Orodispersible mannitol

Abstract

Coagglomerates of mannitol, whose laser volume-average diameter D4,3 is between 1 and 200 μm, and of granular starch, are characterized in that they have a disintegration behavior determined according to a test A such that the relaxation time measured is between 30 and 100 seconds and the swelling force is between 0.8 and 3.0 N.

Claims

1. Orodispersible tablets comprising: as the binders and disintegrating agents, coagglomerates of mannitol in beta-crystalline form and granular starch, the mannitol having a laser mean volume diameter D4, 3 of which is between 1 and 200 μm, the coagglomerates having a laser mean volume diameter D$, 3, of between 60 and 500 μm, the coagglomerates being formed by a process comprising the steps of preparing a suspension of the mannitol and the granular starch in water at a temperature between 15 and 25° C. the mannitol/starch ratio being between 90/10 and 50/50, the suspension having a dry matter content of between 40% and 60% by dry weight, and spray drying said suspension, wherein the coagglomerates are the sole binders and disintegrating agents in the tablets, wherein the tablet has a diameter of 16 mm, a weight of about 1 gram, and a hardness of between 100-110 N.

2. The orodispersible preparation of claim 1 further comprising an ingredient selected from the group consisting of a food ingredient, a pharmaceutical active ingredient, a plant-protection active ingredient and a detergent.

3. The orodispersible preparation of claim 1, wherein the coagglomerates disintegrate in the mouth, according to a test D in less than 40 seconds.

4. The orodispersible preparation as claimed in claim 1, wherein the coagglomerates have a viscosity, measured according to a test B, having a value of between 2.0 and 10.0 mPa.Math.s when placed in suspension in water at a concentration of 42.8% by weight.

5. The orodispersible preparation as claimed in claim 1, wherein the mannitol/starch ratio is between 80/20 and 65/35.

6. The orodispersible preparation as claimed in claim 1, wherein the starch is chosen from the group consisting of standard corn starch, “extra-white” corn starch and potato starch, taken alone or in combination.

7. The orodispersible preparation as claimed in claim 1, wherein said coagglomerates have a laser mean volume diameter D4, 3 of between 100 and 250 μm.

8. The orodispersible preparation as claimed in claim 1, wherein the coagglomerates disintegrate in the mouth, according to a test D, in less than 60 seconds.

Description

EXAMPLE 1: PREPARATION OF COAGGLOMERATES ACCORDING TO THE INVENTION

(1) Various compositions of coagglomerates consisting of mannitol and of starch are prepared, by spray-drying according to the invention, at ratios of 90/10, 85/15, 80/20, 65/35 and 50/50, respectively.

(2) Crystalline mannitol of fine particle size, sold by the applicant company under the name Mannitol 35, having a laser mean volume diameter of approximately 50 μm, and “extra-white” corn starch are used.

(3) The operating conditions for producing these coagglomerates are represented in the following table 1.

(4) TABLE-US-00001 TABLE 1 Nozzle Tp Tp of Tp Coagglomerates Dry Pres- (spraying upstream the static outlet according to Mannitol/starch matter sure system air fluidized bed air the invention ratio (%) (bar) type SK) (° C.) (° C.) (° C.) “A” 90/10 50 20 52*21 170 84 75 “B” 85/15 52 25 52*21 175 84 70 “C” 80/20 55 30 52*21 155 84 60 “D” 65/35 55 25 52*21 160 84 60 “E” 50/50 57 25 52*21 160 84 65 Control 100/0  45 20 52*21 175 84 75 mannitol alone

(5) The characteristics of the coagglomerates of mannitol and of starch according to the invention are given in the following table 2.

(6) TABLE-US-00002 TABLE 2 Disin- Coag- Laser Com- tegra- glomerates particle Viscosity Relax- Swell- pres- tion according size at 42.8% ation ing sion Hard- in the to the (D4, 3- of DM time force force ness mouth invention μm) (mPa .Math. s) (s) (N) (KN) (N) (s) “A” 230 3.6 80 2.08 29.3 110 43 “B” 150 3.8 81 0.96 32.1 100 48 “C” 123 3.8 59 2.17 30.4 110 36 “D” 124 2.7 51 2.77 35.6 102 35 “E” 198 2.6 42 2.73 39.6 100 39 Control 290 3.3 118 0.12 29.6 110 105 mannitol alone

(7) The behavior of the mannitol coagglomerates according to the invention is entirely satisfactory in terms of: disintegration behavior and disintegration time in the mouth, which reflect the ability of the granular starch to act as an effective disintegrating agent; viscosity at 42.8% of DM, which reflects the homogeneity of the coagglomerates resuspended, the added starch not modifying the behavior of said suspension; preserved compression force and hardness.

