Development of Tablets Based on Lannea Microcarpa Engl. Et K. Krause (Anacardiaceae) Extracts for Arterial Hypertension Therapy
Salfo Ouédraogo1*, Josias BG Yaméogo2,3, Bavouma C. Sombié2, Hermine Zime Diawara2, Mathieu Nitiéma1, Lazare Belemnaba1, Tata Kadiatou Traoré2, Sylvin Ouédraogo1 and Rasmané Semdé1
1Département de médecine et pharmacopée traditionnelles-pharmacie (MEPHATRA-PH), Institut de recherche en sciences de la santé, Burkina Faso
2Laboratoire du Développement des médicaments (LADME), Ecole doctorale de la santé, Université Joseph Ki-Zerbo, Burkina Faso
3Laboratoire National de Santé Publique, Ministère de la santé, 09 BP 24 Ouagadougou 09, Burkina Faso
Submission: August 30, 2021; Published: October 05, 2021
*Corresponding author: Salfo Ouédraogo, Département de médecine et pharmacopée traditionnelles-pharmacie (MEPHATRA-PH), Institut de recherche en sciences de la santé, Burkina Faso
How to cite this article:Salfo Ouédraogo, Josias BG Yaméogo, Bavouma C. Sombié, Hermine Zime Diawara, Mathieu Nitiéma, et al. Development of
Tablets Based on Lannea Microcarpa Engl. Et K. Krause (Anacardiaceae) Extracts for Arterial Hypertension Therapy. Glob J Pharmaceu Sci. 2021; 9(1): 555752. DOI: 10.19080/GJPPS.2021.09.555752.
In context of hypertension, research in African traditional medicine allows the identification of safe and effective recipes that lead to the development of phytomedicines or the isolation of molecules that can be used in managing of hypertensive patients.
Objectives: This study aims at formulating and evaluating tablets based on Lannea microcarpa Engl. et K. Krause (Anacardiaceae) extracts for arterial hypertension therapy.
Methodology: Formulations of conventional release tablets containing 250mg and 500mg of extract were made. Several excipients were tested in several steps and wet granulation was performed. A formulation containing a diluent/disintegrant (corn starch), a binding agent (PVP K30) and a lubricant (magnesium stearate) was made. Then a flow agent (colloidal silica) was associated with the formulations of the first step. Finally, the colloidal silica of the previous formulations has been replaced by an anti-adhesive, the talc.
Discussion: The average masses of the 250 mg tablets varied from 263.187 mg ± 16.4 to 379.979 ± 13.1 with coefficients of variation between 2.72% and 6.23%. The average masses of the 500mg tablets varied from 561.047mg ± 15.13 to 783.388 ± 33.82 with coefficients of variation between 2.05% and 4.95%. These tablets had disintegration times of less than 15 minutes. The friability indices (< 1%) of the tablets of formulations FA6, 11, 17 and 18 as well as FB1, 2, 7, 8 and 15 alone complied with the specifications of the European Pharmacopoeia 10th edition. The mean contents were 0.378900 ± 0.010609 mg gallic acid equivalent (GAE)/tablet and 0.757 0.0211 mg GAE/tablet, respectively for the 250mg and 500mg tablets. The individual content of each tablet unit of both strengths was between 85 percent and 115 percent of the mean content and complied with the requirements of the European Pharmacopoeia 10th edition. These analyses led to the choice of FA6 and FB2 as the optimal formulation.
Conclusion: These results show the feasibility of the extracts of the plant in pharmaceutical form for the treatment of arterial hypertension.
High blood pressure (HBP) is leading chronic disease in the world . It is currently a public health problem worldwide, because of its burden. It also increases the risk of stroke, coronary heart disease, heart failure, kidney failure and cognitive impairment . Its management considers the environmental factors, the genetic capital, the medical staff with all the available
therapeutic arsenal (drug treatments, biological analyses,traditional and alternative medicine etc.) . In terms of drug treatment, there are five main classes of antihypertensive drugs that have demonstrated their effectiveness in terms of morbidity and mortality in managing uncomplicated essential hypertension. These include thiazide diuretics, beta-blockers, angiotensin II antagonists (ARBs), ACE inhibitors and calcium channel blockers (CCBs). For these treatments, it is often necessary to take several combinations of drugs under specific conditions (Long-term
treatment, restrictive schedules, etc.) . Therefore, solid oral
forms that are easy to use, and store improve compliance and
offer significant advantages. Despite the recommendations of
national and international learned societies on the management
of hypertension, it remains insufficiently detected, treated, and
controlled, indicating that the impact of these recommendations
remains insufficient or even weak in the general population [5,6].
