Study On Conventional Topical Formulations Biology Essay


Conventional topical formulations are designed to work on the outer layers of the skin. When such products release their active ingredients upon application, a highly concentrated layer of active ingredient is produced that is rapidly absorbed. Thus, there is a genuine need for delivery systems to prolong the time that active ingredients are present, either on the skin surface or within the epidermis while minimizing its transdermal penetration into the body. Moreover, as a result of the high concentration of active agents employed in the conventional topical dosage forms, several side effects are recorded in significant users such as irritation and allergic reactions 1.

Recently, there has been considerable interest in the development of novel microsponge base drug delivery systems to achieve targeted and sustained release of drugs 2. Microsponges are patented polymeric delivery systems consisting of porous microspheres that are mostly used for extended topical administration of a wide range of active ingredients such as emollients, fragrances, essential oils, sunscreens, and anti-infective, anti-fungal, and anti-inflammatory agents. Microsponges offer many advantages such as delivering the active ingredients at minimum dose, enhanced stability, reduced side effects, and the ability to modify drug release profiles 3. Just like a real sponge, each microsphere consists of a myriad of interconnecting voids within a non-collapsible structure and a large porous surface. The resultant microsponge spheres are uniform with a particle size range 5-300 µg, Fig. 1 1.

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Microsphere surrounded by the vehicle acts like microscopic sponges, storing the active ingredient until its release is triggered by skin application. Micropores within the spheres are employed for extensive drug retention. Microsponges consisting of non-collapsible structures with porous surface through active ingredients are released in a controlled manner. 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. Their characteristic feature is the capacity to adsorb or "load" a high degree of active materials into the particle and on to its surface. Its large capacity for entrapment of actives, up to three times its weight, differentiates microsponge products from other types of dermatological delivery systems. The active payload is protected in the formulation by the microsponge particle; it is delivered to skin via controlled diffusion. This sustained release of actives to skin over time is an extremely valuable tool to extend the efficacy and reduce the irritation commonly associated 1.

The microsponge technology was developed by Won in 1987, and the original patents were assigned to Advanced Polymer Systems, Inc. 4. This company developed a large number of variations of the technique and applied to the cosmetic as well as over the counter (OTC) and prescription pharmaceutical products 1. Nowadays, there are several FDA-approved products such as Retin-A Micro® (0.1% or 0.04% tretinoin) and Carac (0.5% 5-flurouracil) that are used for acne treatment and actinic keratoses, respectively 5.

Potential features of microsponge drug delivery systems 6-8

Microsponges are stable over a wide pH range (from 1 to 11) and at a temperature up to 130oC.

Microsponges are compatible with the majority of vehicles and ingredients.

Microsponges have high payload up to 50-60% and can be cost effective.

Microsponges are characterized by free flowing properties.

Microsponges are self-sterilizing as their average pore size is 0.25μm where bacteria cannot penetrate.

Microsponges are non-allergenic, non-irritating, non-mutagenic and non-toxic.

Microsponges can absorb oil up to 6 times their weight without drying.

Advantages of microsponges over other technologies and delivery systems 1-2

Microsponges offer better control of drug release than microcapsules. Microcapsules cannot usually control the release rate of the active pharmaceutical ingredients (API). Once the wall is ruptured the API contained within the microcapsules will be released.

Microsponges show better chemical stability, higher payload and easier formulation compared with liposomes.

In contrast to ointments, microsponges are capable of absorbing skin secretions, therefore, reducing oiliness and shine from the skin. Ointments are often aesthetically unappealing, greasy and sticky resulting in lack of patient compliance.

Characters of drugs to be entrapped in the microsponges 1,7

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There are certain requirements that should be fulfilled (or considered) when active ingredients are entrapped into microsponge:

Should be fully miscible in monomer or have the ability to be miscible by adding small amount of a water immiscible solvent.

Must be inert to monomers and do not increase the viscosity of the preparation during formulation.

It should be water immiscible or almost slightly soluble.

The solubility of active ingredients in the vehicle should be minimum; otherwise the microsponge will be diminished by the vehicle before application.

