to obtain such release properties are referred to as thermoresponsive polymeric systems. Typically, the homo and copolymers of N-substituted acrylic and methacrylate amides [e.g. poly (isopropyl acrylamide)], are used for this purpose. More specifically, there are two types of thermoresponsive polymer systems namely those that exhibit positive and negative temperature dependency. Polymers in the former category display an upper critical solution temperature below which polymer contraction occurs upon cooling. Conversely, negative temperature dependent polymers have a lower critical solution temperature and will contract upon heating above the lower critical solution temperature.^[4]

pH Responsive Drug Release

In the design of dosage forms, a specific goal may be to obtain the release of the drug in the sites that guarantee maximum therapeutic benefits. Within the gastrointestinal tract a range of pH values exist, ranging from about one in the stomach to neutrality within the intestine. Targeting drug release within certain regions of the gastrointestinal tract as a method to enhance drug stability within acidic fluids or to reduce the irritant effects of certain drugs has been used for several decades. For example, enteric polymers have been used as tablet coatings for this purpose, examples of which include cellulose acetate phthalate and cellulose acetate butyrate. These polymers are insoluble in low pH environments; however they are soluble in the less acid regions of the gastrointestinal tract. Following dissolution of the enteric coating, the tablet and hence the drug will dissolve, thereby facilitating drug absorption. Due to this pH dependent solubility, enteric polymers may be described as pH responsive polymers.^[4]

Osmotic pressure controlled

In the oral osmotic pump (Oros®). The drug is mixed with a water-soluble core material. This core is surrounded by a water-soluble semipermible polymer membrane in which is drilled a small orifice. Water molecules can diffuse into the core through the outer membrane to form a concentrated solution inside. An osmotic  gradient is set up across the semipermiable membrane with the result that drug is pushed out of the orifice. The core may be a water-soluble polymer, an inert salt or, as in the case of metoprolol fumarate, the drug itself, whose saturated solution has an osmotic pressure of 32.5 atm. One problem is that of controlling the transit of the device down the GIT, as individual subjects vary considerably in GI transit times. If the system is designed to release drug over a period of 10 hours and total transit time in the gut in 5 hours, then bioavailability will obviously be reduced. The osmotic tablet of nifedipine contains the semipermiable cellulose acetate coating, the swellable hydrogel layer of polyoxyethylene glycol and HPMC and the drug chamber containing nifedipine in Hydroxy Propyl Methyl Cellulose  and Poly Ethylelene Glycol.

Transdermal drug delivery system

Transdermal system dependent ostensibly on rate-controlling membranes are available for the delivery of nitroglycerin, scopolamine, oestradiol (estradiol), fentanyl, clonidine and other drugs. The barrier properties of skin are so variable, however, that one advantage of rate-controlling system generally consist of a reservoir, a rate-controlling membrane and an adhesive layer. Diffusion of the active principle through the controlling membrane governs release rate. The active principle is usually present in liquids form, suspended form and gels are used as dispersion media. In matrix system the active principle is dispersed in a matrix, which consist either of a gel or of an adhesive film. In Transiderm Nitro , the rate- controlling membrane is composed of a poly-ethylene/ vinyl acetate copolymer having a thin adhesive layer (membrane type). Motion sickness: Transderm-Scop (Scopolamine), Hypertension: Catapress-ITS (Clonidine Polyisobutylene), Oestrogen theraphy: Estraderm (Oestradiol), Smoking cessation: Nicotinell (Nicotine) etc. ^[1,2]

