The topical administration

INTRODUCTION

The Microsponge Delivery System (MDS) is a unique technology used for controlled release and prolonged topical administration. The fundamental need of microsponge technology arises from the difficulty experienced with conventional formulations in releasing the active ingredients over an extended period of time. Conventional skin care products releases active ingredients in relatively high concentrations but for a shorter duration. This may lead to some serious side effects due to the penetration of high concentration of active ingredients into the skin. Microsponges are porous microscopic spheres having myriad of interconnected voids of particle size ranges from 10-24 m. They have capacity to entrap a wide range of active ingredients such as emollients, fragrances, essential oils and anti-infectives. These are also capable of absorbing skin secretions, reducing oiliness from the skin. MDS is capable of holding four times their weight in skin secretions. They are embedded in vehicle, storing active ingredients and release its active ingredient on a time mode and also in response to stimuli like rubbing, temperature and pH. Microsponge delivery system modifies the drug release profile and minimizing the transdermal penetration of active ingredient into the body. Micropores within the spheres comprise a total pore density of approximately 1ml/g for extensive drug retention. Microsponge particles are extremely small, inert, indestructible spheres that do not pass through the skin. Rather, they collect in the tiny nooks and crannies of skin and slowly release the entrapped drug, as the skin needs. The empty spheres are then washed away with the next cleansing (Nacht S. et al., 2008).

This delivery system can be incorporated into conventional dosage forms such as creams, lotions, gels, ointments, and powder. MDS technology is being used in cosmetics like skin care, sunscreens and prescription products (Netal et al., 2009).

Advantages over other delivery system

  1. Microsponge system is stable over a wide range of pH 1-11 and temperature up to 130C.
  2. Compatible with most of the vehicles and ingredients.
  3. Higher payload about 50-60%.
  4. Self sterilizing capacity, as the average pore size is 0.25m it prevents the penetration of bacteria inside the spherical particle (Netal et al., 2009).

Acne vulgaris

Acne vulgaris is a common skin disorder affects all age groups, approximately 80% of young adults in the age ranges from 11-30 years are suffering from acne vulgaris. (Cunliffe et al., 1979). It is characterized by non inflammatory,open comedones (black heads) or closedcomedones (white heads) and by inflammatory papules, pustules, and nodules. Comedones are the clinical lesion that results from follicular plugging. Open comedones are dilated pores with a keratin plug, white heads are small cream coloured dome shaped papules without inflammation. Acne vulgaris typically affects those areas of the body that has the greatest number of sebaceous glands including face, neck, upper part of the chest, and back (Guy F Webster, 2002).

Causes of acne vulgaris

Acne has a multifactorial aetiology that is it develops due to a combination of factors affecting the integrity of hair follicles and sebaceous gland. The four major causative factors are:

  1. Increased sebum secretion.
  2. Abnormal follicular differentiation causing blockage of the pilosebaceous duct.
  3. Colonization of the pilosebaceous duct with Propionibacterium acne.
  4. Release of inflammatory mediators.

Other aggravating factors are:

  1. The key factor is genetics that is an innate inclination for follicular epidermal hyper proliferation with subsequent plugging of the follicle.
  2. Endocrine factors that is higher levels of androgenic hormones due to polycystic ovaries and psychological stress and depression.
  3. Accumulation of dead skin cells that block or cover pores.
  4. Some medications may also cause acne like systemic steroids, contraceptives and anabolic steroids (Jeffrey et al., 2004).

Propionibacterium acne isan anaerobic organism present in acne lesions. It promotes inflammation through a variety of mechanisms:

  1. It stimulates inflammation by producing proinflammatory mediators that diffuse through the follicle wall.
  2. It activates the toll-like receptor 2 on monocytes and neutrophils.
  3. Activation of the toll-like receptor 2 then leads to the production of multiple proinflammatory cytokines, including interleukins and tumor necrosis factor.

Acne is most common during adolescence and frequently continues into adulthood and In-vitro resistance of Propionibacterium acnes to commonly used antibiotics has been increasing (Pinar et al., 2002).