(8) The best results are obtained for the coagglomerates of which the mannitol/starch ratio is preferably between 80/20 and 65/35.

EXAMPLE 2: PREPARATION OF COAGGLOMERATES ACCORDING TO THE INVENTION

(9) Three coagglomerates consisting of mannitol and of starch at an 80/20 ratio are prepared, by spray-drying according to the invention, with Mannitol 35 crystalline mannitol and three different granular starches, “extra-white” corn starch, potato starch, and a hydroxypropyl-stabilized, phosphate-crosslinked waxy corn starch, sold by the applicant company under the name Clearam CR 20/10.

(10) The operating conditions for producing these coagglomerates are represented in the following table 3.

(11) TABLE-US-00003 TABLE 3 Nozzle Tp of Coag- (spray- Tp the glomerates ing up- static Tp according Starch Dry Pres- system stream fluidized outlet to the incor- matter sure type air bed air invention porated (%) (bar) SK) (° C.) (° C.) (° C.) “C” Extra- 55 30 52*21 155 84 60 white corn starch “F” Potato 51 25 52*21 160 84 63 starch “G” Clearam 50 28 52*21 160 84 60 CR 20 10

(12) The characteristics of the coagglomerates of mannitol and of starch according to the invention are given in the following table 4.

(13) TABLE-US-00004 TABLE 4 Disin- Coag- Laser Vis- Com- tegra- glomerates particle cosity Relax- Swell- pres- tion according size at ation ing sion Hard- in the to the (D4, 3- 42.8% time force force ness mouth invention μm) of DM (s) (N) (KN) (N) (s) “C” 123 3.8 59 2.17 30.4 110 36 “F” 142 2.7 93 2.73 37.6 109 57 “G” 182 2.6 97 1.26 28.5 108 59

(14) The behavior of the mannitol coagglomerates according to the invention is entirely satisfactory in terms of disintegration time in the mouth. The invention can be realized with native starches or modified starches which have retained a granular form.

EXAMPLE 3: PREPARATION OF COAGGLOMERATES ACCORDING TO THE INVENTION

(15) Three coagglomerates consisting of mannitol and of starch at a ratio, respectively, of 80/20 are prepared by spray-drying, according to the invention, with “Extra-white” corn starch and three crystalline mannitol powders of different particle sizes, Mannitol 25 and Mannitol 35, sold by the applicant company and having, respectively, a laser mean volume diameter of approximately 25 μm and of approximately 50 μm, and a powder of crystalline mannitol having a laser mean volume diameter D4,3 of approximately 110 μm.

(16) The operating conditions for producing these coagglomerates are represented in the following table 5.

(17) TABLE-US-00005 TABLE 5 Nozzle Coag- (spray- Tp Tp of glomerates Dry ing up- the static Tp according mat- Pres- system stream fluidized outlet to the Mannitol ter sure type air bed air invention powder (%) (bar) SK) (° C.) (° C.) (° C.) “C” Maltitol 55 30 52*21 155 84 60 35 “H” Maltitol 50 28 52*21 160 84 62 25 “I” Mannitol 52 30 52*21 155 84 60 with a laser average diameter D4, 3 of 110 μm

(18) The characteristics of the coagglomerates of mannitol and of starch according to the invention are given in the following table 6.

(19) TABLE-US-00006 TABLE 6 Disin- Coag- Laser Vis- Com- tegra- glomerate particle cosity Relax- Swell- pres- tion according size at ation ing sion Hard- in the to the (D4, 3- 42.8% time force force ness mouth invention μm) of DM (s) (KN) (N) (N) (s) “C” 123 3.8 59 2.17 30.4 110 36 “H” 99 3.9 53 2.40 30.7 105 30 “I” 150 2.4 61 1.39 32.5 104 38

(20) The behavior of the mannitol coagglomerates according to the invention is entirely satisfactory in terms of disintegration time in the mouth.

EXAMPLE 4: COMPARATIVE EXAMPLE

(21) The coagglomerates of mannitol and of starch “C” of example 1 are compared with compounds and mixtures as follows: coagglomerate of lactose and of starch prepared by the applicant company according to the teaching of its patent EP 1.175.899, mannitol sold by the applicant company under the trademark Pearlitol® 50C, physical mixture of Pearlitol® 50C and of “extra-white” corn starch in an 80/20 proportion, coagglomerate of starch and of mannitol in an 80/20 ratio, prepared by spray-drying a suspension containing 32% of dry matter and heated to 50° C. so as to completely solubilize the mannitol “F” present. This coagglomerate is in predominantly alpha-crystalline form.

