Microsponges as a Novel Imperative for Drug Delivery System
Ramadevi Bhimavarapu, Ramesetti RamaDevi*, Srinath Nissankararao, Chaitanya Devarapalli ,Sowjanya Paparaju
Sri Siddhartha Pharmacy College, Nuzvid
*Corresponding Author E-mail:- rdmpharm@gmail.com
ABSTRACT:
Microsponge delivery systems (MDS) that can precisely control the release rates or target drugs to a specific body site have an enormous impact on the health care system. The microsponge drug delivery technology is widely applicable to the dermatological drug delivery products. The microsponge drug delivery system has properties like improved stability and enhanced flexibility in formulation. MDS is originally developed for topical delivery of drugs like antiacne, anti-inflammatory, anti-fungal, antidandruffs, antipruritics, rubefacients etc. MDS holds a promising future in various pharmaceutical applications in the coming years by virtue of their unique properties like small size, efficient carrier characteristics enhanced product performance and elegancy, extended release, reduced irritation, improved thermal, physical, and chemical stability so flexible to develop novel product forms. But MDS also expands its application in oral drug delivery, bone and tissue engineering, in detecting the diseases and in RNAi silencing. New classes of pharmaceuticals, biopharmaceuticals (peptides, proteins and DNA-based therapeutics) are fueling the rapid evolution of drug delivery technology. Thus MDS is a very emerging field which is needed to be explored.
KEYWORDS: Microsponge delivery systems (MDS), Characterization, Applications.
INTRODUCTION:
Topical drug delivery systems are formulated either to give local effect or to enter in to the systemic circulation, where skin serves as the portal of entry to the drug and various formulations made available in the market are creams, gels, lotions, ointments, TDS etc. Main drawbacks of topical preparations for local action1.Application of topical drugs suffers many problems such as ointments, which are often aesthetically unappealing, greasiness, stickiness etc. that often results into lack of patient compliance. These vehicles require high concentrations of active agents for effective therapy because of their low efficiency of delivery system, resulting into irritation and allergic reactions in significant users are they may readily absorbed and hence, less duration of action a active medicament and produces the skin irritation problems reported in some research studies and also uncontrolled evaporation of active agents, unpleasant odour potential incompatibility of drug with vehicles1.Thus the need exists for system to maximize amount of time that an active ingredient is present either on skin surface or within the epidermis, while minimizing its transdermal penetration into the body.
The microsponge delivery system fulfills these requirements2. A Microsponge Delivery System (MDS) is Solid porous microspheres patented Polymeric Drug Delivery System Composed of porous microspheres that can entrap wide range of active ingredients and then release them with desired rate3. Microsponge technology allows an even and sustained rate of release, reducing irritation while maintaining efficacy. These microsponges have the capacity to entrap a wide range of active ingredients such as emollients, fragrances, essential oils, sunscreens and anti-infective, etc. are used as a topical carrier system. Release of drug into the skin is initiated by a variety of triggers, including rubbing and higher than ambient skin temperature. Their high degree of cross-linking results in particles that are insoluble, inert and of sufficient strength to stand up to the high shear commonly used in manufacturing of creams, lotions, and powders.4
CHARACTERISTICS OF MICROSPONGES:5
Their Characteristic feature is the capacity to adsorb or “load” a high degree of active materials into the particle and on to its surface4. Microsponge formulations are stable over range of pH 1 to 11; temperature up to 130oC; Microsponge formulations have higher payload (50 to 60%), still free flowing and can be cost effective. self sterilizing as their average pore size is 0.25μm where bacteria cannot penetrate; compatible with most vehicles and ingredients;
Characteristics of Materials to be entrapped in Microsponges6
(Kawashima Y. et al. 1992) most liquid or soluble ingredients can be entrapped in the particles. Actives that can be entrapped in micro-sponges must meet following requirements; It should be either fully miscible in monomer or capable of being made miscible by addition of small amount of a water immiscible solvent. It should be water immiscible or at most only slightly soluble. It should be inert to monomers. It should be stable in contact with polymerization catalyst and conditions of polymerization. (Aritomi et al. 1996)
Advantages of Microsponge Delivery System:7, 8
Microsponges can absorb oil up to 6 times its weight without drying.It provides continuous action up to 12 hours i.e. extended release.Improved product elegancy.Lessen the irritation and better tolerance leads to improved patient compliance.It can also improve efficacy in treatment.They have better thermal, physical and chemical stability.These are non-irritating, non-mutagenic, non-allergenic and non-toxic.MDS allows the incorporation of immiscible products.They have superior formulation flexibility.In contrast to other technologies like microencapsulation and liposomes, MDS has wide range of chemical stability, higher payload and are easy to formulate.Liquids can be converted in to powders improving material processing.It has flexibility to develop novel product forms. MDS can improve bioavailability of the drugs.
