Polyanhydrides
Encyclopedia
Polyanhydrides are a class of biodegradable polymer
s characterized by anhydride bonds that connect repeat unit
s of the polymer backbone chain
. Their main application is in the medical device and pharmaceutical industry. In vivo
, polyanhydrides degrade into non-toxic diacid monomers that can be metabolized and eliminated from the body. Owing to their safe degradation products, polyanhydrides are considered to be biocompatible.
Biodegradable polymers, such as polyanhydrides, are capable of releasing physically entrapped or encapsulated drugs by well-defined kinetics and are a growing area of medical research. Polyanhydrides have been investigated as an important material for the short-term release of drugs or bioactive agents. The rapid degradation and limited mechanical properties of polyanhydrides render them ideal as controlled drug delivery
devices.
One example, Gliadelhttp://www.gliadel.com, is a device in clinical use for the treatment of brain cancer. This product is made of a polyanhydride wafer containing a chemotherapeutic agent. After removal of a cancerous brain tumor
, the wafer is inserted into the brain releasing a chemotherapy
agent at a controlled rate proportional to the degradation rate of the polymer
. The localized treatment of chemotherapy
protects the immune system
from high levels of radiation
.
Other applications of polyanhydrides include the use of unsaturated
polyanhydrides in bone replacement, as well as polyanhydride copolymers as vehicles for vaccine
delivery.
There are three main classes of polyanhydrides: aliphatic, unsaturated, and aromatic. These classes are determined by examining their R groups (the chemistry of the molecule between the anhydride bonds).
Aliphatic polyanhydrides consist of R groups containing carbon
atoms bonded in straight or branched chains. This class of polymers is characterized by a crystalline structure, melting temperature range of 50–90 °C, and solubility in chlorinated hydrocarbons. They degrade
and are eliminated from the body within weeks of being introduced to the bodily environment.
Unsaturated
polyanhydrides consist of organic
R groups with one or more double bonds (or degrees of unsaturation). This class of polymers has a highly crystalline structure and is insoluble in common organic solvents.
Aromatic polyanhydrides consist of R groups containing a benzene
(aromatic) ring. Properties of this class include a crystalline structure, insolubility in common organic solvents, and melting points greater than 100 °C. They are very hydrophobic and therefore degrade slowly when in the bodily environment. This slow degradation
rate makes aromatic polyanhydrides less suitable for drug delivery when used as homopolymers, but they can be copolymerized with the aliphatic class to achieve the desired degradation rate.
various characteristics of polyanhydrides can be altered to achieve the desired product. Characterization of polyanhydrides determines the structure, composition, molecular weight, and thermal properties of the molecule. These properties are determined by using various light-scattering and size-exclusion methods.
monomers with excess acetic anhydride
at a high temperature and under a vacuum to form the polymers. Catalysts may be used to achieve higher molecular weights and shorter reaction times. Generally, a one-step synthesis (method involving only one reaction) is used which does not require purification.
There are many other methods used to synthesize polyanhydrides. Some of the other methods include: microwave heating, high-throughput synthesis (synthesis of polymers in parallel), ring opening polymerization (removal of cyclic monomers), interfacial condensation (high temperature reaction of two monomers), dehydrative coupling agents (removing the water group from two carboxyl groups), and solution polymerization (reacting in a solution).
and composition of polyanhydrides can be determined by H1NMR
spectroscopy
. This will determine the class of polanhydride (aromatic, aliphatic, or unsaturated) as well as the structural features of the polymer
. For example, the analysis of nuclear magnetic resonance
(NMR
) peaks allows one to determine if a copolymer has a random or block-like structure. Molecular weight and degradation rate can also determined by NMR
.
to determine a polyanhydride’s molecular weight, gel permeation chromatography
(GPC), and viscosity
measurements may also be used.
(DSC) is used to determine the thermal properties of polyanhydrides. Glass transition temperature, melting temperature, and heat of fusion can all be determined by DSC. Crystallinity of a polyanhydride can be determined using DSC, Small angle X-ray scattering (SAXS), Nuclear magnetic resonance
(NMR), and X-ray diffraction.
