CZ299779B6 - Fast-dissolving tablets with masking taste of active substance and process of their preparation - Google Patents

Abstract

In the present invention, there are disclosed fast-dissolving tablets containing microparticles or particles of active substance grains or Process and apparatus for salts thereof containing an active substance being selected from the group consisting of analgesics, antipyretics, antiphlogistics, antirheumatics and agents for combating migraine in an amount from about 5 to about 80 percent by weight, disintegrant in an amount from about 1 to about 50 percent by weight, a masking substance of aromatic character in an amount from about 0.1 to about 10 percent by weight, and auxiliary substances being selected from the group consisting of sweeteners in an amount from about 1 to about 5 percent by weight, flow properties enhancing substances in an amount from about 0.1 to about 4 percent by weight, and sliding substances in an amount from about 0.1 to about 3 percent by weight, whereby the size of microparticles or particles of active substance grains ranges within 0.1 to 1.5 mm and microparticles or particles are arranged in the tablet so that the masking substance embeds the active substance. The tablets are prepare in such a manner that first there are prepared microparticles or particles of active substance grains optionally with an admixture of other pharmaceutically acceptable substances either by wet granulation, fluid granulation, or extrusion and spheronization, and the masking substance is applied to the grain particles or to grain microparticles either in a fluid granulator, or in a high-speed granulator by moistening or in a high-speed granulator by spraying.

Description

Quick-dissolving tablets with taste masking active ingredient and process for their preparation

Technical field

The invention is in the field of the preparation of fast-dissolving tablets from the group of analgesics, antipyretics, antiphlogistics, antirheumatic drugs and antimicrobials in which the unpleasant taste of the active ingredient is masked.

BACKGROUND OF THE INVENTION

EP 0 759 296 B1 describes the preparation of fast-dissolving tablets containing Tramadol or a salt thereof. The patent is based on the use of a combination of active ingredient and filler (microcrystalline cellulose) and starch. Microcrystalline cellulose ensures good compressibility and fast i? formulation breakdown. Starch ensures good mechanical strength and durability of prepared tablets. The patent discloses the physicochemical parameters of the prepared tablets (strength 80 to 80)

100 N, 30 to 120 seconds decay).

WO 2004/091 585 describes the preparation of fast dissolving tablets containing micro20 crystalline cellulose. Possible technological processes for the preparation of fast-dissolving tablets are also summarized in this document;

1) freeze-drying - the disadvantage of this process is the high production costs, the process requires special characterization of the active ingredient (eg solubility, fine particle formation, aqueous suspension stability) as well as matrix forming materials (e.g.

gelatine, mannitol, sorbitol, taste masking agents, sweeteners, saw modifiers).

This technology used, for example, as Zydis *, consists in preparing a solution or suspension. which is accurately dispensed into a blister (forming a matrix) that forms the final shape of the tablet. In the next phase, freezing takes place, followed by a sublimation process. In the last stage, the blister is closed. However, this technology is very complicated and requires special equipment.

Another used but simpler technology is Lyoc, which is in fact lyophilization of the emulsion (oil-in-water), where the emulsion is placed directly into the blister (forming a matrix) and subsequently the blister is closed. The disadvantage of this technology is the low mechanical strength of the prepared wafers.

Known is the QuickSolv technology, by means of which tablets are produced by a technology similar to that of Lyoc, i.e. a solid matrix is formed by freezing the aqueous dispersion and / or solution formulation. Water • This is removed with excess alcohol.

2) compression or heat pressing - disadvantages of this technology are high production costs, low mechanical strength, limited stability. The tablets are usually prepared from soluble excipients, which are wetted with solvent, and the wet mass sc is placed in molding dishes. More recently, direct preparation of the molded mass directly from the liquid matrix in which the drug is dissolved or dispersed is used. The solvent evaporates from the drug solution or suspension under normal pressure.

Flashdosc technology is based on the compression of drug microparticles together with the carbohydrate component into a solid matrix. This technology also uses specific devices, resulting in tablets.

5t) which have low mechanical strength.

