CA2047944C - Process for preparing pharmaceutical compositions having an increased active substance dissolution rate, and the compositions obtained - Google Patents
Process for preparing pharmaceutical compositions having an increased active substance dissolution rate, and the compositions obtained Download PDFInfo
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- CA2047944C CA2047944C CA002047944A CA2047944A CA2047944C CA 2047944 C CA2047944 C CA 2047944C CA 002047944 A CA002047944 A CA 002047944A CA 2047944 A CA2047944 A CA 2047944A CA 2047944 C CA2047944 C CA 2047944C
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- terfenadine
- cyclodextrin
- sodium carboxymethylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
Abstract
A process for preparing a pharmaceutical composition having an increased active-substance dissolution rate and a controlled release rate. The process consists of dry co-grinding or dry-mixing an active substance selected from the group consisting of terfenadine, nifedipine, naftazone and carbamazepine, with cyclodextrin or a hydrophylic polymer which is swellable on contact with water selected from the group consisting of crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, carboxymethyl starch, polyvinylalcohols and potassium methacrylate divinylbenzene copolymer, and with a hydrophylic polymer which forms a gel on contact with water selected from the group consisting of hydroxypropylmethyl-cellulose, hydroxypropylcellulose and sodium carboxymethyl-cellulose. Thereafter the obtained mixture is tableted into controlled release tablets. Pharmaceutical compositions are obtained from which the active substance is released quite rapidly into an aqueous medium.
Description
~_ ..~
PROCESS FOR PREPARING PHARMACEUTICAL COMPOSITIONS HAVING AN
INCREASED ACTIVE SUBSTANCE DISSOLUTION RATE, AND THE COMPOSITIONS
OBTAINED
Prior art The problem of increasing the dissolution rate of active substances which are poorly soluble in water is felt in many fields ranging from phytopharmaceuticals to pesticides and in general in all those fields in which bioactive substances are used, but it is the pharmaceutical field which is most concerned with the availability of substances of high water solubility, this being an essential characteristic for obtaining high bioavailability of the active substance.
This requirement is particularly felt in the case of substances which when administered orally must undergo dissolution prior to their passage through biological membranes.
In addition, in the case of solid pharmaceutical forms for oral administration, the release of the active substance is the most important step in determining therapeutic activity.
The release of a therapeutically active substance from a solid pharmaceutical form can be represented by the following scheme:
Medicament in solid _ particle form Medicament in its Disgregation ~ ~ ~ o ~ ~ Dissolution pharmaceutical form iMedicament in ~, Absorption ~ Medicament inj solution the body In the case of pharmaceutical tablets the rate of the first step (disgregation of the pharmaceutical form) can be increased by a proper choice of formulation constituents, whereas the kinetics of the next step (dissolution of the active principle, normally indicated as the dissolution rate) is determined by the physico-chemical characteristics of the active substance and in particular by its solubility in water.
The dissolution rate of the active principle is therefore the limiting factor in the absorption process and its therapeutic activity.
The dissolution of an active substance is also known to be controlled by the Noyes and Withney equation, which can be expressed in the following form:
do D S (CS-C) dt h where:
dc/dt - dissolution rate, ie the quantity of substance which dissolves in unit time D - substance diffusion coefficient (which depends on the M.W., the viscosity of the medium, temperature etc.) h - thickness of diffusion layer S - total surface area exposed to the diffusion fluid CS - concentration of substance in the diffusion layer C - concentration of medicament in the undiluted solution.
Many attempts have made to modify the parameters which influence dissolution rate. Micronized active substances are particularly widely used, to obtain products with a large surface area.
'Ibis expedient has been used to increase the dissolution rate of chloramphenicol palmitate, nitrofurantoin and griseofulvin, even though particularly in this latter case there is a corresponding ,:::..~.
PROCESS FOR PREPARING PHARMACEUTICAL COMPOSITIONS HAVING AN
INCREASED ACTIVE SUBSTANCE DISSOLUTION RATE, AND THE COMPOSITIONS
OBTAINED
Prior art The problem of increasing the dissolution rate of active substances which are poorly soluble in water is felt in many fields ranging from phytopharmaceuticals to pesticides and in general in all those fields in which bioactive substances are used, but it is the pharmaceutical field which is most concerned with the availability of substances of high water solubility, this being an essential characteristic for obtaining high bioavailability of the active substance.
This requirement is particularly felt in the case of substances which when administered orally must undergo dissolution prior to their passage through biological membranes.
In addition, in the case of solid pharmaceutical forms for oral administration, the release of the active substance is the most important step in determining therapeutic activity.
The release of a therapeutically active substance from a solid pharmaceutical form can be represented by the following scheme:
Medicament in solid _ particle form Medicament in its Disgregation ~ ~ ~ o ~ ~ Dissolution pharmaceutical form iMedicament in ~, Absorption ~ Medicament inj solution the body In the case of pharmaceutical tablets the rate of the first step (disgregation of the pharmaceutical form) can be increased by a proper choice of formulation constituents, whereas the kinetics of the next step (dissolution of the active principle, normally indicated as the dissolution rate) is determined by the physico-chemical characteristics of the active substance and in particular by its solubility in water.
The dissolution rate of the active principle is therefore the limiting factor in the absorption process and its therapeutic activity.
The dissolution of an active substance is also known to be controlled by the Noyes and Withney equation, which can be expressed in the following form:
do D S (CS-C) dt h where:
dc/dt - dissolution rate, ie the quantity of substance which dissolves in unit time D - substance diffusion coefficient (which depends on the M.W., the viscosity of the medium, temperature etc.) h - thickness of diffusion layer S - total surface area exposed to the diffusion fluid CS - concentration of substance in the diffusion layer C - concentration of medicament in the undiluted solution.
Many attempts have made to modify the parameters which influence dissolution rate. Micronized active substances are particularly widely used, to obtain products with a large surface area.
'Ibis expedient has been used to increase the dissolution rate of chloramphenicol palmitate, nitrofurantoin and griseofulvin, even though particularly in this latter case there is a corresponding ,:::..~.
marked increase in product toxicity.
It has also been found in the case of nifedipine that a rapid medicament effect can be obtained using the micronized product, whereas a slower effect can be obtained by using the active principle at a coarser particle size. This process, which is not easy to standardize, is claimed in German patents 2209526 and DE A1 3033919.
The problem of increasing the dissolution rate of poorly soluble active substances has been confronted in various other ways, for example by transforming the substance from a crystalline state to an amorphous state which generally results in an increase in dissolution rate [see Gouda M.W. and coll., Drug Develop. Ind.
Pharm. 3, 2'73 (1977)x.
Attempts have been made to attain the same objective by preparing clathrates, inclusion compounds, complexes with polymers such as polyvinylpyrrolidone, polyethyleneglycol, polyvinylalcohol, cellulose and derivatives or, more recently, cyclodextrins.
A more recent method for obtaining an increased dissolution rate is described by Nakay Y and coll. Chem. Pharm. Bull. 25, 3340 (1977), in which the poorly soluble active principle is absorbed onto an inert support having a large surface area.
A different process, claimed in Italian patent application 20474 A/85, comprises solubilizing the poorly water-soluble active principle in an organic solvent (generally apolar) and then loading the obtained solution onto a support of hydrophilic polymer material able to swell on contact with water and aqueous fluids.
However this method requires the use of a very complicated process in that generally the supporting polymer material must be uniformly coated and brought into intimate contact with the organic solution of the active substance.
This means that large quantities of solvent must generally be treated to obtain solutions able to be uniformly distributed on the supporting polymer material.
This process also requires the use of large solvent volumes with considerable drawbacks both from the technical viewpoint (possible flammability or ease of explosion) and economic viewpoint (high cost and need to use explosion-proof plant).
It is also essential to use suitable technical processes able to completely eliminate the apolar solvent from the support, to avoid the risk of any residual solvent presence.
This is obviously of extreme importance in the case of biologically active substances and medicaments for human use, and is evaluated with extreme care by the health authorities on registration of medical specialities containing such active principles.
Summary We have now discovered a new process for preparing pharmaceutical compositions with an increased active substance dissolution rate which overcomes the aforesaid drawbacks and provides optimum process safety and economy.
Said process is characterised in that the active substance is co-ground or dry mixed with cyclodextrins or with a hydrophilic polymer substance which swells on contact with water and the obtained mixtures can be formulated with excipients normally used in the pharmaceutical industry and transformed into capsules or tablets of fast disgregation and dissolution or into controlled-rate release .<~
tablets.
Detailed description of the invention The characteristics and advantages of the process for preparing pharmaceutical compositions with an increased active substance 5 dissolution rate according to the present invention will be more apparent from the following detailed description.
The process consists first of all of co-grinding or dry mixing the active substance with cyclodextrins or with hydrophilic polymer materials which swell on contact with water.
lp Normal mixing or grinding means can be used for said process, such as a pin mill, hammer mill, ball mill and/or fluid jet mills.
A basic characteristic of the invention is the choice of polymer materials, which can be natural or synthetic.
The initial particle size distribution of said polymer materials is not important, and can lie within a wide range provided it falls within the limits of normal pharmaceutical use, neither do they need to have a large surface area.
A characteristic of the compositions of the invention is that when in the form of co-ground or mixed powders, transformed into tablets, they show rapid interaction with water and/or aqueous solutions to result in the development of a swelling pressure. This pressure can be measured with the apparatus described by Conte and toll. in Italian patent No. 19815 A/88 of 17/03/88.
The polymer materials used in the process of the present invention are chosen from the group consisting of crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, carboxymethyl starch, potassium methacrylate-divinylbenzene copolymer (Ambelite IRP88), polyvinylalcohols, hydroxypropyl-cellulose, hydroxypropylcyclodextrin, alpha, beta, gamma cyclodextrin or derivatives and other dextran derivatives, glucans, scleroglucans and derivatives.
Synthetic or semisynthetic polymer materials of different degrees of crosslinking, different molecular weights and different properties and rates of swelling in water can also be used, such as crosslinked polyvinylpyrrolidone and crosslinked sodium carboxymethylcellulose.
Natural polymer materials can also be used such as starches, modified starches, cellulose, variously substituted cellulose W
derivatives and formalin-casein. _ The active substances usable in the process of the present invention are chosen from the group consisting of naftazone, terfenadine, carbamazepine, gliclazide, glibenclamide, bifonazole and nifedipine, diazepam, ketoprofen.
The active substance content of the composition is between 1 and 90%
by weight and preferably between 10 and ~5x by weight.
