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Now-a-days the drug delivery technology background has become highly competitive and rapidly evolving. Developments in the delivery systems are being integrated for optimising the cost-effectiveness and efficacy of the drug therapy.
Drug delivery systems (DDS) can precisely control the drug release rates or to target drug moiety to a specific site in the body has its huge impact on the human health care system. Carrier technology provides an excellent approach to delivery drug molecule by coupling the drug to a carrier particle which can be microspheres, nanoparticles, liposomes, etc. which is able to modulate the release and absorption characteristics of the drug. Here Microspheres plays an important role in particulate drug delivery systems because of their small size and efficient carrier properties. (1)
THE MICROSPONGE DELIVERY SYSTEM
Microsponge Drug Delivery System is a exclusive technology has been used for the controlled release of topically active agents. A Microsponge Drug Delivery System (MDDS) is a highly cross-linked, porous, polymeric microsphere polymeric system consisting of porous microspheres which can entrap wide range of active substances and then release them onto the skin surface over a period of time and in response to trigger".(2) Microsponge Drug Delivery System is a unique technology for the controlled release of topically active moieties and consists of microporous beads, usually 10-25 microns in diameter, containing active drug moiety. When it has applied on to the skin, the Microsponges releases the active substance based on its time mode and also produce response to other stimuli such as rubbing, temperature, pH, etc. MDDS technology can be used in the cosmetics, over-the-counter (OTC) skin care Products, sunscreens and prescription products.(3) Microsponge technology provides entrapment of ingredients and is believed to contribute towards reduced side effects, improved stability, increased elegance, and enhanced formulation flexibility. In addition, abundant studies have confirmed that Microsponge Delivery systems are non-biodegradable, non-mutagenic, non-allergenic, and non-toxic, non-irritant.
The methods of formulation remains same; that include the incorporation of the active substance at its maximum thermodynamic activity in an optimized vehicle. Microcapsules cannot control the release rate of actives. Once the wall ruptures the actives present within microcapsules will be released. While microsponge system in contrast to the above systems will be stable over range of pH 1 to 11, temperature up to 130oC; compatible with most vehicles and ingredients; self sterilizing as average pore size is 0.25Î¼m where bacteria cannot penetrate; higher payload (50 to 60%), still free flowing and can be cost effective.(4) . The spheres in which micropores are present comprise a total pore density of approximately 1mL/g, for extensive drug retention.
Conventional formulations of topical drugs are intended to act on the outer layers of the skin. The Microsponge system can be able to prevent excessive accumulation of ingredients within the epidermis and the dermis. Potentially, the Microsponge system reduce the irritation of effective drugs without reducing their efficacy.(5)
PREPARATION OF MICROSPONGES
Drug is loaded in microsponges and it can be done in two ways, one-step process or by two-step process; which is based on physico-chemical properties of drug to be loaded. If the drug is typically an inert non-polar material, need to create the porous structure which is called porogen.
Liquid-liquid suspension polymerization:
The microspheres can be prepared by suspension polymerization method and it's prepared in liquid-liquid system. During the preparation, the monomers are first dissolved along with active drug substance in a suitable solvent solution of monomer and are then dispersed in the aqueous phase, which consist of additives (surfactant, suspending agents, etc.). The polymerization will be then initiated by adding catalyst or by increasing temperature or irradiation. The steps in the preparation of microsponges are summarized as:
- Selecting of monomer or combination of monomers
- Formation of chain monomers as polymerization starts
- Formation of ladders because of cross linking between chain monomers
- Folding of monomer ladder for the formation of spherical particles- Agglomeration of microspheres, which give rise to formation of bunches of microspheres
- Binding of bunches that form microsponges
The polymerization process results in the formation of a reservoir type of system, which opens at the surface through pores. In certain cases an inert liquid immiscible with water but completely miscible with monomer is used during the polymerization to form the pore network. After the polymerization liquid will be removed leaving the porous microspheres, i.e., microsponges. Impregnating them within preformed microsponges, incorporates the functional substances. Some times solvent can be used for faster and efficient incorporation of the active substances. The microsponges act as a topical carriers for various functional substances, e.g. anti acne, anti inflammatory, anti fungal, rubefacients, etc.(6)
Reaction vessel for microsponge preparation by liquid-liquid suspension polymerization
Microsponge preparation by liquid-liquid suspension polymerization
Quasi-emulsion solvent diffusion:-
Microsponges were prepared by a quasi-emulsion solvent diffusion method by an external phase containing distilled water and the internal phase consists of drug, polymer, solvent, plasticizer, which was added at a quantity of 20% of the polymer. At first, the internal phase should be prepared at 60Â°C and added to the external phase at room temperature. After emulsification, the mixture should be continuously stirred for 2 hours. Then the stirred mixture was filtered to separate the produced microsponges. The product must be washed and dried by vacuum oven at 40Â°C for about 24hours.(7)
Preparation of microsponges by quasi emulsion solvent diffusion method
Preparation of microsponges by quasi emulsion solvent diffusion method
Active moiety can be entrapped into MDDS can then be incorporated into many products (formulations) such as lotions, creams, soaps and powders. When formulating the medium, certain considerations taken into account to attain desired product characteristics.
