Novel Polymers for Drug Delivery

Synthesis and Characterization of Novel Polymers for Drug Delivery

1.0 Biomaterials

Introduction

1 The Use of Biomaterials in Biomedical Applications

Biomaterials are defined as substances, other than foods or drugs (1)[1], which are designed to be used as a whole or as part of a system which is used in a medicinal function to treat, replace, supplement or investigate any tissue, organ or function of the body. [2] (2)However, with the invention of tissue engineering and regenerative medicine the definition has been broadened to include any materials which interact with biological systems to the same healing effect. . Historically biomaterials have been evident in healthcare and in the treatment of disease with some of the earliest examples including the use of gold in dentistry and glass eyes. Most materials used in the 19th and early 20th centuries, whilst demonstrating their usefulness as biomaterials often had complications dues to poor design or their incompatibility with the biological systems in their intended site of action. [3] However, modern biomaterial science has improved as scientists now take into account critical design parameters which are needed for good biomaterial functionality.

Requirements of Biomaterials

An essential requirement for a material to be considered as a biomaterial is sufficient biocompatibility with the numerous biological systems found in the body.2 Biocompatibility is a materials ability to interface with the body without it or its constituents provoking any undesired local or systemic effects.

Biomaterials can be made synthetically or produced by a biological system.

Using Polymers as Biomaterials.

As polymers have proved to be very versatile they are rapidly replacing other material classes such as metals, alloys and ceramics for use as biomaterials. (2)2 This was shown in 2003 as the sales of polymeric biomaterials exceeded $7 billion and accounted for almost 88% of the total biomaterial market that year.[4] Polymers are being used more regularly for tissue engineering or as carriers for the delivery of drugs, proteins, and imaging agents. [5], [6] Developments in polymer technology and the discovery of better routes to their synthesis have enabled them to meet the needs of biomedical applications and their use become more prevalent. In particular modern drug delivery technology has been made possible by the advances in polymer science.[7] . Now, as science has progressed biomaterials are increasingly being employed for sustained delivery applications as 9Shea et al. report that they enhance drug safety and improve patient compliance. They have also presented a number of drug releasing polymer products that have been approved for clinical trial.

Examples of Polymeric Biomaterials

2. Delivery Systems

There are many drug release systems available which have differing mechanisms in which the trigger for release and the rate at which it occurs. Examples of these systems are:

* Prolonged or sustained release; this system prolongs therapeutic blood or tissue levels for an extended period of time

* Zero-order release; the rate of release does not vary with time and so a constant therapeutic drug level is in the body for a sustained period of time.

* Variable release; this system releases the drug at variable rates according to natural processes within the body for example a heart rate altering defect.

* Bio-responsive release; the release rate is controlled by a biological stimulus.

* Self-regulated release; this is when the patient controls the release from the delivery system.

* Rate controlled release; this delivery system has a preset rate at which to release the drug for a set period of time.

Although there are many systems available, not all are available for polymeric drug delivery

Controlled and Sustained Release Systems

Controlled release systems deliver drugs at a deliberate rate for a fixed period of time which is normally from weeks to years. (Langer paper) Release rates are said to be determined by the design of the system and are nearly independent of environmental factors for example the pH of the part of the body the system is being delivered to. Sustained release systems however, are designed to deliver drugs within a day are often affected by environmental conditions leading to variations between patients. Controlled release systems have numerous advantages over conventional drug therapies including improved patient compliance, increased patient comfort, reduced need for follow up care and localised delivery of the drug which will protect drugs which can be affected by other areas of the body. Another important advantage that controlled release systems offer is their ability to maintain the concentration of a drug within the therapeutic window required without causing fluctuations. (Langer paper and Langer review) Immediate release systems for example injections or ingestions the drug concentration at the site of action increases, peaks then declines after every administration. This can lead to fluctuations which are only in the desired therapeutic window for a comparatively short period of time. Clinically, it has been shown, that temporal control can produce a significant benefits. This is most apparent when drug therapy for terminal cancer patients is considered as when the therapeutic drug concentration drops outside the window the patient experiences pain and this controlled release system ensures that the drug is giving the greatest benefit for the longest period of time possible.