The mixing or co-grinding time depends on the means used for the purpose and is for example between 0.1 and 4 hours if a ball mill is used and the particle size of the co-ground product is between 0.1 and 300 u, but this dimensional distribution does not influence the active substance dissolution rate.
The described process of the invention transforms a substance poorly soluble or insoluble in water into an easily and completely soluble product in which the factor limiting the transfer is no longer the solubility of the active principle but other factors and components of the formulation.
2~4794, The mixtures obtained as described are therefore formulated with excipients normally used in the pharmaceutical industry to obtain hard gelatin capsules or tablets of fast disgregation and dissolution or controlled-rate release tablets.
In particular, by formulating the product co-ground or mixed with hydrophilic polymers able to form gels on contact with water, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, scleroglucan, polyvinylalcohol, carboxyvinlypolymers and dextran derivatives, a reduction in the active substance transfer rate is obtained.
Some examples of the present invention are given hereinafter by way of non-limiting illustration.
10.0 g of naftazone (Innothera batch No. 081808) and 90.0 g of crosslinked sodium carboxymethylcellulose (AcDiSol'~- FMC Corporation Philadelphia USA) are placed in the jar of a ceramic ball mill (inner diameter 12 cm, capacity 1 litre) and a series of ceramic balls are added to occupy about half the available volume.
The particle size distribution of the active principle had been previously determined by usual known methods (using a Coulter~
counter), showing a mean diameter of 13.5 microns. The particle size distribution of the support was 20-150 microns.
Grinding is continued for 2 hours at a rotational speed of ~0 rpm.
A homogeneous orange coloured mixture is obtained. A dissolution test was performed on 300 mg of this mixture (equivalent to 30 mg of naftazone) to determine the dissolution rate of the active principle.
The U.S.P. 23rd Ed. apparatus in modified form was used.
Specifically, a vessel was used containing 5.0 1 of H20 at 37~C and a stirring system (paddle) rotating at 100 rpm. The stirrer blade rotated at a distance of 5 cm from the base of the vessel.
Using an automatic withdrawal system (peristaltic pump} the solution was fed to a spectrophotometer for continuous determination of the active principle concentration.
The results obtained are shown in Table I.
TABLE I
Time (min) Active substance dissolved ('6) 3 66.8 6 70.4 g 73.6 15 79.2 18 81.8 21 84.2 3p 90.4 45 97.8 60 100.0 EXAMPLE 2 (Comparison) To determine whether the grinding process alone was able to influence the dissolution rate of the active substance of Example 1, a dissolution test was performed on the following, using the method indicated in Example 1:
a) on 30 mg of naftazone as such (batch No. 081808} having a particle size distribution of between 4.3 and 36.0 microns, determined with a Coulter counter;
b) on 100 g of naftazone ground for 2 hours at '70 rpm in the ball mill in the manner described in Example 1.
On termination of grinding the product was subjected to dimensional analysis (using a Coulter counter mod. T2A) and it was found that the grinding process used had not produced any marked variation in the particle size distribution, which had a mean value of 13.5 microns before grinding and a mean value of 12.8 microns after grinding.
Table II compares the results of the dissolution test.
TABLE II
Time (min) Test a) - Active Test b) - Active substance dissolved % substance dissolved 15 0.8 2.0 30 1.8 3.0 45 3.0 4.0 60 4.0 4.9 An examination of these data shows that grinding has irrelevant influence on the dissolution rate of the active substance.
Using normal methods, flat cylindrical tablets of diameter 11.0 mm were obtained from a co-ground mixture prepared by the process described in Example 1. The press (Korsch EKO) was adjusted to produce 300 mg tablets (with an active principle content of 30 mg).
The tablets obtained showed good disgregation (2-3 minutes) and to excellent technical characteristics. A dissolution test was performed on these tablets using the apparatus and methods previously described for the powder mixture. The test results are given in Table III
TABLE III
Time (min} Active substance dissolved x 3 11.1 6 24.0 l0 9 55.0 12 69.4 i5 83.4 18 94.0 21 100.0 10.0 g of naftazone (Innothera batch No. 081808} and 90.0 g of crosslinked polyvinylpyrrolidone (Polyplasdone XL~ - GAF Corporation, USA) are placed in jar of a ceramic ball mill.(inner diameter the 12 cm, capacity 1 litre) and a series of ceramic balls are added to 2p occupy about half available volume.
the The particle size tribution of the active principle, previously dis determined by usual known methods (using a Coulter counter), was 4.3-36.0 microns.
The particle size distribution of the support was 20-400 microns.
Grinding is continuedfor 2 hours at a rotational speed of ~0 rpm.
A homogeneous orangecoloured mixture is obtained. A dissolution test was performed 300 mg of this mixture (equivalent to on 30 mg of naftazone) to determine the dissolution rate of the active !;
_. ~, principle.
The determination was made using the apparatus and method described in Example 1.
The results obtained are shown in Table IV.
TABLE IV
Time (min) Active substance dissolved (%) 44.9 6 68.0 l0 9 78.6 12 84.7 15 88.4 18 91.2 21 93.1 15 30 96.3 45 99.4 60 100.0 Using the precise procedure described in Example 3, tablets were 20 obtained from the powder mixture prepared as described in Example 4, , these showing a disgregation time of less than 3 minutes and giving the results shown in Table V when subjected to the dissolution test.
TABLE V
Time (min) Active substance dissolved (%) 48.7 6 79.4 89.9 12 94.5 15 97.1 18 98.4 21 99.3 30 loo.o To evaluate the influence of the polymer particle size on the dissolution characteristics of the active principle, a test was performed using crosslinked polyvinylpyrrolidone with a particle size distribution of 20-80 microns.
10.0 g of naftazone (Innothera batch No. 081808) and 90.0 g of crosslinked polyvinylpyrrolidone (Polyplasdone XL10~ - GAF
Corporation, USA) are placed in the jar of a ceramic ball mill (inner diameter 12 cm, capacity 1 litre) and a series of ceramic balls are added to occupy about half the available volume.
Grinding is continued for 2 hours at a rotational speed of 70 rpm.
A homogeneous orange coloured mixture is obtained. A dissolution test was performed on 300 mg of this mixture (equivalent to 30 mg of naftazone) to determine the dissolution rate of the active principle, using the procedure described in Example 1.
Using an automatic withdrawal system (peristaltic pump) the dissolution medium was fed to a spectrophotometer for continuous determination of the active principle concentration.
The results of the dissolution test are shown in Table VI, compared with those obtained using the polymer material of coarser particle size (see Example 4).
;..
w (~~
TABLE VI
Time (min} Active substance Active substance dissolved (Ex.6) % dissolved (Ex.4) 3 62.3 44.9 6 84.6 68.0 9 90.5 78.6 12 93.2 84.7 s5 94.6 88.4 l0 18 95.4 91.2 21 96.0 93.1 30 97.2 96.3 45 98.3 99.4 60 99.3 100.0 15 The results show the the initial polymer particle size significantly influences the release kinetics only during the initial stage (about 15 min}.
Using the precise procedure described in Example 3, tablets were 20 obtained from the powder mixture prepared as described in Example 6, these showing a disgregation time of less than 3 minutes and giving the results shown in Table VII when subjected to the dissolution test.
Again the results are shown compared with those obtained using the 25 polymer material of coarser particle size (see Example 4).
~ 9~
TABLE VII
Time (min) Active substance Active substance dissolved (Ex.7) x dissolved (Ex.S) x 3 31.9 48.7 6 66.4 79.4 9 81.0 89.9 12 88.1 94.5 92.1 97.1 l0 18 94.6 98.4 21 96.5 99.3 30 99,4 100.0 45 100.0 15 10.0 g of naftazone (Innothera batch No. 081808) and 105.58 g of beta-cyclodextrin (Kleptose R~- Roquette Lille France) are placed in the jar of a ceramic ball mill (inner diameter 12 cm, capacity 1 litre), these quantities being chosen to obtain a 1:2 molar ratio between the naftazone and the cyclodextrin.
A series of ceramic balls are added to occupy about half the available volume.
Grinding is continued for 2 hours at a rotational speed of 70 rpm.
A homogeneous orange coloured mixture is obtained. A dissolution test was performed on this mixture (347 mg, equivalent to 30 mg of naftazone) to determine the dissolution rate of the active principle, using the apparatus and method described in Example 1.
The results obtained are shown in Table VIII.
15 4?9.
TABLE VIII
Time (min) Active substance dissolved (x) 3 82.0 6 87.6 9 89.6 12 91.3 92.9 18 94.5 l0 21 95.9 30 98.8 45 100.0 The results show that co-grinding naftazone with beta-cyclodextrin produces rapid dissolution of the active principle (82x in 3 15 minutes).
Using normal methods, flat cylindrical tablets of diameter 11.0 mm were obtained from a co-ground mixture prepared by the process described in Example 8. The press (Korsch EK(~) was adjusted to Produce 394 mg tablets (with an active principle content of 30 mg).
Their complete composition is as follows:
Naftazone 30 mg Beta-cyclodextrin 317 mg Carboxymethyl starch 35 mg Corn starch 10 mg Magnesium stearate 2 mg y The flat tablets obtained showed good disgregation (4 minutes) and excellent technical characteristics. A dissolution test was also performed on these tablets using the apparatus and methods previously described.
The test results are given in Table IX
TABLE IX
Time (min) Active substance dissolved ~G
3 89.6 l0 6 97.3 9 98.4 12 98.9 99.4 18 99.8 15 21 100.0 Modified release forms of naftazone.
The following formulation was made up from the powder mixture obtained in example 1:
Naftazone 30 mg Sodium carboxymethylcellulose 270 mg Hydroxypropylmethylcellulose (Methocel K 4 M~- Colorcon} 75 mg Magnesium stearate 3 mg The relative quantities of naftazone and crosslinked sodium carboxymethylcellulose (in co-ground state) plus the remaining components of the formulation are mixed together in a powder mixer.
ap"
The mixture was pressed to obtain tablets of 12 mm diameter which were subjected to the dissolution test by the method described in Example 1.
The results, given in Table X, show that it is possible to obtain modified release of the active principle, this release slow-down being due not to the reduced solubility of the active principle but to the composition formulation.
TABLE X
Time (min) Active substance dissolved y lQ 0 0 60 19.7 120 27.3 180 36.9 240 47.8 300 58.7 360 6g.1 420 81.1 480 93.3 540 100.0 20.0 g of terfenadine (Resfar batch R-27620-118) and 80.0 g of crosslinked sodium carboxymethylcellulose (AcDiSolR - FMC
Corporation Philadelphia USA) are placed in the jar of a ceramic ball mill (inner diameter 12 cm, capacity 1 litre).
