POLYMERS FOR NOVEL DRUG DELIVERY SYSTEMS

A.PRAVEEN KUMAR,JAYAMUKHI COLLEGE OF PHARMACY

CONTENTS• Introduction• Classification of polymers• Polymers for novel drug delivery systems

• References

–Hydrogels–Microencapsulation–Adhesive biomaterials–Polymers in nanoparticle–Polymers in implants–Polymeric micelles–Polymers in gene therapy–Polymers in tissue engineering

• What is a polymer?

A POLYMER may be defined as a large molecule built up by repeating structural units joined by the covalent bonds.• The smallest unit that repeatedly combines to form the polymer is known as MONOMER.

ORPOLYMERS also known as macromolecules, are very large

molecules consisting of many repeating units and are formed by a process polymerization, which links together small molecule know as MONOMER.

•Degree of polymerization : It is a number,n,of repeated units of monomers per macromolecule is called the degree of polymerization. Ex; Polyethene monomer.

Classification S.No Basis of classification Nature of polymer Common examples

1

2

3

Source of polymer

Structure of polymer

Polarity

A. Natural polymer

B. Semi synthetic polymer

C. Synthetic polymer

A. Linear polymerB. Branched chain polymer

C. Cross linked or network polymers

A. Cationic polymerization polymers

B. Anionic polymerization polymers

Rubber , cotton, silk, woolCellulose rayon , cellulose nitratePVC, poly ethelene,nylon,terylenePolyethelene,PVC.Low density polyethelene.Bakelite, melamine.

Polystyrene, Polyvinyl ethers,Poly Iisobutene. Buna type synthetic rubbers,Polyacrylonitrile,Poly isoprene.

S.No Basis of classification Nature of polymer Common examples

4

5

6

7

Mechanism of Polymerization

Heat treatment

Organic and Inorganic substances

Molecular forces

A. Condensation polymers

B. Addition polymers

A. Thermoplastic polymers

B. Thermosetting polymers

A. Organic polymers

A. Inorganic polymers

A. Elastomers

B. Fibres

C. Thermoplastic polymers

D. Thermosetting polymers

Terylene,Nylon-6,6. Bakelite.Neoprene,Polyvinylpyrrolidone,PVC.

Polyethylene,PVCNylon&sealing wax.Bakelite,polysiloxanes

Leather,Cellulose,Rayon.Glass, silicone rubbers

Buna-N,Buna-S Neoprene.Polyamids,Nylon6,6; Polyesters.Polythene,polystyrene.Bakelite, Urea-HCHO, resins.

S.No Basis of classification Nature of polymer Common examples

8 Pharmaceutical application A. Binding agents

B. Disintegrants

C. PlasticizerD. Thickening agentsE. Coating agents-nonenteric

agents

F. Coating agents-enteric agents

G. Volume expander and anticoagulant

H. Gene transfer agentsI. CosolventsJ. Bulking agents

Acacia, gelatin, sodium alginate.Starch, CMC, cross linked povidone.Polyethelene glycol.Xanthan gumMicro crystalline cellulose(MCC), NaCMC, HPMC,HEC, HPCCellulose acetate phathalate, hydroxymethyl cellulose.Hydroxy ethyl cellulose(HEC)Sodium alginate.PEG300, PEG400.Micro crystalline cellulose(MCC).

Polymers for novel drug delivery

HYDROGELS

Three-dimensional networks of hydrophilic polymer chains that do not dissolve but can swell in water.

High biocompatibility Environmental stimuli respondent: temperature, pH, light High water content capacity Hydrogels contains interactive functional groups attached to the main polymeric chain are usually referred to as smart hydrogels.

• Classification of hydrogels

S.No Basis of classification Nature of hydgogel

1 Origin 1. Natural2. Synthetic

2 Water content or degree of swelling

1. Low swelling2. Medium swelling 3. High swelling4. Super absorbent

3 Porosity 1. Non porus2. Micro porus 3. Macro porus4. Super porus

4 Cross linking 1. Chemically cross linking(covalent bonding)

2. Physical cross linking(non covalent bonding)

5 Bidegradability 1. Biodegradable2. Non degradable

• HYDROGELS IN DRUG DELIVERY

• Drug can be loaded into hydrogels in two ways• First, drug ,initiator and cross linker can be mixed and subsequently polymerized to confine the drug with in matrix• Alternatively , a preformed hydrogel can be allowed to swell equilibrium in a suitable drug solution.

