Patent Application
20080031946
a) Application of the Xanthan Gum by Powdering
Two kilograms of neutral cores of a size between 400 μm and 500 μm (Suglets® provided by NP Pharm, France) on which will be applied the polymeric layer are introduced in a conventional coating pan and set in rotation.
The polymer used here is a hydrophilic polymer with gelling properties: xanthan gum (provided by Rhodia, France and sold as Rhodigel® 200 grade) of which 92% of the particles have a size less than 75 μm.
The neutral cores are first moistened using 300 grams of an alcohol solution of 15% polyvinylpyrrolidone (PVP K 30 grade, provided by ICI, France), which is 45 grams of PVP K 30.
This binding solution is applied by spraying on the surface of the neutrals in rotation via a manual sprayer.
5% by weight of the weight of the neutral microgranules, which is 100 grams, of xanthan gum in the form of dry powder are introduced manually in the coating pan in rotation immediately after the step of the moistening of the neutral cores.
These steps of moistening/powdering are carried out in several repeated cycles each comprising a first phase of the spraying of part of the polyvinylpyrrolidone solution on the surface of the neutral cores (moistening), followed by a phase of powdering corresponding to the projection of part of the xanthan gum powder.
The powdering operation lasts approximately 2 hours and comprises as many cycles of moistening/powdering as are required for the binding of the given quantity of xanthan gum. The rotation of the coating pan is maintained throughout the duration of the powdering phase.
At the end of the powdering operation, a step of the drying of the “powdered” neutrals is performed.
Drying is carried out by maintaining the mass of neutrals at constant temperature for 8 hours. The drying temperature is ideally approximately 40° C. within the mass of neutrals.
b) Application of the Active Layer
The neutrals applied with the polymeric layer of 5% xanthan gum are then subjected to the step of the application of the active principle. This step is carried out in an air fluidized bed (AFB) Kugelcoater® from Hüttlin (Germany), and the spraying parameters are summarized in table 1.
The active principle used is ketoprofen (2-(3-benzylphenyl)propionic acid) provided by SIMS (Italy) at a concentration of 0.4% compared to the weight of the neutral cores, which is 8 grams for 2 kg of neutral cores.
Ketoprofen being virtually insoluble in deionized water (solubility less than 0.1 g/l according to the European Pharmacopeia), but having a pH-dependant solubility, a pH 8 buffer is used to allow its solubilization during the preparation of the layering solution.
The composition of the buffer medium is summarized in table 2.
Ketoprofen is dissolved in the layering solution containing in addition as a binding agent polyethylene glycol of a molecular weight equal to 6000 (PEG6000, ICI, France) also in dissolved form.
The binder is used in an amount of 5% by weight compared to the weight of the neutrals involved, which is 100 grams.
The layering solution is thus comprised of 2000 grams of pH 8 buffer in which 8 grams of ketoprofen and 100 grams of PEG6000 are dissolved. This solution is sprayed on the surface of the microgranules according to the parameters recapitulated in table 1.
c) Drying and Screening
Once applied with the active principle, the microgranules are dried to eliminate any residual trace of the application solvent. The drying temperature is 45° C., applied continuously for 30 minutes.
At the end of the drying step, the microgranules are screened on a 0.625 mm screen in order to guarantee a perfect homogeneity of size within the batch.
d) Compression
Before compression, the assembled neutrals are lubricated with 0.125% w/w of magnesium stearate. Mixing is carried out in a Turbula® mixer for 2 min at 48 rpm.
Compression is carried out on the lubricated microgranules using a Frogerais OA instrumented alternative press mounted with flat punches 1 cm2 in surface. The level of the filling of the matrix is adjusted to obtain tablets of approximately 500 mg in weight. The instrumentation and the associated software (Pecamec®, version 4.3, 2001, J2P Instrumentation) make it possible to make a continuous recording of the forces applied by the upper and lower punches, of the ejection and residual forces, as well as a recording of the displacements of the punches. The 250 MPa pressure stress applied makes it possible to have a sufficient cohesion of the tablets.
e) Dosage and Dissolution of the Tablets
To determine the release kinetics of the various systems studied, a revolving-basket dissolution apparatus (Dissolutest®, Sotax, Switzerland) equipped with 7 vessels whose dissolution media (500 ml) are thermostated at 37° C. is used. This apparatus, connected to a UVIKON 922 (Italy) spectrophotometer, is able to automatically carry out the sampling and the measurement of UV absorbance of the solutions contained in the various vessels. One of the vessels contains a solution of a known concentration in the active principle whose absorbance measured throughout the experiment constitutes the reference from which is calculated the percentage of the active principle dissolved in the vessel containing the solution studied.
The dissolution medium selected is a pH 6.8 buffer. The automatic sampling of the medium during the kinetics is carried out in the following way:
So as to increase the sensitivity of the dosage since the tablets are of a low dose, each dissolution vessel contains 3 tablets. In addition, the dissolution kinetics are carried out on 3 vessels. Table 3 summarizes the parameters used to carry out the dosage and the kinetics of the studied system.