A series of ceramic balls are added to occupy about half the available volume.
Grinding is continued for 2 hours at a rotational speed of 70 rpm.
A homogeneous white coloured mixture is obtained. A dissolution test was performed on 300 mg of this mixture (equivalent to 60 mg of terfenadine) to determine the dissolution rate of the active principle.
The apparatus and method of determination were as described in Example 1, using simulated gastric fluid USPXII (5000 ml) as dissolution fluid.
The results are given in Table XI, where they are compared with those obtained by dissolution of terfenadine as such.
TABLE XI
Time (min) Active substance Terfenadine as such dissolved ;G dissolved x 3 12.2 6 19.1 9 33.2 12 41.7 15 47.5 10.4 21 60.5 30 76.6 15.9 45 87.5 19.4 60 91.0 21.9 Using a Korsch EKO~ press fitted with flat 10 mm diameter punches, tablets weighing 300 mg (corresponding to 60 mg of terfenadine) were prepared from the powder mixture obtained by the process described in Example 11 and were subjected to the dissolution test in 5000 ml .,"
of simulated gastric fluid to USP XXII, to give the results shown in Table XII.
TABLE XII
Time (min) Active substance dissolved ~G
p 0 20.9 6 60.5 9 75.9 12 79.0 l0 15 80.0 18 82.0 21 83.0 30 85.0 45 88.0 15 6o 9o.0 10.0 g of terfenadine (Resfar batch R-27620-118) and 23.73 g of beta-cyclodextrin (Kleptose R~- Roquette - Lille, France) (1:1 molar ratio) are placed in the jar of a ceramic ball mill (inner diameter 20 12 cm, capacity 1 litre). A series of ceramic balls are added to occupy about half the available volume.
Grinding is continued for 2 hours at a rotational speed of 70 rpm.
A homogeneous orange coloured mixture is obtained. A dissolution test was performed on this mixture (202 mg, equivalent to 60 mg of 25 terfenadine) to determine the dissolution rate of the active principle by means of the apparatus and method described in Example 1, using 5000 ml of simulated gastric fluid USPXXII as dissolution fluid.
j~
0 4? 4 The results are given in Table XIII.
TABLE XIII
Time (min) Active substance dissolved x 17.8 6 32.6 g 41.2 12 49.2 15 55.4 to 18 60.0 21 63.4 69.7 45 73.2 60 74.7 Using normal technical methods, flat cylindrical tablets of diameter 10.0 mm were obtained from the powder mixture prepared by the process described in Example 13. The press (Korsch EKO~ was adjusted to produce 230 mg tablets (with an active principle content 20 of 60 mg). Their complete composition is as follows:
Terfenadine 60 mg .
Beta-cyclodextrin (Kleptose R~ 142 mg Polyvinylpyrrolidone 20 mg Corn starch 6 mg 25 Magnesium stearate 2 mg Operating in this manner, flat tablets were obtained showing excellent technical characteristics. A dissolution test was also performed on these tablets using the apparatus and methods previously described.
The test results are given in Table XIV
TABLE XIV
Time (min) Active substance dissolved 3 8.7 6 24.0 9 35.5 l0 12 46.0 53.8 18 58.9 2i 63.3 30 70.3 is 45 73.4 60 78.5 10.0 g of carbamazepine (Fermion - batch No. 87B18) and 40.0 g of crosslinked sodium carboxymethylcellulose (AcDiSolR - FMC
Corporation Philadelphia USA) are placed in the jar of a ceramic ball mill (inner diameter 12 cm, capacity 1 litre).
A series of ceramic balls are added to occupy about half the available volume.
Grinding is continued for 2 hours at a rotational speed of 70 rpm.
A homogeneous white coloured mixture is obtained. A dissolution test was performed on 200 mg of this mixture {equivalent to 40 mg of carbamazepine) to determine the dissolution rate of the active principle by means of the apparatus and method described in Example 1, using water (4000 ml at 37~C) as dissolution fluid.
The results are given in Table XV, where they are compared with those obtained by dissolution of carbamazepine as such.
TABLE XV
Time (min) Active substance Carbamazepine as such dissolved ~ dissolved x 3 27.0 6 54.4 io 9 67.8 12 74.7 i5 79.8 34.0 18 82.9 21 85.5 30 92.5 60.1 45 loo.0 83.0 10.0 g of nifedipine (Industrie Chimiche Italiane- batch No. 3671) and 90.0 g of crosslinked sodium carboxymethylcellulose (AcDiSolR
FMC Corporation Philadelphia USA) are placed in the jar of a ceramic ball mill (inner diameter 12 cm, capacity 1 litre).
A series of ceramic balls are added. Grinding is continued for 2 hours at a rotational speed of 70 rpm..
A homogeneous yellow coloured mixture is obtained. A dissolution test was performed on 100 mg of this mixture (equivalent to 10 mg of nifedipine) to determine the dissolution rate of the active principle.
The apparatus and method of determination described in Example 1 were employed, using water (4000 ml at 37~C) as dissolution fluid.
The dissolution was carried out in a dark environment because of the photosensitivity of nifedipine.
The results are given in Table XVI, where they are compared with those obtained by dissolution of nifedipine as such.
TABLE XVI
Time (min) Active substance Nifedipine as such dissolved x dissolved ,d 3 52.9 6 72.2 g 80.2 15 87.4 0.7 18 90.1 21 92.0 30 95.0 1.8 45 97.7 3.0 60 99.6 3.9 EXAMPLE 3a Starting from co-ground Naftazone-crosslinked sodium carboxymethylcellulose 1:g mixture prepared according to the process given in Example 1, controlled release tablets were obtained containing 30 mg active principle, with the following composition:
Naftazone (Innothera Lot n. 081808) 30 mg Crosslinked sodium carboxymethylcellulose 270 mg (Ac-Di-Sol~) Hydroxypropylmethylcellulose (Methocel K15M~ 50 mg Magnesium stearate 2.5 mg In a powder mixer the amounts of co-ground naftazone-crosslinked sodium carboxymethylcellulose are admixed with hydroxypropylmethylcellulose and magnesium stearate.
Flat tablets of ~b 11 mm were prepared on an alternative Korsch EKO
{Berlin D) press, which were submitted to a dissolution test employing the USPXXII modified apparatus described in Example 1, containing 5000 ml water, at 37~C and with a paddle turning at 100 r.p.m.
The obtained results are reported in the following Table IIIa.
TABLE IIIa Time (min.) Active substance dissolved 3p 15.0 60 23.6 120 34.4 240 56.0 36p 82.7 480 99.3 EXAMPLE 5a Starting from the Naftazone-cross-linked polyvinylpyrrolidone 1:9 mixture prepared according to Example 4, controlled release tablets containing 30 mg active principle were obtained having the following composition:
'ij Naftazone {Innothera, lot 081808) 30 mg Cross-linked polyvinylpyrrolidone (Polyplasdone XL) 270 mg Hydroxypropylmethylcellulose 75 mg (Methocel K4M
In a powder mixer the amounts of co-ground naftazone-cross-linked polyvinylpyrrolidone are admixed with hydroxypropylmethylcellulose.
Flat tablets of ~ 11 mm are prepared on an alternative Korsch EKC
press (Berlin, D) which are submitted to a dissolution test employing the USPXXII modified apparatus described in Example 1, containing 5000 ml water at 37~C, and with a paddle turning at: 100 r.p.m.
The results obtained are reported in Table Va.
TABLE Va Time (mina) Active substance dissolved x 60 32.4 120 43.2 240 52.8 360 57.5 4gp 60.6 600 63.0 720 65.8 840 70.0 960 74.2 1080 76.6 1200 79.0 p J
p 7 94 ~4 EXAMPLE lla In a glass cilinder, 20 g terfenadine (Resfar, lot n. R-27620-118) and 80 g crosslinked sodium carboxymethylcellulose (Ac-Di-Sol~ FMC
Corp. Philadelphia - USA) are poured.
The container is approximately half full.
Stirring in a turbula mixer (Type T2A, W.A. Bachofen, Basel) is performed for 20 min. at 70 r.p.m.
A homogeneous white mixture is obtained.
On 300 mg of the mixture (equal to 60 mg terfenadine) a dissolution test was performed to evaluate the solubilization speed of the active principle.
The USP XXII modified apparatus described in Example 1 was used, containing 5000 ml simulated gastric fluid USP XXII (pH 1.2) at 37~C
and a paddle stirrer at 100 r.p.m.
The results obtained are reported in the following table in comparison with the ones obtained with the corresponding co-ground product of Example 11.
TABLE XIa Time (min.) Active substance Active substance dissolved x dissolved (from mixture) (from Ex. 11) 3 12.2 6 21.0 19.1 9 28.3 33.2 12 34.3 41.7 15 40.3 47.5 21 50.0 60.5 -~~ 244794 30 59.0 76.6 45 64.1 87.5 60 69.3 91.0 EXAMPLE llb Starting from the Terfenadine-cross-linked sodium carboxymethylcellulose (Ac-Di-Sol~ 1:4 co-ground mixture prepared as reported in Example 11, controlled release tablets containing 60 mg active principle were obtained, of the following composition:
Terfenadine (Resfar, lot n. R-27620-118) 60 mg Cross-linked sodium carboxy-methylcellulose {Ac-Di-Sol~) 240 mg Hydroxypropylmethylcellulose (Methocel K41~ 100 mg The amounts of co-ground terfenadine and cross-kinked carboxymethylcellulose are mixed in a powder mixer with the hydroxypropylmethylcellulose.
Flat tablets ~ 10 mm are prepared on an alternative Korsch EKO~
(Berlin, D) press, which are submitted to a dissolution test, using the modified USP XXII apparatus described in Example 1, containing 2p 5000 ml simulated gastric fluid USP XXII, pH 1.2 at 37'C and paddle stirring at 100 r.p.m.
The results obtained are reported in the following Table XI b.
TABLE XI b Time (min.) Dissolved active substance 35.7 60 53.2 a 4794y 2g 120 73.1 240 89.4 360 94.1 480 97.0 600 98.2 720 98.8 840 100.00 EXAMPLE 13 a In a glass cylinder are poured:
Terfenadine (Resfar, lot. n.R-27620-118) 10.0 g ~-cyclodextrine (Kleptose R-Roquette, Lille, F) 23.73 g (1:1 molar ratio).
The container is approximately half full.
Stirring is performed in a Turbula (Tipe 12A, W.A. Bachofen, Basel-CH) mixer for 20 minutes (70 r.p.m.}.
A white homogeneous mixture is obtained.