Formulation Aids:9
Various polymers can form a microsponge ‘cage’. They are Ethyl Cellulose, Eudragit RS100, Polystyrene and PHEMA. In addition to actives, some SPMs contain plasticizers that help stabilize their structure 4, 5, 6, 7. In addition to actives; some microsponges contain plasticizers that help stabilize their structure.
RELEASE MECHANISMS FROM MICROSPONGES 10
Pressure:
Rubbing/ pressure applied can release active ingredient from microsponges onto skin.
Temperature change:
Some entrapped actives can be too viscous at room temperature to flow spontaneously from microsponges onto the skin. Increased in skin temperature can result in an increased flow rate and hence release.
Solubility:
Microsponges loaded with water-soluble ingredients like anti-prespirants and antiseptics will release the ingredient in the presence of water. The release can also be activated by diffusion taking into consideration the partition coefficient of the ingredient between the microsponges and the outside system.
METHOD OF PREPARATION:
1. Solvent Diffusion:
Drug loading in microsponges can take place in two ways, one-step process or by two-step process; based on physicochemical properties of drug to be loaded. If the drug is typically an inert non-polar material, will create the porous structure it is called Porogen. Porogen drug, which neither hinders the polymerization nor become activated by it and stable to free radicals is entrapped with one-step process 11,12
2. Suspension polymerization
When the drug is sensitive to the polymerization conditions, two-step process is used. The polymerization is performed using substitute Porogen and is replaced by the functional substance under mild experimental conditions.
3. Liquid-liquid suspension polymerization:
Microsponges are conveniently prepared by liquid-liquid suspension polymerization. Polymerization of styrene or methyl methacrylate is carried out in round bottom flask. A solution of non-polar drug is made in the monomer, to which aqueous phase, usually containing surfactant and dispersant to promote suspension is added. Polymerization is effected, once suspension with the discrete droplets of the desired size is established; by activating the monomers either by catalysis or increased temperature 13
Figure1: Reaction vessel for microsponge preparation by liquid liquid
Figure2: Preparation of microsponges by quasi emulsion solvent diffusion method
4. Quasi-emulsion solvent diffusion:
As explained in Figure 2 the
microsponges can also be prepared by quasi-emulsion solvent diffusion method
using the different polymer amounts. The processing flow chart is
presented in Fig. 1a. To prepare the inner phase, Eudragit RS 100 was dissolved
in ethyl alcohol. Then, drug can be then added to solution and dissolved under
ultrasonication at 35oC. The inner phase was poured into the PVA solution in
water (outer phase). Following 60 min of stirring, the mixture is filtered to
separate the microsponges. The microsponges are dried in an air-heated oven at
40oC for 12 h and weighed to determine production yield14.
5.Polymerization15
The porous microspheres are prepared by
suspension polymerization method in liquid-liquid systems (D'Souza et al. 2005)
in 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. to aid in formation of suspension). The
polymerization is then initiated by adding catalyst or by increasing
temperature or irradiation. The various steps in the preparation of
microsponges are summarized as (SP Vyas et al. 2002)
Selection of monomer or combination of monomers ; Formation of chain monomers as polymerization begins;
Formation of ladders as a result of cross linking between chain monomers; Folding of monomer ladder to form spherical particles; Agglomeration of microspheres, which give rise to formation of bunches of microspheres; Binding of bunches to form microsponges. The polymerization process leads to the formation of a reservoir type of system, which opens at the surface through pores. In some 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 the liquid is removed leaving the porous microspheres, i.e., microsponges. Impregnating them within preformed microsponges then incorporates the functional substances. Sometimes solvent may be used for faster and efficient incorporation of the active substances. The microsponges act as a topical carriers for variety of functional substances, e.g. anti acne, anti inflammatory, anti purities, anti fungal, rubefacients, etc.