It should maintain (preserve) the spherical structure of microsponge.

It should be stable in polymerization conditions.

Only 10-12 % w/w microsponge can be incorporated into the vehicle to eliminate cosmetic delinquent.

Payload and polymer design of the microsponges for the active must be adjusted to obtain the desired release rate of a given period of time.

Techniques of microsponges preparation

Based upon the physicochemical properties of drug to be loaded in microsponges, method of preparations can take place in two ways: one-step process or two-step process. If the drug is Porogen, (i.e. an inert non-polar substance which will generate the porous structure), it will not deters the polymerization process or become activated by it and also is stable to free radicals. A Porogen drug is entrapped with one-step process (liquid-liquid suspension polymerization). Microsponges are prepared by the following methods:

5.1. Liquid-liquid suspension polymerization

In this method microsponges are prepared by suspension polymerization process in liquid-liquid systems (one step process), Fig.2. At first, the monomers are dissolved with the active ingredients (non-polar drug) in a proper solvent solution of monomer, which are then dispersed in the aqueous phase with agitation. Aqueous phase consist of additives such as surfactants and dispersants to facilitate the formation of suspension. Once the suspension is established with distinct droplets of the preferred size then, polymerization is initiated by the addition of catalyst or by increasing temperature as well as irradiation. The polymerization method leads to the development of a reservoir type of system that opens at the surface through pores. During the polymerization, an inert liquid immiscible with water but completely miscible with monomer is used to form the pore network in some cases. Once the polymerization process is complete, the liquid is removed leaving the microsponge which is permeating within preformed microsponges. This is followed by incorporation of variety of active substances and act as topical carriers. In some cases, solvent can be used for efficient and faster inclusion of the functional substances 9. If the drug is susceptible to the condition of polymerization then, two-step process is used and the polymerization is performed by means of alternate Porogen and it is replaced by the functional substance under mild conditions.

Microsponge preparation's steps can be summarized as follows 7:

Step 1: Selection of monomer and combination of monomers.

Step 2: Formation of chain monomers as polymerization initiated.

Step 3: Formations of ladders as a result of cross-linking between chain monomers.

Step 4: Folding of monomer ladder to form spherical particles.

Step 5: Agglomeration of microspheres to produce bunches of microspheres.

Step 6: Binding of bunches to produce microsponges.

5.2. Quasi-emulsion solvent diffusion

Porous microspheres (microsponges) are also prepared by a quasi-emulsion solvent diffusion method (two-step process). In this method, an internal phase is used which contains polymer such as eudragit RS 100 dissolved in ethyl alcohol. This is followed by the slow addition of the drug to the polymer solution which is then dissolved under ultrasonication at 35oC with the aid of plasticizer such as triethylcitrate (TEC) to facilitate the plasticity. The inner phase is then poured into external phase containing polyvinyl alcohol and distilled water with continuous stirring for 2 hours 10. The mixture is filtered to separate the microsponges. Finally, the microsponge is washed and dried in an air heated oven at 40°C for 12 hours 11.

6. Characterization of microsponges

6.1. Measurement of particle size

Various formulation and process variables can greatly affect the particle size of microsponge formulations. Measurement of particle size of loaded and unloaded microsponges can be performed using laser light diffractometry or any other suitable method. Results can be expressed in terms of mean size range. Cumulative % drug release from microsponges of different particle sizes should be plotted against time to study the effect of particle size on drug release. Particles larger than 30 μm can impart grittiness and hence particles of sizes between 10 and 25μm are preferred to be used in topical formulations 12-13.

6.2. Morphology and Surface topography

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The morphology and surface topography of microsponges can be studied by scanning electron microscopy (SEM). The SEM images of the prepared microsponges are recorded at the required magnification after coating the microsponges with gold-palladium under an argon atmosphere at room temperature. Recording SEM for a fractured microsponge SEM of a fractured microsponge particle can also be done to illustrate its ultra-structure 14-15.

