NSAID Non-steroidal anti-inflammatory drugs

1. Introduction

1.1 Ibuprofen, a Non-steroidal Anti-inflammatory Drug (NSAID)

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used and therapeutically effective groups of drugs in the medicinal field. They suppress inflammation in a similar way as steroids. They are also better than steroids in such a way that they cause less side effects of sedation, addiction and respiratory depression. NSAIDs act by inhibiting cyclooxygenase (COX) enzymes, COX-1 and COX-2. This type of inhibition results in reduced productions of precursors such as thromboxane, prostaglandin and leukotriene that are involved in the inflammatory pathways.

NSAIDs are poorly water-soluble drugs (Hassan et al., 2009). Often, they are microencapsulated using the emulsion solvent diffusion method (Leo et al., 2000) to modify and retard drug release from pharmaceutical dosage form. Further, encapsulation of NSAIDs into polymeric nanoparticles, followed by their encapsulation into polymeric microparticles has proved to reduce the release rate and suppress the undesired initial burst. For instance, Ibuprofen-loaded PCL (Poly-epsilon-caprolactone) nanoparticles inside ethylcellulose/Eudragit RS polymeric microparticles was successfully encapsulated, which effectively exhibited a control of both the release rate and burst effect (Hassan et al., 2009; Socha et al., 2007).

Ibuprofen, an NSAID, was selected as the model drug in this study. The low solubility (0.03-2.5mg/ml) (Khang et al., 2007) and short plasma half-life of approximately 2 hours of Ibuprofen makes it an ideal choice to prepare a controlled release dosage form. Ibuprofen is commonly used to relieve the symptoms of mild and moderate pain and inflammation in conditions such as migraine, dental pain, dysmennorhea, headaches, back pain, muscular pain, rheumatic pain, cold and flu symptoms. Also, it is used to treat chronic diseases such as rheumatoid arthritis in which a controlled release dosage form is desired for symptom relief (Leo et al., 2000).

Although parenteral Ibuprofen formulation has been produced recently, there is no controlled release dosage form available in the pharmaceutical market. Considering that Ibuprofen is a anti-inflammatory agent used widely, this study of preparation of a biodegradable and controlled release parenteral Ibuprofen dosage form, based on nanoparticles will definitely of great interest.

For example, the intraarticular administration of Ibuprofen would offer an effective management of chronic rheumatoid arthritis. Also, it will serve an alternative to corticosteroid administration to avoid the devastating side effects (Hassan et al., 2009; Fernandez-Carballido et al., 2004). Besides, two types of parenteral formulations of Ibuprofen are now available in the pharmaceutical market. One of them is Pedea which is used for the therapy of ductus arteriosus in preterm newborns (Hassan et al., 2009, Aranda and Thomas, 2006). Its use in human pre-mature newborns was also demonstrated to be able to improve the cerebral blood flow regulation and potentially offer some degree of neuroprotection (Aranda and Thomas, 2006). It is a normal aqueous solution dosage form which is injected into the bloodstream, allowing fast therapeutic activity. Another parenteral Ibuprofen formulation is marketed by Cumberland Pharmaceuticals recently– the injectable ibuprofen formulation named Caldolor which is used for the treatment of pain and fever. Caldolor has also proved to have the advantage of reducing pain and fever significantly within 30 minutes.

Although rapid attainment of therapeutic effect can be achieved, the short plasma half-life of Ibuprofen would have resulted in frequent administration in order to maintain plasma therapeutic levels. For instance Caldolor needs to be administered intravenously every 6 hours in order to maintain efficient plasma therapeutic levels. Therefore, controlled drug delivery systems would be a better yet excellent alternative to multiple injections. And, in such case, polymeric nanoparticles will be the best candidate for parenteral drug delivery. This polymeric nanoparticulate drug delivery system would be potentially used to increase bioavailability, provide prolonged therapeutic plasma levels and reduce administration frequency.