Microcapsules and microspheres

Microencapsulation is a technique, which involves the encapsulation of small particles of drug in solid or liquid form , in a polymer film or coat. Microspheres on the other hand are solid, but not necessarily homogenous particles which can entrap drug.  Microspheres can be prepared by a variety of techniques, e.g. coacervation, spray coating etc. Desolvation of water insoluble macromolecules in non-aqueous solvents would lead to the deposition of a coacervate layer around aqueous or solid disperse droplets. The various water-soluble and water-insoluble macromolecules, which have been used in coacervation processes, are arabinogalactan, cellulose acetate phthalate, carboxy methyl cellulose, cellulose nitrate, gelatin, ethyl cellulose, gum Arabic (acacia), poly(ethylene vinylacetate), hydroxyl ethyl cellulose, poly(methyl methacrylate), poly(acrylic acid), polyethyleneimine, poly(vinyl alchol),poly vinyl pyrrolidone, methyl cellulose, starch etc. Desolvation, and thus coacervation, can be induced thermally and this is the basis of some preparative techniques. The conditions for phase separation are best obtained using phase diagram.^[3]

Ocular drug delivery system

Improving the ocular contact time of solutions utilizes the incorporation of polymers into an aqueous medium such as polyvinyl alchol (PVA), polyvinylpyrrolidone (PVP), methylcellulose, carboxymethylcellulose (CMC) and hydroxypropyl cellulose (HPC). The increased solution viscosity reduces the solution drainage. Increasing the solution viscosity of pilocarpine solution from 1to 100 cps through the incorporation  of methyl cellulose reduced the solution drainage rate constant 10 times while only 2-fold increase in pilocarpine concentration in the aqueous humour was obtained. Ocusert has the drug reservoir as a thin disc of pilocarpine-alginate complex sandwiched between two transparent discs of microporous membrane fabricated from ethylene-vinyl, acetate copolymer. The microporous membranes permit the tear fluid to penetrate into the drug reservoir compartment to dissolve pilocarpine molecules are then released at a constant rate of 20 or 40 mg/hr for a hour to seven day management.^[2,3]

Buccal Drug delivery system

Buccal tablets- The use of cellulosic or acrylic polymers generally offers almost immediate, high adhesion performance for prolonged period of time, even with high drug content. Different polymers can be used for the development of laminated and hydrogel systems including cellulose derivatives (methylcellulose, sodium carboxy methylcellulose and hydroxyl ethyl cellulose), natural gums (guar gum, karaya gum and agarose), poly acrylates (poly(acrylic acid), poly (vinyl pyrrolidone) and poly (ethylene glycol)) and gelatin. These polymer exhibit mucoadhesive properties in the presence of water. Poly (acrylic acid) based patches have been successfully for the delivery of opiod analgesics. Chewing gum formulations  consist generally of a gum base of cellulosic or acrylic polymer. The polymer is blended with sugar as well as drug. Drug release from chewing gum formulations is generally rapid but not as immediate as in the case for the fast dissolving tablets.^[1]

Progestasart system

Progestasart intra-uterine device is the example of controlled drug delivery system medicated implant use for contraceptive purpose. The drug release from progestasart occurs by diffusion polymer act as a rate controlling membrane for drug release. Polyethylene and poly(ethyleneco-vinyl acetate) are used in such system. ^[9]

Polymers in drug conjugates

It is one of the strategy for improved delivery of therapeutic agent. The conjugate of polymer and drug composed of drug which is bound covalently to polymer. Strategy of polymer drug conjugate use especially in the field of cancer therapy which is known as „polymer therapeutics‟. Biodegradable polymer are preferred although non-biodegradable synthetic polymer such as PEG and poly (hydroxylpropylmethacrylate) preferred mostly. The easiest way of attaching drug to macromolecule by direct attachment without spacer. HPMA doxorubicin and HPMA-paclitaxel undergone in clinical trials. ^[9,11]

 

Current Status and Future Prospects Of New Drug Delivery System

 With the progress in all spheres of science and technology, the dosage forms have evolved from simple mixtures and pills to the highly sophisticated technology intensive drug delivery systems, which are known as Novel Drug Delivery Systems (NDDS) or otherwise called as New Drug Delivery System (NDDS). Quest for New Drug Delivery System (NDDS) has got new impetus since early eighties to have improved therapeutic outcome from the same drug, because the New Drug Delivery System (NDDS) have several advantages over the conventional dosage form. Since then several New Drug Delivery System (NDDS)have been developed and it constitute a sizable portion of the global market.^[7]