•Release mechanism : 1.Diffusion2.Osmosis3.Ion exchange.

Moisture Trap Disposable Diapers or Sanitary Towels Controlled Release drug delivery Gastric Retention Devices Wound Dressings Hydrogel Modified Fabrics for Cosmetics or Pharmaceuticals Peroral Peptide Delivery Systems (Drugs) Topical Drug delivery Soil Moisture Maintenance Contact Lenses

VARIOUS APPLICATIONS OF HYDROGELS:

MICROENCAPSULATION • Polymer capsules containing active therapeutic

Natural or synthetic polymers can be used to form capsules

Widely adopted in industry – fragrance release, flavour masking etc

• How are they made?

- Interfacial polycondensation –

-polymer forms at boundary of two-phases

-Proteins and cells can be encapsulated

- Controlled gelation in aqueous solution

-E.g. addition of sodium alginate + drug in water

• Mode of drug release

- Physical disruption of capsules

- Diffusion through porous capsule membrane

• Def : bioadhesives are natural or synthetic materials, that can attach to the biological surfaces and be retained there for an extended period of time.

• These drug delivery systems exhibits superior contact, improved adhesion, prolonged residence time, and hence enhanced absorption at a selected application site.

• Such polymers are sometimes referred to as biological ‘glues’ because they are incorporated into drugs to enable the drugs to bind to their target tissues.

ADHESIVE BIOMATERIALS

• EXAMPLES OF BIOADHESIVES POLYMERS

Acacia gum - This natural polymer is a dried gum obtained from the stem and branches of the tree Acacia senegal. It is used as a thickener in pharmaceuticals.

Alginic acid – Is a natural polymer found in the cell walls of brown algae. It is widely used in the manufacture of alginate salts such as sodium alginate which is a constituent of Gaviscon liquid®.

Carbomers – Are polyacrylic acid polymers widely used in the pharmaceutical and cosmetic industries as thickening agents.. Carbomers have a huge advantage in formulation science because they adhere strongly to mucosal membranes without causing irritation, they exhibit low toxicity profiles and are compatible with many drugs.

Hydroxypropyl methylcellulose (HPMC) – This polymer is included in preparations used to moisten contact lenses and in oral gels.

Sodium hyaluronate - A high molecular weight biological polymer made of repeating disaccharide units of glucuronic acid and N-acetyl-D - glucosamine. This polymer is used during intraocular surgery to protect the cornea and also acts as a tear substitute in the treatment of dry eyes.

Other examples of polymers include:– pectin– polyvinyl alcohol (PVA)– polyvinylpyrrolidone (PVP)– tragacanth– chitosan– starch– cellulose derivatives

• Bioadhesive Drug Delivery Systems

In bioadhesive drug delivery systems, the term bioadhesion is used to describe the bonding or adhesion between a synthetic or natural polymer and soft tissues such as epithelial cells.

Mechanism of bioadhesion: The mechanisms involved depend on the nature of the tissue substrate, the dosage form design and physico-chemical environment. some theories explain the mechanism of bioadhesion, those are, 1. Wetting or mechanical theory 2. Electrostatic theory 3. Adsorption theory 4. Biphasic mechanism 5. diffusion or interpenetration theory

1. Wetting or mechanical theory

2. Electrostatic theory

–It treats adhesion as an embedding process.–Adhesion molecule permeate into surface irregularities and ultmately harden, setting up as multiple anchors.–This model is most applicable to liquid bioadhesives.

–It explains the mucuoadhesion process .–In this system, mutual contact of mucin glycoprotiens and polymer materials results in the transfer of electron across the interface. This movement of charge produces an electrical double layer , which induces electroststic attraction between the two surfaces.

–In this system the development of van der waal forces or hydrogen bonding between the polymer and the tissue substrate. ex: In mucoadhesion, water molecule penetration induces the release of polymeric chain from restrictive dry lattice forces. These polymeric chain then diffuse and entangle into mucin molecules.

