Polyanhydrides

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Polyanhydrides are a class of biodegradable polymers characterized by anhydride bonds that connect repeat units 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.

Polymer substance composed of macromolecules with repeating structural units

A polymer is a large molecule, or macromolecule, composed of many repeated subunits. Due to their broad range of properties, both synthetic and natural polymers play essential and ubiquitous roles in everyday life. Polymers range from familiar synthetic plastics such as polystyrene to natural biopolymers such as DNA and proteins that are fundamental to biological structure and function. Polymers, both natural and synthetic, are created via polymerization of many small molecules, known as monomers. Their consequently large molecular mass relative to small molecule compounds produces unique physical properties, including toughness, viscoelasticity, and a tendency to form glasses and semicrystalline structures rather than crystals. The terms polymer and resin are often synonymous with plastic.

A repeat unit or repeating unit is a part of a polymer whose repetition would produce the complete polymer chain by linking the repeat units together successively along the chain, like the beads of a necklace.

In polymer science, the backbone chain of a polymer is the longest series of covalently bonded atoms that together create the continuous chain of the molecule. This science is subdivided into the study of organic polymers, which consist of a carbon backbone, and inorganic polymers which have backbones containing only main group elements.

Contents

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 devices.

In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or pharmacophore but can be modified by the other constituents. Among the various properties of chemical compounds, pharmacological/biological activity plays a crucial role since it suggests uses of the compounds in the medical applications. However, chemical compounds may show some adverse and toxic effects which may prevent their use in medical practice.

Drug delivery methods for transporting a drug in the body as needed to safely achieve its desired effect

Drug delivery refers to approaches, formulations, technologies, and systems for transporting a pharmaceutical compound in the body as needed to safely achieve its desired therapeutic effect. It may involve scientific site-targeting within the body, or it might involve facilitating systemic pharmacokinetics; in any case, it is typically concerned with both quantity and duration of drug presence. Drug delivery is often approached via a drug's chemical formulation, but it may also involve medical devices or drug-device combination products. Drug delivery is a concept heavily integrated with dosage form and route of administration, the latter sometimes even being considered part of the definition.

One example, Gliadel, 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.

Brain tumor type of tumor

A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: cancerous (malignant) tumors and benign (non-cancerous) tumors. Cancerous tumors can be divided into primary tumors, which start within the brain, and secondary tumors, which have spread from elsewhere, known as brain metastasis tumors. All types of brain tumors may produce symptoms that vary depending on the part of the brain involved. These symptoms may include headaches, seizures, problems with vision, vomiting and mental changes. The headache is classically worse in the morning and goes away with vomiting. Other symptoms may include difficulty walking, speaking or with sensations. As the disease progresses, unconsciousness may occur.

Chemotherapy treatment of cancer with one or more cytotoxic anti-neoplastic drugs

Chemotherapy is a type of cancer treatment that uses one or more anti-cancer drugs as part of a standardized chemotherapy regimen. Chemotherapy may be given with a curative intent, or it may aim to prolong life or to reduce symptoms. Chemotherapy is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer, which is called medical oncology.

Immune system A biological system that protects an organism against disease

The immune system is a host defense system comprising many biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, known as pathogens, from viruses to parasitic worms, and distinguish them from the organism's own healthy tissue. In many species, there are two major subsystems of the immune system: the innate immune system and the adaptive immune system. Both subsystems use humoral immunity and cell-mediated immunity to perform their functions. In humans, the blood–brain barrier, blood–cerebrospinal fluid barrier, and similar fluid–brain barriers separate the peripheral immune system from the neuroimmune system, which protects the brain.

Other applications of polyanhydrides include the use of unsaturated polyanhydrides in bone replacement, as well as polyanhydride copolymers as vehicles for vaccine delivery.

In chemistry, saturation has diverse meanings, all based on the idea of reaching a maximum capacity.

Vaccine biological preparatory medicine that improves immunity to a particular disease

A vaccine is a biological preparation that provides active acquired 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, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and to further recognize and destroy any of the microorganisms associated with that agent that it may encounter in the future. Vaccines can be prophylactic, or therapeutic.

Classes

The structure of a polyanhydride molecule with n repeating units. Polyanhydride structure.svg
The structure of a polyanhydride molecule with n repeating units.

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.

Carbon Chemical element with atomic number 6

Carbon is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds. It belongs to group 14 of the periodic table. Three isotopes occur naturally, 12C and 13C being stable, while 14C is a radionuclide, decaying with a half-life of about 5,730 years. Carbon is one of the few elements known since antiquity.

