Drug Development and Industrial Pharmacy

ISSN: 0363-9045 (Print) 1520-5762 (Online) Journal homepage: https://www.tandfonline.com/loi/iddi20

Development and evaluation of dapsone tablets

coated for specific colon release

Priscila Debastiani Barros, Isabela Fernanda Teixeira Dias, Giovane Douglas

Zanin & Élcio José Bunhak

To cite this article: Priscila Debastiani Barros, Isabela Fernanda Teixeira Dias, Giovane
Douglas Zanin & Élcio José Bunhak (2020): Development and evaluation of dapsone
tablets coated for specific colon release, Drug Development and Industrial Pharmacy, DOI:
10.1080/03639045.2020.1716375

To link to this article: https://doi.org/10.1080/03639045.2020.1716375

Accepted author version posted online: 17

Jan 2020.

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Development and evaluation of dapsone tablets coated for specific
colon release

1
Priscila Debastiani Barros; 1Isabela Fernanda Teixeira Dias; 2Giovane
Douglas Zanin; 1Élcio José Bunhak.

1
State University of Western Paraná, 2University Center Foundation Assis Gurgacz,
Cascavel, Brazil

Corresponding author:

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Priscila Debastiani Barros

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+55 49 999003807
Email: prisciladb@unochapeco.edu.br
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Development and assessment of coated dapsone tablets for specific
colon release

Objective: Drug release systems based on colonic microbiota have been explored with
the use of polysaccharides, which are biodegradable. In order to modulate the
release into the colon, dapsone tablets were developed, coated with Surelease®
and chondroitin sulfate. Methods: The formulation was developed using the wet
granulation method, in the form of 9-millimetre circular tablets. The coating was
applied in a perforated basin-type coating using different proportions of

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Surelease® and chondroitin sulfate. The tablets were assessed according to the

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criteria of mean weight, hardness, and friability. The dissolution test was

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performed in the dissolver IV apparatus, in media simulating the gastrointestinal
system environments (pH 1.2 - pH 6.0 and pH 7.2) for 420 minutes. The results

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were analyzed by statistical analysis and factorial design. Results: The results of
mean weight, hardness, and friability met the pharmacopoeial specifications. In
the dissolution test, the results obtained demonstrated that Surelease® is able to
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offer effective protection to the drug, releasing minimum rates when used at 6%
or 10% of the tablet's weight gain. The experiments showed that the drug was not
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able to spread through the coatings manufactured exclusively with Surelease ® or

even when SC was incorporated in different proportions. Only in the formulation
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where SC was included in the highest proportion (10%), and the weight gain of
the tablet was lower (6%), the release of dapsone increased, reaching 9.5% of
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drug released. Through factorial planning, it was observed that the drug release
rate increases when the weight gain of the tablet remains at the lower level (6%),
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while the amount of polysaccharide is increased (90:10). Conclusions: The data

indicate that the proportion of polysaccharide for ethyl cellulose in the film and
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the thickness of the coating are the key parameters in controlling the release of
the drug from the system.

Keywords: Leprosy; chondroitin sulfate; Surelease; polymeric association.

Introduction
Tablets are solid pharmaceutical forms for oral administration, which contain

suitable excipients according to the desired formulation. The coating of solid

pharmaceutical forms is an operation within the pharmaceutical industry that aims to

include one or more thin and solid layers to the core of the tablet [1]. The process

consists of forming a uniform film of a polymer on the surface of the tablets by spraying

a liquid, which can be an active ingredient or a specific coating material [2]. This

technique is used to improve or modify the technological and release characteristics of

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pharmaceutical forms such as capsules, tablets, and granules [3].

In recent years, there has been an increased interest in research on drug release

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systems for delivery in the colon region [4], since the approach has extremely relevant

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applications in the treatment of diseases of the large intestine, such as ulcerative colitis,
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Crohn's disease and colon câncer [5]. The colon has a retention time of approximately

five days, and the mucosa is known for facilitating the absorption of drugs, capable of
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capturing 90% of the water that passes through the organ, turning it into an ideal place

for delivery of drugs. The main objective of the colonic delivery of drugs is to delay the
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release of the drug until it reaches the large intestine. In addition to drugs to treat
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pathologies of the colon, some other criteria are taken into consideration for the
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development of a new colonic formulation, for example, drugs with incomplete

absorption in the upper gastrointestinal tract, with high probability of degradation by the
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stomach and high risk of first-pass metabolism [6].