Despite considerable progress in managing hypertension
in recent years, a large proportion of hypertensive subjects still
have uncontrolled hypertension, especially in Africa. This is
justified by problems of fragmentation, distribution, combined
with difficulties in terms of availability, geographical accessibility
and affordability resulting from an increased lack of universal
health coverage. Because of these socio-cultural and economic
barriers, Africa is becoming more active in developing traditional
medicine in the fight against hypertension . The research
developed in this sense aims to enhance the value of traditional
medicine through actions such as the involvement of herbal
healers, the discovery of new molecules, the formulation of
accessible and usable drugs to treat priority diseases . These
plants are used by traditional practitioners in old liquid forms
derived from macerations, infusions, and decoctions etc., with
stability problems. Possibilities of formulation in several forms
(capsules, tablets, creams, gels, ointments etc.) are studied. Some
are more innovative in modified release or microcapsule forms
. Among these conventional forms, solids such as capsules and
tablets have higher stability, are easier to standardize  and
represent two-thirds of the world market for drugs . Lannea
microcarpa Engl. et K. Krause (Anacardiaceae), a medicinal plant
found in the Sahelo-sudanian and Sudanian savannahs,  is one
of the antihypertensive medicinal plants used by herbal healers
[13,14], and which present some efficacy and safety. Indeed,
ethnobotanical studies have indicated the use of its trunk bark in
the form of decoction in the treatment of hypertension in Burkina
Faso [14-16]. Experimental studies (in vitro, ex vivo and in vivo)
have demonstrated the safety and Anti-hypertensive properties of
freeze-dried aqueous decoct of the bark of the plant trunk [17-
22]. Also studies of physicochemical characterization, quality control and galenic formulation have allowed the development
of capsule forms based on standardized extracts dosed at
250mg [23-25]. Characterization studies showed that the freezedried
aqueous extract was hygroscopic and had poor physicomechanical
properties . This justified the initial choice of
using the capsule form in order to ensure protection against
moisture. Moreover, the process of obtaining the capsules is
simple and less expensive. However, the development of a capsule
form dosed at 500 mg of extract, for use in adult subjects, could
not be achieved because of technological difficulties related to the
high quantity of powder necessary for a capsule of size less than
or equal to 0. Indeed, for pharmaceutical products, it is unusual
to use capsules of size greater than “0”, because of the difficulty
to swallow large capsules . This study aims to develop a
formulation of conventional release tablets based on lyophilized
aqueous extracts of Lannea microcarpa with as few excipients as
possible using a simple process. It aims to provide practitioners
and patients with an easy-to-use alternative treatment based on
extracts of the plant.
Plant material: The plant material consisted of trunk bark
of Lannea microcarpa (Anacardiaceae), collected in the commune
of Loumbila (Burkina Faso), a locality located 20 km from
Ouagadougou. A sample of the plant was identified by a botanist
of the Laboratory of Ecology of the Joseph KI-ZERBO University
concerning the herbarium N° 1544 deposited at the Department
of Forest Production of the National Center of Scientific and
Technological Research (CNRST, Ouagadougou, Burkina Faso). The
harvested bark was dried in a sunlight and dust-free environment
and then pulverized with a Gladiator blade mill. The pulverized
barks were subjected to an extraction by aqueous decoction and
then lyophilized using the CHRIST® benchtop freeze dryer type
Excipients: Different types of excipients have been used and
their characteristics studied to achieve an optimal formulation.
The raw materials used, and their features shown in Table 1.
Residual moisture content: The residual moisture
content of the extracts and the excipients were determined
using the thermogravimetric method [27,28]. One (01) g of each
powder is weighed in triplicate and placed in a previously tared
watch glass in an infrared moisture Analyser (MF-50, US).
