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1.1 Introduction to arthritis
Arthritis is a major cause of disability and morbidity, particularly in older individuals. The symptoms and signs of arthritis and related conditions include pain, stiffness, swelling, muscle weakness, and limitation of movement of the joints. More than 30 percent of females have some degree of osteoarthritis by age 65.
There are four key warning signs of arthritis that include
Pain- Pain from arthritis can be constant, or intermittent. Pain might be isolated to one place or felt in many parts of the body.
Swelling- Some types of arthritis cause the skin over the affected joint to become red and inflamed. The inflammation leads to discomfort to the patient.
Stiffness- Stiffness is a typical arthritis symptom, which is felt upon waking up in the morning, after sitting at a desk, or after sitting in a car for a long time, also after exercise or even felt as persistent stiffness.
Difficulty in moving a joint- The symptom of difficulty in moving a joint or feeling pain in getting up from a chair indicate arthritis or other joint problem.
Arthritis can be categorized into two major groups: degenerative and inflammatory.
Osteoarthritis
Osteoarthritis is a chronic disease of the joint cartilage and bone, often thought to result from wear and tear on a joint, although there are other causes such as congenital defects, trauma and metabolic disorders. In an inflammatory osteoarthritis, the cartilage in joints breaks down. Cartilage is the slippery tissue that covers the ends of bones in a joint. Healthy cartilage absorbs the shock of movement. When cartilage is lost, bones rub together. Over time, this rubbing can permanently damage the joint.2, 4

Osteoarthritis
Rheumatoid Arthritis
Figure 1: Types of Arthritis
(Source: Health Information, Medical Reference Guide, In-Depth Patient Education Reports, University of Maryland medical centre, USA.)
1.1.2 Rheumatoid arthritis
In an inflammatory arthritis such as rheumatoid arthritis, there is a systemic illness with inflammation. Rheumatoid arthritis is an autoimmune disorder which is chronic and progressive and its manifestations are chronic inflammation of the synovial joint and also the joint destruction.
Inflammation is associated with the body’s immune system and attacks the tissue around the joints. Synovial lining layer surrounds the connective tissue in the joints and consists of a few cell layers of mainly fibroblast-like and macrophage-like synoviocytes. In RA, the synovial lining layer expands as a result of newly arrived macrophages from the periphery.4,5
Macrophages in the synovial lining of arthritic joints have been shown to produce many pro-inflammatory cytokines, attract new inflammatory cells and produce enzymes that can damage the cartilage. Inflammatory cells and enzymes responsible for inflammation is caused by release of chemicals from tissues and migrating cells. Most strongly implicated are the prostaglandins (PGs), leukotrienes (LTs), histamine, bradykinin, and, more recently, platelet- activating factor (PAF) and interleukin-15, 6, 7
1.2 Treatment of osteoarthritis and rheumatoid arthritis
Arthritis treatment focuses on relieving symptoms and improving joint function. The medications used to treat arthritis vary depending on the type of arthritis.
Table 1: Comparison of treatment of osteoarthritis and rheumatoid arthritis
Osteoarthritis Rheumatoid arthritis
Weight loss PT/OT, vocational rehabilitation
Orthotics/assistive device Exercise – strengthening, flexibility, aerobic
NSAIDs NSAIDs
Glucocorticoids Glucocorticoids
DMARDs
Methotrexate, sulfasalazine
IL-1 antagonist-Anakinra,
Diacerein DMARDs
Methotrexate, sulfasalazine
TNF antagonists – infliximab, adalimumab
IL-1 antagonist – Anakinra,
Diacerein B-Cell depletion – Rituximab
Non-acetylated salicylate Intra-articular, I/M or oral steroids
Viscosuplementation – hyaluronic acid, glucosamine sulfate,
chondroitin sulfate Viscosuplementation – hyaluronic acid, glucosamine
sulfate, chondroitin sulphate
Surgical therapy – osteotomy,
arthroscopy, joint replacement,
arthroplasty. Surgical therapy – osteotomy,
arthroscopy, joint
replacement, arthroplasty.

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1.2.1 Nonsteroidal anti-inflammatory drugs (NSAIDs)
Nonsteroidal anti-inflammatory drugs, or NSAIDs are the most prescribed medications for treating conditions such as arthritis. These are widely used drugs that act by inhibiting cyclooxygenase and the formation of prostaglandins.
Therefore, inflammation, pain, and fever are reduced. Since the prostaglandins that protect the stomach and promote blood clotting also are reduced, NSAIDs that block both COX-1 and COX-2 can cause ulcers in the stomach and intestines, and increase the risk of bleeding.
