material may be protected by Copyright law (Title 17 U.S. Code)
`
`[ LIT ERATUR E RE V IE W]
`
`Microsphere Technology: Hype or Help?
`
`LEON H. KIRCIK, MD
`Indiana University School of Medicine, Indianapolis, Indiana; Mount Sinai Medical Center, New York, New York;
`DennResearch, PLLC, Louisville, Kentucky
`
`ABSTRACT
`Initiation of effective topical therapy as early as possible within the disease course is associated with improved patient
`expeliences and better therapeutic outcomes in most de1matological diseases. Additionally, patient adherence is
`associated with better outcomes and lower long-te1m treatment costs, while poor adherence is directly linked to poor
`treatment results and patient dissatisfaction. Local cutaneous irritation associated with topical drug fo1mulations has
`been an histolical challenge to therapy initiation and adherence. Retinoids and benzoyl peroxide-essential elements of
`topical acne treatment- are two of the drugs most commonly associated with application-site adverse events. Novel
`approaches to product fo1mulation incorporating microsphere technology may improve treatment tolerability, encow-age
`adherence, and contribute to better long-term therapeutic outcomes. Microsphere technology eliminates the rapid
`delivery of high concentrations of active dmg to the application site and instead facilitates controlled release of
`potentially initating drugs. It is associated with improved treatment outcomes and minimal initation. Microsphere
`formulations of topical tretinoin and benzoyl peroxide currently on the market have demonstrated good efficacy and
`tolerability and are expected to encourage adherence and long-te1m therapeutic benefit.
`(J Clin Aesthet Dermatol. 2011 ;4(5):27- 31.)
`
`Initiation of effective therapy as early as possible within
`
`the disease course is associated with improved patient
`experiences and better therapeutic outcomes in most
`dermatological conditions.'..: Furthe1more, data confilm that
`patient adherence is associated with better outcomes and
`7 Poor adherence is
`lower long-te1m treatment costs.6
`•
`directly linked to poor treatment results and patient
`dissatisfaction.~
`Irritation commonly associated with topical therapies is
`one of the most significant factors contlibuting to lack of
`adherence and therefore therapeutic withdrawal. The local
`application-site reactions may be linked to components of
`the fo1mulation and/or to the active drug itself.8 Among the
`most commonly used topicals, retinoids and benzoyl
`peroxide (BPO) are inherently irritating and historically
`associated with poor tolerability, resulting in limited patient
`10 Still, cwTent guidelines for the treatment of
`adherence.9
`•
`patients with mild-to-moderate acne emphasize the use of
`topical retinoids and either BPO alone or BPO in
`combination with clindamycin.9
`10 In fact, BPO and tretinoin
`•
`are among
`the most commonly prescribed topical
`the
`for acne. 11 Recent concern about
`treatments
`development of bactelial resistance has led to increased
`
`dependence on topical BPO. Propionibacterium acnes(cid:173)
`the commensal micro-organ.ism that contlibutes to the
`development of acne vulgaris-has not developed resistance
`to BPO due to its unique mechanism of action. 12
`In the case of both tretinoin and BPO, irritation is
`concentration-dependent and is shown to be influenced by
`characteristics of the delivery system and formulation as
`well as the patients' skin type. As such, numerous efforts
`have been made to reduce irritation by reducing the
`concentration of active drug or incorporating ingredients
`into the vehicle that are intended to hydrate and offset the
`irritating effects of the drugs.8
`Nonetheless, therapy-associated initation remains a
`prevalent problem that contlibutes to poor patient
`adherence. 12
`18 A recent study of adherence in acne therapy
`•
`represents the largest such study to date. Multivaiiate
`ai1alysis of swvey data showed that poor adherence was not
`directly c01Telated with yow1g age (adherence was lowest in
`those yow1ger thai1 15 years, but was also low in the age group
`from 15--25 yeai-s), the occwTence of side effects, and lack of
`patient satisfaction with treatment, among other factors. 18
`One approach to improving treatment tolerability is
`through controlled-release delive1y of potentially irritatil1g
`
`DISCLOSURE: Dr. Kircik is a consultant and investigator for lntendis; consultant, investigator, speaker, and advisory board member for SkinMedica;
`and consultant, investigator, speaker, and advisory board member for Ortho Dermatologies.