Pathogenesis of acne vulgaris:

Normally, with appropriate hormonal stimulation by testosterone in puberty and through adulthood, the sebaceous glands secrete an oily material called sebum, which rises to the top of the hair follicle and then flows out onto the surface of the skin, causing the normal lubrication of the skin. The basic problem in patients suffering with acne is that the canals through which this oily sebum flows become plugged up. For both hormonal and hereditary reason, the horny epithelial cells lining the infundibular area of the hair follicles stick together, preventing the normal smooth passage of sebum to the skin surface (Pochi et al., 1979). This blockage results in a build up of sebum under the skin surface, which may appear as a whitehead. When the follicular pore is enlarged and sebum has mixed with lining epithelial cells, some of which are pigmented, the result is a blackhead. Thus, formation of the comedo occurs. Blackheads and whiteheads are non inflammatory. However, some patients get inflammatory lesions: pustules, red papules, and ruptured cysts. These lesions result when accumulated sebum and bacterial degradation products rupture through the hair follicle lining into the deeper parts of the skin, the dermis. The bacteria, (Propionibacterium acnes) live in such hair follicles. They break down the more complex fats of the sebum into triglycerides and free fatty acids (FFAs). They digest the triglycerides, but the remaining FFAs are irritating. These FFAs are responsible for creating, a toxic foreign body response that is an inflammatory response with pus cells and vascular dilation. This accounts for the red papules, the whitish pustules, and the ruptured cysts (Andrea et al., 2006).

Treatment of acne:

A wide range of treatments are available, both over the counter and on prescription, which should be effective in almost all type of acne. The most common therapies used depending upon the severity of acne lesions including topical, oral, systemic, hormonal and combination therapy.

Topical treatment of acne vulgaris:

Topical treatment includes the use of topical retinoids and topical antimicrobials. Three main topical retinoids are used that is tretinoin, adapalene and tazarotene. Topical retinoids are preffered over other drugs for the treatment of acne because they target microcomedo which is the precursor of all acne lesions. They also are comedolytic and have intrinsic anti-inflammatory effects, thus targeting two major factors in acne (Cunliffe et al., 2002). Topical antimicrobials for acne include clindamycin, erythromycin, tetracycline, azelaic acid and benzoyl peroxide. These are antibacterial agents that inhibits the growth of Propionibacterium acnes but because of the development of bacterial resistance these are often used in combination with topicalretinoids (Habbema et al., 1989).

Oral antibiotics:

Oral antibiotics used in acne vulgaris have both antimicrobial and anti-inflammatory properties. They reduce Propionibacterium acnes within the follicle and also inhibiting the production of inflammatory cytokines. The main systemic antibiotics used in acne are tetracycline, doxycycline, minocycline and erythromycin and orally used antibiotic is tetracycline (Golub et al., 1998; Gammon et al., 1986).

Hormonal therapy:

Hormonal treatments are well tolerated in women only. In hormonal therapy oral contraceptives, androgen receptor blockers such as flutamide and spironolactone are used in females who have sudden onset of severe acne (Chibula et al.,2000).

Combination therapy:

Combination therapy is required so as to target many pathogenic factors as possible. Combining a topical retinoid with an antimicrobial agent target three pathogenic factors and clinical trials have shown that combination therapy results in significantly faster and greater clearance as compared to antimicrobial therapy alone (Eady et al., 1998).

REVIEW OF LITERATURE

Exhaustive literature survey was done on microsponges, used as topical drug delivery technology, on the disease, acne and the drugs, both in individual and in combination, the following impressions are accumulated:

Review on Microsponges as Topical delivery of active ingredients

Microsponges of benzoyl peroxide were prepared by Mena et al., (1994) using an emulsion solvent diffusion method by adding an organic internal phase containing benzoyl peroxide, ethyl cellulose and dichloromethane into an aqueous phase containing polyvinyl alcohol and by suspension polymerization of styrene and divinyl benzene. The entrapped system released the drug at slower rate than the system containing free BPO. Topical delivery system with reduced irritancy was successfully developed.