6.3. Production yield and Entrapment efficiency

Percentage yield of the microspheres can be determined by accurately calculating the initial weight of raw materials and the final obtained weight of microsponges. Percentage yield can be calculated by using the equation 16-17:

Percentage yield (PY) = (Practical mass of microsponges/ theoretical mass of polymer and drug) X 100

The entrapment efficiency of the microsponges can be calculated according to the equation:

Entrapment Efficiency (EE%) = (Actual Drug content/Theoretical drug content) x 100

6.4. Determination of true density

The true density of microsponges can be measured by an ultra-pycnometer under helium gas and calculated as a mean of repeated determinations 18-19.

6.5. Characterization of pore structure

The volume and diameter of the pores are critical in controlling both the intensity and the duration of effectiveness of the active ingredient. Pore diameter can also affect the passage of active ingredients from microsponges into the vehicle in which the material is dispersed. Porosity parameters of microsponges such total pore volume, total pore surface area, pore size distribution, average pore diameters, shape and morphology of the pores can be determined by using mercury intrusion porosimetry. The technique can also be employed to study the effect of pore diameter and volume on the rate of drug release from microsponges 18,20.

6.6. Viscoelastic properties

Viscoelastic properties of microsponges can be modified to produce beadlets that is softer or firmer according to the needs of the final formulation. The drug release from the microsponges is a function of cross-linking with time, where increased cross-linking tends to slow down the release rate. Hence, Viscosity measurements can be conducted and the viscoelastic properties of microsponges can be optimized to obtain the desired release properties 20-21.

6.7. Physicochemical characterization

6.7.1. Thermoanalytical methods

Thermal analysis using differential scanning calorimetry (DSC) is carried out for the pure drug, polymer and the drug-polymer physical mixture to confirm compatibility. DSC is also performed for the microsponge formulations to ensure that the formulation process does not change the nature of the drug. Samples (approximately 2 mg) are placed in aluminum pans, sealed and run at a heating rate of 20oC/min over a temperature range 40 - 430oC. The thermograms obtained by DSC for the physical mixtures, as well as, microsponges should be observed for broadening, shifting and appearance of new peaks or disappearance of certain peaks. The peak corresponding to the melting of the drug should be preserved in all thermograms 22-23.

6.7.2. Fourier transform infrared spectroscopy (FTIR)

Fourier transform infrared spectroscopy (FTIR) is carried out for the pure drug, polymer and the drug-polymer physical mixture and microsponge formulations. The samples are incorporated in potassium bromide discs and evaluated using FTIR spectrometer. The peaks corresponding to the characteristics bands of the drug should be preserved in the spectra of the microsponges to indicate that no chemical interaction or changes took place during the preparation of the formulations 24-25.

6.7.3. Powder X-ray diffraction (XRD)

Powder X-ray diffraction (XRD) can be performed for both pure drug, polymer and microsponge formulation to investigate the effect of polymerization on crystallinity of the drug. The disappearance of the characteristic peaks of the drug in the formulation could indicate that the drug is dispersed at a molecular level in the polymer matrix 26-27.

6.8. In-vitro release studies , release kinetics and mechanism

In-vitro release studies can be performed using USP dissolution apparatus equipped with a modified basket consisted of 5μm stainless steel mesh at 37°C. The release medium is selected according to the type of formulation, i.e. topical or oral, while considering solubility of active ingredients to ensure sink conditions. Sample aliquots are withdrawn from the medium and analyzed by suitable analytical method at regular intervals of time.

The drug release from topical preparations (e.g. creams, lotions and emulgels) containing microsponges can be carried out using Franz diffusion cells. Dialysis membrane is fitted into place between the two chambers of the cell. A predetermined amount of formulation is mounted on the donor side of Franz cell. The receptor medium is continuously stirred at and thermostated with a circulating jacket. Samples are withdrawn at different time intervals and analyzed using suitable method of assay 21,28.

To determine the drug release kinetics and investigate its mechanism from microsponges, the release data are fitted to different to different kinetic models. The kinetic models used are; first order, zero order, Higuchi and Korsmeyer-Peppas models 29-32. The goodness of fit was evaluated using the determination coefficient (R2) values.