On 202 mg of the mixture (equal to 60 mg terfenadine) a dissolution test was performed to evaluate the solubilization speed of the active principle.
2p The USP XXII modified apparatus described in Example 1 was employed, containing 5000 ml simulated gastric fluid USP XXII (pH 1.2} at 37'C
and a paddle stirrer at 100 r.p.m.
The results obtained are reported in the following table, in comparison with the corresponding co-ground product of Example 13.
.~.~ 4 4 TABLE XIII a Time (min.) Dissolved active Dissolved active substance substance (from mixture) (from Ex. 13) 3 7.8 17.8 6 15.7 32.6 g 22.6 41.2 12 27.9 49.2 32.6 55.4 io 18 36.8 60.0 21 41.2 63.4 30 51.4 69.7 45 62.0 73.2 60 67.8 74.7 15 EXAMPLE 13 b Starting fron the co-ground Terfenadine : ~-cyclodextrin (Kleptose Rj 1:1 mixture prepared according to the process reported in Example 13, controlled release tablets were obtained containing 60 mg active principle, of the following composition:
Terfenadine (Resfar, lot n. R-27620-118) 60.0 mg ~-cyclodextrin (Kleptose R) 144.36 mg Hydroxypropylmethylcellulose (Methocel K4h~) 51.09 mg Terfenadine and ~-cyclodextrin co-ground are admixed with the hydroxypropylmethylcellulose in a powder mixer.
Flat tablets are prepared of 10 mm ~ on an alternative Korsch EKO~
(Berlin, D) press, which are then submitted to a dissolution test ~~ 9 using the USP XXII modified apparatus described in Example 1, containing 5000 ml simulated gastric fluid USP XXII pH 1.2, at 37~C
and with paddle stirring at 100 r.p.m.
The results obtained are reported in Table XIII b:
5 TABLE XIII b Time {min.) Dissolved active substance x 3o 7.9 60 12.1 10 120 18.1 240 33.9 360 48.4 480 61.2 600 72.7 15 720 81.7 840 90.2 960 98.1 1080 100.00 EXAMPLE 15 a 20 In a glass cylinder are poured Carbamazepine (Fermion, lot n. 87B18) 10.0 g Cross-linked sodium carboxymethylcellulose (Ac-Di-Sol-FMC Corp~ , Philadelphia-USA) 40.0 g The container is approximately half full.
25 The mixture is stirred in a Turbula (type T2A, W.A. Bachofen, Basel, CH) mixer for 20 minutes (70 r.p.m.).
A white homogeneous mixture is obtained.
On 200 mg of said mixture {equal to 40 mg Carbamazepine) a dissolution test was performed, to evaluate the solubilization speed of the active principle.
The USP XXII modified apparatus described in Example 1 was employed, containing 4000 ml water at 37~C and a paddle stirrer at 100 r.p.m.
The result obtained are reported in the following table, in comparison with the ones of the corresponding co-ground product of Example 15.
TABLE XV a Time (min.) Dissolved active Dissolved active principle principle lp (from mixture) ;G (from Ex. 15) x 3 ~ 84.8 27.0 6 93.3 54.4 9 97.1 67.8 is 12 98.8 74.4 15 99.3 79.8 18 99.6 82.9 21 99.7 85.5 30 100.0 92.5 20 45 100.0 EXAMPLE 15 b Starting from the co-ground mixture Carbamazepine-cross-linked sodium carboxymethylcellulose (Ac-Di-Sol) 1:4 prepared according to Example 15, controlled release 100 mg active principle tablets were 25 obtained, of the following composition:
Carbamazepine (Fermion, lot n. 87B18) 100 mg Cross-linked sodium carboxymethylcellulose 4 47 ~' (Ac-Di-Sol) 400 mg Hydroxypropylmethylcellulose (Methocel K4M~ 214 mg In a powder mixer the amount of co-ground carbamazepine-cross-linked carboxymethylcellulose are mixed with the hydroxypropylmethylcellulose.
Flat tablets of ~ 12 mm are prepared on an alternative Korsch EKO~
(Berlin, D) press, which are submitted to a dissolution test using the USP XXII modified apparatus described in Example 1, containing 5000 ml water at 37'C, and with a paddle stirrer (100 r.p.m.).
The results obtained are reported in Table XV b.
TABLE XV b Time (min.) Dissolved active substance 60 7.4 120 10.7 240 18.9 360 28.5 6o0 49.8 720 61.0 840 72.1 960 83.4 1080 94.1 2s 1200 99.7 _!
z7 EXAMPLE 15 c Starting from the mixture prepared in the Turbula mixer Carbamazepine-Cross-linked sodium carboxymethylcellulose (Ac-Di-Sol) 1:4 prepared according to Example 15 a, controlled release tablets containing 100 mg active principle, were prepared, having the following composition:
Carbamazepine (Fermion, lot 87B18) 100 mg Cross-linked sodium carboxymethylcellulose ~ 400 m (Ac-Di-Sol) g Hydroxypropylmethylcellulose (Methocel K4Mj 214 mg The previously mixed amounts of carbamazepine and cross-linked sodium carboxymethylcellulose are admixed in a powder mixer with the hydroxypropylmethylcellulose.
Flat ~ 12 mm tablets were prepared on Korsch EKO alternative press, which were then submitted to a dissolution test using the modified USP XXII apparatus described in Example 1, containing 5000 ml water at 37~C under paddle stirring at 100 r.p.m.
The obtained results are reported in the following table.
It has also been found in the case of nifedipine that a rapid medicament effect can be obtained using the micronized product, whereas a slower effect can be obtained by using the active principle at a coarser particle size. This process, which is not easy to standardize, is claimed in German patents 2209526 and DE A1 3033919.
The problem of increasing the dissolution rate of poorly soluble active substances has been confronted in various other ways, for example by transforming the substance from a crystalline state to an amorphous state which generally results in an increase in dissolution rate [see Gouda M.W. and coll., Drug Develop. Ind.
Pharm. 3, 2'73 (1977)x.
Attempts have been made to attain the same objective by preparing clathrates, inclusion compounds, complexes with polymers such as polyvinylpyrrolidone, polyethyleneglycol, polyvinylalcohol, cellulose and derivatives or, more recently, cyclodextrins.
A more recent method for obtaining an increased dissolution rate is described by Nakay Y and coll. Chem. Pharm. Bull. 25, 3340 (1977), in which the poorly soluble active principle is absorbed onto an inert support having a large surface area.
A different process, claimed in Italian patent application 20474 A/85, comprises solubilizing the poorly water-soluble active principle in an organic solvent (generally apolar) and then loading the obtained solution onto a support of hydrophilic polymer material able to swell on contact with water and aqueous fluids.
However this method requires the use of a very complicated process in that generally the supporting polymer material must be uniformly coated and brought into intimate contact with the organic solution of the active substance.
This means that large quantities of solvent must generally be treated to obtain solutions able to be uniformly distributed on the supporting polymer material.
This process also requires the use of large solvent volumes with considerable drawbacks both from the technical viewpoint (possible flammability or ease of explosion) and economic viewpoint (high cost and need to use explosion-proof plant).
It is also essential to use suitable technical processes able to completely eliminate the apolar solvent from the support, to avoid the risk of any residual solvent presence.
This is obviously of extreme importance in the case of biologically active substances and medicaments for human use, and is evaluated with extreme care by the health authorities on registration of medical specialities containing such active principles.
Summary We have now discovered a new process for preparing pharmaceutical compositions with an increased active substance dissolution rate which overcomes the aforesaid drawbacks and provides optimum process safety and economy.
Said process is characterised in that the active substance is co-ground or dry mixed with cyclodextrins or with a hydrophilic polymer substance which swells on contact with water and the obtained mixtures can be formulated with excipients normally used in the pharmaceutical industry and transformed into capsules or tablets of fast disgregation and dissolution or into controlled-rate release .<~
tablets.
Detailed description of the invention The characteristics and advantages of the process for preparing pharmaceutical compositions with an increased active substance 5 dissolution rate according to the present invention will be more apparent from the following detailed description.
The process consists first of all of co-grinding or dry mixing the active substance with cyclodextrins or with hydrophilic polymer materials which swell on contact with water.
lp Normal mixing or grinding means can be used for said process, such as a pin mill, hammer mill, ball mill and/or fluid jet mills.
A basic characteristic of the invention is the choice of polymer materials, which can be natural or synthetic.
The initial particle size distribution of said polymer materials is not important, and can lie within a wide range provided it falls within the limits of normal pharmaceutical use, neither do they need to have a large surface area.
A characteristic of the compositions of the invention is that when in the form of co-ground or mixed powders, transformed into tablets, they show rapid interaction with water and/or aqueous solutions to result in the development of a swelling pressure. This pressure can be measured with the apparatus described by Conte and toll. in Italian patent No. 19815 A/88 of 17/03/88.
The polymer materials used in the process of the present invention are chosen from the group consisting of crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, carboxymethyl starch, potassium methacrylate-divinylbenzene copolymer (Ambelite IRP88), polyvinylalcohols, hydroxypropyl-cellulose, hydroxypropylcyclodextrin, alpha, beta, gamma cyclodextrin or derivatives and other dextran derivatives, glucans, scleroglucans and derivatives.
Synthetic or semisynthetic polymer materials of different degrees of crosslinking, different molecular weights and different properties and rates of swelling in water can also be used, such as crosslinked polyvinylpyrrolidone and crosslinked sodium carboxymethylcellulose.
Natural polymer materials can also be used such as starches, modified starches, cellulose, variously substituted cellulose W
derivatives and formalin-casein. _ The active substances usable in the process of the present invention are chosen from the group consisting of naftazone, terfenadine, carbamazepine, gliclazide, glibenclamide, bifonazole and nifedipine, diazepam, ketoprofen.
The active substance content of the composition is between 1 and 90%
by weight and preferably between 10 and ~5x by weight.
The mixing or co-grinding time depends on the means used for the purpose and is for example between 0.1 and 4 hours if a ball mill is used and the particle size of the co-ground product is between 0.1 and 300 u, but this dimensional distribution does not influence the active substance dissolution rate.
The described process of the invention transforms a substance poorly soluble or insoluble in water into an easily and completely soluble product in which the factor limiting the transfer is no longer the solubility of the active principle but other factors and components of the formulation.
2~4794, The mixtures obtained as described are therefore formulated with excipients normally used in the pharmaceutical industry to obtain hard gelatin capsules or tablets of fast disgregation and dissolution or controlled-rate release tablets.
In particular, by formulating the product co-ground or mixed with hydrophilic polymers able to form gels on contact with water, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, scleroglucan, polyvinylalcohol, carboxyvinlypolymers and dextran derivatives, a reduction in the active substance transfer rate is obtained.