1.2 Controlled Drug Delivery and Drug Targetting

To deliver drugs from the administration site to the target site, a delivery system is needed as drugs could not deliver by themselves (Davis and Illum, 1998; Bala et al., 2004). An ideal drug delivery system will possess both the properties of targeting and controlling the drug release (Thassu et al., 2007). Targeting ensures high effectiveness of the drug and at the same time reduces the possible devastating side effects that may be experienced. This is particularly beneficial when dealing with drugs for instance, drugs used in cancer therapy to ensure that only affected cancer cells but not healthy cells are killed (Brannon-Peppas and Blanchette, 2004). The reduction of side effects can also be attained through controlled release dosing systems. This study will focus on the parenteral controlled-release dosage forms.

1.2.1 Rationale for Parenteral Controlled-release Drug Delivery

Parenteral controlled-release dosage forms have been proved to be useful for treating disease (Kydonieus, 1992). However, there is no single controlled-release technology that has proved to be effective in treating disease because of the diversity of drug properties, dosing levels, treatment durations as well as patient acceptability and cost. Therefore, an excellent controlled release technology is needed to be selected for each drug and associated disease treatment.

The distribution of drug in the body after parenteral administration well depends entirely on the physicochemical properties of the drug. Conventional drug delivery is typically illustrated by drug administered via bolus injection, in which the most of the therapeutic agents in the drug are released immediately after the administration, causing a rapid increase of the plasma drug concentration levels (Uhrich et al., 1999). Drug concentration is then seen to fluctuate between the side effect level and the minimum therapeutic level, resulting in alternate periods of toxicity and ineffectiveness (Stevanovic and Uskokovic, 2009). As a consequence, higher dosage drug is needed to be administered repeatedly to maintain the therapeutic drug concentration at steady state level. Problems, hence, arise as multiple injections are not favoured by most patients.

Therefore, in order to improve efficacy, patient compliance and convenience, a controlled-release parenteral dosage forms that can last for longer period of time after a single administration will be more beneficial. This controlled release over an extended time is also of great benefits for drugs that are rapidly metabolized and eliminated from the body after administration. This is because controlled release maintains drug concentration at steady state level for a sufficient duration at the target sites, where the rate of drug release is equivalent to the rate of drug elimination, thus keeping the drug concentration within the ideal therapeutic window as well as avoiding substantial fluctuations. As a result, frequent injections can be avoided.

1.3 Nanotechnology for Controlled Drug Delivery

In the endeavour to design a parenteral controlled release dosage form, a number of drug delivery systems, such as emulsions, micelles, liposomes and nanoparticles have been developed (Kydonieus, 1992; Hassan et al., 2009). In fact, injectable, biodegradable nanosphere products are the most recent technology developed for parenteral controlled-release dosage forms. This termed nanoparticulate drug delivery system, which comprises of colloidal particles of nanosize range, provides a suitable mean of delivering not only small molecular weight drugs but also macromolecules such as hormones, proteins, peptides and nucleic acids (Bala et al., 2004; Panyam and Labhasetwar, 2003). Furthermore, the nanoparticulate drug delivery system evidences the successful development of the nanotechnology.

The prefix “nano” is derived from the Greek word dwarf (Thassu et al., 2007). One nanometer (nm) is equivalent to one-billionth of a meter. Materials in the nanometer size range can have substantial properties compared with the same materials at a larger size, for instance materials in the micrometer size range (Hans and Lowman, 2002). The term “nanotechnology” was coined in 1974 by Norio Taniguchi, a professor of the Tokyo Science University, Japan to describe materials in nanometers (Kydonieu, 1992). In recent years, nanotechnology has gained much attention that there has been an increasing investment trend from governments and private sector business in many parts of the world to expand research in nanoscale science and technology.

Generally, nanotechnology means any technology performed on a nanoscale that involves both science and engineering (Bhushan, 2004). It encompasses the manufacture and application of biological, chemical and physical systems at scales that range from individual atoms or molecules to nanoscale dimensions. Also, it integrates the resulting nanostructures into larger systems (Bhushan, 2004). Controlled drug delivery nanotechnology has become one of the most advancing areas of science that contributes to human health care. This field of pharmaceutical technology has grown and expanded rapidly these days. And it is believed that such delivery system will definitely bring abundant advantages compared to conventional drug delivery system.