Chemical decomposition is the breakdown of a single entity into two or more fragments. Chemical decomposition is usually regarded and defined as the exact opposite of chemical synthesis. In short, the chemical reaction in which two or more products are formed from a single reactant is called a decomposition reaction.

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.

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 acid 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).

Chemical structure and composition analysis

The chemical structure and composition of polyanhydrides can be determined by H1 NMR 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.

Molecular weight analysis

Aside from using NMR to determine a polyanhydride’s molecular weight, gel permeation chromatography (GPC), and viscosity measurements may also be used.

Thermal properties

Differential scanning calorimetry (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.

Degradation

Comparison of bulk and surface erosion mechanisms. Bulk vs surface erosion.jpg
Comparison of bulk and surface erosion mechanisms.

The erosion and degradation of a polymer describe how the polymer physically loses mass (degrades). 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.

Biocompatibility

Biocompatibility 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.

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Biopolymer polymer produced by a living organism

Biopolymers are polymers produced by living organisms; in other words, they are polymeric biomolecules. Biopolymers contain monomeric units that are covalently bonded to form larger structures. There are three main classes of biopolymers, classified according to the monomeric units used and the structure of the biopolymer formed: polynucleotides, which are long polymers composed of 13 or more nucleotide monomers; polypeptides, which are short polymers of amino acids; and polysaccharides, which are often linear bonded polymeric carbohydrate structures. Other examples of biopolymers include rubber, suberin, melanin and lignin.

In polymer chemistry, polymerization is a process of reacting monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are many forms of polymerization and different systems exist to categorize them.

Petrochemical chemical product derived from petroleum

Petrochemicals are chemical products derived from petroleum. Some chemical compounds made from petroleum are also obtained from other fossil fuels, such as coal or natural gas, or renewable sources such as corn, palm fruit or sugar cane.

Epoxy family of polymer

Epoxy is either any of the basic components or the cured end products of epoxy resins, as well as a colloquial name for the epoxide functional group. Epoxy resins, also known as polyepoxides, are a class of reactive prepolymers and polymers which contain epoxide groups.

A polyamide is a macromolecule with repeating units linked by amide bonds.

An addition polymer is a polymer that forms by simple linking of monomers without the co-generation of other products. Addition polymerization differs from condensation polymerization, which does co-generate a product, usually water. Addition polymers can be formed by chain polymerization, when the polymer is formed by the sequential addition of monomer units to an active site in a chain reaction, or by polyaddition, when the polymer is formed by addition reactions between species of all degrees of polymerization. Addition polymers are formed by the addition of some simple monomer units repeatedly. Generally polymers are unsaturated compounds like alkenes, alkalines etc. The addition polymerization mainly takes place in free radical mechanism. The free radical mechanism of addition polymerization completed by three steps i.e Initiation of free radical, Chain propagation, Termination of chain.

Copolymer when two or more different monomers unite together to polymerize, their result is called a copolymer and its process is called copolymerization

A copolymer is a polymer derived from more than one species of monomer. The polymerization of monomers into copolymers is called copolymerization. Copolymers obtained by copolymerization of two monomer species are sometimes called bipolymers. Those obtained from three and four monomers are called terpolymers and quaterpolymers, respectively.

Polyglycolide chemical compound

Polyglycolide or poly(glycolic acid) (PGA), also spelled as polyglycolic acid, is a biodegradable, thermoplastic polymer and the simplest linear, aliphatic polyester. It can be prepared starting from glycolic acid by means of polycondensation or ring-opening polymerization. PGA has been known since 1954 as a tough fiber-forming polymer. Owing to its hydrolytic instability, however, its use has initially been limited. Currently polyglycolide and its copolymers are widely used as a material for the synthesis of absorbable sutures and are being evaluated in the biomedical field.

PLGA co-polymer of varying ratios of polylactic acid and polyglycolic acid, used as a matrix for drug delivery and for bone regeneration

PLGA, PLG, or poly(lactic-co-glycolic acid) is a copolymer which is used in a host of Food and Drug Administration (FDA) approved therapeutic devices, owing to its biodegradability and biocompatibility. PLGA is synthesized by means of ring-opening co-polymerization of two different monomers, the cyclic dimers (1,4-dioxane-2,5-diones) of glycolic acid and lactic acid. Polymers can be synthesized as either random or block copolymers thereby imparting additional polymer properties. Common catalysts used in the preparation of this polymer include tin(II) 2-ethylhexanoate, tin(II) alkoxides, or aluminum isopropoxide. During polymerization, successive monomeric units are linked together in PLGA by ester linkages, thus yielding a linear, aliphatic polyester as a product.

