Beruflich Dokumente
Kultur Dokumente
tab le t
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Biopharmaceutics Department, Faculty of Pharmacy, Auvergne University, 28 place Henry Dunant 63000 Clermont-
Ferrand, France.
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Summary:
The utilisation of a buccal mucoadhesive tablets may be one of the most successful way to treat buccal
local pathologies. The sustained release of drugs in the buccal cavity helps to overcome constant
salivary secretion in the mouth. The aim of this study was to develop a protocol to measure the
The different parameters of the protocol (time of moistening and volume of hydration), were determined
by using placebo tablets (20% metolose, 80% milk protein). The ideal time of adhesion was found to be
12 minutes divided into two parts, 6 minutes for the initial moistening in which the tablet was completely
immersed in 4 ml of deionised water, and six other minutes of contact between tablet and aluminium
adhesion surface.
In second series of analysis, several series of tablets with variable concentrations of adhesive
substance (milk protein) were prepared, and their adhesion forces measured using previous
parameters. The linear relationship between the milk protein concentration and the adhesion forces
proved the validity of the method. The results were homogeneous, and the force of adhesion
proportional to the amount of milk protein used in the tablet which proved that this excipient possesses
a high adhesive power. The calculation allows the determination of the smallest concentration of
This method is able to measure the adhesivity, and can be used as quality and qualification control for
new excipients.
Introduction:
In order to treat buccal pathologies, conventional lozenge, mouthwash, or gel would be the simplest
dosage forms for the delivery of drugs in the buccal cavity, but these conventional dosage forms had the
produced effective salivary drug levels for more than one hour but repeated administration was
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restricted due to systemic toxicity coming from the large quantity of ingested drug. The action of
mouthwashes was even more transient than that of lozenges, and gels/pastes were difficult to retain in
the mouth [1]. So buccal mucosal sustained release devices might prove to be a viable alternative to the
In case of oral Candida infections, a prolonged therapy with antifungal agent was required, and some
papers documented prolonged release of antifungal agent from buccal devices [2] in the form of an
adhesive tablets. This adhesion was obtained by the use of special excipients like Carbopol 974P,
Besides these excipients, J. M. Aiache et al [11] described the use of “milk protein concentrate” as a
new and convenient excipient in oral drug dosage forms due to its adhesive properties. “Milk protein
concentrates” are naturally-occurring substances obtained directly from pasteurised raw cow milk by
physical method (skimming and ultra filtration) without denaturing or any marked modification of their
nutritional or technological characteristics. The product obtained is a more or less yellow-white powder,
with a milky smelling, and contain beside milk proteins, lactose, fat and mineral salts in varying amounts
According to the proportion and nature of the protein fractions, and the proportion and nature of
associated substances, these powders displayed various properties directly linked to the functional
properties of the proteins they contain. These properties were abundantly studied in food science [6, 7,
8, and 9].
The functional properties of a protein was defined as those non-nutritional properties that influence how
the protein could be used in a food, i.e., the physical and chemical properties that help achieve the
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(i) Hydration properties (protein-water interaction): these included adsorption, swelling,
(iii) Surface properties: these included surfactant, emulsifying and foaming properties.
Last but not the least property, “milk protein” had the advantage to be well tolerated, without toxicity due
During the first steps of the development of an adhesive formulation, it is really difficult to realize early in
vivo study. However the data published by Khanna and al [12] proved that the in vitro measurement of
adhesion was proportional to the in vivo adhesion time. So at this step, it may be sufficient to develop
an in-vitro method to estimate the adhesive power of a tablet, before in vivo testing to confirm the in vitro
data.
Several methods in vitro were described in order to estimate the adhesive power with adequate
materials:
1. Simple test of traction (Chang et al [13], Robinson [14], Marvola [15], Forget [16], and Ishida
[17]), in which the necessary force to tear away a tablet stuck on a standard surface of
2. Traction test with establishment of curve constraint/deformation (Gurny [14], Duchene and
Ponchel [18]): in this method the sample was stuck between two disks, which moved apart with
a constant speed until the sample was pulled out, and then a constraint/ deformation curve was
established.
3. Method using a molecular probe described by Park and Robinson [15]: it consisted in
measuring by an adequate probe the change in the membrane viscosity of cells hanged in
cellular culture when this membrane was in contact with the polymer to be studied.