^{Read More}

• ^{Pharmaceutical Polymers- Definition, Introduction and Classification}
• ^{Properties of Polymer}
• ^{Polymer- Mechanism of Drug release}

 Types of Novel Drug Delivery Systems    

  There are multiple schemes of classification of types and techniques of NDDS - based on therapeutic group of drugs loaded, physical form, intended application route, mechanism of delivery or action, etc. and none would be complete. ^[7]

 Microparticulate Drug Delivery Systems

Drugs encapsulated within polymeric beads in order to control the release, mask unpleasant taste, prevent degradation from atmospheric moisture and to ensure proper delivery as desired. These multi-unit dosage forms are mainly intended for oral drug delivery, though parenteral and other routes of administration have also found commercial and clinical success. Different systems implement various rate controlling mechanism including nonerodible mechanical barrier for diffusion controlled release, microporous membrane systems, water swellable and hydrogel systems, pH sensitive polymer coated systems, gastric floatation systems, mucoadhesive systems, colon-specific delivery systems, etc. a large spectrum of drug have been modulated for release and other properties, e.g. cardiovascular drugs, antipsychotics, antibacterial and chemotherapeutic agents. The selection of polymer for a particular multiparticulate system is crucial and a wide variety of polymers such as cellulose derivatives (methyl, ethyl, hydroxypropyl, hydroxypropyl methyl cellulose), acrylic polymers, biodegradable polymers (Polylactide coglycollic acid, poly lactic acid, polyglycollic acid, etc.) and natural polymers (sodium alginate, albumin, other proteins, chitosan, etc.) are used depending on the requirement of the particular system to be developed ^[6,7] .

Nanoparticles

These are colloidal drug delivery systems in the nanometer size range having wide application potential at present. They have got all characteristics of the liposomes minus the stability problems. They have been utilized to deliver and control the release of drug molecules from suitable polymeric nanoparticles/ nanospheres. Usually FDA approved biocompatible polymers such as poly (L-lactide - D-glycollic acid) have been used, though other polymers such as polyepsilon-caprolactone, chitosan and polyalkyl cyanoacrylates have been also used. Their most promising area of application is tumor targeting capability. Nanoparticles are not only suitable for parenteral administration, but also they have been exploited as advanced systems for drug delivery through cornea, skin, bronchioles and oral routes.^[6,7]

Aquasome

 These are carbohydrate stabilized nanoparticles of ceramics / calcium phosphate having water-like properties which help to protect and preserve the fragile biological molecules. They are comprised of a solid nano-crystalline core coated with oligomeric film to that the drug moieties or biochemically active molecules are adsorbed with or without modification. There three layered structures are self assembled by non-covalent and ionic bonds. Their intended route of administration is parenteral and with advancement of research in this field, other routes might be contemplated.^[6,7]  

Dendrimers

 In search for novel biomaterials for controlled and targeted delivery of bioactives, Starburst Dendrimers are the latest stars that bear promising properties for the delivery of drugs, vaccine, metals or genes to the desired sites. In spite of being polymers they bear similarity with vesicular structures such as micelles, liposomes and globular proteins. The dendrimers are three-dimensional branched structures like trees and hence the name "Dendrimer". They possess a very large number of chain ends and synthesized chemically. Into the branches of dendrimers drugs and other biologically active molecules could be entrapped for controlled and/or targeted delivery initially via parenteral route and subsequently other routes could be tried. ^[6,7]  

Microemulsions

 Microemulsions are transparent thermodynamically stable systems of colloidal nature that are formed from classical emulsions, but at specific phase-volume ratios. They afford solubilization of water-insoluble molecules, thereby improving their bioavailability as well as applicability and reduced ADME problems. A widely used immunosuppressant, Cyclosporin, have been formulated commercially as a microemulsion for increased solubility and bioavailability. Proteins and peptides may also be formulated as oral microemulsions, such as oral insulin systems, and also scope exists in developing oral vaccines through this system. ^[6,7]

