The Microsponge Drug Delivery Systems Biology Essay

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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 control the release rate of drug and targets drug moiety to a specific site in the body and has huge impact on the human health care system. Carrier technology provides an excellent approach to deliver drug molecule by combining the drug to a carrier molecule which can be Microspheres, Nanoparticles, Liposomes, etc. which is able to alter the release and absorption properties 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 DRUG DELIVERY SYSTEM

Microsponge Drug Delivery System is a exclusive technology that 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 exceptional technology for the controlled release of topically active moieties and consists of micro porous 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 prescription products, over-the-counter (OTC) skin care products, cosmetics and sunscreens 3. Microsponge technology offers entrapment of ingredients and is expected to result in increased stability, elegance, flexibility in formulation and reduces side effects. Abundant studies have confirmed that Microsponge Delivery systems are not allergic, and do not cause any toxicity, irritancy. They are non-biodegradable in nature.

The method of formulation remains same that include the entrapment of the drug moiety in an optimized vehicle at its maximum thermodynamic activity. Microcapsules cannot control the rate of release of drug. If the wall ruptures the actives present within microcapsules will be released. The Microsponge system is stable in the pH ranging from 1 to 11, temperature till 130oC, most of the vehicles and also the ingredients are compatible with it. The average pore size is 0.25μm so it pocesses the property of self sterilizing as penetration of bacteria is impossible. Even though the payload is higher which is about 50-60%, it still processes free flowing property and are economic 4. The total pore density of spheres containing microspheres is 1mL/g for more drug retention.

Conventional formulations containing topical drugs are expected to act on the outer layers of the skin. The Microsponge system is intended to act against extreme accumulation of ingredients within the dermis and the epidermis. The major side effect of effective drugs that is irritation is reduced by MDDS without reducing their efficacy 5.

PREPARATION OF MICROSPONGES

Drug is loaded in Microsponges and it can be done by two methods, in one-step and by two-step; which depends on physico-chemical properties of drug to be entrapped. If the drug is inert and non-polar type, there is 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 formulation, monomer is dissolved in a suitable solvent along with the drug substance which is then dispersed in the aqueous phase. This aqueous phase contains the excipients which include suspending agents and surfactants. The polymerization starts by increasing temperature and by the addition of catalyst. The following steps are involved in the preparation of Microsponges:

- Monomer should be selected

- Polymerization gets initiated which results in the formation of chain monomers.

- The resulting chain monomers are cross linked to form ladders.

- Spherical particles are formed from the monomer ladder by folding the ladder- So, formed spherical particles undergo agglomeration to form microsphere bunches.

- These bunches binds to each other and forms Microsponges

The polymerization process forms a reservoir type of system, which opens at the surface by means of pores. After polymerization the liquid will be removed leaving the porous microspheres i.e., Microsponges. Impregnating them within preformed Microsponges, incorporates the functional substances. Sometimes 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

Fig 1: preparation of Microsponge by liquid-liquid suspension polymerization

Quasi-emulsion solvent diffusion:-

Quasi-emulsion solvent diffusion method was applied for the preparation of Microsponges 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 60°C and mixed with the external phase at room temperature. After emulsification, the mixture should be stirred continuously for 2 hours. Then the resulting mixture was filtered to separate the produced Microsponges. The product must be washed and dried using vacuum oven at 40°C for about 24hours7.

Fig 2: Preparation of Microsponges by quasi emulsion solvent diffusion method

FORMULATION CONSIDERATIONS

Active moiety can be entrapped into MDDS can then be incorporated into many products (formulations) such as lotions, creams, soaps etc. 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 the concentration should be less than 10 to 12% w/w Microsponges which will be included into the vehicle.

The design of the Polymer and payload of the Microsponges for the active moieties should be optimized to get the desired release rate.

There remains equilibrium between Microsponge and vehicle (medium) and release of drug from Microsponge depends on the drug concentration present in the vehicle. Drug concentration in vehicle is low due to absorption of the drug into skin. Hence continuous release of actives into the skin can be achieved by this system. The Drug release from the topical 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.