7. Applications of microsponges

7.1. Topical drug delivery

Topical formulations aim to deliver drugs to the outer layers of the skin. Conventional topical formulations release their active ingredients upon application, producing a highly concentrated layer of active ingredient that is rapidly absorbed. However, microsponge systems are designed to deliver a pharmaceutical active ingredient efficiently at the minimum dose. They consist of non-collapsible structures with porous surface through which active ingredients are released in a controlled manner. Therefore, such systems can prevent excessive accumulation of active ingredients within the epidermis and the dermis, thus they can significantly reduce the irritation and side effects caused by drugs without reducing their efficacy. In addition to modification of drug release and reduction of side effects, microsponges are also capable of enhancing the stability of many drugs. The drug loaded porous microsponges can further be incorporated into creams, lotions or powders 33. Microsponges are applied for the topical delivery of several drugs and cosmetic agents as shown in Table 1 2.

Several studies have been performed for the development of microsponges loaded with topically applied drugs. A formulation of hydroquinone (HQ) 4%, with retinol 0.15%, entrapped in microsponge reservoirs, was developed by Grimes 34 for the treatment of melasma and postinflammatory hyperpigmentation. The formulation was intended to release HQ gradually in order to prolong exposure to treatment and to minimize skin irritation. The safety and efficacy of this product were evaluated in a 12-week, open-label study. In this open-label study, the microentrapped HQ 4% with retinol 0.15% was proved to be safe and effective. A microsponge system for retinoic acid was also developed and tested for drug release and anti-acne efficacy. Statistically significant, greater reductions in inflammatory and non-inflammatory lesions were obtained with tretinoin entrapped in the microsponge 35.

Topical application of benzoyl peroxide (BPO), a drug that is mainly used in the treatment of mild to moderate acne and athlete's foot, is commonly associated with skin irritation. It has been shown that controlled release of BPO from a delivery system to the skin could reduce irritation due to reduction of drug release rate from formulation. Several authors21,36-37 developed a microspongic delivery system of BPO using an emulsion solvent diffusion technique, by adding an organic internal phase containing benzoyl peroxide, ethyl cellulose, and dichloromethane into a stirred aqueous phase containing polyvinyl alcohol. BPO microparticles were then incorporated into standard vehicles for release studies. It was found that the presence of emulsifier was essential for microsponge formation and that the drug to polymer ratio, stirring rate and volume of dispersed phase influenced the particle size and drug release behavior of the formed microsponges. Generally, an increase in the ratio drug to polymer resulted in a reduction in the release rate of BPO from microsponges which was attributed to a decreased internal porosity of the microsponges. Further studies showed that the morphology and particle size of BPO microsponges were also affected by drug to polymer ratio, stirring rate and the amount of emulsifier used 15.

Fluocinolone acetonide (FA) is a corticosteroid used in dermatological preparations to lessen skin inflammation and relieve itching, however, the percutaneous absorption increases risk related with systemic absorption of the drug from topically applied formulation. D'souza and Harinath 38 developed topical anti-inflammatory gels of fluocinolone acetonide entrapped in eudragit based microsponge delivery system. The fluocinolone acetonide loaded microsponges were prepared using the quasi-emulsion solvent diffusion method aiming to control the release of drug to the skin which in turn reduces the drug percutaneous absorption and thus lessens its side effects. The prepared microsponges were evaluated for several parameters including particle size analysis, loading efficiency, production yield and surface morphology. Microsponges were then incorporated into carbopol 934 and comparative anti-inflammatory studies were performed with gels containing the free dug.

