The composition of polyols

 

(57) Abstract:

The invention relates to the composition of polyols for the production of tablets. The composition is obtained by joint spray drying or joint granulation in the fluidized bed. The composition consists of at least two polyols, and one possible binders. The composition comprises more than 80 wt.% of the total polyol, at least one non-hygroscopic polyol. Non-hygroscopic polyol is selected from the group consisting of mannitol, lactate, isomaltitol, xylitol and eritria. The composition of polyols has a low hygroscopicity compared with sorbitol and provides high hardness of tablets and fiberboards and smooth surface. 3 S. and 9 C.p. f-crystals, 19 ill., 3 table.

The invention relates to compositions obtained by joint spray drying or joint granulation in the fluidized bed, be sure to include at least two polyol and, if necessary, a binder, with more than 80 weight percent of at least one non-hygroscopic polyol, and to its use as an auxiliary means for the production of tablets.

The polyols and mixtures of polyols them is TBA for pharmaceutically active components, tablets grinding and sucking and other products of the pharmaceutical and confectionery industries. The polyols are generally obtained through hydrogenation of the underlying sugars. They can be obtained in solid form by crystallization, or by using spray drying.

A particular advantage of some polyols is that they are also suitable for direct compression without additional auxiliaries and additives.

Hygroscopic polyols are those polyols which are at a relative humidity of 80% absorb at room temperature for 7 days less than 5% water.

Known polyol is mannitol, lactic, smalltit, xylitol, has a low hygroscopic property of this type, but are characterized by deficiencies in the application for the production of tablets (low degree of hardness of the tablets, the formation of a rough surface, high abrasion). The fundamental advantage is the achievement of high hardness of the tablets, as the carrier in the pharmaceutical composition is often used only in small quantities, and the active components can drastically reduce the hardness of the tablets to such an extent, criminalise in the production of extruded products, mannitol is widely distributed in the pharmaceutical compositions.

However, the use of mannitol leads to increased scope of work, as it usually should be granular in the wet state before pressing with the remaining components of the composition. Directly tableting mannitol also commercially available, but compared to sorbitol can only be achieved unsatisfactory hardness of the tablets.

When using sorbitol, in particular, in the case of spray drying is achieved wonderful hardness of tablets with a corresponding smooth surface of the extruded products. However, the hygroscopicity of sorbitol significantly higher than other polyols, which limits its applicability.

In DE 3245170 proposed receiving a combination of polyols - sorbitol and 10-15% by weight of mannitol using spray drying. This is done with the intention to increase the bending stress tablets. However, the hygroscopicity is substantially not changed. There is no indication that the combinations of polyols which are obtained by spray drying and have a muppet, features as a main component, can be achieved by improving the properties, in particular, high EP 0528604 describes the composition of sorbitol and xylitol, produced through a joint fusion. However, this leads to obtain tablets having a relatively low hardness.

Thus, the aim was to create a composition of polyols which can be obtained without any problems and whose properties in the preparation of tablets, in particular, in relation to the hardness of tablets and binding capacity are improved compared with the known polyols.

It was found that the composition of the polyols obtained by using the joint spray drying, comprising at least 80 wt.% one or more non-hygroscopic polyols, tableting at the same pressure, on the one hand allows to obtain higher hardness of tablets and much more smooth surface, but on the other hand has a markedly lower hygroscopicity compared to sorbitol.

The invention thus relates to a composition consisting of at least two polyols obtained by using the joint spray drying, comprising at least 80 wt.%, at least one non-hygroscopic polyol, in particular mappit.

The term polyol denotes the polyalcohols, xylytol total formularie anhydrides, in particular, C12H24ABOUT11.

In particular, the term polyols denotes hexitol, such as sorbitol and mannitol, pentitol, such as xylitol, however, another possibility is the use of4polyhydric alcohols, such as aritra, or C12polyhydric alcohols, such as lactic. The term composition of polyols denotes the composition of many of polyols, which significantly differs in its composition from the compositions created during the industrial production of mannitol, preferred are those compositions which include but are at least two polyol having different number of carbon atoms, in particular, the term refers to a composition comprising mannitol and, but at least one other hexitol, in particular sorbitol, or codecat, in particular, lactic.