Hygroscopicity was determined using 1.0 g of extract
according to the method described in European Pharmacopoeia
6.0 . The extract was introduced into a suitable desiccator
containing a saturated ammonium chloride solution at 25°C for 24
hours. The percentage increase in mass was calculated according
to the expression: ((m3-m2)/(m2-m1)) x100
The solubility study was performed in distilled water. Solubility
was determined by gradually adding increasing volumes. The
maximum amount of substance required for this assay was 111
mg and the maximum solvent volume was 30 mL according to the
European Pharmacopoeia 5th edition . The mixtures were
stirred vigorously with a magnetic stirrer for 1 minute and then
placed in a thermostatically controlled chamber at a temperature
of 25.0 ± 0.5 °C for 15 minutes.
The flowability of the extracts was realized through the
determination of the compressibility index (carr index) and the
Hausner index. The compressibility index (Carr’s index) and the
Hausner index (Hausner’s index) were determined by measuring
the apparent non-packed volume called bulk density and the
tapped density after compacting the granules until a constant
final volume. It was carried out with test piece according to the
method described in European Pharmacopoeia 6.0 [29,30]. Both
bulk density (BD) and tapped density (TD) were determined
by pouring 10 g of granules from each formula into a 50 mL
measuring test piece. The test piece was tapped three times onto
a hard surface from the height of 2 cm at 2-second intervals.
This volume was considered as a bulk volume. The tapping was
continued until no further change in volume was noted.
This volume was considered as a tapped volume. BD and TD
 were calculated using the following formulas:
Compressibility index or Carr’s index (%) = [(TD-BD) × 100]
BD = weight of the granule/volume of the packing
TD = weight of the granule/tapped volume of the packing
BD = weight of the granule/volume of the packing
TD = weight of the granule/tapped volume of the packing
Hausner’s ratio was determined using the following formula:
Tapped density / Bulk density. A Hausner ratio greater than 1.25
is considered of poor flow ability [31,32].
This study aimed to develop conventional release tablets
containing 250mg and 500mg of extract. The orientation of the
galenic form was based on the one hand, on the physicochemical
properties of the extract and the other hand on the chronic
character of the disease, requiring ease of administration and
conservation to improve the observance of the treatment. These
characteristics were also determining factors in the choice of
excipients and the process to be used to produce the tablets. The
amount of extract per tablet was based on the work of Nitiema
et al., . Mixing tests of excipients alone without extracts and
excipients with extracts have oriented the retained proportions.
The wet granulation technique was used with freeze-dried
aqueous extracts of Lannea microcarpa trunk bark powders as
active substance according to the evaluated characteristics and
b) Formulation strategy
The strategy was to develop formulations that meet the
standards with as few excipients as possible for formulation
development. Therefore, it was, necessary to evaluate the
relevance and the possible need to use or restrict certain
excipients in the formulation. Several excipients were used to
study their impact on the formulations and to arrive at an optimal
formulation. The wet granulation method was chosen because the
properties evaluated were not optimal for direct compression. The
granulation having improved the flow of powders, the influence of
three (03) lubricants (magnesium stearate, colloidal silica, talc)
has been studied.
The first step was to make a series of formulations containing
increasing amounts (10-50% w/w based on total extract weight)
of diluent/disintegrant (corn starch), 4% w/w binding agent (PVP
K30), and 1% w/w lubricant (magnesium stearate), corresponding
to formulations F1 through F6 in Table II. The quantity of diluent
was determined in these proportions of the theoretical mass of
the tablet in order to obtain a homogeneous powder. In the second
set of formulations (F7 to F12), 0.5% flow agent (colloidal silica)
was incorporated into each of the initial formulations F1 to F6.
Finally, in the third set of formulations (F13 to F18), colloidal
silica was replaced with 1% w/w of another flow agent with antiadhesive
The theoretical mass was constituted by the mass of the
internal phase associated with the mass of the external phase with
a mass of internal phase constituted by the mass of the extract
+ half of the mass of diluent/disintegrant + the mass of binder.
The mass of the external phase consisted of half the mass of the
diluent/disintegrant + mass of lubricants.
c) Preparation of granules
The granulation was carried out with a Frewitt (Switzerland)
oscillating pelletizer, equipped with an ERWEKA motor type AR 400 n°48581 (Switzerland). Ethanol at 96° was used as wetting
liquid. Its volume varied from thirteen (13) for F1 to Twentyone
(21) mL for F18. The mass to be granulated was weighed,
mixed, and wetted with ethanol until a wet mass was obtained.
This mass was introduced into the granulator and then subjected
to an oscillatory movement forcing the paste to pass through the
diameter sieves (1, 25mm). The obtained granules were dried in a
Memmert oven (Germany) at a temperature of 45° C for 12 hours.