Extended release action

Reduced irritation and improved patient compliance

Improved the product elegancy

Offerings:

• Advanced oil control

• Extended release

• Reduced irritation formulas

• Allows novel product form 9

• Improved product aesthetics

Flexibility Benefits:

• Improves stability - thermal, physical and chemical10

• Allows incorporation of immiscible

• Liquid can be converted to powders

Drugs used in Microsponge drug delivery system (MDDS)

• Ketoprofen

• Benzyl peroxide

• Retinol

• Fluconazole

• Ibuprofen

• Tretinoin

• Trolamine

MARKETED FORMULATION USING THE MDDS:-

MDDS can be used to improve the efficacy, safety and quality of topical recommendation of personal care products and over-the-counter ("OTC") 11.The Products under development use the Topical Microsponge Drug Delivery System in three major ways which are;

1. As reservoirs that releases the active ingredients over a prolonged period of time,

2. As receptacles which absorb unwanted substances, such as surplus skin oils, or

3. As blocked containers containing ingredients away from the skin intended for superficial action.

Table 1: Marketed products of Microsponges and their advantages

Product name

Advantages

Manufacturer

Retin A Micro

(tretinoin)

About 0.1% and 0.04% tretinoin molecule is entrapped in MDDS for topical management of acne vulgaris. This formulation uses patented methyl methacrylate cross-polymer (MICROSPONGE® System) by which addition of tretinoin in an aqueous gel is possible.

Ortho-McNeil Pharmaceutical Pvt. Ltd.

Carac Cream

Carac cream contain fluorouracil (0.5%), among 0.35% being included into an original Microsponge composing glycol dimethacrylate cross-polymer and dimethicone. Carac was applied once-a-day, a prescribed product used in the management of actinic keratoses (AK) which is a common pre-cancerous skin condition caused due to 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.

Dermik Laboratories

Line Eliminator Dual Retinol Facial cream

Light weight Facial cream with retinol (pure Vitamin A) in MDDS, which pocesses both immediate and time released action against wrinkles.

Avon

Retinol cream

Retinol drug molecule is placed in the Microsponge system in order to protect the strength of the vitamin A. This results in reducing retinol dosage while reducing the risk of irritation. Retinol is derivative of vitamin A used topically to maintain healthy skin, hair and mucous membranes.

Biomedic

Retinol 15 Nightcream

This is a night time cream prepared by Microsponge technology using an optimized formula of Vitamin A, pure retinol. Continuous use of Retinol 15 results in visible damage of fine lines and wrinkles, an obvious progress in the skin decolorations due to aging, and improved skin smoothness can be obtained.

Sothys

EpiQuin Micro

The Microsponge ® system uses microscopic reservoirs that can entrap hydroquinone and retinol. The Microsponges deliver the ingredients into the skin gradually throughout the day. This provide the skin with constant contact to hydroquinone and retinol over time, that minimize skin irritation.13

Skin Medica

Sportscream RS and XS

These posses counter irritant and Topical analgesic-anti-inflammatory actives in a Microsponge® Delivery System (MDS) for treating musculoskeletal conditions.

Embil Pharmaceuticals

Salicylic Peel 20

Deeper BHA peeling agent meant for professional use only: Microsponge technology containing Salicylic acid 20% posse's most powerful stimulating effect on the skin. This improves fine lines, pigmentation, and acne concerns.

Biophora.

Salicylic Peel 30

Deeper BHA peeling agent meant for professional use only: Microsponge technology containing Salicylic acid 30% posse's most powerful stimulating effect on the skin. Improve pigmentation, acne and fine lines.

Micro Peel Plus

The MicroPeel ® Plus system stimulates cell revenue by the appliance of salicylic acid as microcrystal using Microsponge ® technology. The MicroPeel ® Plus forcefully outperforms other superficial chemical peels by liberating dead cells from the skin without damaging the skin.

Biomedic

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 the matte finish throughout the day and prevents shine without any powdery deposit. It contains soothing Green Tea that calm inflammation caused by breakouts. Methicone Silsesquioxane a Cross-polymer that acts as Microsponges to absorbexcess surface oils on skin 14.

Dermalogica

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.

Fountain Cosmetics

Lactrexâ„¢ 12% Moisturizing Cream

This Moisturizing Cream contains 12% lactic acid as neutral ammonium salt, ammonium lactate. Microsponge® technology has been used for comfortable application and prolonged moisturization. It contains water and glycerin, 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 controls shine for hours, without adding oil and provides soothing and purification effect by complexation with skin surface and provides effective skin hydration. Oil Control Lotion is, formulated using oil absorbing Microsponge technology and hydrating botanicals. The natural antiseptic response has observed by complexation with skin and helps to soothe and purify the skin.

