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Now-a-days the drug delivery technology landscape has become highly competitive and rapidly evolving. More developments in delivery systems are being integrated for optimising the efficacy and cost-effectiveness of the therapy.
Drug delivery systems (DDS) which can precisely control the release rates or target drugs to a specific body site have had an enormous impact on the health care system. Carrier technology provides an intelligent approach for drug delivery by coupling the drug to a carrier particle which can be microspheres, nanoparticles, liposomes, etc. that modulates the release and absorption characteristics of the drug. Microspheres are an important part of these particulate DDS because of their small size and efficient carrier characteristics. (1)
The Microsponge Delivery System is a exclusive technology for the controlled release of topical agents. A Microsponge Delivery System (MDS) is "Patented, highly cross-linked, porous, polymeric microspheres polymeric system consisting of porous microspheres that can entrap wide range of actives and then release them onto the skin over a time and in response to trigger".(2) It is a unique technology for the controlled release of topical agents and consists of microporous beads, typically 10-25 microns in diameter, containing active agent. When applied to the skin, the MDS releases the active ingredient on a time mode and also in response to other stimuli (rubbing, temperature, pH, etc). MDS technology can be used in cosmetics, over-the-counter (OTC) skin care, 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 systems are non-irritating, non-mutagenic, non-allergenic, and non-toxic.
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 loading in microsponges 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 in liquid-liquid systems . During their preparation, the monomers are first dissolved along with active ingredients 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:-
All microsponges were prepared by a quasi-emulsion solvent diffusion method by using an external phase containing distilled water and. The internal phase consists of drug, solvent, polymer, plasticizer, which was added at an amount 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 mixture was filtered to separate the formed microsponges. The product should be washed and dried by vacuum oven at 40Â°C for 24hours.(7)
Preparation of microsponges by quasi emulsion solvent diffusion method
Preparation of microsponges by quasi emulsion solvent diffusion method
Actives can be entrapped in MDS can then be incorporated into many products such as creams, lotions, powders and soaps. When formulating the vehicle, certain considerations taken into account to achieve desired product characteristics.
The solubility of actives in the vehicle should be limited. If not the vehicle will deplete the microsponges before the application.
To avoid cosmetic problems; less than 10 to 12% w/w microsponges must be incorporated into the vehicle.
Polymer design and payload of the microsponges for the active should be optimized for required release rate for given time period.
There remains equilibrium between microsponge and vehicle and release of drug form microsponge depends on the concentration drug concentration in the vehicle. Drug concentration in the vehicle is depleted due to absorption of the drug into skin. Hence continuous and steady release of actives onto the skin can be achieved with this system. Drug release from the topical semisolid formulation can be known by using Franz-type static diffusion cells.(8)
Examples of enhanced product performance:
Microsponge have the ability to absorb oil up to 6 times its weight without drying.
Reduced irritation and hence improved patient compliance
Improved product elegancy
Examples of improved formulation flexibility:
Improved physical, chemical, and thermal stability
Incorporation of immiscibles
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 delivery system (MDS)
â€¢ Benzyl peroxide
MARKETED FORMULATION USING THE MDS:-
Microsponge delivery systems can be used to enhance the safety, effectiveness and aesthetic quality of topical prescription, over-the-counter ("OTC") and personal care products (11). Products under development utilize the Topical Microsponge systems in three primary ways which are;
1. As reservoirs that release active ingredients over an extended period of time,
2. As receptacles which absorb undesirable substances, such as excess skin oils, or
3. As closed containers holding ingredients away from the skin intendeds for superficial action.
Retin A Micro
0.1% and 0.04% tretinoin whis is entrapped in MDS for topical treatment of acne vulgaris. This formulation uses patented methyl methacrylate/ glycol dimethacrylate cross-polymer porous microspheres (MICROSPONGEÂ® System) that enables inclusion of the active ingredient, tretinoin, in an aqueous gel.
Ortho-McNeil Pharmaceutical Ltd.