PHYSICAL CHARACTERIZATION OF MICROSPONGES
(i) Particle size determination16
Particle size analysis of loaded and unloaded microsponges can be performed by laser light Diffractometry or any other suitable method. The values can be expressed for all formulations as mean size range. Cumulative percentage drug release from microsponges of different particle size will be plotted against time to study effect of particle size on drug release. Particles larger than 30μm can impart gritty feeling and hence particles of sizes between 10 and 25μm are preferred to use in final topical formulation.
(ii) Morphology and surface topography of microsponges17
For morphology and surface topography, prepared microsponges can be coated with gold–palladium under an argon atmosphere at room temperature and then the surface morphology of the microsponges can be studied by scanning electron microscopy (SEM). SEM of a fractured microsponge particle can also be taken to illustrate its ultra structure.
(iii) Determination of loading efficiency and production yield18
The loading efficiency (%) of the microsponges can be calculated according to the following equation:
Actual Drug Content in Microsponges
Loading efficiency =-------------------------------------------X 100 .....(1) Theoretical Drug Content
The production yield of the microparticles can be determined by calculating accurately the initial weight of the raw materials and the last weight of the microsponge obtained.
Practical mass of microsponges
Production Yield= --------------------------------------X 100............(2)
Theoretical mass (Polymer+drug)
(iv) Determination of true density
The true density of microparticles is measured using an ultra-pycnometer under helium gas and is calculated from a mean of repeated determinations.
(v) Characterization of pore structure 19, 20
Pore volume and diameter are vital in controlling the intensity and duration of effectiveness of the active ingredient. Pore diameter also affects the migration of active ingredients from microsponges into the vehicle in which the material is dispersed. Mercury intrusion porosimetry can be employed to study effect of pore diameter and volume with rate of drug release from microsponges. Porosity parameters of microsponges such as intrusion–extrusion isotherms pore size distribution, total pore surface area, average pore diameters, interstitial void volume, percent porosity, percent porosity filled, shape and morphology of the pores, bulk and apparent density can be determined by using mercury intrusion porosimetry.
The pore diameter of microsponges can be calculated by using Washburn equation16
Where D is the pore diameter (μm); γ the surface tension of mercury (485 dyn cm−1); θ the contact angle (130o); and P is the pressure (psia).
Total pore area (Atot) was calculated by using equation,
Where P is the pressure (psia); V the intrusion volume (mL g−1); Vtot is the total specific intrusion volume (mL g−1).
The average pore diameter (Dm) was calculated by using equation,
Envelope (bulk) density (ρse) of the microsponges was calculated by using equation,
Where Ws is the weight of the microsponge sample (g); Vp the empty penetrometer (mL); VHg is the volume of mercury (mL).
Absolute (skeletal) density (ρsa) of microsponges was calculated by using equation,
Where Vse is the volume of the penetrometer minus the volume of the mercury (mL).
Finally, the percent porosity of the sample was found from equation,
Pore morphology can be characterized from the intrusion–extrusion profiles of mercury in the microsponges as described by Orr. 21
(vi) Compatibility studies22,23
Compatibility of drug with reaction adjuncts can be studied by thin layer chromatography (TLC) and Fourier Transform Infra-red spectroscopy (FT-IR). Effect of polymerization on crystallinity of the drug can be studied by powder X-ray diffraction (XRD) and Differential Scanning Colorimetry (DSC). For DSC approximately 5mg samples can be accurately weighed into aluminum pans and sealed and can be run at a heating rate of 15oC/min over a temperature range 25–430oC in atmosphere of nitrogen.
(vii) Polymer/monomer composition24,25
Factors such as microsphere size, drug loading, and polymer composition govern the drug release from microspheres. Polymer composition of the MDS can affect partition coefficient of the entrapped drug between the vehicle and the microsponge system and hence have direct influence on the release rate of entrapped drug. Release of drug from microsponge systems of different polymer compositions can be studied by plotting cumulative % drug release against time.