Polysaccharides are carbohydrates containing interconnected subunits of

monosaccharides and are found in animal tissues (chitosan, chondroitin sulfate) plants

(Goma Guar, Inulin) and microorganisms (Dextran). They are available in abundance,

at low cost, non-toxic, and with ease of modification, generally stable and safe, with the

capacity to form films [7,8]. The microbiota of the colon, represented mainly by the
species Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria are anaerobic

and are nourished by the fermentation of non-starch polysaccharides. [9].

Bifidobacterium, Bacteroids, Lactobacillus, and enterobacteria are capable of

metabolizing several types of substrates that are not digested in the small intestine,

producing specific enzymes for the fermentation process, such as glucuronidase,

xylosidase, arabinoside, galactosidase and azo-reductases [10]. In view of the diversity

of the colonic microbiota, approximately five hundred different species, this approach

allows the use of coating films in pharmaceutical formulations for the release of the

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drug through the cleavage of polymers by microorganisms [11].

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Chondroitin sulfate (SC) is a natural polysaccharide present in the cellular and

extracellular level of vertebrates and invertebrates. Thus, the main mechanism of

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digestion occurs through the depolymerization of the polysaccharide by the action of
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hydrolytic enzymes produced specifically by the flora present in the large intestine, such

as Bacteroides thetaiotaomicron and Bacteroides ovatus [12,13].

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Leprosy or Hansen's disease is a chronic infectious pathology caused by the

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bacterium Mycobacterium leprae, characterized by affecting the skin and peripheral

nerves, but which can also affect other organs, such as the respiratory tract, lymph
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nodes, bone marrow, testicles and muscles [14-16]. The treatment of leprosy is
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multidrug therapy, introduced by the World Health Organization since 1981 and

adopted by the Ministry of Health in Brazil in 1991, consisting of drugs: Clofazimine,

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Rifampicin, and dapsone [17]. Currently, dapsone is the only molecule derived from

sulfone used in human therapies, being used in medicine for presenting antimicrobial

and anti-inflammatory activity [18-20]. However, despite the drug being effective

against leprosy, it causes vomiting, nausea, and liver toxicity, besides 30 to 40% of

patients present immune reactions with inflammatory complications due to drug therapy
[21,22]. Dapsone was classified as a Class II drug - with low solubility and high

permeability [23]. Despite its therapeutic potential, the limited solubility (0.16 mg/mL

in water) is a disadvantage for the patient, because the dissolution mechanism is

fundamental in the result of the efficacy of a drug, regardless of the route of

administration [20,24]. Moreover, it results in a low therapeutic index, with critical

adverse effects [25].

In this work, aiming at the application of polysaccharide chondroitin sulfate, we

proposed the development of formulations to assess the possibilities of combining this

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compound with the Surelease® polymer, an aqueous dispersion of ethylcellulose, for

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colonic delivery. Dapsone tablets were coated with different concentrations of the

synthetic polymer combined with SC proportions, and the physical-chemical

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characteristics of the tablets were assessed, as well as the drug release rate in different
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means of dissolution simulating the gastrointestinal tract, demonstrating the in vitro

characteristics of the coated tablets.

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Materials and methods

1. Materials
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Dapsone was acquired from FAGRON®. All other components were donated from the
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respective suppliers: Microcrystalline Cellulose 101 (Itacel Farmoquímica Ltda®),

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Monohydrate Lactose (Friesland Campina DMV B.V®), pregelatinized corn starch

(Evonik Resource Efficiency GMBH®), povidone (Ashland Specialty Ingredients),

silicon dioxide (Uzhou Zhanwang Pharmaceutical CO®), magnesium stearate (Peter

Greven®), surelease® (Colorcon®), chondroitin sulphate (Solabia®).

1.2 Methods

Tablets preparation

The 100mg dapsone tablets were prepared using the wet granulation technique.

Compression was performed on a FETTE® machine with a 9 mm circular puncture. The

formulation used for each tablet was dapsone (37%), microcrystalline cellulose (22%),

lactose monohydrate (23%), corn starch (6.5%), povidone 30 (5%), silicon dioxide

(1.9%) and magnesium stearate (1%).