The preferred embodiments are:

a) a composition obtained by dissolving at least two polyols in water and spraying the resulting aqueous mixture in an air stream at a temperature of from 120 to 300oC;

b) a composition obtained by dissolving at least two polyols in water and stirring at a rotation of the resulting mixture in a stream of air at a temperature Malachit and other polyols, in particular mannitol, sorbitol and lactic, are used as polyols;

d) a composition in which the ratio of mannitol to sorbitol/Loctite is between 80: 20 and 99:1, in particular between 90:10 and 98:2. In a particularly preferred embodiment, the ratio is about 95:5, in particular, the ratio of mannitol:sorbitol:lactic is in the range from 90:1:9 90:9:1 to 98:1:1;

e) the composition according to one of the preceding paragraphs, characterized by the fact that [sic] the water content is less than 1 wt.%;

f) composition, which comprises from 0.05 to 5 wt.% connecting the connection;

q) composition, which in its crystal structure has filaments, preferably in the form of needles, the ratio of length and width which is between 15 and 5 to 1.

The invention also relates to extruded products, including composition in accordance with the present invention.

The invention also relates to a method for obtaining a composition consisting of at least two polyols and, if necessary, a binder, comprising the following stages:

a) preparation of an aqueous solution of at least two polyols, solution, comprising more than 80 wt.% the total weight polytope temperature between 120 and 300oWith that causes the evaporation of water, or

b2) mixing during rotation of the resulting solution in a stream of air at a temperature between 40 and 110oWith that causes the evaporation of water.

In a particularly preferred embodiment the composition of polyols in accordance with the present invention essentially comprises from 85 to 99 wt.%, in particular, from 88 to 98% mannitol and 5% to 15%, in particular, 6-12% one or two polyols selected from lactate and sorbitol.

Preferably, the composition of polyols in accordance with this invention comprises more than 90 wt.% and less than 99 wt.% mannitol.

When spray drying is used an aqueous solution of at least two polyols. The solids content is set in advance in the amount of from about 30 to 75 wt. %, in particular from 50 to 72 wt.%, and is prepared preferably by mixing at a temperature of 80oWith two or more solutions of polyols in the desired ratio. Sputtering is performed by grinding with a spray nozzle, preferably with the use of grinding by centrifugation in a dry supplied with centrifuge stream of air heated to a temperature of 120-300oWith, predpochtitel is zdwhu thus, the polyol is dried to a moisture content of from about 0.3 to 1 wt.%. In any case, the water content should be below 1 wt.%.

Granulation in the fluidized bed is performed as described, for example, in P. Grassmann, F. Widmer "Einfuhrung in die Lhermische Verfahrenstechnik" [Introduction to thermal Process engineering], DeGruyter Verlag, Berlin 1974.

Agglomerates polyols which are obtained here by dehydration drops polyols, are heated at a spray-dried to a temperature of about 70oWith, while the incoming air is cooled to approximately the same temperature. The composition of the polyols is collected in vessels, and after cooling immediately becomes suitable for the production of tablets, extruded products or chewing gum.

The polyols thus obtained, due to its filament microstructure have binding capacity in relation to the active components, which is much higher than that of crystalline mannitol, and which corresponds to that of the pure fluids, but do not exhibit undesirable hygroscopicity.

The composition of polyols, characterized by such properties, has a number of advantages in terms of properties of the prepared tablets.

Unexpectedly escolania can be obtained more solid tablets, having a smoother surface than with the types of mannitol with known properties, including the famous TLC types of mannitol and powders polyols after mechanical grinding. The hardness of the tablets is fundamentally important to determine its ability to resorption. When applying the composition of polyols in accordance with the present invention can be obtained optimally smooth and solid tablets even at very low forces pressing. Apparatus for tabletting, with which the pressed composition of polyols in accordance with the present invention can, therefore, operate at relatively low forces pressing and are thus less wear.

Thanks filament structure, the composition of polyols in accordance with the present invention are able to bind even the relatively high number of additives, such as pharmaceutically active ingredients, dyes or other primitively supplements. Even under high load additives obtained homogeneous mixture and extruded products derived from them, have a uniform appearance.