A microsponge based topical delivery system of mupirocin, a topical antibiotic used for skin infections, was developed by Amrutiya et al. 5 aiming to achieve sustained drug release and enhanced deposition in the skin. Microsponges containing mupirocin were prepared by emulsion solvent diffusion method. A 32 factorial design was applied to examine and optimize the effect of formulation and process variables, namely; internal phase volume and stirring speed, on the physical characteristics of microsponges. The optimized microsponges were incorporated into an emulgel base. The mupirocin-loaded formulations were evaluated for in-vitro drug release, ex-vivo drug deposition, and in-vivo antibacterial activity. Drug release studies showed diffusion-controlled release pattern and drug deposition studies using abdominal rat skin demonstrated significant retention of the drug in skin from microsponge-based formulations. The optimized formulations were stable and nonirritant to skin according to Draize patch test. In addition, microsponges-based emulgel formulations exhibited prolonged efficacy in mouse surgical wound model infected with S. aureus. The enhanced retention of mupirocin in the skin from the microsponge based formulations indicates better potential of the delivery system for treatment of primary and secondary skin infections, such as impetigo, eczema, and atopic dermatitis as compared with marketed mupirocin ointment and conventional mupirocin emulgel.

Saboji et al.* 39 developed microsponges containing Ketoconazole drug with six different proportions of Eudragit RS 100 as polymer using quasi-emulsion solvent diffusion method. The microsponge formulations were evaluated for particle size, loading efficiency and production yield. The microsponge formulations showing the best properties were then incorporated into 0.35 %w/w carbopol gel. The ketoconazole microsponges incorporated into gel formulations showed acceptable physical parameters, appropriate drug release profile and marked in-vivo antifungal activity on guinea pig skin.

Administration of hydroxyzine HCl, an antihistaminic drug used in oral formulations for the treatment of urticaria and atopic dermatitis, is usually associated with dizziness, blurred vision, and anticholinergic responses. Therefore, Zaki et al.* 40 investigated the formulation of eudragit RS-100 microsponges of hydroxyzine HCl with the objective of producing an effective drug-loaded dosage form that is able to control the release of the drug into the skin. The oil in an oil emulsion solvent diffusion method was applied for the production of eudragit RS-100 microsponges of the drug using acetone as dispersing solvent and liquid paraffin as the continuous medium. Pore inducers such as sucrose and pregelatinized starch were used to enhance the rate of drug release. Microsponges of nearly 98% encapsulation efficiency and 60-70% porosity were produced. The pharmacodynamic effect of the chosen preparation was tested on the shaved back of histamine-sensitized rabbits. Histopathological studies were also driven for the detection of the healing of inflamed tissues. The prepared systems proved their efficacy for relieving histamine-induced inflammation.

A xanthan gum-facilitated ethyl cellulose microsponges loaded with diclofenac were prepared by Maiti et al. 41 using the double emulsification technique. The prepared microsponges were subsequently dispersed in a carbopol gel base for controlled delivery of the active to the skin. Scanning electron microscopy revealed the porous, spherical nature of the microsponges. Increasing the drug to polymer ratio positively influenced the production yield, drug entrapment efficiency and mean particle diameter. However, compared to the microsponges with high drug to polymer ratio, the flux of entrapped drug through excised rat skin decreased significantly for the microsponges prepared at low and intermediate drug to polymer ratios. In addition, the microsponges prepared at the lowest drug to polymer ratio exhibited a comparatively slower drug permeation profile and thus, were considered most suitable for controlled delivery of diclofenac sodium to the skin. The gel containing these optimized microsponges was comparable to that of a commercial gel formulation and did not show serious dermal reactions.

Deshmukh and Poddar 42 have recently developed a Glabridin microsponge-loaded gel for treating various hyperpigmentation disorders. The microsponges were prepared using the emulsion solvent evaporation method and characterized for drug loading and morphology. Scanning electron microscopy (SEM) and porosity studies confirmed spherical and porous nature. In-vitro diffusion studies of gel formulation depicted highest correlation with Higuchi treatment. Animal studies, carried out using brownish guinea pigs with UV-induced pigmentation model, supported the better depigmenting activity of the microsponges incorporated gels as compared to plain gel.

7.2. Oral drug delivery

A microsponge system offers several advantages for oral drug delivery, such as:

Preserve the active ingredients within a protected environment and offer oral controlled delivery to the lower part of the gastrointestinal tract (GIT).

Microsponge systems improve the solubility of poorly soluble drugs by entrapping these drugs in their porous structure.