In addition, Orasolv technology contains an effervescent component in the formulation, resulting in the preparation of tablets, but it is necessary to work in areas with reduced humidity in order to avoid damage to the tablets.

3) direct compression - this is the easiest way to prepare tablets. These tablets are compressed with less compression force than conventional tablets, making them more porous. The disintegration and solubility of such a tablet is based on the action of a disintegrant and other water-soluble excipients.

FlashTab uses most commonly available excipients. These excipients are used in combination with coated drug particles to form tablets that disintegrate rapidly (U.S. Pat. No. 5,464,632, U.S. Pat. No. 6,106,861).

i o Another technology is called Multiflash. wherein the tablets are comprised of coated microgranules and disintegrating excipients.

AdvaTab technology is often combined with Microcaps technology. which is the taste masking technology. The rapidly dissolving tablet has 10 to 30 times less hydrophobic lubricant than a conventional tablet. The taste masking technology is based on coating drug particles with polymeric membranes of varying degrees of porosity. The membranes are used to create an inert barrier between the drug and the taste cells.

Frosta technology is based on wet granulation. They use certain types of sugars that take

These wet granules are air-dried and then compressed into tablets.

Wowtab technology is based on a similar principle. Various types of sugars are used. The manufacturing process comprises the granulation of low-formable sugars (eg mannilol, lactose, glucose, crytri25 tol), which have a fast dissolution characteristic, with high-formable sugars (maltose, sorbitol, maltitol). The tablets are produced at low compression force. however, it is followed by a special moisture treatment to increase the hardness of the tablet (US Patent 5,576,014).

OraSolvt and DuraSolv technology have several drawbacks, and the tablets are too fragile

3o (packaging on a special packaging line) and high equipment cost. It is based on 2-fold taste masking. The unpleasant taste is covered by sweeteners or flavors, as well as by wrapping and use of an effervescent agent. An effervescent excipient is prepared by coating the crystals of the organic acid using a stoichiometric lower amount of the base material. The coating process is performed by adding a reaction initiator (purified water); the end point of the reaction is determined by measuring the evolution of carbon dioxide. The excipient is then mixed with the active ingredient and other excipients and compressed into tablets.

4) thin films - strips - it is a thin film, which is quickly moistened by the action of saliva in the oral cavity and hydration of the gravity (disintegration) occurs.

Rapidfilm technology is based on this system.

However, not all these technologies solve the problem when the active substance has an unpleasant physico-chemical property, i.e. an unpleasant taste.

The subject-matter of this patent application is the composition and method of preparing fast-dissolving tablets in order to mask taste, good solubility of the tablets, as well as the simplicity of the technological preparation process.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides fast-dissolving taste-masking tablets and a process for preparing such tablets. The tablet contains microparticles or particles of active ingredient or salt particles of 0.1 to 1.5 mm in size. in an amount of up to 80% by weight, a disintegrant in an amount of 1 to 50% by weight, preferably 10 to 30% by weight. and 0.1 to 10% by weight of a masking agent which is a water-soluble flavoring substance. They are substances of naturally identical character. The active substances are selected from the group of analgesics. antipyretics. anti-inflammatory drugs, anti-rheumatic drugs and anti-migraines, ie groups of substances that have an unpleasant taste. In the examples, the active ingredient tablets of the mentioned classes of medicaments are shown: tra5 madol hydrochloride, sumatriptan, succinate, nimesulide, meloxicam.

Among the other excipients, the tabletting composition, in addition to the microparticles or active ingredient-containing particles, further comprises a tablet disintegrant, a flow-enhancing agent, and an anti-sticking lubricant enhancing agent, thereby facilitating the tableting process. As a fast disintegrating agent, it is preferable to use erosioned povidone, crosscarmellose and its sodium or calcium salt or sodium starch sodium in an amount of 1 to 50% by weight. use colloidal silica in an amount of preferably 10 to 30 wt.% talc, preferably in an amount of 0.1 to 5 wt.%, and as an anti-adhesive magnesium stearate or sodium 15 µm stearyl fumarate in an amount of 0.1 to 5 wt.%.