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4. Piccerelle and al (1999), described the use of a texture analyser in order to measure the
The aim of this paper is to present a new and easy method, using a texture analyser, to measure the
adhesion power of bio adhesive tablets containing milk protein, in order to compare several formulations
Tablets
The placebo bio adhesive tablets were made by direct compression after mixing of the different
• Milk protein concentrate was the Prosobel LR 85(supplied by Armor Protein., Bretagne, France).
Japan.)
The table 1 shows the tablets’ composition used for the experimental procedures
Texture analyser:
The texture analyser or texturometer (Texturometer TEC 025 with software TEC v 6.0, supplied by ETIA
SA., Compiègne, France. (Figure 1), was specially designed for the analysis of mechanical texture
It consisted essentially of a displacement unit with a sensitive probe, the movement of this unit being
ordered by two displacement control keys (ascending, and descending) connected to a computer.
The original method for a substance’s texture analysis is based on the real time analysis of the stress
progression in a material. The stress is provoked by the descending probe at a controlled speed, which
makes a compression on the system tested. During this operation, the work, in joule, starting at the
beginning of the compression until the displacement of the unit is automatically stopped, is measured.
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This value called “positive work” represents the resistance to modification under pressure provoked by
the descending probe. Then the probe gets up and the force is again measured, describing some of the
However the direct use of the Texturometer was not possible in the case of bio adhesive tablets in
function of the different requirements (and steps of use) of this type of formulation:
So the tablets have to be fixed on the probe, then wetted so that the adhesive excipient can develop
its properties and stuck on a standardised predefined surface by compression (positive work).After
methacrylate disposable device which was directly screwed on the special 20 Newton probe. The tablet
was immersed in a determined volume of deionised water, introduced in a plastic container, the bottom
The descent of the displacement unit pressed the tablet on the aluminium flat support. The tablet was
then maintained during a given period before ascending the displacement unit to measure the
1. The upper area of a tablet was fixed by means of cyanoacrylate glue on a poly methacrylate
disposable device which was screwed directly on the special 20 Newton probe.
2. Using the manual switch, the displacement unit got moved down until the tablet was completely
immersed into deionised water avoiding any contact with the aluminium surface. This phase
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3. Then under computing command, the displacement unit got down at a constant rate (0,25
mm/s) until reaching the aluminium plate( figures 2) so that the tablet got in touch with it (figure
3, point a), the probe exerted some pressure on the tablet before it was automatically stopped
4. After some minutes (figure 3, point c), the displacement unit was moved up at the same speed
ordered by the computer until reaching its initial level. The adhesion force of the tablet was then
measured by recording the negative work using the software TEC v6.0 (E.T.I.A).
The software TEC v6.0 allowed having a graphical display of all the forces, positive and negative work
(figure 3).
2. the total time necessary for the two phases of the experiment (hydration in the deionised water,
• stayed stuck on the disposable plastic device and can be completely separated from the
• remained intact without any broken part at the end of the test.
This determination was necessary in order to obtain a correct and continuous adhesion layer due to the
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15 tablets (Formulation CP, table 1) were immersed into deionised water for 1 to 15 minutes; one of
each was controlled every 2 minutes by broking in 2 parts the tablets and evaluated by visual
This parameter was necessary to obtain the best volume of water to fill just the plastic container in
Forty tablets (CP formulation, table 1) were tested with several water volumes (1, 2, 4, 5, and 6 ml), 8
c) Determi nation of moistening time an d comp ression du ration: total exp erime ntal
time
With the same protocol, and with a volume of water fixed to 4 ml, forty two tablets (CP formulation, table
1) were tested, six at each run; the total time of experiment was variable from 2 to 20 minutes.
In these two last experiments, the percentage of success was calculated, and the value of related
containing various concentrations of milk protein (20%, 40%, 60%, and 80%). The adhesion force
calculated and the statistical analysis described below was carried out in order to find a possible
relationship between the excipient concentration and the adhesion force which would validate the
Statistical analysis
A chi square test (Proc Freq of SAS 8.02) was applied on the volume and moistening time results, if the
probability was lower than 0.05 then the difference could be was considered as statically significant.
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A one way ANOVA (pro GLM of SAS 8.02) was applied to the negative work values obtained in order to
study the influence of the variation of milk protein concentration and to determine which concentration
In addition a linear relationship was studied in order to establish the potential relation between milk
When the tablets were immersed in the water lower than 10 minutes, the adhesion gel layer was not
continues or very thin. With more than 10 minutes of hydration, a continuous and enough thick layer
was obtained.
So, to determine the water volume, an initial total moistening time of 10 minutes was chosen (5 minutes
for initial moistening phase, and other five minutes for final moistening phase).