The dried grains were sifted to retain grains of homogeneous size.
The quality controls of the granules were carried out according
to the official tests of the European Pharmacopoeia, namely, the
macroscopic characteristics, the residual moisture content, the
compressibility index and the Hausner index per methods 184.108.40.206,
220.127.116.11 and 18.104.22.168 .
d) Preparation of tablet
The mixtures of grains and lubricants were made in a
Stephan® mixer in order to obtain a homogeneous product with a uniform distribution of the lubricant. The theoretical masses of
the tablets were calculated, to compare them with the real masses
obtained after compression. They were calculated according to
the addition of the masses of the internal phases associated with
the masses of the external phases. The tablets were manufactured
with a manual rotary tablet press. Adjustments were made to the
filling volume of the compression chamber and the compression
force. The intervention on the volume of the compression chamber
made it possible to obtain the mass of the tablet containing the
calculated active dose of the extract. These adjustments made
it possible to modulate the mass and hardness of the tablets to
the desired values that meet the standards of the European
Pharmacopoeia. Among the formulations made, the one meeting
all the required qualities of the tablets were retained. The quality
controls of the tablets were carried out according to the official
tests of the European Pharmacopoeia, namely, the tests of mass
uniformity, hardness, friability, disintegration time and chemical
tracer content .
Macroscopic characteristics: The macroscopic and
organoleptic characteristics of the tablets obtained were
described. It is about the appearance, the homogeneity of the
colour, the taste and the smell of the tablets. Tablet dimensions
such as diameter and thickness were also determined using a
Mass uniformity test: This test was performed on twenty
(20) tablets taken randomly from each batch and weighed
individually with a precision balance (Sartorius, France). The
average mass (M), the mass deviations, as a percentage [100 (mi -
M)/M] from the average mass and the coefficient of variation (CV) were calculated. These parameters were compared to the limits
specified in the European Pharmacopoeia 10th edition (2.9.5)
, which states that the individual mass of not more than 2 of
the 20 tablets may deviate from the average mass by more than
the percentage given in Table 3 but the mass of no tablet may
deviate by more than twice that percentage.
Hardness test: This test was carried out on 6 tables taken
at random and introduced individually into the tubes of the
disaggregation apparatus (Pharma test, France). A disc was place
on each table and the disaggregation medium used was distilled
water at 37°C. The time of complete disintegration of the first and
last tablet was noted. (2.9.1) .
Disintegration time : This test was carried out on 6 tablets
taken at random and introduced individually into the tubes of the
disaggregation apparatus (Pharma test, France). A disc was placed
on each tablet and the disaggregation medium used was distilled
water at 37°C. The time of complete disintegration of the first and
last tablet was noted. and the calculated average disintegration
time. The results were compared to the limits specified in the
European Pharmacopoeia 10th edition (2.9.1) .
Friability test : A sample of 20 tablets (m < 650 mg) and
10 tablets (m > 650 mg) was taken at random and placed in a
friabilizer (Erweka, France) rotating at 25 rpm for 4 min. The
tablets were weighed together before and after the test. The
friability index determined must be less than 1%. The test was
repeated 3 times according to the European Pharmacopoeia 10th
edition (2.9.7) .
A sample of 10 tablets was taken at random. Each tablet was
weighed, pulverized with a mortar, and macerated individually
for 10 min, by magnetic stirring, in a beaker containing 50 ml of
distilled water. A 1 ml volume of the filtrate from each sample
was prepared according to the method of Singleton et al and
determined spectrophotometrically at 380 nm . The content
(%, m/m) of phenolic compounds in each tablet was determined
by calculation, and the content of the powder used as raw material
for tablet manufacturing. The test was repeated 3 times according
to the European Pharmacopoeia 10th edition (2.9.6) .
The physicochemical characterization tests of the freezedried
extracts showed that the residual moisture content was
4.39±0.15% (m/m) with a value (17.42±0.36% %) higher than 15
percent for the hygroscopicity test which indicates that the extract
is very hygroscopic according to the European Pharmacopoeia
10. The solubility in water at 25°C of the extract was classified
as easily soluble and those of the mixtures and granules were
partially soluble according to the indications of the European
pharmacopoeia 6.0. The flow properties realized by the tests of
compressibility index (Carr’s index) was superior 38% and the
Hausner index (Hausner’s index) superior at 1.6. This indicates
according to the European Pharmacopoeia that the extracts have very poor flow properties. In contrast, the properties of powders
to flow under given circumstances (fluidity) affects a large number
of industrial applications . One of the most advantageous
processes for manufacturing of tablets is the direct compression
of the active ingredient with suitable excipients [39,40]. However,
for its realization, the active ingredients and excipients must
demonstrate, good fluidity, compressibility and wettability .