Formulation of Hydroquinone (HQ) 4% with retinol 0.15% entrapped in microsponge reservoirs was developed by Grimes et al., (2004) to show the release of HQ gradually and prolong exposure to treatment and minimize skin irritation. The safety and efficacy of this product were evaluated in a 12-week open-label study. A total of 28 patients were enrolled, and 25 completed the study. A broad-spectrum sunscreen was applied once in the morning, 15 minutes after application of the test product. The microentrapped HQ 4%/retinol 0.15% formulation produced improvement at all study end points. Lesion area and colorimetry measurements also were significantly improved. Microentrapped HQ 4% was well tolerated, with only one patient discontinuing because of an allergic reaction, which was not considered serious. In this open-label study, microentrapped HQ 4% with retinol 0.15% was safe and effective.

Microsponges for topical delivery of mupirocin were prepared by quasi emulsion solvent diffusion method for sustained release and enhancing the drug deposition in skin. The effect of formulation and process variables such as internal phase volume and stirring speed on the physical characteristics of microsponges were examined on optimized drug/polymer ratio. Drug release through cellulose dialysis membrane and drug deposition studies using rat abdominal skin were carried out which showed the significant retention of mupirocin in skin that is for 24 hrs. The study was carried out by Netal et al., (2008) and they found that mupirocin as microsponge delivery system shows better stability and non irritant to skin

Prolonged release spherical micro-matrices of ibuprofen were prepared by Yoshiaki et al., (1992) with Eudragit RS by emulsion solvent diffusion method. The internal porosity was controlled by changing the concentration of drug and polymer in ethanol. They found that with the lower concentration of ibuprofen in ethanol, the microsponges produced with higher porosity and therefore more porous microsponges produced stronger tablets.

Microsponges containing ketoprofen and Eudragit RS100 were developed by Tansel et al., (2003) using quasi emulsion solvent diffusion method. They studied the effect of different mixing speeds, drug-polymer ratios, solvent-polymer ratio on the physical characterstics of microsponges and also determine the release rate of drug from microsponges. They found that all the formulations of ketoprofen microsponges modified the release of ketoprofen when compared with drug itself.

Topical anti inflammatory gel of fluocinolone acetonide entrapped in Eudragit based microsponge delivery system was prepared by D`souza et al., (2008). The gel was prepared by quasi emulsion solvent diffusion method and also by suspension polymerization method to control the release of drug to skin. Production yield, particle size, loading efficiency and surface morphology of microsponges was analysed. Microsponges containing drug: Eudragit ratio 5:1 was further investigated for compatibility studies, drug release and anti-inflammatory activity after entrapment in carbopol 934 gel. They found that the microsponges prepared by suspension polymerization method showed slower release as compared to other.

Review of literature for the treatment of Acne vulgaris:

There are a number of physical, hormonal and non-hormonal therapies available for the treatment of acne. Successful treatment is achieved by targeting more than one pathogenic factors that causes acne (Olutunmbi et al., 2008). Topically used agents include retinoids like tretinoin, adapalene and tazarotene and antimicrobial agents like clindamycin, erythromycin tetracycline and benzoyl peroxide (Graupe et al., 1996). Tetracycline and erythromycin can also be used orally. Systemically used agents are antibiotics like tetracycline, doxycycline, minocycline and erythromycin. Hormonal therapy includes oral contraceptives and androgen receptor blockers such as flutamide, spiranolactone and cyproterone acetate (Lookingbill et al., 1985). The drug can be given either alone or in combinations depending upon the type and severity of acne lesions:

  1. For the treatment of comedones only, topical retinoins are used like tretinoin, Adapalene and tazarotene (Cunliffe et al., 1998; Leyden et al., 2002; Webster et al., 2002).
  2. For mild to moderate acne topical antibiotics like benzoyl peroxide,azelaic acid, clindamycin, erythromycin and combination of benzoyl peroxide with erythromycin or clindamycin (Wolf et al., 2003).
  3. For moderate to severe inflammatory acne oral antibiotics including minocycline, doxycycline and tetracycline are used (Gollnick et al., 2003).
  4. For severe papulonodular acne oral isotretinoin is used (Seukern et al., 1999).