1.4 Natural and Synthetic Polymers in Pharmaceutical Systems

Polymers are high molecular weight substances that are made up of repeating monomer units. In order to develop a successful nanoparticulate delivery system, it is essentially important to select an appropriate polymeric matrix. Polymers nanospheres employed to deliver drugs in a sustained release manner can be either biodegradable or non-biodegradable (Uhrich et al., 1999). The controlled release can be achieved by combining the biodegradable polymer with a drug so that the active agent is released from the system in a predesigned way. Despite the fact that controlled drug delivery has various advantages, the possible drawbacks cannot be overlooked: the undesirable by-products from degradation, potential toxicity or non-biocompatibility of the materials used, any surgery involved to remove or implant the system, the likehood of patient discomfort from the delivery device, and the higher cost involved compared with traditional pharmaceutical formulations (Stevanovic and Uskokovic, 2009; Brannon-Peppas, 1997).

Several polymers, including both natural and synthetic polymers have been investigated for formulating biodegradable polymeric nanoparticles. These include polylactide (PLA), polycaprolactone (PCL) and poly(lactide-co-glycolide) (PLGA), which are biodegradable and biocompatible. Among these polymers, PLGA is the most commonly used due to its biodegradability, biocompatibility as well as flexible degradation kinetics (Sahana et al., 2007). In fact, PLGA has been approved by FDA (Food and Drug Administration) for a number of clinical applications (Bhardwaj et al., 2005) such as synthetic resorbable sutures, surgical clips and other surgical implants (Kydonieus, 2005).

1.4.1 Poly(lactide-co-glycolide) (PLGA) as Polymers

PLGA is a copolymer of PLA and PGA. It is synthesised by co-polymerisation of two different monomers, the cyclic dimmers of glycolic acid and lactic acid. During polymerisation, successive monomers of both glycolic and lactic acid are linked together by ester bonds, producing a linear polyester of PLGA. Different forms of PLGA can, thus, be yielded by altering the mixing ratio of lactide to glycolide used in the polymerisation process.

A basic insight of physicochemical and biological properties of the PLGA polymer is vital as it allows the study of the mechanism and rate of drug release from the nanoshperes. PLGA degrades in vivo by hydrolytic cleavage of the ester linkage in the presence of water (Bala et al., 2004; Stevanovic and Uskokovic, 2009). However, the degradation process of polymers is affected by a number of factors. The polymer nature (polydispersity and copolymer composition), the degree of crystallinity, the glass transition temperature of the polymer, organic solvents, type and concentration of stabiliser used are all the common factors (Bala et al., 2004).

The degradation profile of nanoparticulate systems, on the other hand, relies on the hydrophilicity of the polymer. The more hydrophilic the polymer, the higher its rate of degradation (Bala et al., 2004; Stevanovic and Uskokovic, 2009). In fact, the hydrophilicity of the polymer is determined by the crystalline to armorphous ratio, that is consecutively affected by the composition of the copolymer (Bala et al., 2004). Owing to the fact that lactide is more hydrophobic than glycolide, PLGA copolymers with high content of lactide units will be less hydrophilic, thus experiencing slower degradation process. For this reason, the rate of degradation and release profile of PLGA can be modified easily by varying the ratio of lactide to glycolide (Sahana et al., 2007). It is noted that PLGA copolymer with composition of 50:50 ratio shows the fastest degradability rate about 1-2 months in both in vitro and in vivo conditions (Stevanovic and Uskokovic, 2009; Nair and Laurencin, 2007). Extensive investigations were then carried out on different forms of PLGA by changing the ratio of lactide to glycolide. The results showed that the PLGA copolymers of 65:35, 77:25, and 88:15 lactide/glycolide ratios have progressively longer in vivo degradation times, with the 88:15 one lasting about 5-6 months in vivo (Bala et al., 2004; Jain, 2000). During the preparation of PLGA loaded nanoparticles in this study, lactide-rich copolymers will be of great interest in order to formulate a nanosphere with controlled release properties.