The results of these measurements are presented in
It is noted that the release of the active principle is much extended, since 100% is released only at the end of approximately 16 hours.
The qualitative and quantitative composition of the various excipients of the tablets obtained according to example 1 are summarized in table 6.
The characteristics of these tablets are summarized in table 7.
In this example, the method is exactly as in example 1, except that the quantity of xanthan gum used for the constitution of the polymeric layer of the microgranules is 6% by weight compared to the weight of the neutral support involved.
The qualitative and quantitative compositions of the various excipients of the tablets obtained according to example 2 are summarized in table 6.
The characteristics of these tablets are summarized in table 7.
The release kinetics of ketoprofen are determined under the same conditions as those of example 1. The results of these measurements are presented in
In this example, the method is exactly as in example 1, except that the quantity of xanthan gum used for the constitution of the polymeric layer of the microgranules is 15% by weight compared to the weight of the neutral support involved and that the principle involved is no longer ketoprofen but an active principle referred to as number 23015.
The qualitative and quantitative compositions of the various excipients of the tablets obtained after compression according to example 3 are summarized in the following table 4:
The tablets thus obtained were then subjected to a dissolution test in 900 ml of pH 6.8 medium (in a 1 l flask: 6.805 g of KH2PO4, 22.4 ml of 1 N NaOH and 900 ml of purified water; adjusted if necessary to pH 6.8 with soda then brought up to 1 l with water).
Each tablet is placed in a basket, turning at 50 rpm.
Then, at 1, 4, 8, 12, 16, 20 and 24 hours, the dissolution medium is sampled and the sample is assayed by HPLC (high-performance liquid chromatography) with UV detection.
The results obtained for 3 dissolution vessels are summarized in the following table 5:
In this example, the tablets of the microgranules in conformity with the invention, exhibit a T50 equal to 340 min, which is 5 h 40 min, and a T80 equal to 675 min, which is 11 h 15 min.
These results are represented on
a) Application of HPMC by Powdering
As in example 1, a mass of 2 kg of neutrals of 400 μm to 500 μm (Suglets®) is set in rotation in a conventional coating pan.
Then a moistening step similar to that described in example 1 is carried out from an aqueous binding solution of 15% PVP K30 (169 grams of binding solution including 25 grams of PVP).
The polymer of interest is a hydrophilic polymer with gelling properties: HPMC sold under the brand name Metolose® 90 HS, whose viscosity is 100,000 mPa·s. (millipascal second) for a 2% w/w aqueous solution at 20° C.
100 grams of HPMC (which is 5% by weight compared to the weight of the neutrals involved) are introduced manually in the coating pan in rotation. As described in example 1, a drying phase follows the powdering sequence.
b) Application of Ketoprofen by Spraying
The active principle used is ketoprofen at 0.4% by weight compared to the weight of the neutrals involved, which is 8 grams. The active layer is applied in an air fluidized bed (AFB) as in example 1, from a solution containing, in the dissolved state, the active principle and the binding agent (5% PEG6000 by weight compared to the weight of the neutrals) in pH 8 buffer (2000 grams).
c) Drying and Screening
A drying phase and a screening phase identical to those of example 1 are carried out on the mass of microgranules before compression.
d) Compression
Before compression, the assembled neutrals are lubricated with 0.125% w/w magnesium stearate (MgSt). The mixing is carried out in a Turbula® mixer for 2 min at 48 rpm. The mixture is then compressed on a Frogerais OA alternative press by applying a compression force of 250 MPa.
e) Dosage and Dissolution of the Tablets
As in example 1, the tablets obtained are dissolved in a Dissolutest® and the quantity of the active principle released in the medium is measured as a function of time.
The results of these measurements are presented in
It is noted that the release profile of the active principle is also much extended, since only 80% of the active principle is released after 30 minutes as is represented in
B) Qualitative and Quantitative Compositions of the Various Excipients of the Tablets Obtained According to Example 4, and Their Dissolution Characteristics.
In this example, the applicant compared the in vitro dissolution kinetics of the tablets of microgranules of ketoprofen obtained according to the method described in example 4 but from starting neutral cores of a diameter between 250 μm and 355 μm respectively powdered with 5%, 10% and 15% of Metolose® 90SH HPMC (Shin Etsu, Japan, Batch 0203021) whose viscosity is 100,000 mPa·s for a 2% w/w aqueous solution at 20° C. These tablets are obtained after having been subjected to a compression stress of 250 MPa.
As in example 1, the tablets obtained are dissolved in a Dissolutest® and the quantity of the active principle released in the medium is measured as a function of time.
Table 8 also compares the T50 and T80 measured for each batch.
T50=time at which 50% of the active principle is released.
T80=time at which 80% of the active principle is released.
On the other hand, the release kinetics of batch B9 is much slowed compared to the other two batches: the T50 of batch B9 is up to two times higher than that of the T50 of batches B7 and B8 (table 8).
Thus, the applicant has demonstrated that the quantity of 100,000 mPa·s HPMC only truly influences the release kinetics beyond a certain threshold of between 10% and 15% w/w of this polymer. Beyond this threshold, the release kinetics of the active principle are much slowed and a true extended-release profile is observed. In addition, the applicant has noted that this threshold varies as a function of the size of the starting neutral cores.