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Tablets coatings

A Surelease® dispersion diluted at 15% with distilled water was prepared as

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directed by the supplier. Predetermined volumes corresponding to concentrations 5 and

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10% of SC polysaccharide were added to the Surelease® dispersion. The tablets were
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coated until the expected weight gain was achieved in a VECTOR® coater. At the end

of the experiment, six formulations were obtained (Table 01) with different coating film
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compositions (Table 02).

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Table 01 - Formulations obtained from the coating of tablets

Table 02 Composition of coating films
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Determination of the tablets mean weight

The weight determination test enables you to assess whether the coated tablets are
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uniform in weight. The procedure consisted of weighing 20 tablets and determining the

mean weight, and the maximum variation should be up to 5.0% for formulations with

250mg or more. The test was conducted according to the general methodology of the

Brazilian Pharmacopoeia 5th Edition (2010) [26].

Determination of the hardness of the tablets

The hardness test consisted of submitting a sample of 10 tablets to the

ERWEKA® Durometer equipment that measured the force applied to crush them in kp

(KiloPascal). The test was conducted according to the general methodology of the

Brazilian Pharmacopoeia 5th Edition (2010) [26].

Determination of the friability of the tablets

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The friability test was performed in specific equipment called a friabilometer. A

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sample of twenty tablets suffered falls for 4 minutes through 25 rpm rotation of the

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equipment. The test was performed according to the Brazilian pharmacopoeia 5th

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edition [26], the tablets were weighed before and after the test, and the friability was

calculated. Tablets with loss equal or less than 1.5% of their initial weight were
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considered acceptable.
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Assessment of the dapsone release profile from the tablets

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The in vitro dissolution tests were performed in a SOTAX® apparatus of flow

cells, using the following conditions: Medium 1 - HCL 0.1 M pH 1.2; Medium 2 -
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Potassium phosphate buffer pH 6.0; Medium 3 - Potassium phosphate buffer pH 7.2,

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simulating the pH conditions of gastric juice, enteric juice, and colon, respectively. At
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predetermined time intervals of 4, 8, 12, and 16 minutes, aliquots of 10 mL of Medium

1 were automatically collected. At intervals of 20, 30, 40, 60, 80 and 120 minutes the

samples of medium 2 were collected. In the last medium, we analyzed samples from

intervals of 150, 180, 210, 240, 360 and 420 minutes. The tests were performed in

triplicate. The dapsone was analyzed by spectrophotometry in the ultraviolet region at

290 nm, determining the absorbances of the aliquots for each time interval and using the
dissolution medium as white. The concentrations were calculated through the

calibration curve.

Statistical analysis

The statistical analysis of the results of mean weight and hardness was performed

through the analysis of variance (ANOVA) one way (one factor), the factor used was the

formulations with 6 levels (Formulation 01, Formulation 02, Formulation 03, Formulation

04, Formulation 05 and Formulation 06), followed by the Tukey test to verify the difference

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in means between the formulations, where a p-value of less than 0.05 was considered

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statistically. The Minitab 17.0 program was used.

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In order to assess the interactions between the different formulations for the

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production of the coating with potential colonic delivery, a factorial design 2 2 was

performed. The factors used were: Percentage of coating weight gain (X 1) and proportions
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between Surelease® and SC (X2) (Table 03). The response variable (y) was the drug release
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rate. The Statistica 7.0 program was used.

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Results and Discussion

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Preparation and coating of tablets

The dosage of 100mg of the drug was based on the multidrug therapy treatment
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of leprosy, where the patient administers 100mg per day of the drug dapsone. This same

dose is related to the incidence of adverse effects of sulfone, the most common being

methemoglobinemia, which can lead the patient to cyanosis, coma, convulsions, and

even death [27]. Therefore, the development of dapsone 100 mg coated tablets for

colonic delivery becomes extremely interesting, given the high absorption capacity of
the colon and release of the drug by the action of microbiota. The form of the tablet

chosen for development was circular, as it is the most suitable for coating application

since there is less possibility of adhesion between the tablets during the process [28].