There is development of bacterial resistance in case of monotherapy, so as to avoid this bacterial resistance combination therapies are available for the treatment of acne (Cooper et al., 1998).

Topical antiacne preparation containing combination of retinoid (tazarotene or Adapalene), antibiotic (clindamycin phosphate) and/or keratolytic agent (microsponged benzoyl peroxide) in the form of cream and gel was formulated by Ayala et al., (2008), in order to treat every type of acne with higher efficiency, safety and also with fewer adverse effects.

Different types of liposomes containing clindamycin phosphate were prepared by Arnardottir et al., (1996) for the treatment of Acne vulgaris. The release rate of drug from different formulations was determined by using Franz diffusion cell and the cumulative flux of 1% clindamycin phosphate from three different liposome preparations were compared to the flux of clindamycin phosphate from a 0.05 M phosphate buffer solution containing drug in same concentration. From the results it was concluded that the flux was highest for phosphate buffer where the drug exists in uncapsulated form and the highest retention of clindamycin phosphate was obtained from a suspension of multilamellar liposomes.

Review of literature on Benzoyl peroxide:

Tucker et al., (2007) studied the effectiveness of benzoyl peroxide in the management of acne vulgaris by randomised, double-blind clinical studies. From the clinical studies they concluded that benzoyl peroxide is effective against inflammatory and non inflammatory acne lesions and also found that the combination of benzoyl peroxide with antibiotics like clindamycin phosphate and erythromycin improves the efficacy against inflamed acne lesions and no effect on non inflamed lesions.

A comparative study of 2.5%, 5% and 10% strength of benzoyl beroxide gel was done by Mills et al., (1986) by selecting 153 patients with mild to moderate acne. From the data obtained they concluded that 2.5% formulation significantly reduced the number of bacteria that is responsible for causing acne and the side effects were lesser as compared to 5% and 10% benzoyl peroxide gel.

Methods to increase the efficacy and tolerability of benzoyl peroxide for the treatment of acne vulgaris were studied by Fakhouri et al., (2009). Two such methods include the use of microparticle drug delivery system and other is the use of combination therapy as benzoyl peroxide and topical retinoid combination produce superior efficacy to monotherapy.

Review of literature on Tretinoin

Microspheres containing tretinoin were prepared and characterized by Tabbakhian et al., (2008), so as to improve the patient compliance and reduce the undesirable side effects. The release mechanism of tretinoin from the microspheres was a brust release at early stage and followed by slower release rates at later stage.

Review of literature on combination of Benzoyl peroxide and Tretinoin

The study on combined use of topical benzoyl peroxide and tretinoin in the treatment of acne vulgaris was conducted by Hondojo et al., (1979) in which a clinical trial using tretinoin lotion 0.05%, benzoyl peroxide 5% and 10% as topical application was performed on 250 ambulatory patients suffering from various degrees of acne vulgaris. The results indicate that tretinoin applied in the morning and benzoyl peroxide applied at night is the most efficacious regimen to be used, with minimal side effects.

Clinical Assessment of the Combination Therapy with Liposomal Gels of Tretinoin and Benzoyl Peroxide in acne was done by Patel et al., (2001). Four types of gels were prepared that is plain tretinoin gel, liposomal tretinoin gel, plain benzoyl peroxide gel and liposomal benzoyl peroxide gel by using 0.025%w/w of tretinoin and 2.5% w/w of benzoyl peroxide. The results showed that the liposomal tretinoin gel and liposomal benzoyl peroxide gel was significantly more effective in treating comedones, papules and pustules respectively and also reduces side effects.

Efficacy of topical tretinoin, benzoyl peroxide and oral tetracycline combination for the treatment of acne vulgaris was determined by Hossain et al., (2006) in 50 patients. Complete remission was seen in 32 (71.11%), marked improvement in 8 (17.78%) and good response in 5 (11.11%) patients. Application of topical tretinoin cream (0.05%) in the evening, benzoyl peroxide cream (5%) in the morning and oral tetracycline (500 mg bd) before meal was found very effective, safe and cheap in the treatment of comedonal, pustular and pustulo-nodular acne vulgaris.