`ADDRESS CORRESPONDENCE TO: Leon H. Kircik, MD; E-mail: wedodenn@bellsouth.net
`
`(M ay 20 11 • Vo lum e 4 • Number 6 )
`
`1 of 5
`
`Almirall EXHIBIT 2023
`
`Amneal v. Almirall
`IPR2019-00207
`
`

`

`TABLE 1. Comparison of delivery technologies1s
`
`Microsponge/
`spheres
`
`Porous beads with various release mechanisms,
`pressure, temperature, and solvents. The
`entrapment efficiency is about 50--60% and
`release efficiency is variable.
`
`Encapsulation
`
`Enclosed capsules with release dependent on
`mechanical rupture. Release efficiency is 100%.
`
`Liposomes
`
`Lipid bilayers entrap aqueous molecules. Release
`mechanisms and efficiency are variable.
`Entrapment efficiency is approximately 30%.
`
`cl.rugs. Facilitating the delayed release of topically applied
`cl.rugs presented a challenge to drug fo1mulators for some
`time. This obstacle has been overcome through the use of
`microsponge technology that releases the active agent slowly
`over time. Topical microsponge delivery is associated with
`improved therapeutic outcomes and minimal irritation. 14
`Microsponges are biologically ine1t polymer paiticles that
`absorb, trap, or bind drugs or other chemical compounds.
`The macroporous beads, which typically measure 10 to 25µm
`in diameter, release active ingredient over time or in response
`to certain stimuli, such as change in pH, temperature, or
`physical manipulation when mbbed into the skin. 14
`Drugs that are not soluble in water can be entrapped in
`microsponge pores, which are extremely small; thus, the
`drug functions as microscopic particles, producing a greater
`swface ai·ea and increasing the rate of solubilization.1•
`In simplest te1ms, microspheres are formed through a
`quasi-emulsion solvent diffusion method. An organic internal
`phase consisting of drug, ethyl alcohol, polymer, and t1iethyl
`citrate (TEC)/t1ichloromethane is introduced to an external
`phase of distilled water and polyvinyl alcohol (PVA) that is
`allowed to emulsify and then is continuously stirred for two
`hours. This mixture is then filtered to obtain the
`microsponges. 10 Another way of synthesizing microspheres
`is free radical suspension polymerization.
`Paiticle size, pore structure, diameter, volume, and
`release chai-a.ctelistics of the microsponge will dete1mine
`the functional parameters. Paiticle size itself may influence
`the release rate of the active drug from the microsponge:
`The larger the paiticle size, the faster the release rate. The
`amount of the active ingredient in the paiticle also depends
`on the pore value. The diameter of the pores may affect the
`intensity ai1d duration of the effectiveness of active
`ingredient. Resilience of the paiticle depends on cross(cid:173)
`linking during polymelization. More than I O-percent cross(cid:173)
`linking can slow down the release rate. 15
`The ratio of drug to polymer used during production is an
`important dete1minant of both production yield and the
`amount of drug trapped within microspheres. At a 1:1 drug(cid:173)
`to-polymer ratio in a study of experimental BPO
`microsponges, researchers found a very low yield production
`Oess than 15%) and achieved maximal production at a ratio
`of 13:1. Higher drug-to-polymer ratios produce higher drug-
`
`loading efficiency. However, even at the highest ratios of 11: 1
`and 13:1, drug-loading efficiency did not reach 100 percent.