A disintegrant (Cross-linked povidone, Croscarmellose and its sodium or calcium salt, sodium starch glycolate) is preferably used as the disintegrant. Gelatin, povidone, copovidone is preferably used as binder. pregelatinized starch in quantities

0.1 to 5% by weight. Specicell is preferably used as a filler. which is a mixture of microcrystalline cellulose, lactose and sodium carboxymethylcellulose, and Emdex 'Non (imo, which is a hydrated dextrate).

The water-soluble masking agent forms a continuous film on the active agent microparticles while at the same time a particular type of masking agent ensures that the film does not break during tabletting.

An important advantage of the composition of the tablets according to the invention is. that they do not contain any effervescent excipient.

Said tablet manufacturing process and the choice of excipients according to the invention can produce a rapidly disintegrating or rapidly dissolving solid dosage form with satisfactory physical parameters and a desired dissolution profile. The dosage form is made in a simpler, economical manner.

The sc tablets are characterized in that they disintegrate within 60 seconds while fulfilling the conditions laid down by the Slovak Pharmacopoeia for disintegration of tablets and capsules (cup method).

Tablets produced according to this composition and method of manufacture must have a fracture resistance meeting the conditions of the Slovak Pharmacopoeia in the values of 20 to 60 N and a friability of the uncoated tablets of less than 1%.

The invention is further illustrated by the following non-limiting examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Fracture resistance - 45 N, disintegration (water. 37 ° C) = 34 s, friability of uncoated tablets (100 rpm) = 0.40%

-3 CZ 299779 Bo

Starting materials Weight in g Tramadol hydrochloride 0.05000 0,10000 Specicell 140 0.15000 0,30000 Aroma cherry 0.00900 0.01800 Mannitol 0.14100 0.28200 Crospovidone Cl 0,08000 0.16000 Aspartame 0.00400 0.00800 Acesulfame potassium 0.00400 0.00800 Magnesium stearate 0.00800 0.01600 Colloidal silica 0.00400 0.00800 Total core weight in g: 0.45000 0,90000

Manufacturing procedure:

1) The active agent particles are homogenized in a high speed granulation apparatus together with a filler (stirrer 100 to 1500 rpm, 10 minutes time).

2) Wet the homogenized mixture with the prepared granulation medium (stirrer 100 to 1500 rpm. Chopper 100 to 1500 rpm, time 60 to 120 seconds).

3) The moistened granulate is passed through a sieve (200 to 1000 μηι) of the extruder and rounded on a pelletizer for 240 to 300 seconds at 500 to 1200 rpm.

κι 4) The prepared microparticles containing the active agent particles are dried in a fluidized bed dryer at an inlet air temperature of 45-55 ° C, an inlet air flow rate of 1000-2000 nú / h, a product temperature of 25-50 ° C and an outlet air temperature of 25-50 ° C. . The total drying time is 60 to 120 minutes.

5) The resulting microparticles containing active agent particles are crosslinked on a crosslinker.

6) The dried microparticles containing the active agent particles are coated by spinning prepared in a water-soluble aromatic masking agent and coated in a fluidized bed dryer at an inlet air temperature of 30 to 50 ° C, an inlet air flow rate of 1000 to 2000 in7h, a product temperature of 32 to Deň: 32 ° C. an outlet air temperature of 30 to 36 ° C, a nozzle pressure of 0.1 to 0.3 MPa (1 to 3 bar) and a suspension flow rate of 10 to 300g / minute. The total wrapping time is 60 to

1 20 minutes.

7) After coating the granulate sc, the mixture is dried for 5 to 30 minutes at an inlet air temperature of 40 ° C.

8) The dried microparticles, together with the filler and disintegrant, are homogenized in a low speed homogenization apparatus (5 to 15 rpm, 5 to 20 minutes). Next, a glidant and a flowable substance are added to the mixture and homogenized in a low-speed 25-speed homogenizer (5 to 15 rpm, 5 to 20 minutes).

9) Tablets are compressed from the thus prepared tablet on a rotary compression machine.

The dissolution profile was measured by standard procedure (500 mL, 0 µM HCl, 50 rpm, paddles, HPLC assay). The active substance is released from the tablets after 10 minutes.