(viii) Resiliency (viscoelastic properties)26
Resiliency (viscoelastic properties) of microsponges can be modified to produce beadlets that is softer or firmer according to the needs of the final formulation. Increased cross-linking tends to slow down the rate of release.
(ix) Dissolution studies:
Dissolution profile of microsponges can be studied by use of dissolution apparatus USP XXIII with a modified basket consisted of 5μm stainless steel mesh. The speed of the rotation is 150 rpm. The dissolution medium is selected while considering solubility of actives to ensure sink conditions. Samples from the dissolution medium can be analyzed by suitable analytical method at various intervals.
(x) Kinetics of release:
To determine the drug release mechanism and to compare the release profile differences among microsponges, the drug released amount versus time was used. The release data were analyzed with the following mathematical models:
Q = k1tn or logQ = log k1+ n log t …. (3)
Where Q is the amount of the released at time (h),
n is a diffusion exponent which indicates the release mechanism, and k1 is a constant characteristic of the drug–polymer interaction.
From the slope and intercept of the plot of log Q versus log t, kinetic parameters n and k1 were calculated.
For comparison purposes, the data was also subjected to Eq. (4), which may be considered a simple, Higuchi type equation.
Q = k2t0.5 + C ……. (4)
Eq. (4), for release data dependent on the square root of time, would give a straight line release profile, with k2 presented as a root time dissolution rate constant and C as a constant27.
APPLICATIONS OF MICROSPONGE SYSTEMS:
Topical drug delivery using microsponge technology28
Benzoyl peroxide (BPO) is commonly used in topical formulations for the treatment of acne and athletes foot.
Cardiovascular engineering using microsponge technology29
Biodegradable materials with autologous cell seeding require a complicated and invasive procedure that carries the risk of infection. To avoid these problems, a biodegradable graft material containing collagen microsponge that would permit the regeneration of autologous vessel tissue has developed.
Reconstruction of vascular wall using microsponge technology30
The tissue-engineered patch was fabricated by compounding a collagen-microsponge with a biodegradable polymeric scaffold composed of polyglycolic acid knitted mesh, reinforced on the outside with woven polylactic acid.
(ііі) Bone tissue engineering using microsponge technology31
3D biodegradable porous scaffold plays a very important role in articular cartilage tissue engineering. The hybrid structure of 3D scaffolds was developed that combined the advantages of natural type I collagen
and synthetic PLGA knitted mesh.
PATENT INFORMATION OF MICROSPONGE PRODUCTS32
In September 1, 1987, Won; Richard (Palo Alto, CA) of Advanced Polymer Systems, Inc. (Redwood City, CA) received US patent for developing Method for delivering an active ingredient by controlled time release utilizing a novel delivery vehicle which can be prepared by a process utilizing the active ingredient as a porogen (United States Patent 4,690,825).September 8, 1992 , Won; Richard (Palo Alto, CA) of Advanced Polymer Systems, Inc. ( Redwood City , CA ) received US patent for developing Two-step method for preparation of controlled release formulations (United States Patent 5,145,675).Advanced Polymer Systems, Inc. and subsidiaries ("APS" or the "Company") is using its patented Microsponge(R) delivery systems and related proprietary technologies to enhance the safety, effectiveness and aesthetic quality of topical prescription, over-the-counter ("OTC") and personal care products like tretinoin, 5-fluorouracil and Vitamin-A etc. As on July 23, 2006 , the Company has a total of 10 issued U.S. patents and an additional 92 issued foreign patents. 21 patent applications are pending worldwide.Dean, Jr. et al received US patent no. 4863856 for the development of weighted collagen microsponges having a highly cross-linked collagen matrix are described suitable for use in culturing organisms in motive reactor systems. The microsponges have an open to the surface pore structure, pore sizes and volumes suitable for immobilizing a variety of bioactive materials.
Results from various human clinical studies reaffirmed that the technology offers the potential to reduce the drug side effects, maintain the therapeutic efficacy and potentially increase patient compliance with the treatment regimen. Ethical dermatology products have been developed or are under development includes, Tretinoin Acne Medication: In February 1997, the FDA approved for the first ethical pharmaceutical product based on patented Microsponge technology; Retin-A-Micro(TM), which has been licensed to Ortho-McNeil Pharmaceutical Corporation.