`This may be attlibuted to dissolution of the drug in solvent
`or aqueous solution used. Also, increasing d1ug-to-polymer
`ratios are associated with decreasing particle size. 16
`Creation of an optimal formulation also depends on
`stirring rate, which is shown to influence particle size, size
`distribution, and subsequent drug release. The release
`mechanism of the active ingredient can be pressure(cid:173)
`dependant, temperature-dependant, pH-dependant, or
`• Jn,..vitro, eight-hour, release studies
`solubility-dependent.1
`of 2.5%, 5%, and 10% BPO microsphere fo1mulations
`indicated that the cumulative amow1t of drug present in the
`final fo1mulation increased as drug concentration increased.
`At all concentrations, rate of diug release dming the first
`hour was higher than the rate of release in the second hour.
`Flux remained constant for the last seven how-s. This higher
`initial rate of diug release may be due to nonencapsulated
`active drug in the fo1mulation. The constant flux observed
`dwing the next seven how-s is attributed to the release of
`encapsulated drug.16
`Microsphere technologies differ from microencapsulation
`and liposome technologies (Table 1). Microencapsulation
`involves the capture of drug within complete capsules that,
`upon application, ruptw-e and disperse 100 percent of the
`active drug contained inside. Liposomes, by compaiison to
`microspheres, tend to provide a relatively low rate of
`entrapment efficiency (approximately 30%). Microsponge
`technology does not require preservatives, whereas
`liposome technology does for microbiological stability.
`Liposomes also need ultrapure raw matelials for quality
`control, which makes them more expensive, unlike
`microsponge technology. 1•
`
`TRETINOIN MICROSPHERE FORMULATIONS
`Microsphere delive1y fo1mulations of tretinoin reached
`the market more than a decade ago with a significai1tly
`tolerability profile
`relative
`to standard
`improved
`formulations. In a study comparing the efficacy and
`tolerability of tretinoin 0. 1 % microsphere cream to that of
`adapalene 0.1% gel, tretinoin had increased dryness and
`peeling, but the incidence of e1ythema, bw11ing/stinging,
`and itching was similar in both groups. 17 With a newer
`tretinoin 0.04% microsphere fo1mulation, data show that
`cumulative irritancy was either similar to or lower than that
`associated with adapalene.18
`Compared to tretinoin microsphere gel 0. 1%, tretinoin
`microsphere gel 0.04% was associated with fewer patient
`reports of diyness dwing the eai·ly phase of treatment, while
`overall tolerability, as measw-ed by incidence of peeling,
`burning/stinging, and itching, was similar between the two
`groups; the incidence of erythema was reduced in the
`tretinoin group. 19 Another study compared tretinoin
`microsphere gel 0.04% to tretinoin 0.025% cream in subjects
`with healthy skin. Subjects in the investigator-blind,
`evaluator-blind, randomized trial applied the topical
`medications in a split-face fashion for two weeks. There was
`no significai1t difference in tolerability between the two arms
`
`•
`
`[M ay 20 11 • Vo lum e 4 • Num be r 6 )
`
`2 of5
`
`

`

`.E 100
`0
`C 80
`.:
`! ....
`C, 60
`.E
`C .ii
`E
`
`40
`
`CD ... ... 0 20
`.. C
`...
`Cl) u
`CD
`CL
`
`0
`
`89
`
`81
`
`7
`
`0
`
`6 hours
`2 hours
`(cid:127) RETIN-A MICRO 0.1% + EBP
`D Tretlnoln gel 0.025% + EBP
`
`C 100
`·s
`C 80
`.: Cl) ...
`....