With the purpose of studying the influence of coating levels on the drug release

rate, the formulations were developed using two coating levels (6 and 10%) and

polymeric proportions of 90:10 and 95:05 (Surelease:SC). The reduction in the amount

of SC was proposed since the reduced hydrosolubility of formulations for colonic

delivery is essential to resist passage through the stomach and small intestine, where the

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drug release must be minimal [6].

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The same strategy was applied to theophylline mini-tablets by Mohamed et al.

[29]. An increase in the weight of the Surelease® coating and a reduction in the levels of

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hydrophilic constituents in the formulation matrices resulted in a delayed release of the
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drug. However, the hydration capacity of the polysaccharide is also an important

requirement for the release of drugs in the distal portions of the TGI. Hydration should
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be sufficient for the tablet to absorb the fluids of the colon and allow bacteria to access
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the molecule, with consequent formation of pores [13,30].

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Determination of the mean weight of tablets

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The mean weight was obtained according to the Brazilian Pharmacopoeia 5th ed.

[26], where the acceptable weight is a variation of 5.0% of the weight for tablets with
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250mg or more. The Analysis of Variance test (ANOVA) showed that at least one of

the formulations was different. When comparing the six formulations using the Tukey's

test, we identified that the means followed by the same letter do not differ from each

other at 5% significance (Table 03). The mean weight values are related to the amount
of coating applied to the tablet. The tablets presented results within the specification,

according to the Brazilian Pharmacopoeia, 5th ed. [26].

Determination of the hardness of tablets

The strength of the tablet assessed by the hardness test is defined as the force

applied to crush it and is a relevant quality control analysis. Analysis of Variance

(ANOVA) was performed, and it was found that at least one of the formulations was

different. When comparing the six formulations using the Tukey's test, we identified

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that the means followed by the same letter do not differ from each other at 5%

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significance (Table 03). Therefore, formulations 01, 04, 05 and 06 did not present

significant difference between the means of hardness (p>0.05). Formulations 02 and 03

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are different from each other and also differ statistically from formulations 01, 04, 05
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and 06 (p<0.05). Formulation 02 showed the highest mean hardness of 15.6 kp, and is

also the one with the highest percentage of coating, validating the increase in
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mechanical strength provided by the film [28].

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Determination of the friability of tablets

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The tablets should be assessed for mechanical shocks, abrasion, or friction,

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processes that may occur during manufacture, transport, and handling by the patient

[28]. A high index of friability may have interferences in the drug content, with
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decreased therapeutic effect, and may generate questions from the consumer [31]. All

the tablets met the specifications of the Brazilian Pharmacopoeia 5th ed. [26], with a

loss of less than 1.5% of the weight of the tablets (Table 3).

Table 03 Results of physical tests of coated dapsone tablet formulations.

a – Mean of the values obtained for 10 tablets

b – Mean of the values obtained for 20 tablets
Assessment of the dapsone release profile from the tablets

The in vitro dissolution test for drug delivery systems in the colon region with

polysaccharides is a major challenge in research due to the complex physiological

processes that integrate the large intestine. The most commonly used approaches are the

addition of enzymes, cecal content of rats and human faeces, which have limitations and

are often not reproducible methods. New methods are being developed based on

probiotics and prebiotics; however, in-depth research in this regard must be carried out

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for the method to be validated and accepted by regulatory agencies.

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Therefore, the IV apparatus of dissolution is the equipment that best reproduces

the physiological environment of the TGI, especially by the present flow pump that

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circulates the medium of dissolution inside the device. The study followed the
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specifications of the American Pharmacopoeia 41st ed. [32] for dissolution tests for

pharmaceutical forms of delayed-release, using the simulated means of gastrointestinal

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tract fluids.
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The use of apparatus IV as the method of choice to better reproduce the

hemodynamics of physiological fluids was demonstrated by the pioneering works of

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Wakerly and collaborators [33] who prepared tablets of paracetamol coated with
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Surelease® and pectin and submitted to a study of dissolution in flow cells at pH 6.0

phosphate buffer. In another study, the in vivo and in vitro dissolution profile of
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danazol, a poorly soluble drug using an IV apparatus, was recognized by Sunesen et al.

[34].

The systems developed for colonic delivery must exhibit a minimum release of

the drug until it reaches the site of action. Since the estimated time of arrival at the
colon can vary up to 6 hours [9], the study provided an appropriate time to trace

possible specific colon formulations, with a total of 7 hours.

