Drug Delivery Systems : Stability Of Therapeutic Proteins

"Absorption depends on the drug’s ability to cross cell membranes and resist extensive breakdown by the stomach, liver, and intestines.

Arthritis (along with other rheumatic conditions) has been the leading cause of disability among US adults for the past 15 years. According to Dr Vijay Vad, (Dr Vijay Vad, 2009), arthritis is one of the oldest and most chronic diseases in the world. The origins of rheumatic conditions such as arthritis date back to ancient times. Evidence of this include ancient skeletons

Arthritis is a biological term that refers to joint pain or joint disease that affects more than 50 million adults and 300,000 children (Arthritis Foundation). Because of the large variety in the affected population, there are complications in arthritis research due to the differences in its severities and symptoms. One of the most common types of arthritis is rheumatoid arthritis, an autoimmune disease that causes inflammation within the lining of joints resulting in pain and swelling (Arthritis Foundation). It affects more than 1.3 million Americans and approximately 7 million people worldwide (Rheumatoid Arthritis 2016) causing debilitating symptoms to millions of people. Because of its prevalence, research needs to be fully investigated

There are many new ways that are currently being used to improve the oral bioavailability of protein therapeutics. One way is to create microspheres of the product. This can increase bioavailability of the oral route. There are some drugs that are have microsphere technology but no FDA approved oral microspheres peptides. There are a few drug products that have been microencapsulated, Micro-K, Raloxifene Hydrochloride, and insulin. The Micro-K is an FDA approved drug product and it provides an extended release oral dosage form that some patients prefer. It releases potassium slowly in the GI tract like other extended release forms.

Rheumatoid Arthritis (RA) is a common autoimmune disease. The chronic inflammation they induced lead to severe joint swelling and damage2. It is more likely to strike on aged people and females3. In Australia, 400,000 people are suffering from it with different extent3-4. The mechanisms of the disease are well-studied. The synovium is the primary target of the immune system for RA patients. With white blood cells migrated in, the synovium membrane becomes thick and inflamed, which leads to undesired tissue growth3. Various chemical substances are released from the inflamed site and starts affecting surrounding tissues, such as cartilages and ligaments. In severe cases, they might even result in whole-body disorder2-4.

According to Casey, 2015, the common word of the inflammation of the joint is arthritis. Arthritis cane is a long term disabling disease or short-term effect of infection such as viral or bacterial. The losing quality of life, debility and early death of people with the chronic arthritic condition. People with arthritis need a multidisciplinary strategy and significant pharmacological remedy including multiple anti - arthritic drugs under classes of drugs such as disease modifying antirheumatic drug (DARMDs), NSAIDs (non-steroidal drugs, glucocorticoids.

According to the U. S. Pharmacopeia (USP), gels are defined as “semisolid systems consisting of either suspensions made up of small inorganic particles or large organic molecules interpenetrated by a liquid”. (2)

Chitosan (CS) is the second generous linear polysaccharide and a cationic polyelectrolyte present in nature. CS has depicted convenient biocompatibility and increasing membrane permeability characteristics both in vitro and in vivo and can be degraded by lysozyme in serum. On account of its mucoadhesive and permeability, CS has the potential of serving as an adsorption enhancer across intestinal epithelium and it was an illustrated biopharmaceutical fact. CS also enhance insulin absorption without injuring human intestinal epithelial (Caco-2) cells. In the pharmaceutical industry, CS has several uses such as preparing films, beads, intragastric floating tablets, microspheres, and nanoparticles. The research explains the importance of size and

Drug delivery systems (DDS) have been developed in order to control pharmacological parameters such as bioavailability, biodistribution and pharmacokinetics of the administered substances. Bioavailability is defined as the percentage of an administered dose of therapeutic agent that becomes available in the systemic circulation in its active form. Drug delivery systems can enhance bioavailability by increasing in-vivohalf-lives of fragile pharmaceuticals e.g. protection of proteins from enzymatic degradation or by changing their chemical characteristics - e.g. improving solubility of hydrophobic moieties. Biodistribution is defined as the percentage of an administered drug that becomes deposited into specific organs throughout the body at specific time points. Drug delivery systems can alter the biodistribution of a drug by active targeting of specific cell types, passive targeting (accumulation in certain tissues), retention at the injection site or by helping to cross biological barriers.