Based on the specific type of receipt by spraying an aqueous solution, vodorastvorimye additives to the mixture, such as citric acid, sweeteners, in particular, Acesulfame-K, aspartame, saccharin, cyclamate and sucrose, neohesperidin DC, dyes and pharmaceutically active components, preferably vitamins, particularly ascorbic acid and the like.

Binding of the compounds to be added if necessary, are well known to specialists in this field of science and serve to increase the strength of the composition. The preferred binder compounds are derivatives of cellulose, in particular, hypromellose, carboxymethylcellulose or starch.

In addition to the composition of polyols in accordance with the present invention mouldings in accordance with the present invention include one or more components selected from the group consisting of:

pharmaceutically active components and connections allowed by law for food use. The preferred compounds which are legally permitted for food use are natural, identical to natural or synthetic flavoring agents, taste the flavors, vitamins, trace elements, inorganic additives, dyes, lubricants, visualaid is preferably between 0.01 and 80%, in particular between 0.1 and 30%.

These mouldings are produced in a known manner per se by mixing the components in dry form and their subsequent tableting.

Examples:

EXAMPLE 1

Preparing a 50% aqueous solution, including the calculation of dry weight to 95 parts mannitol, 1.5 parts of hydroxypropylmethylcellulose and 3.5 parts of sorbitol.

This solution polyols sprayed using a centrifugal atomizer liquid at a temperature of about 50oIn the upper part of the cylindrical tower of stainless steel. At the same time air is heated to a temperature of about 160oWith and granules polyols injected tangentially into the zone of atomization. The stream of solid particles is removed by the cooling drum is divided into two parts: one part is returned to the zone of the spray tower, and the second part is extracted, subjected to further drying in the fluidized bed, and then packaged. The resulting product can be easily compressed to form tablets having a very smooth surface.

EXAMPLE 2

Preparing a 50% aqueous solution, including the calculation of dry weight 90,5 parts of mannitol and 9.5 parts of sorbitol. The product is similar to that described in example 1 results.

EXAMPLE 3

Preparing a 50% aqueous solution, including the calculation of the dry weight of 95 parts of mannitol and 5 parts of sorbitol. The product obtained by spray drying similar to that described in example 1 may be easily compressed, giving similar to that described in example 1 results.

EXAMPLE 4

Preparing a 50% aqueous solution, including the calculation of the dry weight of 95 parts of mannitol and 5 parts of lactate. The product obtained by spray drying similar to that described in example 1 may be easily compressed, giving similar to that described in example 1 results. In figures la no 5b shows a micrograph obtained by electronic scanning, 50-fold (Fig. 1A through 5A) or 5000-fold magnification (Fig. with 1b through 5b) of various compositions polyols obtained by scanning electron microscope Jeol 630F.

Fig. 1 shows a 5-fold increase in mannitol/Sarbinowo of the product obtained and according to the example 2.

Fig. 1b shows a 5000-fold increase in mannitol/Sarbinowo of the product obtained in accordance with example 2.

Fig. 2A shows a 50-fold increase in mannitol/lactitol of the product obtained in accordance with Prim is according to example 4.

Fig. 3A shows a 50-fold increase in commercially available TLC mannitol (Pearlitol 300).

Fig. 3b shows a 5000-fold increase in commercially available TLC mannitol (Pearlitol 300).

Fig. 4A shows a 50-fold increase mechanically powdered mixture 90,5% mannitol and 9.5% sorbitol.

Fig. 4b shows a 5000-fold increase mechanically powdered mixture 90,5% mannitol and 9.5% sorbitol.

Fig. 5A shows a 50-fold increase mechanically pulverized into a powder mixture of 90% mannitol and 10% lactate.

Fig.5b shows a 5000-fold increase mechanically pulverized into a powder mixture of 90% mannitol and 10% lactate.

In Fig. 1b and 2b clearly shows that the preparations obtained in accordance with the present invention, are agglomerates of very small crystallites in the form of needles, while the agglomerates TLC mannitol (Fig.3b), in contrast, consist of relatively large crystallites substantially different from the first.

Mechanical mixture (Fig.4b, 5b) may contain agglomerates of both types.