5-Fluorouracil (5-FU): 5-FU is an effective chemotherapeutic agent for treating actinic keratosis, a pre-cancerous, hardened-skin condition caused by excessive exposure to sunlight.
Tretinoin Photo-damage Treatment: Microsponge system product for the treatment of photo-damage, which contributes to the premature aging of skin and has been implicated in skin cancer.
Cosmeceutical Products Retinol: Retinol is a highly pure form of vitamin A which has demonstrated a remarkable ability for maintaining the skin's youthful appearance.
List of marketed products using microsponge drug delivery system34
Retin-A-Micro, Carac Cream, 0.5%, Line Eliminator Dual Retinol Facial Treatment, Retinol cream, Retinol 15 Night cream, EpiQuin Micro, Sports cream RS and XS, Salicylic Peel 20, Salicylic Peel 30, Micro Peel Plus, Oil free matte block spf20, Oil Control Lotion, Lactrex™ 12% Moisturizing Cream, Dermalogica Oil Control Lotion, Aramis fragrances, Ultra Guard
Active agents Applications
Sunscreens Improved protection against sunburns and sun related injuries, reduced irritancy and sensitization.
Anti-acne-e.g. Benzylperoxide
Anti-inflammatory-e.g. hydrocortisone
Anti-dandruffs-e.g. zinc pyrithione, selenium sulphide Antipruritics
Skin depigmenting agents-e.g. hydroquinone Sports cream RS and XS
Topical analgesic-anti-inflammatory and counterirritant activity
Retin-A-Micro-0.1% and 0.04% Tretinoin for topical treatment of acne vulgaris.
Carac Cream-contains 0.5% fluorouracil, for the treatment of actinic keratoses (AK),
Line Eliminator Dual Retinol Facial Treatment Lightweight cream with a retinol (pure Vitamin A) in MDS, delivers both immediate and time released wrinkle-fighting action.
Retinol cream-Helps maintain healthy skin, hair and mucous membranes.
Retinol Night cream Pure retinol, Vitamin A, cause diminishment of fine lines and wrinkles, a noticeable improvement in the skin discolorations due to aging, and enhanced skin smoothness.
DRUGS EXPLORED IN MDS9
Trolamine, Benzoyl Peroxide,Ketoprofen,Retinol,Fluconazole,Ibuprofen, Tretinoin, Flurbiprofen, Mupirocin, Dicyclomine and Fluocinolone Acetonide. Most liquid or soluble ingredients can be entrapped in the particles.
DRUG USED IN MICROSPONGE DELIVERY 35
Dicyclomine, an anticholinergic drug, has direct smooth muscle relaxant action, and in addition to being a weak anticholinergic, it exerts antispasmodic action. Its plasma half life is 4 - 6 h. Dicyclomine causes gastrointestinal (GI) side effects like other antispasmodic drugs. The study was designed to formulate a delivery system based on microsponges that would reduce the GI side effects of the drug.
Flurbiprofen, Microsponge system containing flubiprofen was formulated for the colonic delivery of the drug for targeted action.
Benzylperoxide, Benzoyl peroxide (BPO) is commonly used in topical formulations for the treatment of acne and athletes foot. Skin irritation is a common side effect, and it has been shown that controlled release of BPO from a delivery system to the skin could reduce the side effect while reducing percutaneous absorption. Therefore, the ethylcellulose microsponge system was formulated containing BPO which were able to control the release of BPO to the skin.
Fluocinolone acetonide, (FA) is a corticosteroid primarily used in dermatology to reduce skin inflammation and relieve itching. The percutaneous absorption increases risk associated with systemic absorption of topically applied formulation. Controlled release of drug to the skin could reduce the side effect while reducing percutaneous absorption. Therefore, FA en-trapped microporous microparticles (microsponges) were formulated to control the release of drug to the skin.
Retinol, the use of vitamins like tocopherol, retinol in cosmetic formulations like creams, gels is limited due to high instability so oil and water soluble microsponge delivery of the retinol has been developed.