Example 2

Fracture resistance ~ 40 N, disintegration (water. 37 ° C) = 42 s, friability non-coated tablets (100 rpm35 rpm) = 0.35%

-4 CZ 299779 B6

Starting materials Weight in g Sumatriptan succinate 0,07000 0.14000 Specicell 140 0,10000 0,20000 Crosscarmellose Na 0.05000 0,10000 Strawberry aroma 0.00800 0.01600 Emdex Non Gmo 0,07200 0.14400 Crospovidone Cl 0,08000 0.16000 Aspartame 0.00400 0.00800 Acesulfame potassium 0.00400 0.00800 Magnesium stearate 0.00800 0.01600 Colloidal silica 0.00400 0.00800 Total core weight in g: 0,40000 0,80000

Tablets were prepared using the same preparation technology as described in Example 1. The dissolution profile was measured by a standard procedure (900 mL, OJM HCl, 75 rpm, rations, UV determination) ^kL . The active substance is released from the tablets after 5 minutes.

Example 3

Starting materials Weight in g Nimesulid 0.05000 0,10000 Specicell 140 0,10000 0,20000 Aroma orange 0.00500 0.01000 Mannitol 0,04500 0,09000 Crosscarmellose Ca 0,08000 0.16000 Aspartame 0.00400 0.00800 Acesulfame potassium 0.00400 0.00800 Magnesium stearate 0.00800 0.01600 Colloidal silica 0.00400 0.00800 Total core weight in g: 0,30000 0,70000

Tablets are prepared using the same preparation technology as described in Example 1.

Example 4

Fracture resistance = 36 N, disintegration (water, 37 ° C) = 20 sec. Friability of uncoated tablets (100 rpm / 4 min) = 0.21%.

-5GB 299779 B6

Starting materials Weight in g Meloxicam 0.01250 0,02500 Microcrystalline cellulose 0,06000 0.12000 Aroma mandarin 0.00300 0.00600 Mannitol 0.05150 0,09000 Carboxymethylstarch Na 0,06000 0.12000 Aspartame 0.00300 0.00600 Acesulfame potassium 0.00300 0.00600 Magnesium stearate 0.00400 0.00800 Colloidal silica 0.00300 0.00600 Total core weight in g: 0,20000 0,40000

Tablets are prepared using the same preparation technology as described in Example 1.

Example 5

Fracture resistance ~ 49 N, disintegration (water, 37 ° C) = 26 sec. Friability non-coated tablets (100 rpm / 4 min) - 0.15%

Starting materials Weight in g Tramadol hydrochloride 0.05000 0,10000 Aroma lime 0.01000 0,02000 Menthol 0.00500 0.01000 Emdex Non Gmo 0.09790 0.19580 Crospovidone Cl 0.16800 0.33600 Aspartame 0.00680 0.01360 Acesulfame potassium 0.00680 0.01360 Magnesium stearate 0.00300 0.00600 Colloidal silica 0.00250 0.00500 Total core weight in g: 0.35000 0,70000

Manufacturing procedure:

1) The disintegrant, together with the aromatic masking agent, is homogenized in a low speed15 in a homogenizer (5 to 15 rpm for 5 to 20 minutes).

2) The active agent particles together with the filler are homogenized in a low speed homogenizer (5 to 15 rpm, 5 to 20 minutes).

3) The premixes are combined and homogenized together in a low speed homogenizer (5 to 15 rpm, 5 to 20 minutes).

2) 4) Next, a glidant and a flow agent are added to the mixture and homogenized in a low speed homogenizer (5 to 15 rpm, 5 to 20 minutes).

5) Tablets are compressed from the thus prepared tablet on a rotary compression machine.

-6GB 299779 B6

Example 6

Starting materials Weight in g Sumatriptan succinate 0,07000 0.14000 Microcrystalline cellulose 0,07000 0.14000 Aroma peppermint 0.01200 0,02400 Menthol 0.00500 0.01000 Mannitol 0,05900 0,11800 Croscarmellose Na 0,07000 0.14000 Aspartame 0.00300 0.00600 Acesulfame potassium 0.00300 0.00600 Magnesium stearate 0.00500 0.01000 Colloidal silica 0.00300 0.00600 Total core weight in g: 0,30000 1 0,60000

Tablets are prepared using the same preparation technology as described in Example 5.

