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Because current treatments for arthritis result in unwanted side effects and tend to be expensive, natural products devoid of such disadvantages and offer a novel opportunity. Agents derived from plants that can modulate the expression of pro-inflammatory signals clearly have potential against arthritis. These include flavonoids, terpenes, quinones, catechins, alkaloids, polyphenols, anthocyanins and anthoxanthins, all of which are known to have anti-inflammatory effects.
Systemic side effects of orally administered NSAIDs, corticosteroids and DMARDs used to treat RA involves bone loss, osteoporosis, peptic ulcers and buffalo hump, special drug delivery systems are required to deliver them to the site of action(targeted) and designed to provide targeted and controlled drug delivery with minimum side effects. We can incorporate the API in novel drug delivery systems like, SLN (Solid Lipid Nano particles), Nano Lipid Vesicles, Liposomes, Hydro gels, Specially Coated Tablets and Capsules, Pulse Release Tablets, Patches, Depot formation, Controlled release microchip, Polymeric carriers, Resealed erythrosomes, which provides optimum, controlled, effective and targeted drug release profile .
5.1. Oral route
Commonly the drugs used in treatment of RA are administered by oral route. Because of the frequent administration and side effects of orally administered medication following approaches are made for desired release profile like extended release dosage forms.
Extended Release dosage forms fall into one of the following two technologies:
A. Hydrophilic, hydrophobic or inert matrix systems: These consist of a rate controlling Polymer matrix through which the drug is dissolved or dispersed.
B. Reservoir (coated) systems: Where drug-containing core is enclosed within polymer coatings. Depending on the polymer used, two types of reservoir systems are considered
(a) Simple diffusion/erosion systems: Where a drug-containing core is enclosed within hydrophilic and/or water-insoluble polymer coatings. Drug release is achieved by diffusion of the drug through the coating or after the erosion of the polymer coating.
(b) Osmotic systems: Where the drug core is contained within a semi-permeable polymer membrane with a mechanical/laser drilled hole for drug delivery. Drug release is achieved by osmotic pressure generated within the tablet core .
Micro-porous membrane coating on the soluble salts of indomethacine is done by pelletization technique and it will result in extended release formulation . Other approach is Pulsatile drug delivery system which involves release of drug from the formulation on specific intervals with lag phases . Combination product of NSAIDâ€™s and steroids can provide better care with minimum gastric erosion and that is proved by marketed formulation ArthrotecÂ® (Diclofenac Sodium and Misoprotol) [35, 36].
Controlled-Release Microchip: The conventional controlled drug release from polymeric materials is in response to specific stimuli such as electric and magnetic fields, ultrasound, light, enzymes. Microchip technology has been applied to achieve pulsatile release of liquid solutions. A solid-state silicon microchip was invented at the Massachusetts Institute of Technology (Cambridge, MA), which incorporates micrometer-scale pumps and flow channels to provide controlled release of single or multiple chemical substances on demand .
5.2. Parenteral route
Parentral route of drug administration is the second highly preferred route for the treatment of RA as administration of certain drugs and biological can be done by only this route and also provide immediate relief. But non-convenience and not possible self-administration are main drawbacks.
PLA and PLGA Nanoparticles encapsulating anti-arthritic drugs gives both sustained as well as targeted drug delivery. Higaki et al studied that glycolic acid nanoparticles containing corticosteroids will provide slow release and targeted delivery .
HumiraÂ® pen and SimpleJectâ„¢ are examples of self administration devices available in the market. Both of these are delivered through sub-cutaneous route and provide drastic relief in rheumatic pain [40, 41].
Lipid Microspheres, liposome and co-polymeric blocks are excellent carriers among the all other carriers for Parentral administration because they provide high stability and safety . Microspheres are best carrier for stable as well as fragile drug molecules, they increases patient comfort and compliance. Lipid microspheres have additional benefits like they provide targeted approach as they tend to accumulated in the inflamed area and by nature they provide controlled release . Liposome is showing same advantages as lipid microspheres, Prednisolone containing TRX-20 liposome is the best example . Microsphere and liposome can also be used in combination therapy. A combination of methotrexate and monoclonal antibody within liposome is well known example. Drug is encapsulated within liposome and antibody is attached to liposome provides two important functions: controlled and targeted release.
5.3. Topical route
Gastric bleeding and peptic ulcer are the major side effects in systemic drug delivery of NSAIDs and which is easily overcome by topical route . Poloxomer containing Methotrexate is one of the example showing feasibility of topical route of administration, it produces higher drug concentration at the site of the action beneath the skin . Iontophoresis is special method for delivering the drug across the barriers of the skin by applying electric transmission, applied potential pushes the drug molecule to penetrate across the skin. Cannabidiol when administered orally to treat RA has many systemic side effects, however iontophoretic trans-dermal administration prevent inflammation and edema . Oleo Hydrogel is lipid micro or nano emulsion which enhances absorption and penetration, also addition of penetration enhancers like DMSO increases effectiveness of topical formulation.
In RA hypoxia is common so this can be utilize as to target our drug to hypoxic joint. Bioreductive drug targeting involves the same mechanism that oxygen suppresses the release of the drug while lack of it cause release. Self alkylating system involves alteration of nucleophile into bioreductive structure to favor intramolecular cyclisation over nucleophilic attack from DNA molecules .
Nasal route provides effective, convenient, accurate and repeatable dosing. Intranasal route of drug administration provides total bioavailability as same as Parentral or more than that. It is non-invasive and rapid acting route of drug administration . Glycoprotein-39 administration in mice model through intranasal route shows effective treatment of RA .
Studies which are involving various types of the connective tissue collagen are in advancement and are showing positive signs of reducing rheumatoid disease activity. Finally, genetic engineering and research is likely to bring forth many new opportunities for earlier diagnosis and accurate treatment in the near future. Gene array analysis a Gene profiling method is being identified as a helpful method in defining responsiveness of people towards medications. Studies are under way that is using gene array analysis to determine which patients will be at more risk for more aggressive disease. This is all occurring because of improvements in technology.
Pharmacological therapy is the cornerstone in the management of established RA. Pharmacological and non-pharmacological therapies are necessary to reach these goals. This management plan may be adjusted during patient follow-up using information from measurements of disease activity, disability and joint damage. The ability of the new biological response modifiers to intervene in the disease process has generated enthusiasm for therapeutic interventions and for the possibility of future drugs that target individual inflammatory pathways. However, this excitement is tempered by the potential for long-term side-effects and toxicity.
Generally, MTX is regarded as the first choice in the DMARD, and MTX is most often used in combination strategies. Combinations of MTX and TNF blocking agents and MTX with sulphasalazine and/or hydroxychloroquine have shown good efficacy/toxicity ratios. Intramuscular gold, have also been shown to be effective in clinical trials. For optimal treatment in clinical practice, a longitudinal management plan should be defined for each individual patient with established RA, including the goals of treatment. However, it is difficult to predict how patients will respond to first line and second line therapy. Patients not responding to initial therapy are candidates for therapy change including combination strategies.