PLGA is undoubtedly the ideal choice of polymer selected to be used in designing a controlled release nanoparcticulate delivery system. Because of its biodegradability, no surgical procedures are needed to remove the system when the drugs are depleted. Besides, it is degraded in vivo, by random, nonenzymatic, hydrolytic cleavage of ester linkages to toxicologically safe by-products (the original monomers- lactic and glycolic acid) that are either excreted renally or elimininated as carbon dioxide gas and water via Krebs’ cycle (Bala et al., 2004; Galindo-Rodriguez et al., 2005). Furthermore, PLGA has a glass transition temperature above physiological temperature (45-55°C) that provides it adequate strength to be formulated as a successful controlled drug delivery system (Bala et al., 2004). Because PLGA have proved to be biocompatible and to have extensive toxicological documentation, their approvals for use in fabricating nanospheres will be less costly and more straightforward than approvals of new polymers for fabrication in the pharmaceutical industry. For this reason, PLGA copolymers are selected as the colloidal carrier for parenteral controlled-release dosage forms in this study.

1.4.2 Therapeutic Uses of PLGA Polymers in Contemporary Clinical Formulations

The use of the PLGA polymer for the development of new parenteral controlled drug delivery dosage forms appears to be very promising. Nanospheres with various release patterns can be prepared by altering the polymer species, molecular weight or monomer mixing ratio. FDA has approved PLGA for a number of medical applications. For instance, Lupron Depot®, a controlled release formulation for treatment of advanced prostate cancer, was the first PLGA product cleared by FDA (Bala et al., 2004). The effective dose this formulation, which contains leuprolide acetate encapsulated in biodegradable microspheres of 75:25 lactide/glycolide polymer, was reduced 1/4 – 1/8 of that required in the conventional drug formulation (Sahana et al., 2007). Another successful development of controlled drug delivery systems includes anticancer drug, Doxorubicin formulated into PLGA nanoparticles, that exhibited controlled release over 1 month (Bala et al., 2004). In the following research work, Ibuprofen loaded PLGA nanoparticles are intended to be prepared with a view to possess the identical desired controlled release properties.

1.4.3 Preparation of PLGA loaded nanoparticles

Several approaches have been proposed for the preparation of PLGA nanoparticles. However, the choice of preparation method well depends on the type of the polymer and drug used, the intended use as well as the duration of the treatment. The standard procedures of emulsion-diffusion evaporation, salting-out and nanoprecipitation method are all widely used to prepare PLGA particles in the nanosize range. The first step of these methods often involves emulsification of a solution of drug in a solution of organic polymer (Stevanovic and Uskokovic, 2009). The dispersion formed is then processed in accordance with one of the aforestated methods.

During both emulsion-diffusion evaporation and salting out approaches, the polymer PLGA is dissolved in an organic solvent such as chlorinated solvent, dichloromethane and chloroform, tetrahydrofuran, acetone or ethyl acetate. The mixed organic solution of both polymer and drug is later mixed with an aqueous solution containing both stabiliser and emulsifying agents. The emulsion formed is then exposed to a high-energy source for example an ultrasonic device, homogenizer or colloid mill to form a stable oil-in-water (o/w) emulsion. The organic solvent is later evaporated under reduced pressure or continuous stirring, resulting in the formation of fine dispersion of nanoparticles containing therapeutic drugs. Factors such as homogeniser stirring rate, concentration of polymer, presence of surfactants and stabilisers will influence the size of the particles formed (Bala et al., 2004; Stevanovic and Uskokovic, 2009). Therefore, it is important to standardise these parameters in order to produce particles of desired size range.

The nanoprecipitation method, on the other hand, is based on the interfacial deposition of a polymer following displacement of a semi-polar solvent miscible with water from a lipophilic solution (Bala et al., 2004; Govender et al., 1999). The PLGA polymer and drug are then dissolved in a semi-polar water-miscible solvent, either acetonitrile or ethanol, forming the organic phase. The organic phase is then mixed with an aqueous solution containing stabiliser and stirred magnetically at room temperature to allow rapid solvent evaporation. The nanoparticles are finally purified using ultracentrifugation, ultrafiltration, gas chromatography, dialysis procedures to remove stabiliser residues or any free drug. This purification process must be carefully carried out to avoid any loss of biologically active ingredients.

1.5 Aims and Objectives

Realising the benefits and importance of controlled drug release in clinical applications, the objective of the present study is to prepare and characterise Ibuprofen loaded PLGA nanoparticles for parenteral delivery, with a view to prolong the ibuprofen blood residence time after injection. The objective will be achieved by the following specific aims:

1. Preparation of Ibuprofen loaded PLGA nanoparticles.

2. Characterization of the nanoparticles for size, zeta potential, and entrapment efficiency.

References

Aranda JV, Thomas R, 2006. Systemic review: Intravenous Ibuprofen in preterm newborns. Elsevier: Seminar in Perinatology.