`C, 60
`C
`·2
`'ii; 40
`E
`Cl) ... 20
`... 0
`.... C
`Cl) u ... Cl)
`
`0
`
`CL
`
`94
`
`84
`
`19
`
`6 hours
`2 hours
`• RETIN-A MICRO 0.1 %
`• Tretinoin gel 0.025%
`
`Figure 1. Stability in presence of erythromycin-BPO (EBPO)
`
`Figure 2. Stability with UY light exposure
`
`despite the fact that microsphere formulation had the higher
`tretinoin concentration, as indicated by measures of
`erythema, skin dryness, itching, and stinging. 18
`In addition to enhanced tolerability, microsphere
`fo1mulations provide the benefit of improved drng
`stability.20.21 Tretinoin has been shown
`to degrade
`significantly upon exposure to ultraviolet (UV) radiation as
`well as when combined with BPO. However, when
`microsphere-encapsulated tretinoin was exposed to UV and
`BPO, it was only minimally degraded. At two and six hours
`after exposure to UV radiation, 89 and 81 percent of the
`initial tretinoin remained stable, respectively. At two and six
`hours after being combined with clindamycin/BPO, 86 and
`80 percent of the tretinoin remained stable, respectively
`the
`tretinoin not in
`(Figure 1). By contrast, for
`microspheres, just 19 and 10 percent of the UV-exposed
`tretinoin remained unchanged and 7 and O percent of the
`BPO-exposed tretinoin, remained, respectively, at two and
`six hours.2' (Figure 2) These findings have been confirmed
`in vivo. A recent study shows that patients who cleansed
`the face with a BPO 5% wash each morning followed by
`topical tretinoin gel microsphere 0.04% had a response
`similar to that seen in individuals who used the same wash
`each morning and tretinoin microsphere gel together each
`evening.22 Patients (n=247) 12 years of age or older
`participated in the 12-week study. These findings suggest
`that tretinoin was not degraded by BPO. The once-daily
`regimen was well tolerated and may be associated with
`better adherence than the two-times-a-day regimen.
`Of note, treatment with topical tretinoin microsphere
`0.1% gel is associated with a more significant reduction in
`facial shine, a common concern among acne patients. For
`the single-center, double-blind, split-face study, 35 subjects
`(ages 12- 24 years) with moderate acne vulgalis and
`
`moderate facial oiliness, applied assigned medications for
`four consecutive days. At three hours after the final
`application, patients rated the reduction in facial "shine" as
`significantly greater on the sides treated with tretinoin gel
`microsphere 0.1% versus tretinoin cream 0.05%. Similarly,
`investigators noted significantly reduced facial shine at three
`and six hours post-treatment. Photographic analyses also
`showed that, while both treatments produced reductions in
`facial shine, decreases were greater on tretinoin gel
`microsphere 0.1 %-treated sides.23
`
`BENZOYL PEROXIDE MICROSPHERE FORMUlATIONS
`As noted, BPO, which has been used in the topical
`treatment of acne for more than 60 years, has re-emerged as
`a key component of effective topical acne therapy because it
`is not associated with the development of P. acnes
`resistance. Also, recent research suggests that high
`concentrations of BPO may not be necessaiy for better
`therapeutic outcomes. In fact, at 2.5, 5, and 10%
`concentrations, BPO had equivalent efficacy in inflammatory
`acne. However, higher concentrations were associated with
`increasing incidence of adverse effects.24
`The use of microsphere delivery of BPO has been
`associated with improved tolerability and good efficacy. In(cid:173)
`vivo human studies have shown that entrapped BPO
`significantly reduced counts of P. acn,es (p<0.001) and
`aerobic bacte1ia
`(p<0.001)
`and
`the
`free
`fatty
`acid/tliglyceride ratio in skin lipids.25 Controlled laboratory
`studies comparing various investigational formulations of
`BPO showed that topicals containing plain BPO particles
`had the highest release rates while BPO microspheres