Some examples of the present invention are given hereinafter by way of non-limiting illustration.
10.0 g of naftazone (Innothera batch No. 081808) and 90.0 g of crosslinked sodium carboxymethylcellulose (AcDiSol'~- FMC Corporation Philadelphia USA) are placed in the jar of a ceramic ball mill (inner diameter 12 cm, capacity 1 litre) and a series of ceramic balls are added to occupy about half the available volume.
The particle size distribution of the active principle had been previously determined by usual known methods (using a Coulter~
counter), showing a mean diameter of 13.5 microns. The particle size distribution of the support was 20-150 microns.
Grinding is continued for 2 hours at a rotational speed of ~0 rpm.
A homogeneous orange coloured mixture is obtained. A dissolution test was performed on 300 mg of this mixture (equivalent to 30 mg of naftazone) to determine the dissolution rate of the active principle.
The U.S.P. 23rd Ed. apparatus in modified form was used.
Specifically, a vessel was used containing 5.0 1 of H20 at 37~C and a stirring system (paddle) rotating at 100 rpm. The stirrer blade rotated at a distance of 5 cm from the base of the vessel.
Using an automatic withdrawal system (peristaltic pump} the solution was fed to a spectrophotometer for continuous determination of the active principle concentration.
The results obtained are shown in Table I.
TABLE I
Time (min) Active substance dissolved ('6) 3 66.8 6 70.4 g 73.6 15 79.2 18 81.8 21 84.2 3p 90.4 45 97.8 60 100.0 EXAMPLE 2 (Comparison) To determine whether the grinding process alone was able to influence the dissolution rate of the active substance of Example 1, a dissolution test was performed on the following, using the method indicated in Example 1:
a) on 30 mg of naftazone as such (batch No. 081808} having a particle size distribution of between 4.3 and 36.0 microns, determined with a Coulter counter;
b) on 100 g of naftazone ground for 2 hours at '70 rpm in the ball mill in the manner described in Example 1.
On termination of grinding the product was subjected to dimensional analysis (using a Coulter counter mod. T2A) and it was found that the grinding process used had not produced any marked variation in the particle size distribution, which had a mean value of 13.5 microns before grinding and a mean value of 12.8 microns after grinding.
Table II compares the results of the dissolution test.
TABLE II
Time (min) Test a) - Active Test b) - Active substance dissolved % substance dissolved 15 0.8 2.0 30 1.8 3.0 45 3.0 4.0 60 4.0 4.9 An examination of these data shows that grinding has irrelevant influence on the dissolution rate of the active substance.
Using normal methods, flat cylindrical tablets of diameter 11.0 mm were obtained from a co-ground mixture prepared by the process described in Example 1. The press (Korsch EKO) was adjusted to produce 300 mg tablets (with an active principle content of 30 mg).
The tablets obtained showed good disgregation (2-3 minutes) and to excellent technical characteristics. A dissolution test was performed on these tablets using the apparatus and methods previously described for the powder mixture. The test results are given in Table III
TABLE III
Time (min} Active substance dissolved x 3 11.1 6 24.0 l0 9 55.0 12 69.4 i5 83.4 18 94.0 21 100.0 10.0 g of naftazone (Innothera batch No. 081808} and 90.0 g of crosslinked polyvinylpyrrolidone (Polyplasdone XL~ - GAF Corporation, USA) are placed in jar of a ceramic ball mill.(inner diameter the 12 cm, capacity 1 litre) and a series of ceramic balls are added to 2p occupy about half available volume.
the The particle size tribution of the active principle, previously dis determined by usual known methods (using a Coulter counter), was 4.3-36.0 microns.
The particle size distribution of the support was 20-400 microns.
Grinding is continuedfor 2 hours at a rotational speed of ~0 rpm.
A homogeneous orangecoloured mixture is obtained. A dissolution test was performed 300 mg of this mixture (equivalent to on 30 mg of naftazone) to determine the dissolution rate of the active !;
_. ~, principle.
The determination was made using the apparatus and method described in Example 1.
The results obtained are shown in Table IV.
TABLE IV
Time (min) Active substance dissolved (%) 44.9 6 68.0 l0 9 78.6 12 84.7 15 88.4 18 91.2 21 93.1 15 30 96.3 45 99.4 60 100.0 Using the precise procedure described in Example 3, tablets were 20 obtained from the powder mixture prepared as described in Example 4, , these showing a disgregation time of less than 3 minutes and giving the results shown in Table V when subjected to the dissolution test.
TABLE V
Time (min) Active substance dissolved (%) 48.7 6 79.4 89.9 12 94.5 15 97.1 18 98.4 21 99.3 30 loo.o To evaluate the influence of the polymer particle size on the dissolution characteristics of the active principle, a test was performed using crosslinked polyvinylpyrrolidone with a particle size distribution of 20-80 microns.
10.0 g of naftazone (Innothera batch No. 081808) and 90.0 g of crosslinked polyvinylpyrrolidone (Polyplasdone XL10~ - GAF
Corporation, USA) are placed in the jar of a ceramic ball mill (inner diameter 12 cm, capacity 1 litre) and a series of ceramic balls are added to occupy about half the available volume.
Grinding is continued for 2 hours at a rotational speed of 70 rpm.
A homogeneous orange coloured mixture is obtained. A dissolution test was performed on 300 mg of this mixture (equivalent to 30 mg of naftazone) to determine the dissolution rate of the active principle, using the procedure described in Example 1.
Using an automatic withdrawal system (peristaltic pump) the dissolution medium was fed to a spectrophotometer for continuous determination of the active principle concentration.
The results of the dissolution test are shown in Table VI, compared with those obtained using the polymer material of coarser particle size (see Example 4).
;..
w (~~
TABLE VI
Time (min} Active substance Active substance dissolved (Ex.6) % dissolved (Ex.4) 3 62.3 44.9 6 84.6 68.0 9 90.5 78.6 12 93.2 84.7 s5 94.6 88.4 l0 18 95.4 91.2 21 96.0 93.1 30 97.2 96.3 45 98.3 99.4 60 99.3 100.0 15 The results show the the initial polymer particle size significantly influences the release kinetics only during the initial stage (about 15 min}.
Using the precise procedure described in Example 3, tablets were 20 obtained from the powder mixture prepared as described in Example 6, these showing a disgregation time of less than 3 minutes and giving the results shown in Table VII when subjected to the dissolution test.
Again the results are shown compared with those obtained using the 25 polymer material of coarser particle size (see Example 4).
~ 9~
TABLE VII
Time (min) Active substance Active substance dissolved (Ex.7) x dissolved (Ex.S) x 3 31.9 48.7 6 66.4 79.4 9 81.0 89.9 12 88.1 94.5 92.1 97.1 l0 18 94.6 98.4 21 96.5 99.3 30 99,4 100.0 45 100.0 15 10.0 g of naftazone (Innothera batch No. 081808) and 105.58 g of beta-cyclodextrin (Kleptose R~- Roquette Lille France) are placed in the jar of a ceramic ball mill (inner diameter 12 cm, capacity 1 litre), these quantities being chosen to obtain a 1:2 molar ratio between the naftazone and the cyclodextrin.
A series of ceramic balls are added to occupy about half the available volume.
Grinding is continued for 2 hours at a rotational speed of 70 rpm.
A homogeneous orange coloured mixture is obtained. A dissolution test was performed on this mixture (347 mg, equivalent to 30 mg of naftazone) to determine the dissolution rate of the active principle, using the apparatus and method described in Example 1.
The results obtained are shown in Table VIII.
15 4?9.
TABLE VIII
Time (min) Active substance dissolved (x) 3 82.0 6 87.6 9 89.6 12 91.3 92.9 18 94.5 l0 21 95.9 30 98.8 45 100.0 The results show that co-grinding naftazone with beta-cyclodextrin produces rapid dissolution of the active principle (82x in 3 15 minutes).
Using normal methods, flat cylindrical tablets of diameter 11.0 mm were obtained from a co-ground mixture prepared by the process described in Example 8. The press (Korsch EK(~) was adjusted to Produce 394 mg tablets (with an active principle content of 30 mg).
Their complete composition is as follows:
Naftazone 30 mg Beta-cyclodextrin 317 mg Carboxymethyl starch 35 mg Corn starch 10 mg Magnesium stearate 2 mg y The flat tablets obtained showed good disgregation (4 minutes) and excellent technical characteristics. A dissolution test was also performed on these tablets using the apparatus and methods previously described.
The test results are given in Table IX
TABLE IX
Time (min) Active substance dissolved ~G
3 89.6 l0 6 97.3 9 98.4 12 98.9 99.4 18 99.8 15 21 100.0 Modified release forms of naftazone.
The following formulation was made up from the powder mixture obtained in example 1:
Naftazone 30 mg Sodium carboxymethylcellulose 270 mg Hydroxypropylmethylcellulose (Methocel K 4 M~- Colorcon} 75 mg Magnesium stearate 3 mg The relative quantities of naftazone and crosslinked sodium carboxymethylcellulose (in co-ground state) plus the remaining components of the formulation are mixed together in a powder mixer.
ap"
The mixture was pressed to obtain tablets of 12 mm diameter which were subjected to the dissolution test by the method described in Example 1.
The results, given in Table X, show that it is possible to obtain modified release of the active principle, this release slow-down being due not to the reduced solubility of the active principle but to the composition formulation.
TABLE X
Time (min) Active substance dissolved y lQ 0 0 60 19.7 120 27.3 180 36.9 240 47.8 300 58.7 360 6g.1 420 81.1 480 93.3 540 100.0 20.0 g of terfenadine (Resfar batch R-27620-118) and 80.0 g of crosslinked sodium carboxymethylcellulose (AcDiSolR - FMC
Corporation Philadelphia USA) are placed in the jar of a ceramic ball mill (inner diameter 12 cm, capacity 1 litre).
A series of ceramic balls are added to occupy about half the available volume.
Grinding is continued for 2 hours at a rotational speed of 70 rpm.
A homogeneous white coloured mixture is obtained. A dissolution test was performed on 300 mg of this mixture (equivalent to 60 mg of terfenadine) to determine the dissolution rate of the active principle.
The apparatus and method of determination were as described in Example 1, using simulated gastric fluid USPXII (5000 ml) as dissolution fluid.
The results are given in Table XI, where they are compared with those obtained by dissolution of terfenadine as such.