Example 7

Starting materials Weight in g Nimesulid 0.05000 0,10000 Microcrystalline cellulose 0,10000 0,20000 Carboxymethyiškrob Na 0.05000 0,10000 Aroma aniseed 0.00400 0.00800 Menthol 0.00200 0.00400 Mannitol 0,07700 0.15400 Aspartame 0.00400 0.00800 Acesulfame potassium 0.00400 0.00800 Magnesium stearate 0.00500 0.01600 Colloidal silica 0.00400 0.00800 Total core weight in g: 0,30000 0,60000

The sc tablets are prepared using the same preparation technology as described in Example 5.

Example 8

Fracture resistance = 38 N, disintegration (water, 37 ° C) 35 s, small size uncoated tablets (100 ol / 4 min) = OJ 8%

-7EN 299779 B6

Starting materials Weight in g Meloxicam 0.01250 0,02500 Microcrystalline cellulose 0.05000 0,10000 Aroma mandarin 0.00200 0.00400 Emdex Non Gmo 0.07650 0.15300 Crospovidone Cl 0.05000 0,10000 Sacharin Na 0.00200 0.00400 Magnesium stearate 0.00400 0.00800 Colloidal silica 0.00300 0.00600 Total core weight in g: 0,20000 0,40000

Tablets are prepared using the same preparation technology as described in Example 5.

Example 9

Fracture resistance - 42 N. disintegration (water. 37 ° C) = 285 s, friability of non-coated tablets (100 rpm) ~ 0.34%

Starting materials Weight in g Tramadol hydrochloride 0.05000 0,10000 Gelatine 0.00420 0.00840 Aroma cherry 0.00300 0.00600 Menthol 0.00500 0.01000 Emdex Non Gmo 0.10070 0.20140 Crospovidone Cl 0.16800 0.33600 Aspartame 0.00680 0.01360 Acesulfame potassium 0.00680 0.01360 Magnesium stearate 0.00300 0.00600 Colloidal silica 0.00250 0.00500 Total core weight in g: 0.35000 0,70000

Manufacturing procedure:

1) The active ingredient microparticles are lyomogenised in a high-speed granulator together with 15 filler (agitator 500 to 1500 rpm, time 5 to 20 minutes).

2) Prepare granulation medium (binder dissolves in water at max. 50 ° C). The granulation medium thus prepared is cooled to 25 ° C and moistened with a homogenized mixture (agitator 500 to 1500 rpm, chopper 500 to 1500 rpm, 60 to 120 seconds).

3) The moistened granulate is dried in a fluid-bed dryer at a temperature of 45-55 ° C, an inlet air flow rate of 1000-2000 nm / h, a product temperature of 25-50 ° C and an outlet air temperature of 25 ° C. The total drying time is 60 to 120 minutes.

4) The dried granulate is sieved on an oscillating sieve device through a prescribed mesh size.

4a) The dried milled granulate, together with the filler, masking agent and disintegrant 25, is homogenized in a low-speed monogenisation apparatus (5 to 15 rpm, time 5 to minutes). Next, the glidant and the flow agent are tableted and homogenized in a low speed homogenizer (5 to 15 rpm. For 5 to 20 minutes).

-8EN 299779 B6

4b) The dried granulate is coated with a preformed water-soluble aromatic masking agent and fluidly coated in a fluid-bed dryer at an inlet air temperature of 30 to 50 ° C, an inlet air flow rate of 1000 to 2000 m 7h, a product temperature of 32 to 36 ° C, outlet air from 30 to 36 ^Q C, nozzle pressure 0.1 to 0.3 MPa (1-3 bar) and the flow of slurry from 10 to 300 g / min. The total coating time is 60 to 120 minutes.

5) After coating the granulate, the mixture is dried for 5 to 30 minutes at an inlet air temperature of 40 ° C.