`provided a low and consistent d1ug delivery. 26
`In a selies of cases recently published, BPO microsphere
`gel was associated with favorable efficacy and a ve1y low
`
`(M ay 20 11 • Vo lu me 4 • Numb er 6 )
`
`3 of5
`
`0
`
`

`

`4-Week Mean Reductions
`
`12-Week Mean Reductions
`
`0
`
`-10 BPO Microsphere
`
`-1
`BPOSt dard Gel
`
`-20
`
`-30
`
`-40
`
`-30
`
`-26
`
`-40
`
`-12
`
`,
`
`I
`
`o r
`BPO M icrosphere
`
`-10
`
`-20
`
`-30
`
`-40
`
`-39
`
`-25
`
`"1
`
`J
`
`Inflammatory
`
`Non-inflammatory
`
`Total
`
`Inflammatory
`
`Non-inflammatory
`
`Total
`
`Figure 3. Four-week mean reductions
`
`Figure 4. Twelve-week mean reductions
`
`investigator-blinded,
`initation.27 An
`for
`potential
`randomized, multicenter, 12-week study involving 48
`subjects age 12 and older with mild-to-moderate facial acne
`vulgaiis compared BPO microsphere cream 5.5% twice daily
`to BPO gel 6% twice daily.28 By Week 4, both the BPO
`microsphere cream 5.5% and BPO gel 6% groups
`demonstrated statistically significant mean percent
`reductions in inflammatory and total lesions (P<0.05)
`compared to baseline. BPO microsphere cream 5.5%
`showed a significant mean reduction in noninflammatory
`lesions, but BPO gel 6% did not. BPO microsphere 5.5%
`cream provided a greater, though not statistically significant,
`reduction in inflammatory, noninflammatory, and total
`lesions at both Week 4 (Figure 3) and Week 12 (Figure 4).
`Complete clearance or mai·ked improvement of acne was
`observed by the investigators in 33 percent of subjects
`treated with BPO microsphere cream 5.5% and 16 percent
`of subjects treated with BPO gel 6% at Week 12.
`Tolerability scores were significantly better for BPO
`microsphere cream 5.5% than for standard BPO gel 6%. 1n
`the BPO gel 6% group, there was a 79-percent incidence of
`skin tolerability reactions-stinging (22%), itching (26%),
`scaling (9%), dryness (13%), and erythema (9%). By
`contrast, the incidence of skin tolerability reactions was 37
`percent in the BPO microsphere cream 5.5% group. These
`included stinging (4%), scaling (29%), and dryness (4%).
`One subject withdrew from the trial due to skin irritation
`after four days of application of BPO gel 6%.
`Microsphere delivery can also be incorporated into wash
`formulations. 1n a study comparing BPO microsphere 5.5%
`wash to a gentle nonmedicated cleanser once daily in
`patients age 12 or older, tolerability as rated by investigators
`and subjects was very good for both products. BPO
`microsphere 5.5% wash tended to be associated with lower
`
`but not statistically significant ratings for erythema, dryness,
`and scaling as rated by investigators at Day 14 and Day 21.
`Basically, BPO microsphere 5.5% wash was as tolerable as a
`gentle nonmedicated cleanser.29
`As
`in the case of tretinoin microsponges, BPO
`microsponges appear to reduce sebum accumulation and
`associated facial shine. In one split-face trial, subjects
`cleansed the face with a gentle skin cleanser, then applied
`BPO microsphere cream 5.5% to one half of the face and no
`product to the control side. Measmements were taken with
`a sebumeter at baseline and 30 minutes, two hours, four
`homs, and six homs after the regimen. Actively treated sides
`had greater smface sebum reduction at all timepoints.80
`
`CONCLUSION
`Although topical drug therapy is associated with benefits,
`such as reduced lisk of systemic side effects, certain drugs
`have a tendency to induce local irritation. Novel formulations
`have attempted to improve tolerability through various
`means, including the avoidance of initati.ng excipients, the
`incorporation of moistwizing ingredients into the vehicle
`base, and the use of controlled-release microsphere delivery.
`By facilitating controlled-release delive1y of potentially
`initati.ng drugs, topical microspheres are associated with
`improved therapeutic outcomes and minimal irritation.