TABLE XI
Time (min) Active substance Terfenadine as such dissolved ;G dissolved x 3 12.2 6 19.1 9 33.2 12 41.7 15 47.5 10.4 21 60.5 30 76.6 15.9 45 87.5 19.4 60 91.0 21.9 Using a Korsch EKO~ press fitted with flat 10 mm diameter punches, tablets weighing 300 mg (corresponding to 60 mg of terfenadine) were prepared from the powder mixture obtained by the process described in Example 11 and were subjected to the dissolution test in 5000 ml .,"
of simulated gastric fluid to USP XXII, to give the results shown in Table XII.
TABLE XII
Time (min) Active substance dissolved ~G
p 0 20.9 6 60.5 9 75.9 12 79.0 l0 15 80.0 18 82.0 21 83.0 30 85.0 45 88.0 15 6o 9o.0 10.0 g of terfenadine (Resfar batch R-27620-118) and 23.73 g of beta-cyclodextrin (Kleptose R~- Roquette - Lille, France) (1:1 molar ratio) are placed in the jar of a ceramic ball mill (inner diameter 20 12 cm, capacity 1 litre). A series of ceramic balls are added to occupy about half the available volume.
Grinding is continued for 2 hours at a rotational speed of 70 rpm.
A homogeneous orange coloured mixture is obtained. A dissolution test was performed on this mixture (202 mg, equivalent to 60 mg of 25 terfenadine) to determine the dissolution rate of the active principle by means of the apparatus and method described in Example 1, using 5000 ml of simulated gastric fluid USPXXII as dissolution fluid.
j~
0 4? 4 The results are given in Table XIII.
TABLE XIII
Time (min) Active substance dissolved x 17.8 6 32.6 g 41.2 12 49.2 15 55.4 to 18 60.0 21 63.4 69.7 45 73.2 60 74.7 Using normal technical methods, flat cylindrical tablets of diameter 10.0 mm were obtained from the powder mixture prepared by the process described in Example 13. The press (Korsch EKO~ was adjusted to produce 230 mg tablets (with an active principle content 20 of 60 mg). Their complete composition is as follows:
Terfenadine 60 mg .
Beta-cyclodextrin (Kleptose R~ 142 mg Polyvinylpyrrolidone 20 mg Corn starch 6 mg 25 Magnesium stearate 2 mg Operating in this manner, flat tablets were obtained showing excellent technical characteristics. A dissolution test was also performed on these tablets using the apparatus and methods previously described.
The test results are given in Table XIV
TABLE XIV
Time (min) Active substance dissolved 3 8.7 6 24.0 9 35.5 l0 12 46.0 53.8 18 58.9 2i 63.3 30 70.3 is 45 73.4 60 78.5 10.0 g of carbamazepine (Fermion - batch No. 87B18) and 40.0 g of crosslinked sodium carboxymethylcellulose (AcDiSolR - FMC
Corporation Philadelphia USA) are placed in the jar of a ceramic ball mill (inner diameter 12 cm, capacity 1 litre).
A series of ceramic balls are added to occupy about half the available volume.
Grinding is continued for 2 hours at a rotational speed of 70 rpm.
A homogeneous white coloured mixture is obtained. A dissolution test was performed on 200 mg of this mixture {equivalent to 40 mg of carbamazepine) to determine the dissolution rate of the active principle by means of the apparatus and method described in Example 1, using water (4000 ml at 37~C) as dissolution fluid.
The results are given in Table XV, where they are compared with those obtained by dissolution of carbamazepine as such.
TABLE XV
Time (min) Active substance Carbamazepine as such dissolved ~ dissolved x 3 27.0 6 54.4 io 9 67.8 12 74.7 i5 79.8 34.0 18 82.9 21 85.5 30 92.5 60.1 45 loo.0 83.0 10.0 g of nifedipine (Industrie Chimiche Italiane- batch No. 3671) and 90.0 g of crosslinked sodium carboxymethylcellulose (AcDiSolR
FMC Corporation Philadelphia USA) are placed in the jar of a ceramic ball mill (inner diameter 12 cm, capacity 1 litre).
A series of ceramic balls are added. Grinding is continued for 2 hours at a rotational speed of 70 rpm..
A homogeneous yellow coloured mixture is obtained. A dissolution test was performed on 100 mg of this mixture (equivalent to 10 mg of nifedipine) to determine the dissolution rate of the active principle.
The apparatus and method of determination described in Example 1 were employed, using water (4000 ml at 37~C) as dissolution fluid.
The dissolution was carried out in a dark environment because of the photosensitivity of nifedipine.
The results are given in Table XVI, where they are compared with those obtained by dissolution of nifedipine as such.
TABLE XVI
Time (min) Active substance Nifedipine as such dissolved x dissolved ,d 3 52.9 6 72.2 g 80.2 15 87.4 0.7 18 90.1 21 92.0 30 95.0 1.8 45 97.7 3.0 60 99.6 3.9 EXAMPLE 3a Starting from co-ground Naftazone-crosslinked sodium carboxymethylcellulose 1:g mixture prepared according to the process given in Example 1, controlled release tablets were obtained containing 30 mg active principle, with the following composition:
Naftazone (Innothera Lot n. 081808) 30 mg Crosslinked sodium carboxymethylcellulose 270 mg (Ac-Di-Sol~) Hydroxypropylmethylcellulose (Methocel K15M~ 50 mg Magnesium stearate 2.5 mg In a powder mixer the amounts of co-ground naftazone-crosslinked sodium carboxymethylcellulose are admixed with hydroxypropylmethylcellulose and magnesium stearate.
Flat tablets of ~b 11 mm were prepared on an alternative Korsch EKO
{Berlin D) press, which were submitted to a dissolution test employing the USPXXII modified apparatus described in Example 1, containing 5000 ml water, at 37~C and with a paddle turning at 100 r.p.m.
The obtained results are reported in the following Table IIIa.
TABLE IIIa Time (min.) Active substance dissolved 3p 15.0 60 23.6 120 34.4 240 56.0 36p 82.7 480 99.3 EXAMPLE 5a Starting from the Naftazone-cross-linked polyvinylpyrrolidone 1:9 mixture prepared according to Example 4, controlled release tablets containing 30 mg active principle were obtained having the following composition:
'ij Naftazone {Innothera, lot 081808) 30 mg Cross-linked polyvinylpyrrolidone (Polyplasdone XL) 270 mg Hydroxypropylmethylcellulose 75 mg (Methocel K4M
In a powder mixer the amounts of co-ground naftazone-cross-linked polyvinylpyrrolidone are admixed with hydroxypropylmethylcellulose.
Flat tablets of ~ 11 mm are prepared on an alternative Korsch EKC
press (Berlin, D) which are submitted to a dissolution test employing the USPXXII modified apparatus described in Example 1, containing 5000 ml water at 37~C, and with a paddle turning at: 100 r.p.m.
The results obtained are reported in Table Va.
TABLE Va Time (mina) Active substance dissolved x 60 32.4 120 43.2 240 52.8 360 57.5 4gp 60.6 600 63.0 720 65.8 840 70.0 960 74.2 1080 76.6 1200 79.0 p J
p 7 94 ~4 EXAMPLE lla In a glass cilinder, 20 g terfenadine (Resfar, lot n. R-27620-118) and 80 g crosslinked sodium carboxymethylcellulose (Ac-Di-Sol~ FMC
Corp. Philadelphia - USA) are poured.
The container is approximately half full.
Stirring in a turbula mixer (Type T2A, W.A. Bachofen, Basel) is performed for 20 min. at 70 r.p.m.
A homogeneous white mixture is obtained.
On 300 mg of the mixture (equal to 60 mg terfenadine) a dissolution test was performed to evaluate the solubilization speed of the active principle.
The USP XXII modified apparatus described in Example 1 was used, containing 5000 ml simulated gastric fluid USP XXII (pH 1.2) at 37~C
and a paddle stirrer at 100 r.p.m.
The results obtained are reported in the following table in comparison with the ones obtained with the corresponding co-ground product of Example 11.
TABLE XIa Time (min.) Active substance Active substance dissolved x dissolved (from mixture) (from Ex. 11) 3 12.2 6 21.0 19.1 9 28.3 33.2 12 34.3 41.7 15 40.3 47.5 21 50.0 60.5 -~~ 244794 30 59.0 76.6 45 64.1 87.5 60 69.3 91.0 EXAMPLE llb Starting from the Terfenadine-cross-linked sodium carboxymethylcellulose (Ac-Di-Sol~ 1:4 co-ground mixture prepared as reported in Example 11, controlled release tablets containing 60 mg active principle were obtained, of the following composition:
Terfenadine (Resfar, lot n. R-27620-118) 60 mg Cross-linked sodium carboxy-methylcellulose {Ac-Di-Sol~) 240 mg Hydroxypropylmethylcellulose (Methocel K41~ 100 mg The amounts of co-ground terfenadine and cross-kinked carboxymethylcellulose are mixed in a powder mixer with the hydroxypropylmethylcellulose.
Flat tablets ~ 10 mm are prepared on an alternative Korsch EKO~
(Berlin, D) press, which are submitted to a dissolution test, using the modified USP XXII apparatus described in Example 1, containing 2p 5000 ml simulated gastric fluid USP XXII, pH 1.2 at 37'C and paddle stirring at 100 r.p.m.
The results obtained are reported in the following Table XI b.
TABLE XI b Time (min.) Dissolved active substance 35.7 60 53.2 a 4794y 2g 120 73.1 240 89.4 360 94.1 480 97.0 600 98.2 720 98.8 840 100.00 EXAMPLE 13 a In a glass cylinder are poured:
Terfenadine (Resfar, lot. n.R-27620-118) 10.0 g ~-cyclodextrine (Kleptose R-Roquette, Lille, F) 23.73 g (1:1 molar ratio).
The container is approximately half full.
Stirring is performed in a Turbula (Tipe 12A, W.A. Bachofen, Basel-CH) mixer for 20 minutes (70 r.p.m.}.
A white homogeneous mixture is obtained.
On 202 mg of the mixture (equal to 60 mg terfenadine) a dissolution test was performed to evaluate the solubilization speed of the active principle.
2p The USP XXII modified apparatus described in Example 1 was employed, containing 5000 ml simulated gastric fluid USP XXII (pH 1.2} at 37'C
and a paddle stirrer at 100 r.p.m.
The results obtained are reported in the following table, in comparison with the corresponding co-ground product of Example 13.