The erosion and degradation of a polymer
describe how the polymer physically loses mass (degrade
s). The two common erosion mechanisms are surface and bulk erosion. Polyanhydrides are surface eroding polymers. Surface eroding polymers do not allow water to penetrate into the material. They erode layer by layer, like a lollipop. The hydrophobic backbone with hydrolytically labile anhydride linkages allows hydrolytic degradation to be controlled by manipulating the polymer
composition. This manipulation can occur by adding a hydrophilic group to the polyanhydride to make a copolymer. Polyanhydride copolymers with hydrophilic groups exhibit bulk eroding characteristics. Bulk eroding polymers take in water like a sponge (throughout the material) and erode inside and on the surface of the polymer.
Drug release from bulk eroding polymers is difficult to characterize because the primary mode of release from these polymers is diffusion
. Unlike surface eroding polymers, bulk eroding polymers show a very weak relationship between the rate of polymer degradation and the rate of drug release. Therefore, the development of surface eroding polyanhydrides incorporated into the bulk eroding polymers is of increased importance.
and toxicity
of a polymeric material is evaluated by examining systemic
toxic responses, local tissue
responses, carcinogenic and mutagenic responses, and allergic responses to the material's degradation products. Animal studies are conducted to test the polymer’s effect on each of these negative responses. Polyanhydrides and their degradation products have not been found to cause significant harmful responses and are considered to be biocompatible.
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
s characterized by anhydride bonds that connect repeat unit
Repeat unit
An essential concept which defines polymer structure, the repeat unit or repeating unit is a part of a polymer chain whose repetition would produce the complete polymer by linking the repeat units together successively along the chain, like the beads of a necklace.A repeat unit is sometimes called...
s of the polymer backbone chain
Backbone chain
In polymer science, the backbone chain or main chain of a polymer is the series of covalently bonded atoms that together create the continuous chain of the molecule....
. Their main application is in the medical device and pharmaceutical industry. In vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
, polyanhydrides degrade into non-toxic diacid monomers that can be metabolized and eliminated from the body. Owing to their safe degradation products, polyanhydrides are considered to be biocompatible.
Applications
The characteristic anhydride bonds in polyanhydrides are water-labile (the polymer chain breaks apart at the anhydride bond). This results in two carboxylic acid groups which are easily metabolized and biocompatible.Biodegradable polymers, such as polyanhydrides, are capable of releasing physically entrapped or encapsulated drugs by well-defined kinetics and are a growing area of medical research. Polyanhydrides have been investigated as an important material for the short-term release of drugs or bioactive agents. The rapid degradation and limited mechanical properties of polyanhydrides render them ideal as controlled drug delivery
Drug delivery
Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals. Drug delivery technologies modify drug release profile, absorption, distribution and elimination for the benefit of improving product efficacy and safety, as well...
devices.
One example, Gliadelhttp://www.gliadel.com, is a device in clinical use for the treatment of brain cancer. This product is made of a polyanhydride wafer containing a chemotherapeutic agent. After removal of a cancerous brain tumor
Brain tumor
A brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...
, the wafer is inserted into the brain releasing a chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
agent at a controlled rate proportional to the degradation rate of the polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
. The localized treatment of chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
protects the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
from high levels of radiation
Radiation
In physics, radiation is a process in which energetic particles or energetic waves travel through a medium or space. There are two distinct types of radiation; ionizing and non-ionizing...
.
Other applications of polyanhydrides include the use of unsaturated
Saturation (chemistry)
In chemistry, saturation has six different meanings, all based on reaching a maximum capacity...
polyanhydrides in bone replacement, as well as polyanhydride copolymers as vehicles for vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
delivery.
Classes of Polyanhydrides
Aliphatic polyanhydrides consist of R groups containing carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
atoms bonded in straight or branched chains. This class of polymers is characterized by a crystalline structure, melting temperature range of 50–90 °C, and solubility in chlorinated hydrocarbons. They degrade
Chemical decomposition
Chemical decomposition, analysis or breakdown is the separation of a chemical compound into elements or simpler compounds. It is sometimes defined as the exact opposite of a chemical synthesis. Chemical decomposition is often an undesired chemical reaction...
and are eliminated from the body within weeks of being introduced to the bodily environment.