Indeed, it is only above this range of concentrations that the polymer layer is dense enough to form a true network responsible for the release of the active principle according to a truly extended profile.
In this example, the applicant measured the dissolution profiles of ketoprofen from the tablets of microgranules obtained by the powdering according to the method described in example 5 of a synthetic polymer of the family of carbomers: Carbopol® 971 P (Noveon, USA, batch 0308024) which can be used in formulations for extended-release tablets.
The batches C1, C2 and C3 represent tablets of microgranules powdered with 2%, 5% and 10%, respectively, of this carbomer and compressed at 150 MPa.
The neutrals applied with the polymeric layer of Carbopol® 971 P are then subjected to the ketoprofen application step. As in example 1, this step is carried out in a Hüttlin (Germany) Kugelcoater® air fluidized bed (AFB).
Indeed, the T50 of batch C1 is 8 h whereas the T50 of batch C3 (which contains five times more polymer than batch C1) is approximately 18 h (see table 9).
This example shows that the use of this polymer makes it possible to observe much-extended release kinetics: the T80 of the three batches are all greater than 20 h, and this without the beginnings of a plateau.
In addition, the applicant has demonstrated that, as is shown in
This property is particularly advantageous insofar as it can be used in order to know the T50 of a given percentage of Carbopol® or, conversely, to evaluate what percentage of Carbopol® must be used to obtain a given T50.
In this example, the applicant endeavored to demonstrate the disintegrating character of the tablets of microgranules obtained in accordance with the method described in example 5, except that no active principle is bound on the previously-powdered granules: the step of the application by spraying in the AFB is not carried out in this example.
The details of the composition of the various batches are presented in table 10.
The powdering is carried out as described in the preceding examples with 3 types of excipients with disintegrating properties: branched polyvinylpyrrolidone (batch D1), sodium carboxymethyl starch (batch D2) and croscarmellose sodium (batch D3).
For this purpose, for each type of disintegrant 2 sub-batches, each comprised of the tablets of powdered microgranules at 0.5% (batches D1, D2 and D3) and at 1% (batches D1′, D2′ and D3′) of the disintegrating polymer, were tested.
A disintegration test was carried out under the conditions recommended by the European Pharmacopeia. In such a test, the tablets are placed in hollow cylindrical tubes at the bottom of which is a metal screen of a 2 mm mesh that retains the tablet inserted in each tube. The entire apparatus is submerged in a water bath. The tubes are then subjected to a regular, alternating vertical movement of approximately 30 cycles per minute.
The total disintegration time of the tablet is measured when no residue of the tablet remains on the surface of the screen.
For each of these batches the time of disintegration of the last disaggregated tablet was determined on a total of 6 tablets by sub-batches.
In addition, for each sub-batch the applicant tested 2 different compression force values, expressed in table 11 in the form of the result in terms of cohesion acquired, that is, a rupturing stress of approximately 0.3 MPa and a rupturing stress of approximately 0.5 MPa.
Batches D1 and D1′: the branched polyvinylpyrrolidone used respectively at 0.5 and 1% for the constitution of batch D1 is sold under the brand name Polyplasdone® XL10 (ISP, Switzerland, batch 0404046), which is a disintegrant that is insoluble in water and is generally used at concentrations from 2% to 5% in tablets prepared by wet granulation, dry granulation or direct compression.
This polymer is characterized by a large hydration capacity but with a low tendency to form a gel.
Batches D2 and D2′: in this example, with a concern for a comparison with the other disintegrants tested, the applicant used the sodium carboxymethyl starch Explosol® (Blanver, Brazil, 0311044) at 0.5% and 1% w/w for the constitution of the tablets of microgranules of batches D2 and D2′.
Low-substituted sodium carboxymethyl starches and sodium starch glycolate are low-substituted and branched starch derivatives which can be used in direct compression or after wet granulation.
Batches D3 and D3′: the croscarmellose sodium used in this example at 0.5 and 1%, respectively, for batches D3 and D3′ is Vivasol® (Pirna, Germany, Lot 0404041), or branched sodium carboxymethylcellulose. It is an excipient classically used in oral dosage forms as a disintegrant in tablets or granules.
This example shows first of all that the disintegrant-based tablets obtained according to the characteristics of the present invention well exhibit a capacity to disaggregate quickly (in less than 3 minutes) in an aqueous medium, and this for very small quantities of the polymer.
In addition, this example shows the influence of compression force on the disintegration rate of these tablets. Thus, quite logically, the lower the force of compression (and of rupture), the more rapidly the tablets obtained disaggregate. Indeed, the less the powdered microgranules are compressed, the wider the porous network will be, and the more easily will the liquid medium pass through, thus favoring the rapid disintegration of the structure.
On the other hand, this example shows that the influence of the nature of the disintegrating polymer used on the disintegration time of the tablets is minimal, even none.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0313188 | Nov 2003 | FR | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/FR04/02890 | 11/10/2004 | WO | 00 | 8/16/2007 |