.~.~ 4 4 TABLE XIII a Time (min.) Dissolved active Dissolved active substance substance (from mixture) (from Ex. 13) 3 7.8 17.8 6 15.7 32.6 g 22.6 41.2 12 27.9 49.2 32.6 55.4 io 18 36.8 60.0 21 41.2 63.4 30 51.4 69.7 45 62.0 73.2 60 67.8 74.7 15 EXAMPLE 13 b Starting fron the co-ground Terfenadine : ~-cyclodextrin (Kleptose Rj 1:1 mixture prepared according to the process reported in Example 13, controlled release tablets were obtained containing 60 mg active principle, of the following composition:
Terfenadine (Resfar, lot n. R-27620-118) 60.0 mg ~-cyclodextrin (Kleptose R) 144.36 mg Hydroxypropylmethylcellulose (Methocel K4h~) 51.09 mg Terfenadine and ~-cyclodextrin co-ground are admixed with the hydroxypropylmethylcellulose in a powder mixer.
Flat tablets are prepared of 10 mm ~ on an alternative Korsch EKO~
(Berlin, D) press, which are then submitted to a dissolution test ~~ 9 using the USP XXII modified apparatus described in Example 1, containing 5000 ml simulated gastric fluid USP XXII pH 1.2, at 37~C
and with paddle stirring at 100 r.p.m.
The results obtained are reported in Table XIII b:
5 TABLE XIII b Time {min.) Dissolved active substance x 3o 7.9 60 12.1 10 120 18.1 240 33.9 360 48.4 480 61.2 600 72.7 15 720 81.7 840 90.2 960 98.1 1080 100.00 EXAMPLE 15 a 20 In a glass cylinder are poured Carbamazepine (Fermion, lot n. 87B18) 10.0 g Cross-linked sodium carboxymethylcellulose (Ac-Di-Sol-FMC Corp~ , Philadelphia-USA) 40.0 g The container is approximately half full.
25 The mixture is stirred in a Turbula (type T2A, W.A. Bachofen, Basel, CH) mixer for 20 minutes (70 r.p.m.).
A white homogeneous mixture is obtained.
On 200 mg of said mixture {equal to 40 mg Carbamazepine) a dissolution test was performed, to evaluate the solubilization speed of the active principle.
The USP XXII modified apparatus described in Example 1 was employed, containing 4000 ml water at 37~C and a paddle stirrer at 100 r.p.m.
The result obtained are reported in the following table, in comparison with the ones of the corresponding co-ground product of Example 15.
TABLE XV a Time (min.) Dissolved active Dissolved active principle principle lp (from mixture) ;G (from Ex. 15) x 3 ~ 84.8 27.0 6 93.3 54.4 9 97.1 67.8 is 12 98.8 74.4 15 99.3 79.8 18 99.6 82.9 21 99.7 85.5 30 100.0 92.5 20 45 100.0 EXAMPLE 15 b Starting from the co-ground mixture Carbamazepine-cross-linked sodium carboxymethylcellulose (Ac-Di-Sol) 1:4 prepared according to Example 15, controlled release 100 mg active principle tablets were 25 obtained, of the following composition:
Carbamazepine (Fermion, lot n. 87B18) 100 mg Cross-linked sodium carboxymethylcellulose 4 47 ~' (Ac-Di-Sol) 400 mg Hydroxypropylmethylcellulose (Methocel K4M~ 214 mg In a powder mixer the amount of co-ground carbamazepine-cross-linked carboxymethylcellulose are mixed with the hydroxypropylmethylcellulose.
Flat tablets of ~ 12 mm are prepared on an alternative Korsch EKO~
(Berlin, D) press, which are submitted to a dissolution test using the USP XXII modified apparatus described in Example 1, containing 5000 ml water at 37'C, and with a paddle stirrer (100 r.p.m.).
The results obtained are reported in Table XV b.
TABLE XV b Time (min.) Dissolved active substance 60 7.4 120 10.7 240 18.9 360 28.5 6o0 49.8 720 61.0 840 72.1 960 83.4 1080 94.1 2s 1200 99.7 _!
z7 EXAMPLE 15 c Starting from the mixture prepared in the Turbula mixer Carbamazepine-Cross-linked sodium carboxymethylcellulose (Ac-Di-Sol) 1:4 prepared according to Example 15 a, controlled release tablets containing 100 mg active principle, were prepared, having the following composition:
Carbamazepine (Fermion, lot 87B18) 100 mg Cross-linked sodium carboxymethylcellulose ~ 400 m (Ac-Di-Sol) g Hydroxypropylmethylcellulose (Methocel K4Mj 214 mg The previously mixed amounts of carbamazepine and cross-linked sodium carboxymethylcellulose are admixed in a powder mixer with the hydroxypropylmethylcellulose.
Flat ~ 12 mm tablets were prepared on Korsch EKO alternative press, which were then submitted to a dissolution test using the modified USP XXII apparatus described in Example 1, containing 5000 ml water at 37~C under paddle stirring at 100 r.p.m.
The obtained results are reported in the following table.
TABLE XV c Time (min.) Active substance dissolved ,'G
60 7.8 120 11.2 240 19.0 360 28.1 480 38.2 Goo 48.9 l0 720 59.8 840 71.1 960 82.6 1080 94.1 1200 100.1 EXAMPLE 16 a In a glass cylinder protected from light, were poured:
Nifedipine (Industrie Chimiche Italiane, lot 3671) 10.0 g Cross-linked sodium carboxymethylcellulose (Ac-Di-Sol~ FMC Corp., Philadelphia, USA) 90.0 g The cylinder was approximately half full.
Stirring was performed in a Turbula apparatus {Type T2A, W.A.
Bachofen, Basel, CH) for 20 minutes (70 r.p.m.).
A homogeneous light yellow mixture was obtained.
On 100 mg of said mixture (equal to 10 mg Nifedipine) a dissolution text was performed to evaluate the solubilization speed of the active principle.
The USP XXII modified apparatus described in Example 1 was used, containing 5000 ml water at 37~C and a paddle stirrer at 100 r.p.m.
The apparatus was screemed from the light.
The results obtained are reported in the table in comparison with the ones of the corresponding co-ground product of Example 16.
5 TABLE XVI a Time (min.) Dissolved active Dissolved active substance substance (from mixture) % (from Ex. 16) 3 5.8 52.9 6 19.0 72.2 9 28.8 80.2 12 34.6 84.4 15 39.9 87.4 18 44.1 90.1 15 21 48.4 92.0 30 57.0 95.0 66.0 97.0 60 71.0 99.6 EXAMPLE 16 b 20 Starting from the Nifedipine-cross-linked carboxymethylcellulose (Ac-Di-Sol~ mixture 1:9 prepared in the Turbula mixer according to Example 16 a, controlled release tablets containing 30 mg active principle were prepared, having the following composition:
Nifedipine (Ind.Chim.It., lot 3671). 30 mg 25 Cross-linked sodium carboxymethylcellulose (Ac-Di-Sol) 270 mg Hydroxypropylmethylcellulose (Methocel K100M) 130.4 mg 4~~
Magnesium stearate 2.17 mg Colloidal silica 2.17 mg The co-ground nifedipine-cross-linked sodium carboxymethylcellulose mixture is admixed with hydroxypropylmethylcellulose, magnesium stearate and colloidal silica in a powder mixer.
Flat tablets of ~ 10 mm were prepared on an alternative Korsch EKO~
(Berlin, D) press, which were submitted to a dissolution test in the dark using the USP XXII modified apparatus described in Example 1, containing 5000 ml water at 37'C, under paddle-stirring at 100 r.p.m.
The obtained results are reported in the table.
TABLE XVI b Time (min.} Dissolved active substance 120 10.6 240 17.1 360 24.5 480 32.8 600 42.6 720 53.6 840 65.6 960 77.0 1080 84.2 1320 98.2 In a glass cylinder protected from light were poured:
Nifedipine (Ind. Chim. Ital., lot 3671) 25.0 g Cross-linked sodium carboxymethylcellulose 1-:;
(Ac-Di-Sol FMC Corp., Philadelphia, USA) 75.0 g The cylinder was approxymately half full.
Stirring was performed in a Turbula mixer (Type T2A, W.A. Bachofen, Basel, CH) for 20 minutes (70 r.p.m.).
A homogeneous yellow mixture was obtained.
On 400 ml of the mixture (equal to 10 mg Nifedipine) a dissolution test was performed to evaluate the solubilization speed of the active principle.
The modified USP XXII modified apparatus described in Example 1 was employed, containing 4000 ml water at 37~C, under paddle stirring at 100 r.p.m. The test was performed in the dark.
The table reports the results obtained.
TABLE XVII
Time (min.) Dissolved active substance ;G
(from mixture) i5 34.5 30 48.5 45 55.3 60 59.4 75 61.9 90 63.8 105 65.1 120 66.9 EXAMPLE 17 a Starting from the Nifedipine-cross-linked sodium carboxymethylcellulose 1:3 mixture prepared in the Turbula~ mixer according to Example 17, controlled release 30 mg active principle tablets were obtained, of the following composition:
Nifedipine (Ind.Chim.Ital., lot 36'71) 30 mg Cross-linked sodium carboxymethylcellulose (Ac-Di-Sol) 90 mg Hydroxypropylmethylcellulose (Methocel K100hI) 42 mg Magnesium stearate 0.81 mg The previously mixed relative amounts of nifedipine-cross-linked sodium carboxymethylcellulose are admixed with the hydroxypropylmethylcellulose and the magnesium stearate in a powder mixer.
Flat tablets of ~ 8 mm are prepared on a Korsch EKO~ (Berlin) alternative press, which are submitted in the dark to a dissolution test using the modified USP XXIIapparatus described in Example 1, containing 5000 ml water at 3'7'C under paddle stirring (100 r.p.m.).
The obtained results are reported in the table.
-~~
TABLE XVII a Time (min.) Dissolved active substance ;G
60 12.7 120 20.6 240 34.1 360 48.5 480 64.1 600 77.9 io 720 87.1 840 92.6 960 94.8 1080 97.0
60 7.8 120 11.2 240 19.0 360 28.1 480 38.2 Goo 48.9 l0 720 59.8 840 71.1 960 82.6 1080 94.1 1200 100.1 EXAMPLE 16 a In a glass cylinder protected from light, were poured:
Nifedipine (Industrie Chimiche Italiane, lot 3671) 10.0 g Cross-linked sodium carboxymethylcellulose (Ac-Di-Sol~ FMC Corp., Philadelphia, USA) 90.0 g The cylinder was approximately half full.
Stirring was performed in a Turbula apparatus {Type T2A, W.A.
Bachofen, Basel, CH) for 20 minutes (70 r.p.m.).
A homogeneous light yellow mixture was obtained.
On 100 mg of said mixture (equal to 10 mg Nifedipine) a dissolution text was performed to evaluate the solubilization speed of the active principle.