CONCLUSION:
Microsponges have a discrete advantage over the existing conventional topical dosage forms for the treatment of dermatological diseases. A Microsponge Delivery System can entrap wide range of actives and then release them onto the skin over a time and in response to trigger. It is a unique technology for the controlled release of topical agents and consists of microporous beads loaded with active agent for topical and also use for oral as well as biopharmaceutical drug delivery. Formulations can be developed with incompatible ingredients with prolonged stability without use of preservatives. Safety of the irritating and sensitizing drugs can be increased and programmed release can control the amount of drug release to the targeted site. Hence, the microsponge drug delivery system focus as an important tool for future inventions in controlled drug delivery system. Thus, microsponge has got a lot of prospective and is a very up-and-coming field which is needed to be explored.
REFERENCES
1 Chowdary K P, and Rao Y S, “Mucoadhesive Microspheres for Controlled Drug Delivery”, Biol. Pharm. Bull., 2004, 27(11), 1717-1724.
2 Netal A, Bajaj A and Madan M, Development of Microsponges for Topical Delivery of Mupirocin, AAPS Pharm. Sci. Tech, 10(2), 2009:123-128.
3 Nacht S, Kantz M. The Microsponge, “A Novel Topical Programmable Delivery System”. 1992; 42:299-325.
4 Delattre L, Delneuville I.Biopharmaceutical aspects of the formulation of dermatologicalvehicles. Journal of the European Academy of Dermatology and Venereology 1995; 5: S70.
5 Aritomi H, Yamasaki Y, Yamada K,Honda H and Koshi M.Development of sustained release formulation of Chlorpheniramine maleate using powder coated microsponges prepared by dry impact blending method. Journal of Pharmaceutical Sciences and Technology 1996;56(1): 49-56.
6 Kawashima Y, Niwa T, Takeuchi H, Hino T, Ito Y. Control of Prolonged Drug Release and Compression Properties of Ibuprofen Microsponges with Acrylic Polymer, Eudragit RS, by Changing Their Intraparticle Porosity. Chemical & pharmaceutical bulletin 1992;40(1):196-201.
7 Vyas S P, Khar R K, “Targeted and controlled drug delivery- Novel carrier system”. CBS Publication, New Delhi, Edition 1, 2002:453.
8. Embil K and Nacht S, “The microsponge delivery system (MDS): a topical delivery system with reduced irritancy incorporating multiple triggering mechanisms for the release of actives”. J. Microencapsulation 1996; 308:124-132.
9. Kirti Deshmukh, Sushilkumar S. Poddar. Solid Porous Microsphere: Emerging trend in pharmaceutical technology. International Journal of Pharma and Bio Sciences. Vol2/Issue1/Jan-Mar 2011.
10. Shah V.P.,(1989) Determination of In-vitro Release from Hydrocortisone Creams. International Journal of Pharmaceutics. 53: 53-59.
11 Weiss R, Drug Delivery in the Space Age, Consultant Pharmacist, 4 Jan. 19(23). 1989: 15-17.
12 Won R, United States Patent No. 5,145,675 Two step method for preparation of controlled release formulations.1992.
13 Jelvehgari M, Siahi-Shadbad M R, Azarmi S, Gary P and Nokhodchi A, The microsponge delivery system of benzoyl peroxide: Preparation, characterization and release studies, Int. J.Pharm., 308, 2006:124–132.
14 Martin A, Swarbrick J and Cammarrata A, Chapter 19, In: Physical Pharmacy- Physical Chemical Principles in Pharmaceutical Sciences. 3rd Ed. 1991 pp 527.
15 D'Souza, Masvekar R. R, Pattekari P. P, Pudi S. R, More H N, Microspongic delivery of Fluconazole for topical application, 1-Indo japanis Conference: Mumbai; 2005.
16. Martin A., Swarbrick J. & Cammarrata A.,(1991) Chapter 19, In: Physical Pharmacy- Physical Chemical Principles in Pharmaceutical Sciences. 3rd Ed., pp 527.
17 .Emanuele A. D., Dinarvand R., Preparation, Characterization and Drug Release from Thermo responsive Microspheres, International Journal of Pharmaceutics , 1995, 237-242.