Unsaturated
Saturation (chemistry)
In chemistry, saturation has six different meanings, all based on reaching a maximum capacity...
polyanhydrides consist of organic
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
R groups with one or more double bonds (or degrees of unsaturation). This class of polymers has a highly crystalline structure and is insoluble in common organic solvents.
Aromatic polyanhydrides consist of R groups containing a benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....
(aromatic) ring. Properties of this class include a crystalline structure, insolubility in common organic solvents, and melting points greater than 100 °C. They are very hydrophobic and therefore degrade slowly when in the bodily environment. This slow degradation
Degradation
Degradation may refer to;* Biodegradation, the processes by which organic substances are broken down by living organisms* Cashiering or degradation ceremony, a ritual performed when cleric is deprived of office or a knight is stripped of the honour...
rate makes aromatic polyanhydrides less suitable for drug delivery when used as homopolymers, but they can be copolymerized with the aliphatic class to achieve the desired degradation rate.
Synthesis and characterization
Polyanhydrides are synthesized using either melt condensation or solution polymerization. Depending on the synthesis method used,various characteristics of polyanhydrides can be altered to achieve the desired product. Characterization of polyanhydrides determines the structure, composition, molecular weight, and thermal properties of the molecule. These properties are determined by using various light-scattering and size-exclusion methods.
Polymerization
Polyanhydrides can be easily prepared by using available, low cost resources. The process can be varied to achieve desirable characteristics. Traditionally, polyanhydrides have been prepared by melt condensation polymerization, which results in high molecular weight polymers. Melt condensation polymerization involves reacting dicarboxylic acidDicarboxylic acid
Dicarboxylic acids are organic compounds that contain two carboxylic acid functional groups. In molecular formulae for dicarboxylic acids, these groups are often written as HOOC-R-COOH, where R may be an alkyl, alkenyl, alkynyl, or aryl group...
monomers with excess acetic anhydride
Acetic anhydride
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...
at a high temperature and under a vacuum to form the polymers. Catalysts may be used to achieve higher molecular weights and shorter reaction times. Generally, a one-step synthesis (method involving only one reaction) is used which does not require purification.
There are many other methods used to synthesize polyanhydrides. Some of the other methods include: microwave heating, high-throughput synthesis (synthesis of polymers in parallel), ring opening polymerization (removal of cyclic monomers), interfacial condensation (high temperature reaction of two monomers), dehydrative coupling agents (removing the water group from two carboxyl groups), and solution polymerization (reacting in a solution).
Chemical structure and composition analysis
The chemical structureChemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...
and composition of polyanhydrides can be determined by H1NMR
NMR
NMR may refer to:Applications of Nuclear Magnetic Resonance:* Nuclear magnetic resonance* NMR spectroscopy* Solid-state nuclear magnetic resonance* Protein nuclear magnetic resonance spectroscopy* Proton NMR* Carbon-13 NMR...
spectroscopy
Spectroscopy
Spectroscopy is the study of the interaction between matter and radiated energy. Historically, spectroscopy originated through the study of visible light dispersed according to its wavelength, e.g., by a prism. Later the concept was expanded greatly to comprise any interaction with radiative...
. This will determine the class of polanhydride (aromatic, aliphatic, or unsaturated) as well as the structural features of the polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
. For example, the analysis of nuclear magnetic resonance
Nuclear magnetic resonance
Nuclear magnetic resonance is a physical phenomenon in which magnetic nuclei in a magnetic field absorb and re-emit electromagnetic radiation...
(NMR
NMR
NMR may refer to:Applications of Nuclear Magnetic Resonance:* Nuclear magnetic resonance* NMR spectroscopy* Solid-state nuclear magnetic resonance* Protein nuclear magnetic resonance spectroscopy* Proton NMR* Carbon-13 NMR...