As the porous structure of the microsponge is very small in size, the drugs entrapped will be reduced to microscopic particles with higher surface area, and consequently improved rate of solubilisation.

Maximize the amount of drugs to be absorbed, as the time it takes the microsponge system to pass through the intestine is considerably increased.

Several studies have been investigated for the development of microsponges loaded with topically applied drugs. Jain and Singh 43 prepared colon specific formulations by loading paracetamol in eudragit RS 100 based microsponges using quasi-emulsion solvent diffusion method. Compression coating of microsponges with pectin: HPMC mixture followed by tableting was used. The in-vitro drug release studies were done on all the formulations and the results were evaluated kinetically and statistically. The study concluded that the release data followed Higuchi matrix but diffusion was the main mechanism of drug release from microsponges. In-vitro studies showed that compression coated colon specific tablet formulations started the release of drug at the 6th hour resultant to the arrival time to proximal colon.

In another study, Gonul et al.44 studied the effects of pressure and direct compression on tableting of microsponges using ketoprofen as a model drug. ketoprofen microsponges were prepared by two methods: quasi-emulsion solvent diffusion method with eudragit RS 100 and direct compression method. Different pressure values were investigated with the tablet powder mass to determine the optimum pressure value for the compression of the tablets. Results of the study indicated that microsponge compressibility was superior compared to the physical mixture of the drug and polymer. It was concluded that microsponges can produce mechanically strong tablets due to the plastic deformation of sponge like structure.

Jain and Singh 24 studied the potential of formulating dicyclomine loaded eudragit based microsponge by means of a quasi-emulsion solvent diffusion method for colonic delivery. The compatibility of the drug with various formulation components was studied. Surface morphology and shape of the microsponges were demonstrated using scanning electron microscopy (SEM). The compatibility studies showed that there is was no chemical interaction throughout the preparation of the formulations and that the drug remains stable in all the formulations. The release rate of the drug from the microsponges was decreased with increasing the drug: polymer ratio. Kinetic studies showed that the main mechanism of drug release followed Higuchi matrix controlled diffusion. An initial burst effect showed that the drug release was bi-phasic with 16 - 30 % of the drug released in the 1st hour. Cumulative release for the microsponges over 8 hours was ranged from 59 - 86 %. The authors concluded an approach for the alteration of microsponges of dicyclomine for prolonged drug release. The distinctive compressibility of microsponges can be applied to get efficient local action as microsponges may be taken up by macrophages which are present in colon.

Colon specific drug delivery system containing flurbiprofen (FLB) microsponges was investigated by Orlu et al. 45. The authors formulated microsponges containing FLB and eudragit RS 100 using quasi-emulsion solvent diffusion method. Also, FLB was loaded into a commercial Microsponge® 5640 system by means of entrapment method. Compression coating and pore plugging of microsponges with pectin: HPMC mixture followed by tableting was used to prepare colon specific formulations. The prepared microsponges were spherical in shape and found to be 30.7- 94.5 μm in diameter and showed high porosity values (i.e. 61-72%). The pore shapes of microsponges prepared by quasi-emulsion solvent diffusion method were found as spherical whereas by entrapment method it was found as cylindrical holes. Due to the plastic deformation of sponge-like structure of microsponges, mechanically strong tablets were produced for colon specific drug delivery. In vitro studies revealed that colon specific tablet formulations prepared by compression coating, started to release the drug at the 8th hour resultant to the proximal colon arrival time due to the addition of enzyme which could followed a modified release pattern, whereas the drug release from the colon specific formulations prepared by pore plugging the microsponges showed an increase at the 8th hour which was the time point that the enzyme addition was made.

8. Conclusion

Microsponge has become a rapidly evolving technology that can be widely applied in the pharmaceutical field. Owing to their microporous structure and their ability to release actives on a time mode or in response to other stimuli, microspones can effectively control the release rate of drugs and target them to specific sites. They offer several advantages including reduced side effects and improved stability. Thus, microsponge delivery systems are regarded as a promising vehicle for the controlled and targeted release of various topical and oral active agents.