Role of Polymers in Drug Delivery

The effectiveness of polymers in drug delivery has been well documented which is shown by the numerous patents and literature available. Polymers that are used for controlled release have been classified into 4 major categories; diffusion-controlled, solvent- activated, magnetically controlled and chemically controlled. (Drug delivery systems and ordered book) Diffusion controlled systems are where the drug slowly disperses through a polymer system into the bloodstream either from a system where the drug is enclosed in the polymer or the drug is diffused throughout the polymer. The properties of the drug and polymer determine the diffusion and drug release rate. There are two solvent activated systems; one which uses osmotic pressure to release the drug from a region of high drug concentration and another system which relies on the system swelling with exposure to liquid and the drug permeating at a controlled rate through the polymer. Magnetically controlled systems have been developed specifically for cancer chemotherapy where the systems contain magnetic microspheres which produce area specific localisation. Chemically controlled systems also have two different systems differentiated by the way in which the drug is attached to the polymer. The pendant chain system is one in which the drug molecule is either directly or indirectly linked to the polymer backbone and when in the presence of enzymes of the body the drug is either hydrolysed or cleaved off at a controlled rate to enter into the bloodstream. The other chemically controlled system, one which is being investigated in this report, is a bioerodible system. This is when the drug is dispersed uniformly through polymers which gradually decompose. Drug Delivery Systems reports that the fact that the bioerodible systems have numerous advantages, including no need for the system to be removed surgically that this system is likely to be developed and used more than any other polymer type of the future. Possible diagram in Langer Paper

1) Applications

A number of drug releasing polymer products have been approved for clinical use.

3. Drug Delivery Routes

3.1 Drug Delivery Routes

The route of administration chosen for a drug (ROA) is an important factor which may have a profound effect on the speed and efficiency at which the drug reacts. Routes of administration can be split into two main groups; enteral, any form of administration that involves the gastrointestinal tract, and parenteral. Enteral routes include sublingual/buccal, oral and rectal while parental routes are transdermal, subdermal, inhalation, vaginal and nasal. (Innovations in drug delivery) The ROA is said to be determined by the physical characteristics of the drug. The success or failure of a system can depend on the anatomy of the route and the tailoring of the formulation to it. (RoA book) The choice of an appropriate route of administration for a specific bioactive will be influenced by many factors such as required time of onset of action or drug targeting issues. Other numerous factors as well as features related to the properties of the bioactive materials itself, such as solubility and stability. Specialised drug delivery systems constitute a relatively recent addition to the field of pharmaceutical technology. (DDaT book) However, simple dosage forms possess many disadvantages for drug delivery. Parenteral delivery is highly invasive, generally requires intervention by clinicians and the effects are usually short-lived. Oral administration is highly convenient but many drugs cannot be given by this route due to pharmacological properties such as poor absorption or instability in the gastrointestinal tract. Creams and ointments can be at a disadvantage as they are limited to topical rather than systemic effects. (DDaT) Below various routes of administration are listed.

Parenteral Drug Delivery

Parenteral drug delivery is the main clinical route used as an alternative to oral administration when this is not possible. These are injections which can be

Oral Drug Delivery

3.2 Routes Available to Polymers

PGS and PGSA.

An example of a biodegradable polymer that h

PGS has been synthesised, in literature, by a traditional reflux method but this has proved to be unsuitable as it requires harsh conditions and long reaction times required to cure the polymer. (synth)

This has deemed it unsuitable for its original desired functions of aiding or replacing damaged tissues and containing cells or temperature sensitive molecules. A new method has been reported that used photopolymerisation to prepare polymeric networks for tissue engineering applications as well as for minimally invasive medical procedures. This involves acrylate groups being incorporated into the PGS polymer to form PGSA. These groups can take part in chemical cross-linking between the polymer chains by photo-induced free chemical polymerisation. This was done by the addition of a photo initiator exposure to ultra violet light. and unsuitable as PGS was designed to be used for tissue supports and was hoped to be polymerisised in situ to be used in hospital theatres however this is not possible. A new method was discovered which used UV curing to photopolymerise and PGSA have both been synthesised by the traditional reflux method (langer paper)

Drug Dissolution

Article: http://www3.interscience.wiley.com/journal/113293576/abstract

2.0 Theoretical

2.1. Polymers

Synthetic polymers have considerable commercial importance and are known by several common names such as macromolecules or plastics. [8]Polymers are large molecules with molar masses said to range from several thousands to several millions.[9] They are constructed of many smaller structural units known as monomers, which are covalently bonded together in any conceivable pattern at various lengths. Monomers need to have two bonding sites in order to undergo polymerisation reactions where the monomer units are linked together to form a polymer chain. The number of bonding sites a polymer contains is known as its functionality and determines whether the polymer will be linear or branched. Bifunctional monomers with only two bonding sites form linear polymers whereas polyfunctional polymers with three or more bonding sites form branched polymers. Branched polymers have the ability to develop into large three dimensional networks containing branches and crosslinks. Polymeric materials are said to exhibit high strength, have a glass transition temperature, exhibit rubber elasticity and have high viscosity as melts and solutions. 5