The solubility of active drug molecules in the medium (vehicle) should be limited. If not the vehicle will lessen the microsponges before the application.
To avoid problems in cosmetic formulations; less than 10 to 12% w/w microsponges must be included into the vehicle.
Polymer design and payload of the microsponges for the active moieties should be optimized for required release rate for given period of time.
There remains equilibrium between microsponge and vehicle (medium) and release of drug from microsponge depends on the drug concentration in the vehicle. Drug concentration in the vehicle is low due to absorption of the drug into skin. Hence continuous and steady release of actives onto the skin can be achieved by this system. The Drug release from the topical semisolid dosage forms can be known by means of Franz-type static diffusion cells. (8)
Examples of enhanced product performance:
Microsponges have the ability to absorb oil, 6 times its weight without drying.
Extended release action
Reduced irritation and improved patient compliance
Improved the product elegancy
Examples of improved formulation flexibility:
Improved physical, chemical, and thermal stability
Incorporation of immiscible
Liquids can be converted in to powders improving material processing
Flexibility to develop novel product forms (9)
â€¢ Advanced oil control
â€¢ Extended release
â€¢ Reduced irritation formulas
â€¢ Allows novel product form
â€¢ Improved product aesthetics
â€¢ Advanced oil control - absorb up to 6 times its weight without drying
â€¢ Extended release - continuous action up to 12 hours
â€¢ Reduced irritation - getter tolerance means broader consumer acceptance
â€¢ Improved product aesthetics - gives product an elegant feel
â€¢ Improves stability - thermal, physical and chemical (10)
â€¢ Allows incorporation of immiscible
â€¢ Improves material processing - liquid can be converted to powders
â€¢ Allows for novel product forms
Drugs explored in Microsponge drug delivery system (MDDS)
â€¢ Benzyl peroxide
MARKETED FORMULATION USING THE MDDS:-
MDDS can be used to improve the effectiveness, safety and aesthetic quality of topical recommendation, over-the-counter ("OTC") and personal care products (11).The Products under development use the Topical Microsponge Drug Delivery System in three major ways which are;
1. As reservoirs releases the active ingredients over a prolonged period of time,
2. As receptacles which absorb unwanted substances, such as excess skin oils, or
3. As closed containers holding ingredients away from the skin intended for superficial action.
Retin A Micro
About 0.1% and 0.04% tretinoin molecule is entrapped in MDDS for topical management of acne vulgaris. This formulation uses patented methyl methacrylate/ glycol dimethacrylate cross-polymer (MICROSPONGEÂ® System) that enables addition of the active ingredient, tretinoin, in an aqueous gel.
Ortho-McNeil Pharmaceutical Pvt. Ltd.
Carac cream contain fluorouracil (0.5%), among 0.35% being included into an original Microsponge that is composed of methyl methacrylate / glycol dimethacrylate cross-polymer and dimethicone. Carac is applied once-a-day, a prescribed product used in the management of actinic keratoses (AK), a common pre-cancerous skin condition caused by over-exposure to the sun. This product has number of advantages over existing topical therapy, which include less irritation with shorter period of therapy and reduced dosage rate (12).
Line Eliminator Dual Retinol Facial cream
Lightweight Facial cream with retinol (pure Vitamin A) in MDDS, which processes both immediate and time released wrinkle-fighting action.
The retinol drug molecule is placed in the microsponge system in order to protect the strength of the vitamin A. This results in retinol dosage while reducing the possibility of irritation. Retinol is a vitamin A derivative used topically to maintain healthy skin, hair and mucous membranes.