The USP XXII modified apparatus described in Example 1 was used, containing 5000 ml water at 37~C and a paddle stirrer at 100 r.p.m.
The apparatus was screemed from the light.
The results obtained are reported in the table in comparison with the ones of the corresponding co-ground product of Example 16.
5 TABLE XVI a Time (min.) Dissolved active Dissolved active substance substance (from mixture) % (from Ex. 16) 3 5.8 52.9 6 19.0 72.2 9 28.8 80.2 12 34.6 84.4 15 39.9 87.4 18 44.1 90.1 15 21 48.4 92.0 30 57.0 95.0 66.0 97.0 60 71.0 99.6 EXAMPLE 16 b 20 Starting from the Nifedipine-cross-linked carboxymethylcellulose (Ac-Di-Sol~ mixture 1:9 prepared in the Turbula mixer according to Example 16 a, controlled release tablets containing 30 mg active principle were prepared, having the following composition:
Nifedipine (Ind.Chim.It., lot 3671). 30 mg 25 Cross-linked sodium carboxymethylcellulose (Ac-Di-Sol) 270 mg Hydroxypropylmethylcellulose (Methocel K100M) 130.4 mg 4~~
Magnesium stearate 2.17 mg Colloidal silica 2.17 mg The co-ground nifedipine-cross-linked sodium carboxymethylcellulose mixture is admixed with hydroxypropylmethylcellulose, magnesium stearate and colloidal silica in a powder mixer.
Flat tablets of ~ 10 mm were prepared on an alternative Korsch EKO~
(Berlin, D) press, which were submitted to a dissolution test in the dark using the USP XXII modified apparatus described in Example 1, containing 5000 ml water at 37'C, under paddle-stirring at 100 r.p.m.
The obtained results are reported in the table.
TABLE XVI b Time (min.} Dissolved active substance 120 10.6 240 17.1 360 24.5 480 32.8 600 42.6 720 53.6 840 65.6 960 77.0 1080 84.2 1320 98.2 In a glass cylinder protected from light were poured:
Nifedipine (Ind. Chim. Ital., lot 3671) 25.0 g Cross-linked sodium carboxymethylcellulose 1-:;
(Ac-Di-Sol FMC Corp., Philadelphia, USA) 75.0 g The cylinder was approxymately half full.
Stirring was performed in a Turbula mixer (Type T2A, W.A. Bachofen, Basel, CH) for 20 minutes (70 r.p.m.).
A homogeneous yellow mixture was obtained.
On 400 ml of the mixture (equal to 10 mg Nifedipine) a dissolution test was performed to evaluate the solubilization speed of the active principle.
The modified USP XXII modified apparatus described in Example 1 was employed, containing 4000 ml water at 37~C, under paddle stirring at 100 r.p.m. The test was performed in the dark.
The table reports the results obtained.
TABLE XVII
Time (min.) Dissolved active substance ;G
(from mixture) i5 34.5 30 48.5 45 55.3 60 59.4 75 61.9 90 63.8 105 65.1 120 66.9 EXAMPLE 17 a Starting from the Nifedipine-cross-linked sodium carboxymethylcellulose 1:3 mixture prepared in the Turbula~ mixer according to Example 17, controlled release 30 mg active principle tablets were obtained, of the following composition:
Nifedipine (Ind.Chim.Ital., lot 36'71) 30 mg Cross-linked sodium carboxymethylcellulose (Ac-Di-Sol) 90 mg Hydroxypropylmethylcellulose (Methocel K100hI) 42 mg Magnesium stearate 0.81 mg The previously mixed relative amounts of nifedipine-cross-linked sodium carboxymethylcellulose are admixed with the hydroxypropylmethylcellulose and the magnesium stearate in a powder mixer.
Flat tablets of ~ 8 mm are prepared on a Korsch EKO~ (Berlin) alternative press, which are submitted in the dark to a dissolution test using the modified USP XXIIapparatus described in Example 1, containing 5000 ml water at 3'7'C under paddle stirring (100 r.p.m.).
The obtained results are reported in the table.
-~~
TABLE XVII a Time (min.) Dissolved active substance ;G
60 12.7 120 20.6 240 34.1 360 48.5 480 64.1 600 77.9 io 720 87.1 840 92.6 960 94.8 1080 97.0
Claims (13)
1. A process for preparing a pharmaceutical composition having an increased active-substance dissolution rate and a controlled release rate, the process consisting of dry co-grinding or dry-mixing an active substance selected from the group consisting of terfenadine, nifedipine, naftazone and carbamazepine, with cyclodextrin or a hydrophilic polymer which is swellable on contact with water selected from the group consisting of crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, carboxymethyl starch, polyvinyl-alcohols and potassium methacrylate divinylbenzene copolymer, and with a hydrophilic polymer which forms a gel on contact with water selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose and sodium carboxymethylcellulose, and thereafter tableting the obtained mixture into controlled release tablets.
2. The process as claimed in claim 1, wherein the quantity of said active substance used is between 1 and 90%
by weight, based on the total weight of said active substance and of said cyclodextrin or swellable polymer.
by weight, based on the total weight of said active substance and of said cyclodextrin or swellable polymer.
3. The process as claimed in claim 1 or 2, wherein said cyclodextrin is chosen from the group consisting of alpha, beta, and gamma-cyclodextrin or derivatives thereof.
4. The process as claimed in claim l, wherein said active substance is terfenadine, and it is co-ground or mixed with cross-linked sodium carboxymethylcellulose and with the hydrophilic polymer which forms a gel on contact with water.
5. The process as claimed in claim 4, wherein the quantity of the terfenadine is between loo and 75o by weight of the whole mixture.
6. The process as claimed in claim 4 or 5, wherein the particle size of terfenadine is between 0.1 and 300 microns.
7. The process as claimed in any one of claims 1 to 6, wherein said active substance is co-ground with grinding means selected from the group consisting of pin mills, hammer mills, ball mills and fluid jet mills.
8. The process as claimed in any one of claims 1 to 6, wherein said active substance is co-ground in a ball mill for a time between 0.1 and 4 hours.
9. A pharmaceutical composition in the form of tablets having an increased active-substance dissolution rate and a controlled release rate, the composition comprising an active substance selected from the group consisting of naftazone, terfenadine, nifedipine and carbamazepine, which active substance has been dry co-ground or dry mixed with cyclodextrin or a hydrophilic polymer which is swellable on contact with water selected from the group consisting of crosslinked sodium carboxymethylcellulose, crosslinked sodium polyvinylpyrrolidone, carboxymethyl starch, polyvinylalcohols and potassium methacrylate divinylbenzene copolymers, and with a hydrophilic polymer which forms a gel on contact with water selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose and sodium carboxymethylcellulose.
10. The pharmaceutical composition as claimed in claim 9, in which said cyclodextrin is selected from the group consisting of alpha, beta, gamma-cyclodextrin and derivatives thereof.
11. The pharmaceutical composition as claimed in claim 9 or 10, wherein said active substance content is between 1 and 90% by weight, based on the total weight of said swellable polymer or cyclodextrin and said active substance.
12. The pharmaceutical composition as claimed in claim 9, or 11, comprising terfenadine, crosslinked sodium carboxymethylcellulose and said gel-forming hydrophilic polymer.
13. The pharmaceutical composition as claimed in claim 12, in which said gel-forming hydrophilic polymer is hydroxypropylmethylcellulose, and terfenadine is present in an amount between 10% and 75% by weight of the whole mixture.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT21091REG.A | 1990-07-27 | ||
| IT02109190A IT1246188B (en) | 1990-07-27 | 1990-07-27 | PROCEDURE FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS HAVING INCREASED SPEED OF DISSOLUTION OF THE ACTIVE SUBSTANCE AND COMPOSITIONS OBTAINED. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2047944A1 CA2047944A1 (en) | 1992-01-28 |
| CA2047944C true CA2047944C (en) | 2002-03-12 |
Family
ID=11176602
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002047944A Expired - Lifetime CA2047944C (en) | 1990-07-27 | 1991-07-26 | Process for preparing pharmaceutical compositions having an increased active substance dissolution rate, and the compositions obtained |
Country Status (5)
| Country | Link |
|---|---|
| US (2) | US5476654A (en) |
| EP (1) | EP0468392A1 (en) |
| JP (1) | JP3488475B2 (en) |
| CA (1) | CA2047944C (en) |
| IT (1) | IT1246188B (en) |
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| IT1215332B (en) * | 1987-01-12 | 1990-02-08 | Crinos Industria Farmaco | PHARMACEUTICAL COMPOSITION CONTAINING SULGLICOTIDE FOR THERAPY OF GASTRIC ULCER |
| ES2060737T3 (en) * | 1988-02-25 | 1994-12-01 | Yamanouchi Europ Bv | PROCEDURE FOR PREPARING A PHARMACEUTICAL GRANULATE. |
| IT1227626B (en) * | 1988-11-28 | 1991-04-23 | Vectorpharma Int | SUPPORTED DRUGS WITH INCREASED DISSOLUTION SPEED AND PROCEDURE FOR THEIR PREPARATION |
| US5082669A (en) * | 1989-07-20 | 1992-01-21 | Dainippon Pharmaceutical Co., Ltd. | Rapid-releasing oral particle pharmaceutical preparation with unpleasant taste masked |
| US5231089A (en) * | 1991-12-02 | 1993-07-27 | University Of Florida | Method of improving oral bioavailability of carbamazepine |
-
1990
- 1990-07-27 IT IT02109190A patent/IT1246188B/en active IP Right Grant
-
1991
- 1991-07-22 EP EP91112214A patent/EP0468392A1/en not_active Ceased
- 1991-07-26 CA CA002047944A patent/CA2047944C/en not_active Expired - Lifetime
- 1991-07-29 JP JP21040791A patent/JP3488475B2/en not_active Expired - Lifetime
-
1994
- 1994-10-11 US US08/321,123 patent/US5476654A/en not_active Expired - Lifetime
-
1995
- 1995-09-07 US US08/524,739 patent/US5849329A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04234316A (en) | 1992-08-24 |
| EP0468392A1 (en) | 1992-01-29 |
| CA2047944A1 (en) | 1992-01-28 |
| IT9021091A0 (en) | 1990-07-27 |
| JP3488475B2 (en) | 2004-01-19 |
| US5849329A (en) | 1998-12-15 |
| US5476654A (en) | 1995-12-19 |
| IT9021091A1 (en) | 1992-01-27 |
| IT1246188B (en) | 1994-11-16 |
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| EEER | Examination request | ||
| MKEX | Expiry |