EXAMPLE 5

Tablets for sucking, wt.h.:

The composition of the polyols obtained in accordance with example 2, with the addition of 0.8 wt. % citric acid the new characters) - 1,5

Magnesium stearate - 2,5

The components are mixed and pressed at a pressure of 30 kN to obtain tablets with a diameter of 13 mm and a weight of 500 mg.

EXAMPLE 6

Tablets of vitamin C, by weight.h.:

Ascorbic acid - 105,0

Aromatic components of orange - 10,0

The composition of the polyols obtained in accordance with example 2 - 1377,5

Magnesium stearate - 7,5

The components are mixed and pressed at a pressure of 11 kN to obtain tablets with a diameter of 18 mm and a weight of 1500 mg.

EXAMPLE 7

Tablets caffeine, wt.h.:

The composition of polyols in accordance with example 1 - 462,5

Aromatic components of coffee - 25,0

Caffeine - 10,0

Magnesium stearate - 2,5

The components are mixed and pressed at a pressure of 30 kN to obtain tablets with a diameter of 13 mm and a weight of 500 mg.

EXAMPLE 8

The study of the properties of tablets

Tablets are prepared using various polyols:

The tablet diameter: 11 mm Weight tablet: 450 mg

The height of the pill: from 3.7 to 3, 9 mm Pressure: 15 kN

Used underground

And: Dried spray dried mannitol:sorbitol=90,5:9.5mm from the case 2.

C. the Dried spray dried mannitol:sorbitol=95:5 in example 3.

mannitol.

E: Crystalline mannitol.

F: Mechanically powdered mixture of mannitol to sorbitol in a ratio of 95:5.

G: Mechanically powdered mixture of mannitol with lactitol in the ratio 95:5.

N: Sorbitol Instant Pharma obtained from Merck KGaA, Darmstadt.

Properties of the tablets of these products are presented in table 1.

Tablets in accordance with the present invention, due to their hardness and low abrasion, have a more pleasant properties at sucking than the comparison samples (mannitol).

EXAMPLE 9

The study of the hygroscopic polyols.

The polyols b, C, D, E, F, H from example 8 was stored for 7 days at ambient air humidity 76%.

The water absorption products is presented in table II.

A mixture of polyols, prepared in accordance with the present invention, demonstrated in comparison with commercially available TLC mannitol (D) slightly higher hygroscopicity, but it is significantly reduced compared to sorbitol (H).

EXAMPLE 10

Study retention (ability to form ordered stable mixtures) polyols.

The polyols b and D are sifted che is about the size of the particles less than 40 microns.

Thus obtained mixture is briefly subjected to fragmentation by the air above the sieve hole size of 100 microns. The active ingredient remaining in the mixture, measured colorimetrically.

The holding capacity of the material of the carrier, measured in this way (the degree of opening in%) can be obtained from table III.

Holding capacity significantly improved compared with TLC mannitol.

EXAMPLE 11

Comparison of the behavior pelletizing compositions polyols and commercially available TLC-mannitol.

The tested material meets the compositions obtained according to example 3 (95 parts mannitol, 5 parts of sorbitol), it is mixed with 1% of magnesium stearate, based on the weight of the total weight of the composition, and pressed to form tablets. For comparison, components in the same mass relations together pounded into powder. In addition, the respective compositions are examined after preparation by co-sputtering and drying 60 parts of mannitol with 40 parts of sorbitol or joint grinding into powder mannitol and sorbitol in their respective weight relationship, followed by mixing with 1% magnesium stearate, based on the total mass Costa, compound with breaking grooves

The weight of tablets: 500 mg

Device for testing the fracture resistance: - Erweka TBH 28 (adapted to Schleuniger)

Test abrasion: - Erweka Friabilator THE

The prepared tablets were subjected to x-ray analysis and DSC analysis.

X-ray diffraction analysis was carried out using a Siemens D5000 diffractometer, operating in the samples from the powder.

Get sample:

Approximately 0.5 g of sample was slightly crushed in an agate mortar, were applied to the Mylar film and covered with a second film of Mylar. The Mylar film was fixed on a sample holder suitable for the diffractometer.

Measuring conditions:

The mode of transmission, the power generator 40 kV/30 mA, si-K1-radiation (primary monochromator), position sensitive detector (3,3 kV) measurement interval: 5o-80o(2); time step: 24 s; step size: 0.05 too.