(22) The following table 7 gives the results obtained.

(23) TABLE-US-00007 TABLE 7 Disin- Laser Vis- Com- tegra- particle cosity Relax- Swell- pres- tion size at ation ing sion Hard- in the (D4, 3- 42.8% time force force ness mouth μm) of DM (s) (N) (KN) (N) (s) Lactose + 125 2.2 70 0.68 33.3 100 37 starch coag- glomerate (85/15) Pearlitol ® 50 4.2 ND ND ND ND ND 50C Physical Ap- 3 ND ND ND ND ND mixture prox- Pearlitol ® imate- 50C + ly 45 starch (80/20) “F” 120 208 180 0.54 25.2 108 122 “C” 123 3.8 59 2.17 30.4 111 36

(24) It proved to be impossible to prepare tablets with Pearlitol® 50C alone or as a mixture with the starch. The Pearlitol® 50C and the “extra-white” corn starch have a very fine particle size and, as a result, do not exhibit a free flow. It is therefore impossible for them to fill the die, which is the first step in obtaining a tablet on a tableting press.

EXAMPLE 5: DEVELOPMENT BY DIRECT COMPRESSION AND CHARACTERIZATION OF ORODISPERSIBLE TABLETS WITH ACTIVE INGREDIENTS

(25) a) Formulation of the Orodispersible Tablets by Direct Compression

(26) The coagglomerate of mannitol of fine particle size and of native starch is used as binder, as diluting agent and as disintegrating agent. Plant magnesium stearate (Barlôcher) is used as lubricant. The composition of each tablet is described in the following table 8.

(27) TABLE-US-00008 TABLE 8 formulation of the orodispersible tablets with active ingredients Formulation Formulation Formulation 1 2 3 Mannitol/native starch 94.6%  74.6% 97.4%  coagglomerate Hydrochlorothiazide 5.0% Roche crystalline ascorbic acid 25.0% Sodium fluoride 2.2% Plant magnesium stearate 0.4%  0.4% 0.4% Total 100%   100% 100% 

(28) The coagglomerate and the active molecule are mixed for five minutes using a Turbula T2C epicycloidal mixer (Willy A. Bachofen AG Maschinenfabrik, CH-4005 Basle). The lubricant is added to this mixture. The formulation is mixed for five minutes in the epicycloidal mixer.

(29) The mixture is tableted on a Korsch XP1 instrumented alternative press (Korsch AG, Breitenbachstraβe 1, Germany), fitted with flat punches having a diameter suitable for the formulation (table 9) with beveled edges, at a rate of 20 tablets per minute.

(30) TABLE-US-00009 TABLE 9 tableting on the Korsch XP1 alternative press. Formulation Formulation Formulation 1 2 3 Punch diameter (mm) 13 16 7
b) Characterization of the Orodispersible Tablets

(31) The tablets formulated are evaluated according to the pharmacopeia methods: weight (Erweka TBH 30N precision balance), thickness (micrometer), hardness (Schleuniger), friability (Erweka). The disintegration time in the mouth is determined by carrying out the test E as described in this patent. The results are summarized in the following table 10.

(32) TABLE-US-00010 TABLE 10 characteristics of the orodispersible tablets formulated Formulation Formulation Formulation 1 2 3 Weight 505.4 ± 0.67 1020 ± 3.41  104.4 ± 0.19  (mg ± standard deviation) Thickness  2.96 ± 0.007  3.74 ± 0.011 1.93 ± 0.01 (mm ± standard deviation) Hardness  77.4 ± 1.35 68.8 ± 6.99 82.8 ± 2.28 (N ± standard deviation) Friability (%) 0.26 2.25 0.16 Disintegration 20 ± 5 28 ± 4  22 ± 2  time in the mouth (s ± standard deviation)

(33) The formulations developed contain only three ingredients: the mannitol/starch coagglomerate, the active agent, and the compression lubricant. The coagglomerate according to the invention therefore makes it possible to rapidly and easily formulate orodispersible tablets, although the formulation of the latter is reputed to be complex. Furthermore, all three of these tablets with active ingredients have a very short disintegration time in the mouth, less than 30 seconds, as recommended by the health authorities.