Retinol 15 Nightcream
This is a night time cream prepared by Microsponge technology using a stabilized formula of Vitamin A, pure retinol. Continuous use of Retinol 15 will result in the visible damage of fine lines and wrinkles, an obvious progress in the skin discolorations due to aging, and improved skin smoothness can be obtained.
The Microsponge Â® system uses microscopic reservoirs that can entrap hydroquinone and retinol. The microsponges release the ingredients into the skin gradually throughout the day. This provides the skin with continuous exposure to hydroquinone and retinol over time, that minimize skin irritation.(13)
Sportscream RS and XS
Topical analgesic-anti-inflammatory and counterirritant actives in a MicrospongeÂ® Delivery System (MDS) for the treatment of musculoskeletal conditions.
Salicylic Peel 20
Deep BHA peeling agent for (professional use only): Salicylic acid 20%, Microsponge Technology, Excellent exfoliation and stimulates the skin for more resistant skin types or for faster results. This improves fine lines, pigmentation, and acne concerns.
Salicylic Peel 30
Deeper BHA peeling agent meant for professional use only: Salicylic acid 30%, Microsponge Technology, Most powerful exfoliation and stimulation of the skin. Improves fine lines, pigmentation, and acne concerns.
Micro Peel Plus
The MicroPeel Â® Plus system stimulates cell revenue by the application of salicylic acid in the form of microcrystals using Microsponge Â® technology. The MicroPeel Â® Plus aggressively outperforms other superficial chemical peels by freeing dead cells from the skin without damaging the skin.
Oil free matte block spf20
Which Protects skin from UV rays and control oil production by this invisible sunscreen. Microsponge technology will absorb oil,that maintains an all-day matte finish and preventing shine without any powdery residue. Oil free formula contains soothing Green Tea that calm inflammation caused by breakouts. Cornstarch and Vinyl Dimethicone/ Methicone Silsesquioxane Cross-polymer that act as microsponges to absorb excess surface oils on skin (14).
Oil Control Lotion
A light lotion that contains technically advanced microsponges which absorb oil onto the skin surface throughout the day, for getting matte finish. The naturally- antibiotic Skin Response Complex soothes inflammation and tightness that promote healing.
Lactrexâ„¢ 12% Moisturizing Cream
This Moisturizing Cream contains 12% lactic acid as neutral ammonium salt, ammonium lactate. MicrospongeÂ® technology has been used for comfortable application and prolonged moisturization. Lactrexâ„¢ also contains glycerin and water, a natural humectant, to make softer and help in moisturising dry, peeling, and fractured skin.
SDR Pharmaceuticals, Inc., Andover , NJ , U.S.A. 07821
Dermalogica Oil Control Lotion
Dermalogical Oil Control Lotion eliminates shine for hours, without adding excess oil and provides soothing and purification effect by complexation with skin surface. And provides effective skin hydration. Oil Control Lotion is a feather-light lotion, formulated using oil absorbing Microsponge technology and hydrating botanicals. The naturally antiseptic response has observed by Complexation with skin and helps to soothe and purify the skin.
John and Ginger Dermalogica Skin Care Products
High Performance Antiperspirant Spray with Sustained release action (24 hrs) of fragrance from the microsponges. The microsponge formed in the form of ultra light powder, as it is micro in size, and it can easily absorb fragrance oil for maintaining a free-flowing feature where release is controlled due to temperature and moisture.
Aramis Inc .
Microsponge system containing dimethicone protects baby's skin from the diaper rash.
Scott Paper Company
Tretinoin Acne Medication: This reduces the irritating side effects of Tretinoin.
5-Fluorouracil (5-FU): 5-FU is an efficient chemotherapeutic agent used in the management of a pre-cancerous, actinic keratosis, hardened-skin condition caused due to too much exposure to sunlight.
Tretinoin Photo-damage Treatment: Microsponge system product mainly used in the treatment of photo-damage, which results in the premature aging of skin and has been concerned in skin cancer.
APPLICATIONS OF MICROSPONGE SYSTEMS:-
Microsponges are porous, polymeric microspheres that are used mostly for topical and oral administration. It provides the formulator a wide range of alternatives to develop drug and cosmetic products. Microsponges are designed to deliver the drug efficiently at the minimum dose and also to enhance stability, reduce side effects and modify drug release.