`Microsphere formulations of topical tretinoin and BPO
`currently on the mai·ket have demonstrated good efficacy
`and tolerability and are expected to encourage adherence
`and
`long-term
`therapeutic benefit. Microsphere
`encapsulation protects the stability of d1ugs; it makes
`tretinoin photostable and enables the use of convenient
`topical combination regimens with BPO. Fmthemwre,
`microspheres appeai· to absorb sebum from the skin's
`swface, reducing oiliness, which is a common complaint
`
`•
`
`[ May 2011 • Vo l ume 4 • Number 6 )
`
`4 of5
`
`

`

`among acne patients. This apparent effect is not shown to
`increase the incidence of skin dryness or initation, which
`are consistently rated as
`lower with microsphere
`formulations compared to standard formulations. Studies
`and clinical expelience confilm the efficacy and improved
`tolerability of topical tretinoin and BPO microsphere
`formulations. Microsponge technology can be used with any 18.
`topical treatment and should be more widely available,
`especially with potentially initating molecules.
`REFERENCES
`Goodman G. Acne and acne scarring.-the case for active and
`1.
`early inteivention. Aust Fam Physician. 2006;35 (7) 503--504.
`Tristani-Firouzi P, Krueger GG. Efficacy and safety of
`treatment modalities for psoriasis. Cuti.s. 1998;61(2
`Suppl):11- 21.
`Feldman SR. Approaching pso1iasis differently: patient(cid:173)
`physician relationships, patient education and choosing the
`1ight topical vehicle.J Drugs Derma.toL 2010;9(8):90~911.
`Richards fil, Fo1tune DG, Griffiths CE. Adherence to
`treatment in patients with psoriasis. J Eur Acad Dermatol
`VenereoL 2006;20(4):370-379.
`Lee IA, Maibach Hl. Pharmionics in dermatology: a review of
`topical medication adherence. Am J Clin DermatoL
`2006;7:231- 236.
`Zaeng!ein AL. Making the case for early treatment of acne.
`Clin Pediatr (Phila). 2010;49(1):5'h59.
`Balkrishnan R, Kulkarni AS, Cayce K, Feldman SR.
`P!'edictors of healthcare outcomes and costs related to
`medication use in patients with acne in the United States.
`Outis. 2006;77(4):251- 255.
`Kircik, LH, Bikowski JB, Cohen DE, et al. Vehicles matter, Vol
`l. Practical Dermat.ology. 2010;7(6 Suppl):1- 16.
`Gollnick H, Cunliffe W, Berson D, et al, Global Alliance to
`Improve Outcomes in Acne. Management of acne: a report
`from a Global Alliance to Improve Outcomes in Acne. J Am
`AcadDerma.toL 2003;49(1 Suppl):Sl-S37.
`10. Thiboutot D, Gollnick H, Bettoli V, et al, Global Alliance to
`lmprove Outcomes in Acne. New insights into the
`management of acne: an update from the Global Alliance to
`Improve Outcomes in Acne group. J Am Acad Dermat.oL
`2009;60(5 Suppl):Sl-850.
`11. Ghali F, Kang S, Leyden J, et al. Changing the face of acne
`therapy. Outi.s. 2009;83(2 Suppl):4-15.
`12. Del Rosso JQ. Selection of therapy for acne vulgaris:
`balancing concerns about antibiotic resistance. Cuti.s.
`2008;82(5 Suppl):12- 16.
`13. Dreno B, Thiboutot D, Gollnick H, et al, Global Alliance to
`lmprove Outcomes
`in Acne. Large-scale worldwide
`obseivational study of adherence with acne therapy. Int J
`Derma.tol 2010;49( 4):448-456.
`14. Embil K, NachtS. The Microsponge Delivery System (MDS):
`a topical delivery system with reduced irritancy incorporating
`multiple triggering mechanisms for the release of actives. J
`Microencapsul. 1996;13(5):575-588.
`15. Chadawar V, Shaji J. Microsponge deliveiy system. Ourr 30.
`Drug Deliv. 2007;4(2):123-129.
`Jelvehgari M, Siahi~hadbad MR, Azarmi S, Martin GP,
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`16.