Thus, with a total moistening time of 10 min, the following results were obtained (figure 4)
The Chi square test applied on volume results demonstrated a difference between the volume (p=
0.0047).
This figure shows that two values of water (4 and 6) gave the most accepted results; the lower value
was chosen which allowed studying tablets without any loss of water, and excessive moistening.
The chi square values applied on the moistening time results demonstrated a difference between them
p= 0.0012.
The results demonstrated the optimal immersion time in the water was 12 or 14 minutes. With lower
time, the tablet was broken into two fragments: the upper part remains stuck on the mobile head of the
texture analyser, the lower part remains stuck on the surface of adhesion, because the moistening was
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not homogeneous (insufficient time of moistening). When the moistening time was relatively long (about
20 min), few accepted results was obtained, certainly due to the excessive moistening of the tablet and
Thus, final results of the preliminary phase was that the water volume of 4 ml and the moistening time of
12 minutes divided into two parts, six minutes for the initial moistening phase, and six other minutes for
final moistening phase where the tablet was in contact with the aluminium surface.
Second step
The adhesion force (represented by the negative work) was measured and the mean was calculated for
all the tablets of each series. The results are presented in table 2.
The symbol NA indicates that the results were not accepted (broken tablet or tablet separated from
disposable device). This effect was certainly due to an important power of adhesion, so important that
the tablet was broken or detached from the disposable device before been extracted from the aluminium
surface..
The mean of negative work was calculated for every group of tablets (20%, 40%, 60%, and 100%); the
figure 6 demonstrated the variation of adhesive forces vs. the milk protein percentage.
Even when the tablets had no milk protein a negative work values were recorded, this is certainly due to
an adhesive proprieties of other excipient (metolose). The regression analysis demonstrated a linear
relationship between the milk protein concentration and the negative work with a slope of
was of 0, 61 (p=0.0053).
Theses values stayed indifferent when the milk protein concentration rose, but from milk concentration
of around 38%, negative work values started statistically to rise, this might help to find optimal milk
protein concentration. That being confirmed by the ANOVA that showed a difference between the
various milk protein concentration (p=0.0467), the difference being located between 80% and 20%-40%
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Concl usi on
• The described method allows an objective and accurate measurement of the adhesion power or
adhesion force of a dosage form containing one or more specific adhesive excipients.
it “mimic” quite the use of these dosage form in vivo, i.e the moisture of the dosage form ,and
The results are reproducible with the parameters determined, and the force of adhesion was
this method could be used to determine the optimal concentration of excipients necessary to
This method has been used for other mixtures containing different adhesives excipients and the
results, published in an international meeting shown the confirmation of the first data [20].
• However other studies are required to insure that a relationship exists between in vitro and in
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Refe rence s:
[2] S. SHADOMY and M. A. PFALLER, in Manual of Clinical Microbiology, 5th ed., A. BALOWS et al.
[4] J.N. WIT and R. BOER, Neth. Milk Dairy J., 29, 198-211 (1975).
[8] J.E. KINSELLA, C.R.C. Crit. Rev. Food Sci. Nutr., 7, 219-280 (1976).
[9] J.C. CHEFTEL et al., in Protéine alimentaire, Paris, Tec & Doc Lavoisier (1985).
[10] D.H. CHOU and C.V. MORR, J. Am. Oil Chem. Soc., 56, 53A-52A (1979).
[11] J. M. AIACHE et al., 19: 401-405 (1998).
[12] R. KHANNA.et al., Drug Development and Industrial Pharmacy, 23 (8), 831-837 (1997).
[18] D. DUCHENE and G. PONCHEL, European journal of Pharmaceutics and biopharmaceutics 44 15-
23 (1997).
[20] J. M. AIACHE et al., Proc. 4th World Meeting ADRITELF/APGI/AP, Florence, (2002).
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Se ries Com Se ries Aver age wei ght Averag e hard ness
80% Metolose
2C 20% milk protein 265 70
80% Metolose
4C 40% milk protein 248 65
60% Metolose
6C 60% milk protein 258 63
40% Metolose 60
100C 100% milk protein 240 60
Table 1: tablets’ composition
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Figure 1: The Texture analyser
Figure 2: Photo of aluminium adhesion support with its base, and plastic container
Figure 6: variation of adhesive forces when the milk protein percentage changed
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Figure 1
Figure 2
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Figure 3
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Figure 4
Figure 5
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Figure 6
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