AIM

To Prepare and evaluate topical microspongic cream containing combination of Benzoyl peroxide and Tretinoin for the treatment of Acne Vulgaris.

OBJECTIVE

To prepare and characterize controlled release microsponge based topical drug delivery system.

Microsponge delivery system prevents the abrupt release of active ingredients due to the presence of small pores and they release the active ingredients on a time mode as skin needs.

To reduce the side effects.

As the microsponge delivery system prevents the transdermal penetration of active ingredients, the drug does not enter systemic circulation. Therefore the systemic side effects will be reduced.

It also prevents the excessive accumulation of active ingredients into the dermis and epidermis and therefore reduces the side effects like drying of skin,burning and irritation.

To determine the therapeutic efficacy of prepared formulation.

Therapeutic efficacy will be determined by in vivo studies by using Rabbit Ear Model.

RATIONALE

  1. Microsponge technology allows controlled release of active ingredients, reducing side effects and maintaining therapeutic efficacy.
  2. Minimize the transdermal penetration of drug.
  3. Site specific delivery of drug will be given in the form of microsponges.

MATERIALS AND METHODS

The following materials that are Analytical Reagent (A.R.) / Laboratory Reagent (L.R.) grade or the best possible pharmaceutical grades available, will be used for the formulation of Microspongic cream, as supplied by the manufacturer.

Method of microsponge preparation

Quasi emulsion solvent diffusion method

This method is used when the drug is sensitive to polymerization conditions. Polymerization is performed by using suitable porogen under milder conditions. This method consists of two phases internal phase and external phase. To prepare the internal phase, dissolve polymer in ethyl alcohol and maintain the temperature up to 60C. Then add the drug to solution. This internal phase is then pour into external phase containing distilled water and polyvinyl alcohol at room temperature. Following 60 min of stirring then filter the mixture to separate the microsponges. The microsponges are dried in an air-heated oven at 40oC for 12 h and weigh to determine production yield. (Tansel Comgolu et al., 2003, M. Jelvehgari et al., 2006)

EXPERIMENT PERFORMED

Calibration curve

Calibration curve of Tretinoin and Benzoyl peroxide were plotted in Ethanol because both the drugs are freely soluble in Ethanol and insoluble in water and phosphate buffer.

Preparation of microsponges:

Microsponges were prepared by quasi emulsion solvent diffusion method using an external phase containing 50mg of polyvinyl alcohol in 200 ml of distilled water. The internal phase was prepared by mixing benzoyl peroxide (281mg) and ethyl cellulose in dichloromethane. Firstly the internal phase was prepared and then added to the external phase with continuous stirring for 1hr. at room temperature. After 1hour stirring dichloromethane was removed from the solution and then the formed microsponges were filtered and washed with distilled water. Then dried at room temperature and weighed. The production yield was calculated by the following formula:

Cream was prepared by melting all the ingredients at about 70C and then adding water and completely triturated. Once the cream prepared, the active component that is tretinoin and microsponges containing benzoyl peroxide was thoroughly mixed at the room temperature.

In vitro drug release study of prepared microspongic cream:

In vitro drug release studies were carried out using Franz diffusion cell with a receptor compartment volume of 25 ml and an effective diffusion area 2.54cm2. Receptor solution composed of distilled water/acetone (1:1v/v) was added to the cell and temperature was maintained at 37C and solution was stirred continuously at 600rpm. A water/acetone mixture was selected as receptor solution to provide adequate sink conditions because of the extremely low or no solubility of benzoyl peroxide and tretinoin in either water or saline. The wistar rat skin was mounted on the receptor compartment with the stratum corneum side facing donor compartment. The donor was filled with 200mg of prepared microspongic cream. At appropriate time interval 5ml of samples were withdrawn and immediately replaced by an equal amount of receptor solution up to 24hrs. The samples were analyzed by UV Spectrophotometer at 234.8nm for benzoyl peroxide and 348.6nm for tretinoin. Then the amount of drug released was calculated.