Indeed, hygroscopicity plays an essential role in particle-particle
interactions and can contribute to a poor fluidity of the powder
and negatively affect the physical and chemical stability of the
powder . Previous studies have shown that freeze-dried
extracts of Lannea microcarpa, like dry plant extracts in general,
are complex materials that tend to be hygroscopic and sticky
with poor physical and mechanical properties . Therefore,
the addition of suitable excipients and/or the use of appropriate
processing technologies prior to compression is necessary. Thus,
the amount of excipients that can be added becomes a critical step
to manufacture tablets of reasonable size by compression [44,45].
Therefore, pre-treatment becomes almost mandatory to obtain
dry plant extracts suitable for compression [46-48]. Granulation
is then an alternative to this pre-treatment to improve the flow
with fewer excipients.
The physicochemical characterization tests of the Lannea
Microcarpa based granules showed that granules were uniforms,
brown in colour, with a weak, uncharacteristic odour and a slightly
bitter taste (Figure 1). The granules had almost homogeneous
grains because they were prepared using the same process with a
sieve of the same mesh size. This is probably related to the fact that
in the mixture some constituents, namely the excipients, are not
soluble in water [49;50]. The residual moisture contents (RMC)
are respectively 7.26±0.38% for the extracts and recorded in Table
4 for the granules formulations. All granules had a residual water
content of less than 10%. This low moisture content could indicate
better stability because it avoids possible enzymatic reactions and
the development of microorganisms [51,52]. The compatibility
tests performed by settling were classified into indices according
to Table 4. They gave Hausner indices that ranged from 1.06±0.03
to 1.13±0.02 from F1 to F18, respectively, and Carr indices that
ranged from 7.60±0.01 to 11.63±0.09 from F1 to F18. Therefore,
all granules had good flow properties according to the European
Pharmacopoeia. These indices are useful for characterizing the
fluidity of granules and predicting their compressibility’s. Among parameters, flow of powders within these processes play a critical
role in obtaining desirable characteristics of end products .
These analyses indicated that these granules could be used for
The results of mass uniformity, hardness and friability are
presented in Tables 5 & 6.
The average masses of the tablets dosed at 250mg are recorded
in Table 5 and varied from 263.187 mg ± 16.4 for FA1 to 379.979
± 13.1 for FA18 with coefficients of variation between 2.72% and
6.23%. The average masses of the tablets dosed at 500mg are
recorded in Table 6 and varied from 561.047mg ± 15.13 for FB1
to 783.388 ± 33.82 for FB18 with coefficients of variation ranging
from 2.05% to 4.95%. As a percentage of the average mass, the
deviations in individual tablet mass fell within limits allowed by
the European Pharmacopoeia. These parameters make it possible
to know if the tablets have the desired masses. The coefficients
made it possible to measure the degree of dispersion of masses
of the tablets around each average mass. Also, this parameter
could be used in stability studies because any increase in mass
during the storage period indicates absorption of moisture
highlighting unsuitable conditions. The mass uniformity ensures
that, the distribution of the powder mixture in the setting unit
is uniform and sufficiently precise during the manufacturing
process . The analysis of mass variations shows that the 250 mg formulations had coefficients of variation that were
relatively higher than those dosed at 500 mg. This indicates that
the 500mg tablets had more homogeneous masses . The
mean hardness ranged from 24.9 N ± 0.61 to 57.32 N ± 2.35 for
the 250 mg tablets and from 27.9 N ± 0.64 to 61.9 N ± 2.91. This
variation could be related to the compatibility of each mixture but
also a variation of the compression force. Indeed, during the use
of a manual press, the compression force could be more or less
important during each operation since development processes
often focus on improving tablet characteristics such as hardness,
disintegration time, stability and friability. This also provides an
opportunity for the manipulator to set certain parameters to the
desired characteristics. The understanding of the impact of the
characteristics of the raw materials and the different parameters
related to the manufacturing process allows to quickly solve
the problems encountered, optimize the production of tablets
and adapt to any modification (raw material, equipment, etc.)