They are known to cause GI toxicity, leading to the formation of peptic ulcers, unwanted antiplatelet effects (nonselective inhibitors of cyclooxygenase), cardio toxicity, renal toxicity and anaphylactic reactions in selected patients.1,2,3 This class of drugs include diclofenac Na, aceclofenac, naproxen, ibuprofen, ketoprofen etc. The side effects of indomethacin, such as ulceration of the kidney and central nervous system (CNS) toxicity, limit its use as a drug for rheumatoid arthritis. Encapsulation of this drug in liposomes may reduce the toxic effects.3, 4
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1.2.2 Corticosteroids
These are medications that suppress the immune system and symptoms of inflammation. These are often injected into painful osteoarthritis joints. Steroids are used to treat autoimmune forms of arthritis. Steroids have multiple side effects, including upset stomach, gastrointestinal bleeding, high blood pressure, thinning of bones, cataracts, and increased infections. The risks are most pronounced when steroids are taken for long periods of time or at high doses. Close supervision by a physician is essential.4, 5
Besides the poor safety profile, also the poor pharmacokinetic behavior limits the usefulness of corticosteroids in systemic therapy. Corticosteroids are drugs with a relatively high clearance rate and a large volume of distribution. This implies that to reach pharmacologically active drug levels at the site of inflammation, high and frequent doses must be administered. The majority of these systemically administered doses localizes in healthy non-target tissues if not rapidly excreted from the body.4, 5, 6
1.2.2.1 Disease-modifying anti-rheumatic drugs
These have been used traditionally to treat rheumatoid arthritis and other autoimmune causes of arthritis. These drugs include gold salts, penicillamine, sulfasalazine, and hydroxychloroquine. More recently, methotrexate has been shown to slow the progression of rheumatoid arthritis and improve quality of life. Methotrexate itself can be highly toxic and requires frequent blood tests for patients on the medication.2, 3
1.3 Need of Study
Arthritis is a major cause of disability and morbidity, particularly in older individuals. The symptoms and signs of arthritis and related conditions include pain, stiffness, swelling, muscle weakness, and limitation of movement of the joints.
The currently available oral dosage forms of NSAIDs like tablet and capsules etc. are more likely to produce above mentioned adverse effects of these drugs. The intravenous administration of these drugs leads to distribution throughout the whole body and rapid clearance, thus a high and frequent dosing is necessary to achieve an effective concentration of drug at inflamed target sites. Moreover, the activities of drug in many different tissues increase the risk of adverse effects in patients. Topical delivery of drugs can be a suitable option and is associated with advantages such as avoidance of hepatic first-pass metabolism, improved patient compliance and ease of access, provides a means to quickly terminate dosing, sustained therapeutic drug levels, possible self administration, non-invasive, avoids food related interaction, reduction of doses as compared to oral dosage forms and intravenous therapy and most important is avoidance of gastrointestinal adverse effects.
The topical drug delivery also suffers from some shortcomings such as poor permeability through skin, unpredictable drug release and skin irritation. These shortcomings can be overcome if we develop a transdermal drug delivery system in nanoscaled drug carriers, with enhanced localization to the target site and sustained drug release.
1.4 Approaches for targeted drug delivery
To increase the amount of drug at the target site after systemic administration and to decrease localization at non target tissues, drug targeting approach may offer perspective through passive or active drug targeting.

Figure 2: Approches for target drug delivery
Drug targeting makes use of colloidal carrier systems in which the drug is incorporated or to which the drug is attached. Distribution of the carrier-associated drug to organs/tissues is reduced, as the carrier cannot diffuse into extravascular tissues.
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1.4.1 Passive targeting
Passive targeting is the drug targeting that can be achieved without any integration of a specific targeting moiety on the surface of particle. Interestingly, the approach of passive drug targeting can effectively be employed in inflammatory diseases.
Inflammation generally results in locally increased vascular permeability. It has been observed that, nanoparticles accumulate at the sites of inflammation in arthritic joints probably due to enhanced local capillary permeability.
The immune-related cells like macrophages is commonly present at the site of inflammation and it has been observed that microspheres and nanoparticles can be taken up efficiently by the macrophages, usually by the process of phagocytosis.4, 5, 6
Therefore, uptake of particles into such immune related cells and also by the disruption of the epithelium may lead to the selective accumulation of the nanocarrier based drug delivery system in the desired area of inflammation.4, 9
1.4.2 Active targeting
Active targeting of refers to the conjugation of site-directing ligands to the surface of Colloidal drug carriers to obtain specific binding to cell receptors on the surface of the target cells. Ligands may be antibodies, glycoproteins and glycolipids. The US patent bearing no- US 20070286896 in page no-38 says that the sugar chain present in glycolipids and glycoproteins play an important role in active targeting.