Procedure:

The measurement starts immediately after preparation of the sample. The recorded x-ray diffraction pattern is compared with a reference pattern.

DSC analysis (differential scanning calorimetry) was performed using the cell system (2100) associated with centralave measurements:

Sample vessel: - standard open Cup

Atmosphere: - 0.15 l/min of N2< / BR>
Temperature calibration: - o-terphenyl (T=55,1oC) anisic acid (T= 183,2oC)

The heating rate: - 2oC/min

The initial temperature of the sample vessel: - room temperature

The DSC measurement is performed in the range from room temperature to 180oC.

DSC curve is analyzed between 50 and 175oWith using programs 4.1 General" view of the heating rate in the form ofoC/min

Figure 6 - 14:

Fig.6

Mannitol:sorbitol 95:5, pounded into powder.

X-ray analysis: ARTICLE:24,0, s, SS:0,050 dg WL:1.5406.

Fig.7

Mannitol:sorbitol 95:5, joint spray.

X-ray analysis: ARTICLE:24,0, s, SS:0,050 dg WL:1.5406 A.

Fig.8

Mannitol:sorbitol 95:5, joint spray.

X-ray analysis: ARTICLE:24,0, s, SS:0,050 dg WL:1.5406 A.

Fig.9

Mannitol:sorbitol 60:40, pounded into powder.

X-ray analysis: ARTICLE:24,0, s, SS:0,050 dg WL:1.5406 A.

Fig.10

Mannitol:sorbitol 60:40 joint spray.

X-ray analysis: ARTICLE:24,0, s, SS:0,050 dg WL:1.5406 A.

Fig.11

Mannitol:Sorbi is S="ptx2">

DSC analysis.

Fig.13

Comparison between the properties of the tablets from combinations of polyols and commercially available L-mannitol:abrasiveness.

Fig.14

Comparison between the properties of the tablets from combinations of polyols and commercially available TLC-mannitol: the hardness of tablets.

1. Composition for the production of tablets, consisting of at least two polyols and, if necessary, a binder, containing more than 80 wt. % of the total content of polyols, at least one non-hygroscopic polyol selected from the group consisting of mannitol, lactate, isomaltitol, xylitol and eritria obtained through co-spray drying or joint granulation in the fluidized bed.

2. The composition according to p. 1, obtained by dissolving at least two polyols in water and spraying the resulting solution in a stream of air at a temperature of 120-300oWith that causes the evaporation of water.

3. The composition according to p. 1, obtained by dissolving at least two polyols in water and mixing during rotation of the resulting solution in a stream of air at a temperature of 40-150oWith that causes the evaporation of water.

and lactic, mannitol, sorbitol, lactic, and/or smalltit, and/or xylitol, and/or aritra, in particular mannitol, sorbitol and lactic.

5. The composition according to p. 4, characterized in that the ratio of mannitol to sorbitol/Loctite is between 80: 20 and 99: 1, in particular between 90: 10 and 98: 2.

6. The composition according to p. 4, wherein the ratio of mannitol : sorbitol : lactic is between 90: 1: 9 90: 9: 1 and 98: 1: 1.

7. Composition according to one of the preceding paragraphs, characterized in that the residual water content is less than 1 wt. %.

8. Composition according to one of the preceding paragraphs, characterized in that it contains 0.05 to 5 wt. % binder.

9. Composition according to one of the preceding paragraphs, characterized in that it has the filaments in the crystal structure.

10. Tablets or extruded articles comprising the composition in accordance with one of the PP. 1-9.

11. Pills to p. 10, comprising at least one pharmaceutically active compound.

12. A method of obtaining a composition for the production of tablets, consisting of at least two polyols and, if necessary, binders, vklyuchalis. % of the total content of one or more polyols, non-hygroscopic polyols selected from the group consisting of mannitol, lactate, isomaltitol, xylitol and Eretria; b1) spraying the resulting solution in a stream of air at a temperature of 120-300oWith that causes the evaporation of water, or b2) mixing during rotation of the resulting solution in a stream of air at a temperature of 40-150oWith that causes the evaporation of water.

 

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