Bala I, Hariharan S, Ravi Kumar MNV, 2004. PLGA nanoparticles in drug delivery: The State of the Art: Critical Review in Therapeutic Drug Carrier Systems. 21(5), 387-422.

Bhardwaj V, Hariharan S, Bala I, Lamprecht A, Kumar N, Panchagnula R, Ravi Kumar MNV, 2005. Pharmaceutical aspects of polymeric nanoparticles for oral delivery. Journal of Biomedical Nanotechnology. 1, 1-23.

Bhushan B, editor, 2004. Springer handbook of nanotechnology. New York: Springer.

Brannon-Peppas L, Blanchette JO, 2004. Nanoparticle and targeted systems for cancer therapy. Advanced Drug Delivery Reviews. 56, 1649-1659.

Brannon-Peppas L, 1997. Polymers in controlled drug delivery. Medical Plastics and Biomaterials Magazine.

Davis SS, Illum L, 1998. Drug delivery systems for challenging molecules. International Journal of Pharmaceutics. 176, 1–8.

Fernandez-Carballido A, Herrero-Vanrell R, Molina-Martinez IT, Pastoriza P, 2004. Biodegradable ibuprofen-loaded PLGA microspheres for intraarticular administration. Effect of Labrafil addition on release in vitro. International Journal of Pharmaceutics. 279, 33-41.

Govender T, Stolnik S, Garnett MC, Illum L, Davis SS, 1999. PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug. Journal of Control Release 1999. 57, 171–185.

Hans ML, Lowman AM, 2002. Biodegradable nanoparticles for drug delivery and targeting. Current Opinion in Solid State and Materials Science. 6, 319-327.

Hassan AS, Sapin A, Lamprecht A, Emond E, Ghazouani FE, Maincent P, 2009. Research paper: Composite microparticles with in vivo reduction of the burst release effect. European Journal of Pharmaceutics and Biopharmaceutics.

Jain RA, 2000. The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials. 21, 2475–2490.

Jiang BB, Hu L, Gao CY, Shen JC, 2005. Ibuprofen-loaded nanoparticles prepared by a co-precipitation method and their release properties. International Journal of Pharmaceutics. 304, 220-230.

Khang G, ChanYang J, TaeKo J, SooPark J, SukKim M, Rhee JM, BangLee H, 2007. Preparation and characterisation of ibuprofen using self-emulsifying drug delivery system in vivo. Key Engineering Materials. 342-343, 541-544.

Kydonieus A, editor, 1992. Treatise on controlled drug delivery. New York: Marcel Dekker, Inc.

Leo E, Forni F, Bernabei MT, 2000. Surface drug removal from ibuprofen-loaded PLA microspheres. International Journal of Pharmaceutics. 196, 1–9.

Nair LS, Laurencin CT, 2007. Biodegradable polymer as biomaterials. Progress in Polymer Science. 32, 762-798.

Panyam J, Labhasetwar V, 2003. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Advanced Drug Delivery Reviews. 55, 329–347.

Sahana DK, Mittal G, Bhardwaj V, Ravi Kumar MNV, 2007. PLGA nanoparticles for oral delivery of hydrophobic drugs: Influence of organise solvent on nanoparticles formation and release behaviour in vitro and in vivo using Estradiol as a model drug. Wiley InterScience.

Socha M, Hasan AS, Lamprecht A, Ghazouani FE, Sapin A, Hoffman M, Maincent P, Ubrich N, 2007. Effect of the microencapsulation of nanoparticles on the reduction of burst release. International Journal of Pharmaceutics. 344, 53–61.

Stevanovic M, Uskokovic D, 2009. Poly(lactide-co-glycolide)-based Micro and Nanoparticles for the Controlled Drug Delivery of Vitamins. Current Nanoscience. 5, 00-00.

Thassu D, Deleers M, Pathak Y, editors, 2007. Nanoparticulate drug delivery systems. Vol 166. New York: Drugs and the Pharmaceutical Sciences.

Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM, 1999. Polymeric systems for controlled drug release. Chemical Reviews. 99, 3181-3198.