Formulation tablets 01 and 02, containing dapsone and Surelease® 6% and 10%,

presented minimum drug release during 7 hours of study (Figure 1). This behaviour is

desired in formulations that are directed to the colon since the formation of pores must

be delayed in the upper TGI to minimize premature release [5]. It is observed that there

was no significant difference in drug release altering the ethylcellulose from 6 to 10%

of weight gain because both offered effective protection. Another observation is that the

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higher the proportion of Surelase®, the lower the rate of drug release.

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In the time interval of 360 to 420 minutes, one of the formulation 01 tablets

disintegrated the coating film and released about 11% dapsone. However, it is important

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to note that the other two tablets of formulation 05 presented low levels of drug release
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at the end of the tests, 4.4 and 4.5%. This divergence can be explained by pharmacy

technical variations from tablet to tablet, changes in the parameters of the coating
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process, or small cracks in the coating caused by the inoculation of the tablet in the cell,
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since the use of tweezers was made. The Dapsone nucleus had more than 75% dissolved

within the first 45 minutes, characteristic of a pharmaceutical form of immediate

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release.
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In previous works, the efficacy of ethyl cellulose in offering protection to the

drug was demonstrated. Siew et al. [35] obtained pellets resistant to simulated fluids of
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the gastrointestinal tract using enzymes in the dissolution medium, as well as with the

use of faeces from healthy individuals at pH 7.2. This can be explained by the

characteristic time-dependent polymer of ethylcellulose [36].

Figure 1 - Graphical representation of the dissolution of Dapsone coated tablets in (%) Dissolved x Time (min) -
Core, formulations 01 and 02.
 Figure 2 shows the four results obtained in the dissolution tests with the different

coating formulations. The formulations 05 and 06, with the lowest proportion of

polysaccharide (5%), had no significant differences in the release of dapsone, 3.7%, and

3.0%, respectively, regardless of the percentage of Surelease®. A similar value was

observed in formulation 04, of 2.6% of drug released, which despite containing a higher

proportion of polysaccharide, the 10% weight gain coating with ethylcellulose showed

effective protection with minimal release.

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The experiments showed that the drug was not able to spread through the

coatings manufactured exclusively with Surelease® or even when SC was incorporated

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in different proportions. Only in formulation 03, where SC was included in the highest

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proportion (10%), and the weight gain of the tablet was lower (6%), the release of
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dapsone increased, reaching 9.5% of drug released. The results indicate that coatings

containing higher amounts of SC, but with lower thickness, may be able to provide
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drugs specifically for the colon compared to coatings containing higher amounts of
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ethylcellulose. This fact suggests that the higher the concentration of SC, the higher the

percentage of drugs released. This fact can be explained by the high water solubility of
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the polysaccharide [13].

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Figure 2 - Graphical representation of the dissolution of dapsone tablets of formulations 03, 04, 05 and 06 in (%)
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Dissolved x Time (min)

The rate of drug release may increase significantly in the colonic environment

due to the presence of microorganisms. This fact can be demonstrated by studies that

used faeces as a means of dissolution or in vivo studies. Karrout et al. [37] coated

theophylline pellets with ethyl cellulose and Nutriose, a type of fibre that serves as a
substrate for the enzymes secreted by the colonic microbiota. The study concluded that

the most promising concentration was in the proportion of 1:05 and a weight gain of

20% of ethylcellulose. Within 24 hours of the study with HCL fluids and phosphate

buffer pH 6.8, around 25% of the drug was released, while with the faeces study within

24 hours more than 50% of the drug had been released. In this experiment, it was

evident the significant difference in the release of the drug in contact with faeces,

approximately double the percentage.

In previous works, the potential degradation of chondroitin sulfate by colonic

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microbiota was observed. Ramasamy et al. [38] obtained a rapid increase in the release

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rate of aceclofenac tablets coated with SC and pH-dependent polymer in the fluid

containing cecal material. Wei et al. [39] demonstrated that SC is mainly fermented by

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the species Bacteroids, Bifidobacterium and Clostridium, which significantly increased
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their proportions and their metabolites in the TGI in the presence of the polysaccharide.

These results reinforce the application of SC as a component of the coating of drugs

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directed to the colon, where bacteroids are abundant.