[56,57]. The analysis of the crumbling rates indicates that for
the 250 mg tablet formulations, only the FA6, 11, 12, 17 and 18
tablets had crumbling rates within the norms according to the
European Pharmacopoeia 10th edition (33). This friability rates
(< 1%) of the tablets indicates that these tablets will have good
shock resistance during storage and distribution operations
(35,58). These crumbling rates of less than 1% indicate good
resistance to crumbling and good cohesion of the particles during
compression. It is related to the quality and quantity of the
binding agent used (PVP) and or the variation of the compression
force. This is made possible by pelletizing, which has a number
of advantages, including improved particle compactibility,
reduced dust emission and air entrapment during compression,
and better homogenization of the mixture (59). Other studies
confirm the improved mechanical performance of tablets by
wet compression compared to conventional tablet forming
routes (60, 61). For example, Bi et al., (60) show that lactose
tablets are ten times stronger mechanically when made with the
wet compression process than with conventional methods. In
addition, the water added to the mixture to be compressed plays
a key role because it allows the binder to dissolve and coat the
particles in the mixture more easily. In addition, solid bridges are
formed within the tablet during the drying period. These bridges
allow the tablet to acquire a better mechanical strength than that
obtained by other compression methods, where only Van der
Waals forces and hydrogen bonds intervene to ensure the bonds
between the particles, the solid bridges possibly present being
created during the preceding stages (granulation in particular)
(60,62). The disintegration times of the tablets took place in
an acceptable conditions. All formulations had disintegration
times of less than 15 minutes, although some had relatively high
values close to 15 minutes. They were, therefore, in conformity
with the requirements of the European Pharmacopoeia 10th
edition. (Table 6). Into the overall analysis, the formulations had
different disintegration times depending on their composition.
This disintegration of all the tablets, lower than 15 minutes, was
linked to the nature of the excipients, in particular corn starch,
which leads to a sufficient disintegration in the proportions used.
Indeed, corn starch is also used as disintegrating agents in order
to accelerate the disintegration of the tablet, thus the release of
the active ingredient in water and digestive juices. This suggests a
relatively rapid release of the active substances contained in these
tablets in the digestive tract (52).
RML = Residual Moisture Level, SD = Standard deviation, Cv = Coefficient of variation
RML = Residual Moisture Level, SD = Standard deviation, Cv = Coefficient of variation
The phenolic compound contents of the tablets were
determined by calculation, from the calibration line whose
equation is y = 10.459x + 0.0335 with a regression coefficient
R2 = 0.9993. This resulted in an average content of 0.378900 ±
0.010609 mg gallic acid equivalent (GAE)/tablet and 0.757 ±
0.0211 mg GAE/tablet, respectively for the 250mg and 500mg
tablets. From the content uniformity study represented by (Tables
7 & 8) the unique content of each tablet unit of both strengths is
between 85 percent and 115 percent of the average content, which
indicates that these tablets comply with the requirements of the
European Pharmacopoeia. In effect, this pharmacopeia indicates
that tablets fail the test if the individual content of more than one
unit is not within these limits or if the unique content is outside
the limits of 75 percent to 125 percent of the average content.
The present study was conducted to develop tablets for the
treatment of hypertension. The formulation strategy used in
this work allowed to realize mixtures of the active ingredient
(lyophilized aqueous extract of Lannea microcarpa) with corn
starch, PVP, colloidal silica, talc and magnesium stearate. The
tablets were obtained by compression after wet granulation of
the mixtures. The comparative analysis of the pharmacotechnical
characteristics of the different formulations indicates that the
FA6 and FB2 formulations showed the best properties such as
disintegration, disintegration and hardness and meeting the
requirements of the European Pharmacopoeia 10th edition.
Additional studies such as the dissolution test and the stability
study are necessary to conclude on the quality of the formulation.
These pharmaceutical forms dosed at 250mg and 500mg in
addition to being new will offer an alternative, because the
use of mixtures in the form of powder and granules followed
by a filling of capsules did not allow to obtain quickly a galenic
form dosed at 500mg and meeting the recommendations of the
pharmaceutical standards. This alternative in the management of
the disease, allows reducing the production cost by compressed
forms resulting from fast and straightforward manufacturing
process with the least possible excipient and which do not use
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