3. Adsorption theory

4. Biphasic mechanism

–In initial stage, the adsorptive contact is induced by surface energy effects and is associated with a spreading process.–In the second stage, the diffusion of polymer chian across the interfacial region may promote bonding process.

5. Diffusion or interpenetration process.–It describes the concentration gradient- driven passive diffusion of both polymer and mucin glycoprotien molecule into each other until physical entanglement between the two types of molecules devolops.–This model can also explains the mucuoadhesion process .

TARGETS FOR BIOADHESIVE FORMULATIONS :

Bioadhesive or mucoadhesive formulation have been targetted to various anatomical locations to aid drug delivery and absorption. these structures posseses mucous membranes which protect the cell from damage. drug delivery to each anatomical region is displayed in side table.

Body siteBody site SystemsSystems

Eye Mucoadhesive eye drops / inserts

Nasal cavity Nasal drug delivery systems

Oral cavity Dental gels / buccal systems

Skin Patches, tapes, dressings

Vagina Local vaginal delivery systems

Rectum Local/systemic rectal delivery systems

NANOPARTICLES • In nanoparticle drug delivery, the drug is incorporated into a

suitable oriented particle system and delivers the drug toward its site of action in the body and improve its cellular interaction.

• Nanoparticles varying in size from 10-1000nm.• The drug is dissolved , entrapped, encapsulated or attached to a

matrix.• Nanocapsules are the vescicular system in which the drug fills a

cavity encased by a polymeric membrane and the drug is uniformely dispersed.

• A successful nanoparticle system should have a high loading capasity because this facilitate the administration of a smaller over all quantity of carrier.

• A high loading capacity can be achieved by incorporating the drug at the time of particle synthesis or alternatively by adsorbing the drug onto preformed particles.

• The rate of drug release from the nanoparticle and susequent polymer degradation are important parameters for a successful formulation.

• The rate of drug release depends upon the 1. Properties of the nanoparticle polymer 2. Method of drug loading into the nanoparticle• Mechanism of drug release

–In case of matrix devices, the drug release occurs by diffusion or the erosion of matix.–In case of hydrogel nanoparticle,the drug release occurs by the swelling of hydrogel. [swelling can be manipulated by either adding of hydrophilic groups or controlled by extent of cross linking]

POLYMERS IN IMPLANTS • This drug delevery system is to use hydrolytically labile polymers into which a drug could be physically dispersed under mild conditions and drug release controlled by hydrolytic erosion of the polymer matrix over a period of time with a simultaneous or subsequent degradation of polymer in the tissue• Implants can be prefabricated and administered with the help of specialized injection devices such as trocars, often under local anesthesia.

• MANUFACTURE OF IMPLANTS : 1.Hot-melt extrusion 2.compressing polymer and drug mixture 3. injection molding to yield different sizes and shapes (flat films, rolled implants, rods, etc..)

• ATRIGEL : The discomfort associated with implantation procedure can be alleviated by use of in situ forming implants that are formed at the site of injection on injecting a polymeric solution. This approach was adapted by Atrix Laboratories in developing a proprietary technology called Atrigel.• In this system, biodegradable and water-insoluble polymers such as PLGA,PLA, polycaprolatones, etc. are dissolved in biocompatible organic solvents such as N-methyl-2-pyrrolidone (NMP), triacetin, etc. along with the drug.• The drug-polymer solution or suspension is then injected subcutaneous or intramuscular route.• On coming in contact with physiological surroundings, NMP slowly dissipates into the surrounding tissues, and water permeates into the polymer solution.• This process leads to phase separation and subsequent coagulation of the polymer to form an implant in situ that traps the drug.

SOME OTHER IMPLANTS :

• Zoladex :a PLGA-based biodegradable implant developed by AstraZeneca PLC, delivers goserelin acetate in palliative treatment of prostate carcinoma.

• Gliadel Wafer : made of polyanhydrate copolymer matrix poly[bis(p-carboxyphenoxy) propane: sebacic acid] delivers the chemotherapeutic agent carmustine for the treatment of brain tumors.

• Eligard : which delivers leuprolide acetate over extended time frames, is an example of an in situ forming implant system that was developed by Atrix Laboratories, Inc.