6) The dried granulate, together with the filler and disintegrant, are homogenized in a low speed homogenizer (5 to 15 rpm, 5 to 20 minutes). Next, a glidant and a tablet flow agent are added to the mixture and homogenized in a low speed and homogenizer (5-15 rpm, 5-20 minutes).

7) Tablets are compressed from the thus prepared tablet on a rotary compression machine.

Example 10

Starting materials Weight in g Sumatriptan succinate 0,07000 0.14000 Microcrystalline cellulose 0,07000 0.14000 Povidon 0.00500 0.01000 Aroma pepermint 0.00500 0.01000 Menthol 0.00500 0.01000 Emdex Non Gmo 0.08950 0.17900 Crospovidone Cl 0.14000 0,28000 Aspartame 0.00500 0.01000 Acesulfame potassium 0.00500 0.01000 Magnesium stearate 0.00300 0.00600 Colloidal silica 0.00250 0.00500 Total core weight in g: 0,40000 0,80000

Tablets are prepared using the same preparation technology as described in Example 9.

Example 11

Starting materials Weight in g Nimesulid 0.05000 0,10000 Pregelatinized starch 0.00500 0,10000 Aroma aniseed 0.00150 0.00300 Menthol 0.00100 0.00200 Mannitol 0,08350 0.16700 Crospovidone Cl 0.05000 0,10000 Sodium saccharin 0.00300 0.00600 Magnesium stearate 0.00300 0.00600 Colloidal silica 0.00300 0.00600 Total core weight in g: 0,20000 0,40000

Tablets are prepared using the same preparation technology as described in Example 9.

-9EN 299779 Bň

Example 12

Starting materials Weight in g Meloxíkam 0.01250 0,02500 gelatine 0.00200 0.00400 Aroma lime 0.00100 0.00200 Emdex Non Gmo 0.07450 0.14900 Crospovidone Cl 0.05000 0,10000 Aspartame 0.00200 0.00400 Acesulfame potassium 0.00200 0.00400 Magnesium stearate 0.00300 0.00600 Colloidal silica 0.00300 0.00600 Total core weight in g; 0.15000 0,30000

In Examples 1 to 12, in addition to cross-linked povidone, β crossearmelose and its sodium or calcium salt or sodium carboxymethyl starch may also be used successfully. The masking substance is an aromatic substance - cherry, orange, strawberry, lime, mandarin, peppermint or anise.

Industrial usability

The present invention is useful in the pharmaceutical industry for the production of fast-dissolving tablets of the analgesic class. antipyretics, antiphlogistics, antirheumatics and anti-immigrants with a masked taste i? active substance.

Claims (4)

2o PATENT CLAIMS Quick-dissolving tablets containing microparticles or grain particles of active substances or their pharmacologically acceptable salts, characterized in that they are: that they contain the active ingredient 2? from the group of analgesics, antipyretics, anti (logistics, antirheumatics and anti-immigrants in an amount of 5 to 80% by weight) disintegrant in an amount of 1 to 50% by weight, aroma masking agent in an amount of 0.1 to 10% by weight in an amount of 1 to 5 wt%, flow improvers in an amount of 0.1 to 4 wt% and glidants in an amount of 0.1 to 4 wt% 3% by weight, the microparticles or particles of active substance grains having a size of 0.1 to 3% by weight 30 mm and are arranged in the tablet so that the active substance is coated with the masking substance. Fast-dissolving tablets according to claim 1, characterized in that they disintegrate or dissolve within 60 seconds. The quick dissolving tablet according to claim 1, characterized in that cross-linked povidone is used as a disintegrant. Fast-dissolving tablets according to claim 1, characterized in that flavoring substances, preferably cherry, mandarin, lime, pcpr40 mini or anise flavor, are used as masking agents. - 10GB 299779 B6 A process for the production of tablets according to claim 1, characterized in that microparticles or grain particles containing the active substance, optionally with the addition of other pharmaceutically acceptable substances, are produced by one of the following methods: a. wet granulation. Fluid granulation 5 b. extrusion and spheronization and masking agent are applied to the grain particles or microparticles either: a. in a fluidized bed granulator b. in a high speed granulator by wetting e. Spraying in a high speed granulator.