18 Kilicarslan, M., Baykara, T., 2003. The effect of the drug/polymer ratio on the properties of Verapamil HCl loaded microspheres. Int. J. Pharm. 252, 99–109.
19. Poresizer Model No. 9310, Micromeritics Instrument Corp., Nor-cross , Georgia .
20. Washburn, E.W., 1921. Note on a method of determining the distribution of pore sizes in a porous material. Proc. Natl. Acad. Sci. U.S.A. 7, 115–116.
21 Orr Jr., C., 1969. Application of mercury penetration to material analysis.Powder Technol. 3,117–123.
22 Kawashima Y, Niwa T, Takeuchi H, Hino T, Itoh Y, Furuyama S. Characterization of polymorphs of tranilast anhydrate and tranilast monohydrate when crystallized by two solvent change spherical crystallization techniques. J. Pharm. Sci.1991; 81:472-478.
23 Bodmeier R, Chen H. Preparation and characterization of microspheres containing the anti-inflammatory agents, indomethacin, ibu-profen, and ketoprofen. J.Control. Release.1989; 10:167-175.
24 Jones DS, Pearce KJ. Investigation of the effects of some process variables on, microencapsulation of propranolol HCl by solvent evaporation method. Int. J. Pharm. 1995; 118: 99-205.
25 Wakiyama N, Juni K, Nakano M. Preparation and evaluation in vitro of polylactic acid microspheres containing local anesthetic. Chem. Pharm. Bull. ( Tokyo ). 1981; 29:3363-3368.
26 Barkai A, Pathak V, Benita S. Polyacrylate (Eudragit retard) microspheres for oral controlled release of nifedipine. I. Formulation design and process optimization. Drug Dev. Ind. Pharm. 1990;16:2057- 2075.
27. Juni K, Nakano M. Preparation and evaluation invitro of polylactic acid microsphers containing local anesthetic. Chem Pharm Bull 1981;29:3363-3368
28 Jelvehgari M, Siahi-Shadbad MR, Azarmi S, Gary P, Martin, Nokhodchi A. The microsponge delivery system of benzoyl peroxide: Preparation, characterization and release studies. International Journal of Pharmaceutics 2006;308:124-132.
29 Chen G, Ushida T, Tateishi T. Poly (DL-lactic-co-glycolic acid) sponge hybridized with collagen microsponges and deposited apatite particulates. Journal of Biomedical Materials Research 2001;57(1):8-14.
30 Iwai S, Sawa Y, Ichikawa H, Taketani S, Uchimura E, Chen G, Hara M, Miyake J, Matsuda H. Biodegradable polymer with collagen microsponge serves as a new bioengineered cardiovascular prosthesis. J. Thorac. Cardiovasc. Surg. 2004;128(3):472-479.
31 Orlu M, Cevher E, Araman A. Design and evaluation of colon specific drug delivery system containing flurbiprofen microsponges. Int. J. Pharm. 2006;318:103-117.
32 Dean, Jr., Robert C.; Silver, Frederick H.; Berg, Richard A.; Phillips, Philip G.;Runstadler, Jr., Peter W.; Maffia, Gennaro J., United States Patent 4863856, Weighted collagen microsponge for immobilizing bioactive materials, 1989.
33 Koral Embil V. P., OTC External Analgesic Cream / Topical Analgesic-Anti-inflammatory, Counterirritant utilizing the Microsponge Delivery System (MDS) for controlled release of actives, UK Patent Application No: 0101058.6, 2000.
34 James J L, Shalita A, Diane T, Kenneth W, and Guy W, Topical Retinoids in Inflammatory Acne: A Retrospective, Investigator- Blinded, Vehicle-Controlled, Photographic Assessment, Clin. Therapeutics, 27, 2005:216-224.
35 Geeta Patel, Patel JK. Use of a Microsponge in Drug Delivery Systems, Pharmaceutical processing, 2008, 158.
Received on 01.05.2013 Modified on 20.05.2013
Accepted on 25.05.2013 © RJPT All right reserved
Research J. Pharm. and Tech. 6(8): August 2013; Page 842-848