RESULTS AND DISCUSSION:

REFERENCES

  • Amrutiya, N., Baja, A., Madan, M., 2009. Development of Microsponges for Topical drug delivery of Mupirocin. AAPS. 10, 402-409.
  • Bensouilah, J., 2002. Aetiology and management of Acne Vulgaris. Int. J. Aromatherapy. 12, 99-104.
  • British Pharmacopoeia I, 2000. The Stationary office, London, pp. 40-41.
  • Chen, G., Ushida, T., Tateishi, T., 2000. A biodegradable hybrid sponge nested with collagen microsponges. J. Biomed. Mater. Res., 51, 273-79.
  • Comog, T., Gonul, N., Tamer, B., 2003. Preparation and in vitro evaluation of modified release ketoprofen microsponge II. Farmaco. 58, 101-106.
  • Cooper, A, J., 1998. Systematic review of propionibacterium acnes resistance to systemic antibiotics. Med J Aust. 169, 259-261.
  • Cunliffe, W, J., Poncet, M., Loesche, C., 1998. A comparison of the efficacy and tolerability of adapalene 0.1% gel vs tretinoin 0.025% gel in patients with acne vulgaris: a meta analysis of five randomized trials. Br. J. Dermatol. 139, 48-56.
  • D`Souza, Jhon, I., Harinath, N., 2008. Topical anti-inflammatory gels of Fluocinolone acetonide entrapped in eudragit based microsponge delivery system. Res. J. Pham. Tech. 1, 502-506.
  • D'souza, J.I., Masvekar, R.R., Pattekari, P.P., Pudi, S.R., More, H. N., 2005. Microspongic Delivery of Fluconazole for topical application. 1st Indo- Japanese International Conference on Advances In Pharmaceutical Research And Technology, Mumbai, India, 25-29.
  • Dines, 1985. Monohydroxy Benzoyl peroxide and compositions for treating acne. US Patent 4520133.
  • Fakhouri, T., Yentzer, B, A., Feldman, S, R., 2009. Advancement in benzoyl peroxide based acne treatment- methods to increase both efficacy and tolerability. J. D. Dermatol. 1-8.
  • Gollnick, H., Cunliffe, W, J., Berson, D., 2003. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J. Am. Acad. Dermatol. 49, S1-S37.
  • Esterly, N, B., Furey, N, L., Flanagan, L, E., 1978. The effect of antimicrobial agents on chemotaxis. J. Invest. Dermatol. 70, 51-55.
  • Grimes, P. E., 2004. A microsponge formulation of Hydroquinone 4% and Retinol 0.15% in the treatment of melasma and post-inflammatory hyperpigmentation, Cutis. 74, 362-8.
  • Graupe, K., Cunliffe, W, J., Gollnick, H, P., Zaumseil, R, P., 1996. Efficacy and safety of topical azelaic acid (20%): an overview of results from European clinical trials and experimental reports. Cutis. 57, 20-35.
  • Guy, F.W., 2002. Acne vulgaris: A Clinical Review. B M J. 325, 475-79.
  • Handojo, I., 1979. The combined use of topical Benzoyl peroxide and Tretinoin in the treatment of acne vulgaris. Int. J. Dermatol. 18, 489-496.
  • Hossain, M, M., Amin, A., 2006. Efficacy of topical Tretinoin, Benzoyl peroxide and oral Tetracycline combination in Acne vulgaris. T. A. J. 19, 10-12.
  • Horton, R., Demers, L, M., 1985. Tissue production of androgens in women with acne. J. Am. Acad. Dermatol. 12, 481-487.
  • Jeffrey, S., Orringer, S. K., Ted, H., Wendy, S., Soyun, C., Craig, H., 2004. Treatment of Acne Vulgaris with a Pulsed Dye Laser. JAMA. 291, 2834-2839.
  • Jelvehgari, M., Shadbad- Siahi, M. R., Azarmi, S., Gary, P., Martin, Ali N., 2006. The microsponge delivery system of Benzoyl peroxide: Preparation, characterization and release studies. Int. J. Pharm. 308, 124-132.