`
`17.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`Nokhodchi A. The microsponge delivery system of benzoyl
`peroxide: preparation, characterization and release studies.
`IntJ Pharm. 2006;308(1-2):124-32.
`Nyirady J, Grossman RM, Nighland M, et al. A comparative
`tiial of two retinoids commonly used in the treatment of acne
`vulgaris. J Derma.to/.og Treat. 2001;12(3):149-157.
`Leyden JJ, Grossman R, Nighland M. Cumulative initation
`potential of topical retinoid formulations. J Drugs Derma.tol
`2008;7(8 Suppl):Sl4-Sl8.
`Bei-ger R, Rizer R, Barba A, et al. 'Iretinoin gel microspheres
`0.04% versus 0.1 % in adolescents and adults with mild to
`moderate acne vulgruis: a 12-week, multicentei·, randomized,
`double-blind, pru-allel-group, phase IV trial. Clin Ther.
`2007;29(6):1086-1097.
`Nyirady J, Lucas C, Yusuf M, Mignone P, Wisniewski S. The
`stability of tretinoin in tretinoin gel microsphere 0.1 %. Cutis.
`2002;70(5) :295- 298.
`Nighland M, Yusuf M, Wisniewski S, Huddleston K, Nyirady J.
`The effect of simulated solar UV irradiation on tretinoin in
`tI-etinoin gel microsphere 0.1% and tretinoin gel 0.025%.
`Cutis. 2006;77(5):313-316.
`Pariser D, Bucko A, Flied R, et al. 'Iretinoin gel microsphere
`pump 0.04% plus 5% benzoyl peroxide wash for treatment of
`acne vulgaris: morning/morning regimen is as effective and
`safe as morning/evening regimen. J Drugs DermatoL
`2010;9(7):805--813.
`Nyirady J, Nighland M, Payonk G, et al. A comparative
`evaluation of tI-etinoin gel microsphere, 0.1 %, versus
`tI-etinoin cream, 0.025%, in reducing facial shine. Cutis.
`2000;66(2):153-156.
`Fakhouri T, Yentzer BA, Feldman SR. Advancement in
`benzoyl pei·oxide-based acne treatment: methods to increase
`both efficacy and
`tolerability. J Drugs DermatoL
`2009;8(7):657-661.
`Wester RC, Patel R, Nacht S, et al. Controlled release of
`benzoyl peroxide from a porous microsphe1-e polymeric
`system can 1-educe topical irritancy. J Am Acad Derma.tol
`1991;24(5 Pt 1):720-726.
`Nokhodchi A, Jelvehgari M, Siahi MR, Mozafari MR. Factors
`affecting the morphology ofbenzoyl peroxide microsponges.
`Micron. 2007;38(8):834-840.
`Bikov.ski J, Del Rosso JQ. Benzoyl peroxide microsphere
`cream as monotherapy and combination treatment of acne. J
`Drugs Derma.toL 2008;7(6):590-595.
`Smith SR, Kempers S. A study of 5.5% benzoyl peroxide
`microsphere cream versus 6% benzoyl peroxide gel in the
`treatment of acne vulgaris. Cosmet DermatoL
`2006;19:537-542.
`Del Rosso JQ, Kircik L. Comparison of the tolerability of
`benzoyl peroxide microsphere cream wash versus gentle
`cleansei· when used in combination with clindamycin and
`tI-etinoin gel: a multicenter, investigator-blind, randomized
`study. Poster presented at: Amelican Academy of
`Deimatology 67th Annual Meeting; San FI-ancisco, California;
`March 6-10, 2009.
`Del Rosso JQ. Benzoyl pei·oxide formulations: what is the
`science supporting microsphere vehicle technology and
`clinical use. J ClinAesthet DermatoL 2009;2(9):46-54. •
`
`( May 2011 • Vo l ume 4 • Number 6 )
`
`5 of 5
`
`G
`
`