2.1.1Synthesis of polymers

Monomers are linked together to form polymer chains by a process called polymerisation. It was W. H. Carothers, in 1929, who proposed that the way in which polymers are prepared, by either stepwise reactions of monomers or by chain reactions, be divided into two distinct groups.6 These he named these condensation polymers, which are characteristically formed by reactions where a small molecule is eliminated in each step and addition polymers where there is no loss. However, it was noted that there were exceptions and so the term condensation was replaced with step-growth or step-reaction to include polymers which grow in a step growth fashion but do not eliminate a small molecule. In stepwise growth polymerisation a linear polymer chain of monomer residues is made by the stepwise intramolecular condensation or addition of the reactive groups in bifunctional monomers.1 In addition polymerisation each polymer is formed over a very short period of time and is then excluded from further participation in the reaction. The reaction time is individual to the chain and is sub divided into three processes.[10] These are initiation where the chain starts to grow, propagation where the chain is continuing to grow and termination which stops chain growth. Addition polymerisations can be carried out by different mechanisms depending on the monomer being used. These are radical, cationic and anionic polymerisation.

2.2 Riboflavin

Riboflavin is from the flavin family which are yellow coloured compounds with the basic structure of 7,8-dimethyl-10-alkylisoalloxazine.[11] Riboflavin is found in nature and was initially isolated from milk whey in 1879 and given the name lactochrome.14, 15, 16 It was not until the 1920s when the further research into this bright yellow pigment took place and it was realised it was a major constituent of vitamin B. 14, 15 Flavins are distributed in tissues but not as free riboflavin, they were found to be in flavocoenzymes, mainly as its derivatives, flavin adenine dinucleotide (FAD) and as flavin mononucleotide (FMN) 14 . Riboflavin and its derivatives are recognised by their ability to participate in both one and two electron transfer processes.14, [12] Riboflavin exhibits strong absorption in the ultraviolet and visable region and act as sensitisers in the photodegradation of a wide range of substrates by free radical or singlet oxygen-mediated mechanisms.14, 16 The electronic absorption spectrum of riboflavin in aqueous solution exhibits a peak at 445nm, which is referred to as the first maximum and shows a π→π* transition.14, 17

2.3 UV-Vis Spectrometry

Ultraviolet-visible spectroscopy is a technique which uses ultraviolet and visible light to determine the

2.4 NMR Spectrometry

Nuclear Magnetic Resonance is a spectroscopic method from which chemical and structural information on a molecule can be gathered. It analyses the magnetic properties of certain atomic nuclei to determine different electronic local environments of the atoms in the compound being tested.

[1] Ratner, B. D., Hoffman, A. S., Schoen, J. F. & Lemons, J. E. Biomaterials Science, an Introduction to Materials in Medicine 1-8 (Academic, San Diego, 1996).

[2] Williams DF. The Williams dictionary of biomaterials.

Liverpool: Liverpool University Press; 1999

[3] Langer Tirrell Nature

[4] Medical Device and Diagnositc Industry, 2005 /http://www.devicelink.com/mddi/archive/05/05/024.html

[5] Polymer-drug conjugates: Progress in polymeric prodrugs

Jayant Khandare a, Tamara Minko

[6] J.D. Clapper et al. / Polymer 48 (2007) 6554e6564

[7] Engineered polymers for advanced drug deliverySungwon Kim , Jong-Ho Kim , Oju Jeon , Ick Chan Kwonb, Kinam Park

[8] Fundamentals of Polymers Kumar Gupta

[9] Polymers: Chemistry and Physics Book

[10] Polymer Chemistry An Introduction G. Challa

[11] BOOK Flavins Photochemistry and Photobiology Eduardo Silva, Ana M Edwards

[12] Chemical and Biological Versatility of Riboflavin

16, M.B. Tayler and G.K. Radda, Flavins as photosensitizers, Methods Enzymol.,1971, 18, 496-506

17, Kiyoshi SHIGA, Yasuzo NISHINA, Iwao OHMINE,

Kihachiro HORIIKE, Sabu KASAI, Kunio MATSUI,

Hiroshi W ATARI, and Toshio YAMANO J. Biochem. 87, 281-287 (1980)

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