Pharmaceutical formulations are important in the treatment of human and animal disease conditions (Thiele-Bruhn and Beck, 2005). Pharmaceutical chemicals (PHCs) are recognized as biologically active compounds and their molecular weights may range from 200 to 500 / 1000 Dalton. Currently, there is little information on the total global administration of drugs to humans and animals. Despite the unavailability of data, the total sales of formulations were $518 billion in 2004 (Kümmerer, 2009). This figure is even projected to increase to nearly $1.2 trillion by 2016 with the influence of merging markets, biologics and generics (IMS Health, 2012). Therefore, their increased production, sales and consumption may translate to higher pharmaceutical residues in the environment. An ingested drug becomes metabolized and a portion apparently, is excreted through urine and / or feces in both metabolized and un-metabolized forms. Consequently, they reach receiving-surface waters since conventional wastewater treatment systems are inefficient (Zuehlke et al., 2004; Daughton, 2007). Pharmaceutical products available to the United States (U.S.) population are categorized under prescription and over-the-counter medications.

Oral controlled release and site specific drug delivery system has been of great interest in pharmaceutical field to achieve improved therapeutic advantage. Drug absorption in the gastrointestinal tract is a highly variable procedure and prolonging gastric retention of the dosage form extends the time for drug absorption. Gastro retentive drug delivery system is one of such novel approaches to prolong gastric residence time, thereby targeting site specific drug release in the stomach for local or systemic effects. This approach is useful particularly for the drugs which have narrow absorption window in the upper part of gastro intestinal tract. Various approaches of gastro retentive drug delivery system, such as floating and non-floating, have been discussed in this review. This review also gives an overview of merits, demerits and evaluation parameters of gastro retentive system.

With the emergence of more novel and effective drug therapies, increased importance is being placed upon the methods by which these drugs are being delivered to the body. Different methodologies have been heavily investigated as possible solutions , one of these methods are intelligent or ‘Smart polymeric drug-delivery systems’. “Stimuli responsive” and “self regulating” drug delivery systems have captured the imagination of researchers, in large part because they suggest a means to mimic the physiological homeostatic feedback mechanisms that are essential for health. As dysregulation of homeostasis is a feature of many diseases such as diabetes and cancer.

Qt = amount of drug dissolved in time t, Qo=initial amount of drug, k=zero order kinetics constant

Lipid based delivery systems which are composed of both liposomes and emulsions are called biphasic systems. Biphasic vesicle systems provide several advantages as a topical carrier system such as have multichamber structure allow encapsulation and co-encapsulation of various therapeutics of different weight range with different solubilities. Biphasic systems are evaluated for many vaccine candidates including proteins, nucleotides, recombinant subunits and classical old inactivated or killed vaccines and now became applicable to purposes in human as well as in animals [150,148,149]. Baca-Estrada et al., [150] has shown topical delivery of hen egg lysozyme (HEL) and leukotoxin antigens in biphasic delivery system induce strong Th-2 cellular response and induce secretion of IgG1 antibody response. Foldveri et al., [151] formulated biphasic delivery system of plasmid DNA (pDNA) and shown that it delivered significant quantities of pDNA into the viable layers of human skin in vitro and induce 5 times higher anti-IgD levels compared with naked DNA alone and secrete IL-4 by cells and induce cellular immune response. Babiuk et al., [152] demonstrated that topical delivery of plasmid in biphasic lipid delivery system results to induce cellular and humoral response. Transcutaneous immunization induces Th-2 whereas intradermal administration induces Th-1 type cellular immune response.

The purpose of writing this review was to investigate, compile, recent, current and past literatures. In recent years several advancements has been made in research and development of oral drug delivery system. Various drugs, which are unstable in alkaline pH, soluble in acidic pH, having narrow absorption window, site of action specific to stomach can be developed by using this technique. Gastro-retentive drug delivery systems (GRDDS) can improve the controlled delivery of drugs that have an absorption window by continuously releasing the drug for a prolonged period of time before it reaches to absorption site. These include floating system, swelling system, expanding system, low density systems, high density system, bioadhesive and mucoadhesive systems etc. In fact the buoyant dosage unit enhances gastric residence time (GRT) without affecting the intrinsic rate of emptying. GRDDS is an approach to prolong gastric residence time, thereby targeting site-specific drug release in upper gastro intestinal tract improving the oral sustained delivery of drug. For minimizing the limitations and achieving better gastric retention various combinational approaches floating and swelling, floating and bio-adhesion, etc., multi-particulate systems, super porous hydrogel etc., have been discussed. The present review addresses briefly about suitable drug candidates, formulation considerations, physiological difficulties and classification, factors effecting gastric retention, merits,