Active targeting aims at improving the therapeutic availability of colloidal drug carriers to target cells within the pathological site and to minimize undesired side effects to non-target cells within the pathological tissue.10
The most remarkable advantage of nanoscaled drug carriers over conventional drug delivery systems is the ability to improve selective drug delivery to the site of action by drug targeting which can be classified further into the active and passive drug targeting approaches.
1.5 Transdermal delivery of anti-arthritic drugs
Transdermal delivery of drugs has many advantages such as avoidance of hepatic first-pass metabolism, improved patient compliance and ease of access, provide a means to quickly terminate dosing sustained therapeutic drug levels, possible selfadministration, non-invasive (no needles or injections needed), avoids food related Interaction, reduction of doses as compared to oral dosage forms and intravenous therapy. Transdermal route allows drug to diffuse out of its vehicle onto the surface tissues of skin.
In fact ease of applicability makes this route more comfortable for the patient which results in better patient compliance.11,12,13
Transdermal drug administration is a localized drug delivery system in which drug can be applied through any part of skin of body. Skin is main route of transdermal drug delivery system. It is important to know the structure of skin and its barrier properties, which allowed the development of more easily applicable and novel transdermal formulations. Several drugs can be given by transdermal route with proved successfully safety and efficacy for both transdermal as well as systemic action. The pH of the skin varies from 4 to 5.6. Generally, the oral route is considered as the most common route of delivery of drugs. Though oral route has the benefit of ease of administration, it also suffers from shortcomings like poor bioavailability, the tendency to produce rapid blood level spikes leading to a need for high and /or frequent dosing. To overcome these difficulties there is a need for the development of new drug delivery system; which can improve the therapeutic efficacy and safety of drugs, for that purpose one has to select such a delivery in which is drug is given by transdermal route. Skin is main route of transdermal drug delivery system. Most of transdermal formulations are applied by the skin so, basic knowledge of skin anatomy and physiology is very important. The skin is the largest single organ of the body. The success of transdermal delivery depends on the ability of the drug to permeate the skin in sufficient quantities to achieve its desired therapeutic effect.14, 15
1.5.1 Advantages of transdermal drug delivery system
Provides targeted and localized action
Avoid gastrointestinal drug absorption difficulties caused by gastrointestinal pH and enzymatic activity and drug interaction with food and drinks.
Avoidance of the first pass effect.
Non-invasive and have patient compliance.
Can be easily removed from the skin.
Economic.
Reduction of doses as compare to oral dosage forms.
Localized effect with minimum side effects.12, 13
1.5.2. Ideal properties of drug candidate for transdermal Drug Delivery and marketed compositions
Table 2: Ideal properties of drug for TDDS
Sl.no NSAID Strength Trade name Manufacturing company
1 Diclofenac Sodium 1% Topical gel Diclofenac Sodium Amneal Pharmaceuticals, USA
2 Diclofenac Sodium 3% Topical gel Diclofenac Sodium Actavis Mid Atlantic, New
Zealand
3 Diclofenac Sodium 3% Topical gel Diclofenac Sodium Taro Pharmaceuticals, USA
4 Diclofenac Sodium 3% Topical gel Diclofenac Sodium Tolmar Inc. northern Colorado
5 Diclofenac Sodium 3% Topical gel Solaraze Fougera Pharmaceuticals, US
6 Diclofenac Sodium 1% Topical gel Voltaren Glaxo Smithkline, UK
7 Acelofenac 1.5% Topical gel hifenac gel Intas Pharmaceuticals Ltd, India
8 Acelofenac 1.5% Topical gel Accept gel Vivid Biotech,India
9 Indomethacin 1.5% Topical gel VI-Gel Diamond Lab, Philippines
10 Indomethacin 1.5% Topical gel Elmetacin Medinova, Switzerland
11 Indomethacin 1.5% Topical gel M-CIN Macro Pharma, India,
12 Indomethacin 0.75% Topical
gel Satogesic Sato Pharma, Japan
13 Indomethacin 1.0% Topical gel Indobene gel Merckle GmbH, Blaubeuren,
Germany
Table 3: Marketed transdermal compositions of NSAID’s
Parameter Properties
Dose Dose Should be low (20-50 mg/day)
Molecular weight 0.5Å~10-3 cm/hr
Melting point

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