  • Kawashima, Y., Niwa, T., Takeuchi, H., Hino, T., Itoh, Y., 1992. Control of prolonged drug release and compression properties of Ibuprofen microsponges with Acrylic polymer, Eudragit RS, by changing their Intraparticle Density. Chem. Pharmaceut. Bull. 40, 196-201.
  • Krautheim, A., Gollnick, H, P., 2004. Acne: Topical treatment. Clindermatol. 22, 398-407.
  • Leyden, J, L., Tanghetti, E, A., Miller, B., 2002. Once daily Tazarotene 0.1% gel versus once daily Tretinoin 0.1% microsponge gel for the treatment of facial acne vulgaris: a double blind randomized trial. 69, 12-19.
  • Lucky, A, W., Cullen, S, I., Jarratt, M, T., Quigley, J, W., 1998. Comparative efficacy and safety of two 0.025% Tretinoin gels: Results from a multicentre, double-blind, parallel study. J. Am. Acad. Dermatol. 38, S17-S23.
  • Mena, P., Martinez, A.R., Gallardo, V., 1994. A Topical formulation: for Benzoyl peroxide, factors affecting release of Benzoyl peroxide in topical formulations. Cosmetics and Toiletries.109, 75-80.
  • Mills, O, H., Kligman, M., Pochi, P., Comite, H., 1986. Comparing 2.5%, 5% and 10% benzoyl peroxide on inflammatory acne . Int. J. Dermatol. 25, 664-667.
  • Mine, O., Erdal, C., Ahmet, A., 2006. Design and evaluation of colon specific drug delivery system containing Flurbiprofen microsponges. Int. J. Pharm. 318, 103-117.
  • Nacht, S., Katz, M., 1990. The Microsponge: a novel topical programmable delivery system, in: D.W. Osborne, A.H. Amman (Eds.). Topical Drug Delivery Formulations, Marcel Dekker: New York, Basel. 299- 325.
  • Olutunmbi, Y., Paley, K., Joseph, C., 2008. Adolescent female acne: Etiology and Management. J. Pediatr. Adolesc. Gynecol. 21, 171-176.
  • Patel, V, B., Misra, A., Marfatia, Y, S., 2001.Clinical assessment of combination therapy with Liposomal gels of Tretinoin and Benzoyl peroxide in acne. AAPS Pharm. Sci. Tech. 3, 1-5.
  • Pinar, Y., Basak, F.G., Ibrahim, K., 2002. The effect of Benzoyl peroxide and Benzoyl peroxide/Erythromycin combination on the anti-oxidative defence system in papulopustular acne. Eur. J. Dermatol. 12, 53-57
  • .
  • Seukeran, D, C., Cunliffe, W, J., 1999. The treatment of acne fulminans: a review of 25 cases. Br J Dermatol. 141, 307-309.
  • Tabbakhian, M., Sharifian, A., Shatelebi, M. A., 2008. Preparation and in vitro characterization of Tretinoin containing microspheres suited for dermatological preparations. R.P.S. 3, 31-40.
  • Tucker, R., Walton, S., 2007. The role of Benzoyl peroxide in the management of acne vulgaris. P. J. 279, 48-53.
  • Taylor, G, A., Shalita, A, R., 2004. Benzoyl peroxide based combination therapies for Acne vulgaris: A comparative review. Am. J. Clin. Dermatol. 5, 261-265.
  • Thiboutot , D. M., Weiss, J., Do, A, B., 2007. Adapalene-Benzoyl peroxide, a fixed dose combination for the treatment of Acne vulgaris. J. Am. Acad. Dermatol. 57, 791-799.
  • Webster, G, F., Guenther, L., Poulin, Y,P., 2002. A multicenter, double-blind, randomized comparison study of the efficacy and tolerability of once daily Tazarotene 0.1% gel and Adapalene 0.1% gel for the treatment of facial acne vulgaris. Cutis. 69, 4-11.
  • Wolf, J, E., Kaplan, D., Kraus, S, J., 2003. Efficacy and tolerability of combined topical treatment of acne vulgaris with Adapalene and Clindamycin: a multicenter, randomized investigator blinded study. J. Am. Acad. Dermatol. 49, S211-S217.

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