Polylactic acid polymer

Polylactic acid or polylactide (PLA) is a thermoplastic aliphatic polyester derived from renewable biomass, typically from fermented plant starch such as from corn, cassava, sugarcane or sugar beet pulp. In 2010, PLA had the second highest consumption volume of any bioplastic of the world.

Hot-melt adhesive solvent-free and at room temperature more or less solid products which are applied to the adhesive surface when hot

Hot melt adhesive (HMA), also known as hot glue, is a form of thermoplastic adhesive that is commonly sold as solid cylindrical sticks of various diameters designed to be applied using a hot glue gun. The gun uses a continuous-duty heating element to melt the plastic glue, which the user pushes through the gun either with a mechanical trigger mechanism on the gun, or with direct finger pressure. The glue squeezed out of the heated nozzle is initially hot enough to burn and even blister skin. The glue is tacky when hot, and solidifies in a few seconds to one minute. Hot melt adhesives can also be applied by dipping or spraying, and are popular with hobbyists and crafters both for affixing and as an inexpensive alternative to resin casting.

Polyester category of polymers

Polyester is a category of polymers that contain the ester functional group in their main chain. As a specific material, it most commonly refers to a type called polyethylene terephthalate (PET). Polyesters include naturally occurring chemicals, such as in the cutin of plant cuticles, as well as synthetics such as polybutyrate. Natural polyesters and a few synthetic ones are biodegradable, but most synthetic polyesters are not. The material is used extensively in clothing.

Biodegradable polymer

Biodegradable Polymers:-Biodegradable polymers are a special class of polymer that breaks down after its intended purpose by bacterial decomposition process to result in natural byproducts such as gases (CO2, N2), water, biomass, and inorganic salts. These polymers are found both naturally and synthetically made, and largely consist of ester, amide, and ether functional groups. Their properties and breakdown mechanism are determined by their exact structure. These polymers are often synthesized by condensation reactions, ring opening polymerization, and metal catalysts. There are vast examples and applications of biodegradable polymers.

Many opportunities exist for the application of synthetic biodegradable polymers in the biomedical area particularly in the fields of tissue engineering and controlled drug delivery. Degradation is important in biomedicine for many reasons. Degradation of the polymeric implant means surgical intervention may not be required in order to remove the implant at the end of its functional life, eliminating the need for a second surgery. In tissue engineering, biodegradable polymers can be designed such to approximate tissues, providing a polymer scaffold that can withstand mechanical stresses, provide a suitable surface for cell attachment and growth, and degrade at a rate that allows the load to be transferred to the new tissue. In the field of controlled drug delivery, biodegradable polymers offer tremendous potential either as a drug delivery system alone or in conjunction to functioning as a medical device.

A thermoset polymer matrix is a synthetic polymer reinforcement first developed for structural applications, such as glass-reinforced plastic radar domes on aircraft and graphite-epoxy payload bay doors on the space shuttle. In polymer matrix composites, polymers act as binder or matrix to secure in place incorporated particulates, fibres or other reinforcements.

PHBV polymer

Poly(3-hydroxybutyrate-co-3-hydroxyvalerate), commonly known as PHBV, is a polyhydroxyalkanoate-type polymer. It is biodegradable, nontoxic, biocompatible plastic produced naturally by bacteria and a good alternative for many non-biodegradable synthetic polymers. It is a thermoplastic linear aliphatic polyester. It is obtained by the copolymerization of 3-hydroxybutanoic acid and 3-hydroxypentanoic acid. PHBV is used in speciality packaging, orthopedic devices and in controlled release of drugs. PHBV undergoes bacterial degradation in the environment.

Poly(ethylene adipate)

Poly(ethylene adipate) or PEA is an aliphatic polyester. It is most commonly synthesized from a polycondensation reaction between polyethylene glycol and adipic acid. PEA has been studied as it is biodegradable through a variety of mechanisms and also fairly inexpensive compared to other polymers. Its lower molecular weight compared to many polymers aids in its biodegradability.

Biodegradable athletic footwear is athletic footwear that uses biodegradable materials with the ability to compost at the end-of-life phase. Such materials include natural biodegradable polymers, synthetic biodegradable polymers, and biodegradable blends. The use of biodegradable materials is a long-term solution to landfill pollution that can significantly help protect the natural environment by replacing the synthetic, non-biodegradable polymers found in athletic footwear.

Polyorthoesters are polymers with the general structure –[–R–O–C(R1, OR2)–O–R3–]n– whereas the residue R2 can also be part of a heterocyclic ring with the residue R. Polyorthoesters are formed by transesterification of orthoesters with diols or by polyaddition between a diol and a diketene acetal, such as 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5.5]undecane.

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