The system have following applications: (15)
Sunscreens have durable product effectiveness, improved defence against sunburns and even sun related injuries even at high concentration and with reduced sensitization and irritancy.
e.g. Benzoyl peroxide
Prolonged efficacy with decreased skin irritation and sensitization.
Prolonged activity through reduced allergic response of skin and Dermatoses.
Sustained release of actives ingredients.
e.g. Selenium sulphide, zinc pyrithione
Reduced unlikeable smell along with lowered irritation with prolonged safety and efficacy.
Extended and improved activity.
Skin depigmenting agents
Improved stability against oxidation with improved aesthetic and efficacy appeal.
Prolonged activity along with reduction in irritancy greasiness.
NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) - A Brief review
The anti-inflammatory, anti pyretic and analgesic drugs are a mixed group of compounds often chemically unrelevant (even though most of them are organic acids), which however share certain side effects and therapeutic actions.
Algesia is an ill- defined unpleasant sensation usually evoked by an external or internal noxious stimulus.
A drug that selectively relieves pain by acting in the CNS, are on peripheral pain mechanism without altering the consciousness. (16)
In contrast to opioid analgesics the non opioid analgesics as a group
Relieve pain without interacting with opioid receptors.
Reduce elevated body temperature
Possess anti inflammatory property and are known as Non steroidal Anti Inflammatory Drugs.
Have antiplatelet activity at various degrees. These effects are achieved with doses that do not produce significant depression of CNS.
"Inflammation" can be defined or defensive but exaggerated local tissue reaction in response to exogenous or endogenous insult. It is complex phenomenon, comprising of biochemical as well as immunological factors, it is recognized by following symptoms.
Anti inflammatory agents are believed to act by disrupting arachidonic acid cascade. These drug are widely used for the treatment of minor pain and also for management of edema and the tissue damage from arthritis. The inhibition of cyclo oxygenase enzyme is probably only one of several mechanisms for anti-inflammatory activity.
Their effectiveness in various inflaming conditions is due to their ability to speed up the breakdown of micro-polysaccharides, in addition, to inhibiting PG synthesis. They also stabilize liposome and cool down other mediators of inflammation.
Anti inflammatory drugs act by interesting with any one of he several mechanism including immunological mechanisms such as antibody production, or antigen - antibody complexation, activation of complement, cellular activities such as phagocytes, interface with formation and release of the chemical mediators of inflammation or stabilization of lysosomal membranes. Aspirin is the considered to be first drug of choice, with a acetaminophen, and NSAIDs being employed in patients who do not tolerate salicylates.
DISCOVERY OF NSAIDs
The development of the first of the category of what are known as the NSAIDs (non steroidal anti-inflammatory drugs) such as Aspirin ,which was recognized as Progenitor, was Phenylbutazone in 1946 and Indomethacin in 1960's (17) and later Etodolac in 1970's (18). Phenylbutazone was initially employed as a combination with antopyrine. However, it has greater analgesic and anti-inflammatory activity than antipyrine and was the best part of 30 years successfully used for arthritic and other painful inflammatory conditions.
INTRODUCTION OF INFLAMMATION
Prostaglandins belong to a set of compounds known to be eicosanoids. When cell membranes on the skin surface are damaged, arachidonic acid is released into the cytoplasm where it serves as a substrate for the lipooxygenase (eg: 5- lipooxygenase), Cycloxygenase (eg: Prostaglandin H (synthase), Prostaglandin synthase and other enzymes.
Even though there are three main mammalian lipoxygenases, they are 5-lipooxygenase, the one with the most clinical significance is 5- lipooxygenase. It is 5- lipooxygenase that is responsible for the conversion of Arachidonic acid to 5-hydroperoxyeicosatetraenoicacid, which is then enzymatically converted to leukotriene A4 (LTA4). Leukotriene A4 is a precursor molecule for the other leukotrienes and can be enzymatically converted to leukotriene B4 (LTB4), which attracts many cells of myeloid origin. Cycloxygenase 1- related prostaglandins which are produced by many tissues and participate in the maintenance of a variety of physiological effects. Cyclooxygenase 2, is the isoform which is responsible for the production of inducible prostaglandins.