 Liposomes

 These are uni-/multilamellar phospholipid vesicles composed of concentric spherical layers of aqueous zones  sandwiched between phospholipid membranes. Both water and oil soluble drugs can be encapsulated in the liposomes either in the aqueous zone or the lipid-bilayers according to their solubility. They are often referred to as "artificial cells" as they resemble one in almost all practical aspects. They showed immense potential in delivery of anti-tumor therapeutics as well as anti-fungals. Drugs such as Amphotericin B, Doxorubicin and Daunorubicin have been successfully launched in market as liposomes. ^[6,7]  

Niosomes

These are vesicles like liposomes, but made up of nonionic surfactants and like liposomes. They can also entrap hydrophilic as well as lipophilic drugs. They have better stability than liposomes and hence have greater interest for industrial adoption. The non-ionic surfactant systems make niosomes inherently target-specific to tumor, liver and brain. They have been reported to be useful as targeting systems of drugs for treatment of cancer and in therapy of microbial diseases caused particularly by virus and parasites. Tumor targeting of Methotrexate in mice model have been highly successful. Since no special handling / storage precautions are required for niosomes, their commercial exploitation would be easier. They are biodegradable and reduce systemic toxicity of various antitumor and antimicrobial agents by localizing the drug to specific sites of action. ^[6,7]

Multiple

 These are emulsions of emulsions in which the internal phase consists of dispersed globules, which are made of a simple (two-phase) emulsion. There are two types - oil/water/ oil or water/oil/water, i.e., two similar phases separated by an immiscible phase, which is sometimes called liquid membrane that acts as a semipermeable membrane for drug molecules to diffuse through it at a controlled rate. A promising use of multiple emulsions is drug targeting via antibody / ligand tagging to the carrier droplets. Also, because of their globular size drugs may be targeted to lungs and reticulo endothelial systems (RES). The techniques of multiple emulsions formulation has also been used to prepare micro- and nano-particles for controlled and targeted drug delivery. ^[6,7]

 

References

1.      S.P. Vyas, Roop K. Khar, Controlled Drug Delivery - Concepts and Advances, 1 ^st ed: 2002, Vallabah Prakashan, Pg.No: 1-50, 294 – 229, 411-446.

2.      N.K. Jain, Controlled and Novel Drug Delivery, 1^st ed: 1997; Reprint: 2008, CBS Publishers & Distributers, Pg .No . 82-96.

3.      Roop K Khar, SP Vyas, Farthan J Ahmad, Gaurav K Jain ,Lachman/Lieberman’s, The Theory and Practice of Industrial Pharmacy, 4^th ed, Pg.No: 403-448, 576-596.

4.      Naveen Kumar , Sonia Pahuja, Ranjit Sharma, Pharmaceutical Polymers - A Review , International Journal of Drug Delivery Technology 2019; 9(1); 27-33

5.      Priyanka Shinde*1 , Manodaya Patil2 and Akshay Patil3, Methods, types and applications of pharmaceutical polymers, WJPPS , Volume 6, Issue 8, 784-797.

6.      Tiwari R, Prakash AR, Shukla S and Pandey A:Controlled drug release for poorly water soluble drugs- a role of polymeric nanoparticles. Int J Pharm Sci Res 2014; 5(5): 1661-70.doi: 10.13040/IJPSR.0975-8232.5 (5).1661-70.

7.      Subhash Mandal, C. M. (2010). Status and Future Prospects of New Drug Delivery System. Pharma Times , 42 (4), 13-16.

8.      Stephen L. Rosen, Fundamental Principles of Polymeric Practices, A Wiley-Interscience Publication, Second edition, 1993; 1-200.

9.      David Jones, Pharmaceutical Applications of Polymers for Drug Delivery, Rapra Technology, 2004; 15(6).

10.  Eeckman F, Moes A J, Amighi K, Synthesis And Characterization Of Thermosensitive Copolymers For Oral Controlled Drug Delivery, European Polymer Journal, April, 2004; 873-81.

11.  P.J. Watts, M.C. Davies and C.D. Melia, Critical Reviews in Therapeutic Drug Carrier Systems, 1990; 7: 235.