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The lipophilic characteristic of dapsone is added to the results discussed above

as a justification for the choice of the drug for colonic delivery as the object of the
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study. In previous studies, Alamelu and Rao [40] associated dapsone and chitosan in a
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formulation of liposomes and obtained a delayed and controlled release of the drug of

up to three days, in a pH 7.4 dissolution medium, simulating the colonic conditions. The
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same behaviour of the rate of dissolution and absorption of the drug was observed when

tested in rat plasma.

In addition, the tests performed by Chaves et al. [41] assessing the intestinal

permeability and toxicity of dapsone reinforces the applicability of the drug as a colon-

directed drug. The in vitro assessment of dapsone nanosystems in Caco-2 cells

demonstrated low toxicity to the cells after 8 hours of study and sufficient intestinal

permeability for drug absorption. These results reinforce the application of dapsone as a

promising candidate drug for the transport of drugs for specific release in the large

intestine.

Statistical analysis

The factorial design has been used by several authors in studies to assess and

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optimize formulations for specific drug delivery. Fernandes et al. [42] assessed the

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influence of two different surfactants on the development of ibuprofen nanocrystals

through a two-level factorial design. The dissolution rate was assessed as a dependent

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variable by Verma et al. [43], and different levels of chitosan and PEG-400 as film
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formers to mask the flavour. Table 4 shows the experimental design matrix used in this

work, together with the results obtained for the dapsone release rate.
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Table 04 – Matrix containing decoded variables and results obtained in the dissolution tests.

The results of the drug release rate were analyzed by the methodology of
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interaction between the factors (figure 3) and by the graph of the response surface
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(Figure 4) and from which we obtained the following adjusted equation for the model

using the factorial design 22: where

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Y: Represents the dapsone dissolution rate; X1 the coating weight gain (%) and X2 the
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polymeric ratio between Surelease® and SC (%).

y = 4,84 - 1,74 X1 – 1,29 + 1,69 X1 X2 + e

The interaction graph (Figure 3) shows that when the polymeric proportion is

95:05, regardless of the coating weight gain, the mean value of the dissolution rate is

3.55, indicating that the coating level does not interfere with the release of the drug

when a 5% amount of polysaccharide is added. When we set the polymeric proportion

at 90:10, when increasing the coating level (from 6 to 10%), the rate of drug release is

decreased, from 9.5% to 2.65% on average.

Figure 3 – Interaction graph between coating weight gain and polymeric proportion for dapsone release

The response surface graph (Figure 4) demonstrates the same relationship, in

order to increase the drug release rate, the weight gain of the tablet should remain at the

lower level (6%), while the amount of polysaccharide should be increased (90:10).

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Figure 4 – Dapsone release rate response surface graphic

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In the study by Wilson and Basit [5], it was observed that the relationship

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between the polymeric proportion of ethylcellulose: polysaccharide had a strong effect

on the response of the mesalazine release rate. The highest percentage of dissolution of
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the drug was observed when a higher amount of amylose and lower levels of ethyl
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cellulose were used as weight gain. These results seem to be influenced by the

characteristic of ethylcellulose being insoluble in water and the bacterial digestion

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suffered by amylose in the colonic environment, which generates pores in the film

structure, allowing the diffusion to the external environment.

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It has been evidenced that ethylcellulose has the characteristic of forming

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resistant films, and its drug release process is by diffusion through the layers, forming
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an impermeable barrier to water, controlling the swelling of the polysaccharide in the

coating [44]. On the other hand, in the experiments performed, the highest percentage of

released dapsone (9.5%) was obtained in formulation 08, which indicates an important

contribution of hydration of the polysaccharide to the release of the drug from the

formulations. The data suggest that the rate of release may be altered with the inclusion

of pore-forming agents.
 Another study demonstrates the relevant role of polymers in the coating.

Theophylline granules coated with amylose and ethyl cellulose were assessed in eight

healthy individuals [45]. The drug was detected in the blood only when marker tablets

reached the colon, a fact explained by the characteristic time-dependent on

ethylcellulose. The controlled release of the drug was possible due to the ability of the

bacteria to digest amylose and form pores. Still, the concentrations of the drug in the

blood did not vary significantly among the study participants, because even small

differences in flora between individuals did not seem to interfere in the rate of drug

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release based on this system, due to the abundant innate microflora capable of digesting

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polysaccharides.