As such, COX-2- related prostaglandins are considered to be "nonphysiologic" and represent a therapeutically and clinically relevant group of compounds that are primarily involved in inflammation. Vasodilation, changes in capillary permeability, potentiation of other chemical mediators of inflammation (eg: Histamine), chemo taxis, and hyperalgesia are all aspects of inflammation that are initiated and perpetuated by the presence of COX-2-related prostaglandins. It is important to note that COX-1 and COX-2 are structurally distinct. They have different number of amino acids and sequences, as well as different morphologies. A smaller valine at the 523 position of COX-2 forms access to a "side pocket" unique to COX-2. This side pocket is exploited as the binding site for NSAIDs which preferentially bind with COX-2.
MECHANISM OF PRODUCTION OF PAIN
The prostaglandins (PG'S) AND Leucotrienes (LT) are biologically active derivatives of arachidonic acid of 20 carbon atom polyunsaturated essential fatty acids that are released from cell membrane phospholipids. They are the major lipid derivative autocoids.These PG's and Leucotrienes causes tenderness in tissue and responsible for the production of pain and inflammation.
Mechanism of production of pain
MECHANISM OF ACTION OF NSAIDs
During inflammation, pain and fever, arachidonic acid is liberated from phosphor lipid fraction of the cell membrane. Arachidonic acid is converted via cyclo-oxygenase (cox-1 and 2) pathways to prostaglandins (PG's) the steps are:
Oxidation of arachidonic acid to endoperoxide PGG2
Its subsequent reduction to hydroxyl endoperoxide PGH. PGH later transforms into primary prostanoids PG-E, PG PGD PGI TXA
The major differences in cox-1 and cox-2 lies in pathophysiological functions:
Cox -1 activity is constitutively present in nearly all cell types at a constant level.
Cox -2 activity is normally absent from cells (except those of kidneys and brain) but is inducible by TNF, IL in activated leucocytes and other inflammatory cells. Thus Cox -1 is physiological while Cox -2 is pathological (19).
Prostaglandins sensitize blood vessels to the effects of other inflammatory mediators thus increase permeability.PGE-E and PGI particularly produce hyperalgesia associated with inflammation.
NSAIDs mainly acts by inhibiting the Cox-1 and Cox 2 and further blocks the synthesis of prostaglandins and leukotrienes.NSAID's are effective as analgesics only in pathological states or in experimental models where PG 's are synthesized locally. Many NSAIDs non selectively inhibit Cox -1 and Cox -2 while others act more selectively on Cox -2 Thus piroxicam and Indomethacin are selective for Cox - 1 where as Nabumetone is selective for Cox - 2. Propionic acid derivatives like Ibuprofen, Phenamates and Aspirin inhibit Cox -1 and cox -2 equally.
Although inhibition of prostaglandin biosynthesis can explain many of the therapeutic effects of NSAID's, other mechanisms may also play an important role. Thus indomethacin inhibits phosphodiesterase and thus increases the intra cellular concentration of cyclic AMP. Cyclic AMP has been shown to stabilize membranes including lysosomal membranes in polymorpho nuclear leucocytes. Thus prevents the release of enzymes important in inflammatory response. Weak prostaglandin inhibitors act by inhibiting the activation of T-Lymphocytes which are abundant in inflamed tissues, and release cytokines which play an important role in mediating inflammation.
In addition to acting on cyclo-oxygenase, diclofenac and indomethacin inhibit the lipoxygenase path way, thus decreasing the production of leucotrienes. They also stabilize lysosomes and cool down other mediators of inflammation. NSAIDS may also unmask T-cell suppressing activity, there by suppressing the production of rheumatoid factors.
Gastro intestinal tract: Gastric irritation, erosions, peptic ulceration, gastric bleeding, perforation, esophagitis.
Renal: Sodium and water retention, chronic renal failure, intestinal nephritis, papillary necrosis.
Hepatic: Raised transaminases, hepatic failure.
CNS: Head-ache, mental confusion, behavioral disturbances, seizure precipitation.
Hematological: Bleeding, thrombocytopenia, agranulocytosis
Others: Asthma, exacerbation, skin rashes, pruritis, nausea vomiting, epigastric distress is common.
As analgesic for head ache, muscle, toothache, dysmenorrhoea, neuralgias, back ache, mayalgia, joint pain etc.
As antipyretic: For the treatment of fever
Acute rheumatic fever.
Post myocardial infarction and post stroke patients.