This cream contains 0.5% fluorouracil, with 0.35% being incorporated into a patented porous microsphere (Microsponge) that is composed of methyl methacrylate / glycol dimethacrylate cross-polymer and dimethicone. Carac is a once-a-day topical prescription product used in the treatment of actinic keratoses (AK), a common pre-cancerous skin condition caused by over-exposure to the sun. The product has a number of advantages over existing topical therapies, which include less irritation with shorter duration of therapy and reduced dosage frequency (12).
Line Eliminator Dual Retinol Facial cream
Lightweight cream with retinol (pure Vitamin A) in MDS, that pocesses both immediate and time released wrinkle-fighting action.
The retinol molecule is kept in the microsponge system inorder to protect the potency of the vitamin A. This results in retinol dosage while reducing the possibility of irritation. Retinol is a topical vitamin A derivative that helps to maintain healthy skin, hair and mucous membranes.
Retinol 15 Nightcream
This is a night time treatment cream with Microsponge technology using a stabilized formula of pure retinol, Vitamin A. Continued use of Retinol 15 will result in the visible diminishment of fine lines and wrinkles, a noticeable improvement in the skin discolorations due to aging, and enhanced skin smoothness can be achieved.
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.
Embil Pharmaceutical Co. Ltd.
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 improve 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 procedure stimulates cell turnover 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 the skin of all dead cells without damage to the skin.
Oil free matte block spf20
Protects skin from damaging UV rays and control oil production with 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 feature-light lotion that contains technically advanced microsponges which absorb oil on the skin's surface during 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 water and glycerin, a natural humectant, to soften and help in moisturising dry, flaky, cracked skin.
SDR Pharmaceuticals, Inc., Andover , NJ , U.S.A. 07821
Dermalogica Oil Control Lotion
Exclusive skin response complex that soothes and purifies, and provides effective skin hydration, without adding excess oil; eliminates shine for hours with Dermalogica Oil Control Lotion. Oil Control Lotion is a feather-light lotion, formulated using oil absorbing Microsponge technology and hydrating botanicals. The naturally antiseptic Skin Response Complex helps to soothe and purify the skin.
John and Ginger Dermalogica Skin Care Products
24 Hour High Performance Antiperspirant Spray with Sustained release of fragrance in the microsponge. The microsponge comes in the form of an ultra light powder, as it is micro in size, and can absorb fragrance oil easily while maintaining a free-flowing characteristic where release is controlled due to moisture and temperature.
Aramis Inc .
Microsponge system that contains dimethicone that protects baby's skin from diaper rash.
Scott Paper Company
Tretinoin Acne Medication: This reduces the irritating side effects of Tretinoin.
5-Fluorouracil (5-FU): 5-FU is an effective chemotherapeutic agent used in the treatment of actinic keratosis, a pre-cancerous, hardened-skin condition caused due to excessive 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 implicated 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 long lasting product efficacy, improved protection against sunburns and sun related injuries even at elevated concentration and with reduced irritancy and sensitization.
e.g. Benzoyl peroxide
Prolonged efficacy with decreased skin irritation and sensitization.
Long lasting activity with reduced allergic response of skin and Dermatoses.
Sustained release of actives ingredients.
e.g. zinc pyrithione, selenium sulfide
Reduced unpleasant odour along with lowered irritation with prolonged safety and efficacy.
Extended and improved activity.
Skin depigmenting agents
Improved stability against oxidation with improved efficacy and aesthetic appeal.
Prolonged activity along with reduction in irritancy greasiness.
NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) - A Brief review
The anti-inflammatory, analgesic and anti pyretic drugs are a heterogeneous group of compounds often chemically unrelated (although most of them are organic acids), which nevertheless share certain therapeutic actions and side effects.
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, Or on peripheral pain mechanism with out 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 non steroidal anti-inflammatory drugs (NSAIDs) of which Aspirin 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 group of compounds known as eicosanoids. When cell membranes are damaged, arachidonic acid is liberated into the cytoplasm where it serves as a substrate for the lipooxygenase (eg: 5- lipooxygenase), Cycloxygenase (eg: Prostaglandin synthase, Prostaglandin H (synthase), and other enzymes.
Although there are three main mammalian lipoxygenases, the one with the most clinical significance is 5- lipooxygenase. It is 5- lipooxygenasethat 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 clinically and therapeutically 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.