John and Ginger Dermalogica Skin Care Products

Aramis fragrances

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 altered due to temperature and moisture.

Aramis Inc .

Ultra Guard

Microsponge drug delivery 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 hardened-skin condition caused due to too much exposure to sunlight, actinic keratosis.

Tretinoin Photo-damage Treatment: Microsponge system product mainly used in the treatment of photo-damage, which results in the early aging of skin and has been concerned in skin cancer.

APPLICATIONS OF MICROSPONGE SYSTEMS:-

Microsponges are polymeric microspheres that are porous and are used mainly for topical and oral administration. It provides the formulator a wide range of alternatives to formulate drug and cosmetic products. Microsponges are designed to enhance the stability of the drug and to deliver the drug at a minimum dose in an effective manner. Microsponge drug delivery system will modify the drug release and reduce the side effects.

The system has following applications: 15

Table 2: Applications of Microsponge systems

Active agents

Applications

Sunscreens

Sunscreens have durable product effectiveness, improved defence to sunburns and even sun related injuries even at high concentration and with reduced sensitization and irritancy.

Anti-acne

e.g. Benzoyl peroxide

Prolonged efficacy with decreased skin irritation and sensitization.

Anti-inflammatory

e.g. hydrocortisone

Prolonged activity through reduced allergic response of skin and Dermatoses.

Anti-fungals

Sustained release of actives ingredients.

Anti-dandruffs drugs

e.g. Selenium sulphide, zinc pyrithione

Reduced unlikeable smell along with lowered irritation with prolonged safety and efficacy.

Antipruritics

Extended and improved activity.

Skin depigmenting agents

e.g. hydroquinone

Improved stability against oxidation with improved aesthetic.

Rubefacients

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 irrelevant (even though most of them are organic acids), which however share certain side effects and therapeutic actions.

ALGESIA (Pain)

Algesia is an unpleasant sensation usually caused by an external or internal noxious stimulus.

ANALGESIA

A drug that selectively acts on CNS and relieves pain, 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.

Heat

Redness

Swelling

Dolar

Anti inflammatory agents are believed to act by disrupting arachidonic acid cascade. These drugs are widely used for the treatment of minor pain and also for management of edema and the tissue damage from arthritis. The inhibition of cyclooxygenase 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 any one of the several mechanism including immunological mechanisms such as antibody production, or antigen - antibody complexation, activation of complement, cellular activities such as phagocytes, interfere 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 an acetaminophen, and NSAIDs being employed in patients who do not tolerate salicylates.

DISCOVERY OF NSAIDs

The development of the first category of what are known as the NSAIDs 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 antipyrine. 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 acts as a substrate for the lipooxygenase, cyclooxygenase and prostaglandin synthase which gets released into the cytoplasm after skin damage.

Even though there are three main mammalian lipoxygenases, 5- lipooxygenase pocesses the most clinical significance. Arachidonic acid gets converted to 5-hydroperoxyeicosatetraenoic acid in the presence of 5-lipooxygenase, which is then converted to leukotriene A4 (LTA4) in the presence of enzymes. Leukotriene B4 (LTB4) is produced form Leukotriene A4 by enzymatic reaction. Prostaglandins that are related to cyclooxygenase-1 play role in the maintenance of various physiological effects. Cyclooxygenase-2 is the isoform which is responsible for the production of inducible prostaglandins.

As such, prostaglandins that are related to COX-2 are mainly involved in inflammation. These types are considered to be "nonphysiologic". The point to be noted is that COX-1 and COX-2 are structurally distinct. They differ in their morphologies and number of amino acids as well as sequences. COX-2 posses's a unique feature that it has a "side pocket" due to the presence of smaller valine at 523 position. This side pocket is 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. They are the major lipid derivative autocoids. These PG's and Leucotrienes cause tenderness in tissue and responsible for the production of pain and inflammation.

Fig 3: Mechanism of production of pain

MECHANISM OF ACTION OF NSAIDs

During inflammation, pain and fever, arachidonic acid is liberated from phospholipids 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.

ADVERSE EFFECTS

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.

USES

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.

Rheumatoid arthritis.

Osteoarthritis,

Post myocardial infarction and post stroke patients.

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