• Posuredex : a PLGA-based implant developed by Oculex Pharmaceuticals/Allergan, delivers a dexamethasone in curing the signs and symptoms of macular edema.

POLYMERIC MICELLES• The polymeric micelles are used as a drug carriers. These drug carriers are mostly used for the targeting hydrophobic drugs.• POLYMERIC MICELLE : It is a macromolecular assembly that forms from block copolymers or graft copolymers, and has a spherical inner core and an outer shell.• In micellar structure, one segment of the block copolymer can provide enough interchain cohesive interactions.• The cohesive interactions in the inner core utilized as thedriving force of micelle formation.• The cohesive interactions in the polymeric micelles are,

1. Hydrophobic interaction2. Electrostatic interaction3. p-p interaction4. Hydrogen bonding

1. HYDROPHOBIC INTERACTIONS

Most of drug molecules possess a hydrophobic character, hydrophobic interactions are used most commonly for drug targeting.

2. ELECTROSTATIC INTERACTIONS

• The electrostatic interactions may be applied to macromolecules with electric charges at a high density. Ex: DNA and RNA, Proteins with a large number of charged groups(aspartic acid, lysine)

3. HYDROGEN BONDING & π-π INERACTIONS

These may work cooperatively with other cohesive interactions. Ex: drugs with aromatic rings, π-π interactions are considered towork cooperatively with hydrophobic interactions.

• drugs can be incorporated into a polymeric micelle by 2 methods, 1. Chemical conjugation 2. Physical entrapment• drugs can be incorporate into both the inner core and outer shell.• The inner core is considered an appropriate site for drug incorporation for the following two reasons,

The first reason is that possible interactions between theincorporated drug molecules and the outer shell segment ofthe block copolymer may lead to intermicellar aggregation. The second reason concerns a shielding functionof the outer shell for drug targeting.

The Advantages of Polymeric Micelles for Drug Targeting :

1. Very small diameter (10–100 nm)2. High structural stability3. High water solubility4. Low toxicity5. Separated functionality

The Purposes of the Incorporation of Drugs into Polymeric Micelles :

1. Drug targeting2. Controlled or sustained release of drug3. Solubilization of drug

EXAMPLES OF DRUG TARGETING WITH POLYMERIC MICELLE CARRIERS :

DRUG POLYMERIC CARRIER USEDOXORUBICIN PEG-poly(asparticacid)

block copolymers Anticancer

CISPLATIN PEG-poly(aspartic acid) block copolymers

Antitumor-activity

TAXOL PEG-PLA based polymeric micelles

Anticancer

AMPHOTERICIN

PEG-poly(N-hexyl aspartamide)-based block copolymers

Systemic fungal infections

POLYMERS IN THERAPEUTIC GENE THERAPY GENE THERAPY : The genetic materials are transferred into

patients so that the resulting circumvention of genetic abnormalities can bring out therapeutic effects in the patients.

GRAFT POLYMER : A polymer, with one or more species of blocks connected to the main chain as side chains, the side chains having constitutional or configurational features that differ from those in the main chain. constitutional unit- whose repetition describes a regular polymer constitutional unit- a unit having one or more sites of defined stereoisomerism

SOME OF CATIONIC GRAFT COPOLYMERS :

1. Poly(L-lysine)-PLL2. Poly[N-(2-hydroxypropyl)methacrylamide]-

HPMA3. Polyethyleneimine –PEI4. Poly(2-dimethylamino)ethyl Methacrylate-

pDMAEMATARGETTED POLYMERIC GENE CARRIERS :

There are numerous targeting ligands that can be utilized for cell-specific gene transfer, including asialoglycoprotein, lactose, low-density lipoproteins (LDL), folic acid, antibodies,and so on.

POLYMERS IN TISSUE ENGINEERING Tissue engineering is to employ the novel biomaterials to facilitate the regeneration or replacement of damaged tisse or diseased tisse. OR Tissue engineering is intended to achieve regeneration by growing a viable new tissue or organ.

SCAFFOLD : The organization of cultured cells can be guided by growing them on a substrate known as a scaffold. OR

The temporary materials structured in such a way as to guide growth of cells in vitro or in vivo