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Conclusions
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This study demonstrated that it is possible to explore polymeric associations to

trigger the release of dapsone into the colon from chondroitin sulfate-based systems,
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especially by the synergism between the time-dependent characteristic and the

biodegradability by microbiota. The data indicate that the proportion of polysaccharide

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for ethyl cellulose in the film and the coating thickness are the key parameters in
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controlling the drug release from the system. Formulations with an association of
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polymers and polysaccharides can provide the basis for the development of potential

formulations for the treatment of neglected diseases. However, in vitro and/or in vivo

colo-specificity assays should confirm the specific vulnerability.

Acknowledgments

The authors thank to companies Almapal® (São Paulo/SP) by donation of the

dapsone, Solabia® (Maringá/PR) by donation of the chondroitin sulfate and Colorcon®

by the donation of the Surelease.

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Table 01 - Formulations obtained from the coating of tablets
Formulations Composition
®
Formulation 01 Dapsone 100mg + Surelease 6%
Formulation 02 Dapsone 100mg + Surelease® 10%
Formulation 03 Dapsone 100mg + Surelease® 6% and chondroitin sulfate 90:10
Formulation 04 Dapsone 100mg + Surelease® 10% and chondroitin sulfate 90:10
Formulation 05 Dapsone 100mg + Surelease® 6% and chondroitin sulfate 95:05
Formulation 06 Dapsone 100mg + Surelease® 10% and chondroitin sulfate 95:05

Table 02 Composition of coating films

Formulations Surelease® (%) Chondroitin Sulfate (%)
Formulation 01 100 0
Formulation 02 100 0
Formulation 03 90 10
Formulation 04 90 10

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Formulation 05 95 05

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Formulation 06 95 05

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Table 03 Results of physical tests of coated dapsone tablet formulations.
Formulations Average weight (mg) b Hardness (Kp)a Friability (%)b

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01 286,37 ± 2,68 D 12,7 ± 1,01 B <1,5
02 314,65 ± 6,09 A 15,6 ± 1,48 A <1,5
03 289,41 ± 6,26 C 11,06 ± 0,57 C <1,5
04 307,91 ± 5,31 B 12,70 ± 0,85 B <1,5
an
05 292,29 ± 4,28 C 12,46 ± 0,56 B <1,5
06 305,66 ± 6,31 B 13,06 ± 1,30 B <1,5
a – Average of the obtained values for 10 tablets
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b – Average of the obtained values for 20 tablets

Table 04 – Matrix containing decoded variables and results obtained in the dissolution tests
ed

Surelease® proportion:
Coating weight gain (%) X1 Dapsone release rate (%)
Chondroitin Sulfate X2
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6 90:10 9,0
(-1) (-1)
10 90:10 3,3
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+1 (-1)
6 95:05 4,0
(-1) (+1)
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10 95:05 3,5
(+1) (+1)
6 90:10 10,0
(-1) (-1)
10 90:10 2,0
(+1) (-1)
6 95:05 3,3
(-1) (+1)
10 95:05 3,6
(+1) (+1)
Figure 1 - Graphical representation of the dissolution of Dapsone coated tablets in (%) Dissolved x Time (min) -
Core, formulations 01 and 02.

Graphic of Cumulative Profile: (%) Dissolved x Time (min)

100

80

60
(%) Dissolved

Nucleus

40 Formulation 02
Formulation 01
20

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0
0 60 120 180 240 300 360 420

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Time (minutes)

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Figure 2 - Graphical representation of the dissolution of dapsone tablets of formulations 03, 04, 05 and 06 in (%)
Dissolved x Time (min)
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Graphic of Cumulative Profile: (%) Dissolved x Time (min)

100
M

80
ed

60
(%) Dissolved

Formulation 03
Formulation 04
pt

40
Formulation 05
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Formulation 06
20
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0
0 30 60 90 120 150 180 210 240 270 300 330 360 390 420
Time (minutes)
Figure 3 – Interaction graph between coating weight gain and polymeric proportion for dapsone release

Interaction graphic
10 Coating
weight
9 6%
10 %
8
Dapsone release (%)

t
ip
2
9010 9505
Polymeric proportion

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Figure 4 – Dapsone release rate response surface graphic

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ed
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