) peaks allows one to determine if a copolymer has a random or block-like structure. Molecular weight and degradation rate can also determined by NMR
NMR
NMR may refer to:Applications of Nuclear Magnetic Resonance:* Nuclear magnetic resonance* NMR spectroscopy* Solid-state nuclear magnetic resonance* Protein nuclear magnetic resonance spectroscopy* Proton NMR* Carbon-13 NMR...
.
Molecular weight analysis
Aside from using NMRNMR
NMR may refer to:Applications of Nuclear Magnetic Resonance:* Nuclear magnetic resonance* NMR spectroscopy* Solid-state nuclear magnetic resonance* Protein nuclear magnetic resonance spectroscopy* Proton NMR* Carbon-13 NMR...
to determine a polyanhydride’s molecular weight, gel permeation chromatography
Gel Permeation Chromatography
Gel permeation chromatography is a type of size exclusion chromatography , that separates analytes on the basis of size. The technique is often used for the analysis of polymers. As a technique, SEC was first developed in 1955 by Lathe and Ruthven. The term gel permeation chromatography can be...
(GPC), and viscosity
Viscosity
Viscosity is a measure of the resistance of a fluid which is being deformed by either shear or tensile stress. In everyday terms , viscosity is "thickness" or "internal friction". Thus, water is "thin", having a lower viscosity, while honey is "thick", having a higher viscosity...
measurements may also be used.
Thermal properties
Differential scanning calorimetryDifferential scanning calorimetry
Differential scanning calorimetry or DSC is a thermoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample and reference is measured as a function of temperature. Both the sample and reference are maintained at nearly the same temperature...
(DSC) is used to determine the thermal properties of polyanhydrides. Glass transition temperature, melting temperature, and heat of fusion can all be determined by DSC. Crystallinity of a polyanhydride can be determined using DSC, Small angle X-ray scattering (SAXS), Nuclear magnetic resonance
Nuclear magnetic resonance
Nuclear magnetic resonance is a physical phenomenon in which magnetic nuclei in a magnetic field absorb and re-emit electromagnetic radiation...
(NMR), and X-ray diffraction.
Degradation
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
describe how the polymer physically loses mass (degrade
Chemical decomposition
Chemical decomposition, analysis or breakdown is the separation of a chemical compound into elements or simpler compounds. It is sometimes defined as the exact opposite of a chemical synthesis. Chemical decomposition is often an undesired chemical reaction...
s). The two common erosion mechanisms are surface and bulk erosion. Polyanhydrides are surface eroding polymers. Surface eroding polymers do not allow water to penetrate into the material. They erode layer by layer, like a lollipop. The hydrophobic backbone with hydrolytically labile anhydride linkages allows hydrolytic degradation to be controlled by manipulating the polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
composition. This manipulation can occur by adding a hydrophilic group to the polyanhydride to make a copolymer. Polyanhydride copolymers with hydrophilic groups exhibit bulk eroding characteristics. Bulk eroding polymers take in water like a sponge (throughout the material) and erode inside and on the surface of the polymer.
Drug release from bulk eroding polymers is difficult to characterize because the primary mode of release from these polymers is diffusion
Diffusion
Molecular diffusion, often called simply diffusion, is the thermal motion of all particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size of the particles...
. Unlike surface eroding polymers, bulk eroding polymers show a very weak relationship between the rate of polymer degradation and the rate of drug release. Therefore, the development of surface eroding polyanhydrides incorporated into the bulk eroding polymers is of increased importance.
Biocompatibility
BiocompatibilityBiocompatibility
Biocompatibility is related to the behavior of biomaterials in various contexts. The term may refer to specific properties of a material without specifying where or how the material is used , or to more empirical clinical success of a whole device in...
and toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
of a polymeric material is evaluated by examining systemic
Systemic
Systemic refers to something that is spread throughout, system-wide, affecting a group or system such as a body, economy, market or society as a whole. Systemic may also refer to:-In medicine:...
toxic responses, local tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
responses, carcinogenic and mutagenic responses, and allergic responses to the material's degradation products. Animal studies are conducted to test the polymer’s effect on each of these negative responses. Polyanhydrides and their degradation products have not been found to cause significant harmful responses and are considered to be biocompatible.