DE1810705B2 - Stabilization of vitamins - Google Patents

Description

15th

It is known that vitamins are unstable.

Attempts have therefore already been made to combine the vitamins with various coating substances, such as albumin, cellulose derivatives, glycerine partiaesters of fatty acids, Waxing tocopherol polyethylene glycol succinate, acacia and polyethylene glycol to provide thereby to achieve a stabilization of the vitamins. However, these preparations with the coating have the Disadvantage that, in contrast to simple granulation, they require a greater amount of equipment, Require work and time. From this it could not be deduced that a stabilized preparation consisting exclusively of active ingredients and vitamins without jo To produce foreign substances.

Another publication, namely DT-OS 16 17 418 describes a preparation made from 1-hexyl-dimethyI-xanthine and α-pyridinecarboxylic acid. This well-known Preparation shows no stabilizing effect for the ii Vitamins.

The production of solid dosage forms with delayed release of active ingredient has now been proposed. Thereafter, at least one therapeutically effective substance that can be absorbed more quickly by the body is contained in a Melt or solution with at least one therapeutic substance that is more slowly absorbed by the body suspended for a different effect, whereby the more slowly absorbed substance is used in excess, and wherein the solidified melt is granulated and the granules are solidified in a manner known per se Processed dosage forms.

The invention now relates to the use of at least one 1,3- or 3,7-dimethylxanthine, which in 7- or I-position by an alkyl radical with 5 to 15> o C atoms or is substituted by a hydroxyalkyl or oxoalkyl radical having 6 C atoms, for Stabilization of one or more vitamins of series A, B, C and E up to an amount of 30% by weight while suspending in the melt the substituted xanthine, which after solidification turns into granules is processed.

In addition to the specified xanthine compounds, the vitamin preparation obtained in this way can also contain other pharmaceutically active substances ineo be worked on.

The optimal proportions between the vitamins to be stabilized and the xanihin compound depends, among other things, on the desired biological. Effects of vitamins and the therapeutic < > ■; Effects of the other components of the combination. It is further dependent on the physical properties of the individual components, such as the melting point or mixed melting point of the individual components and their solidification points. It is obvious that the xanthine compound is used at least in such an amount as is necessary to sufficiently stabilize the vitamin to match the intended effect of the vitamins. Using relatively high melting xanthine compounds, for example those which melt about 8O ⁰ C, it is advisable, of course, to process these only with vitamins, which in turn tolerate such temperature loads.

In addition to the stabilization, a further effect can optionally be achieved, which consists in that the release of vitamins and possibly other therapeutically active substances from the Composition is delayed depending on the rate of dissolution and absorption of the xanthine compound used in the gastrointestinal tract, i.e. that the active substance is released over a longer period of time. This is particularly desirable in this case if z. B. for therapeutic reasons a prolonged effect of a vitamin should be achieved.

The stabilization of the vitamins achieved according to the invention surprisingly also occurs when no stabilizers, such as are usually used for vitamin stabilization according to the prior art, are added. A use of the The latter can, however, be advantageous in order to further improve the stabilizing effect.

The stabilization of the vitamins effected according to the invention is extraordinarily surprising in that it is not only found in mixtures with indifferent diluents, but also in complex ones Medicines that still contain a number of chemically differently structured compounds.

The combinations obtained according to the invention are intended in particular for oral administration, however, another application, e.g. B. rectal type, possible.

The selection of the component into which the other components are to be incorporated is based according to the melting points and the mutual quantitative ratio. Usually you get the higher Incorporate melting components into the lower melting components, with the higher melting components in the lower melting points can be incorporated in solid or liquid form. This is above all then favorable if the proportion of the lower-melting components predominates. But it is also possible to bring a three-component system for distribution, e.g. B. by using the component melts the mean melting point and incorporates the other two components, especially if the substance with the lowest melting point is only present in a relatively small amount.

Appropriately, the mixture present in homogeneous distribution with cooling, for. B. by means of Cooling belts or cooling rolls brought to solidify in order to achieve a rapid and thus even solidification achieve.

As substituted xanthines, for. B. those with straight-chain or branched alkyl radicals in question. Examples of alkyl radicals that may be mentioned are hexyl, Octyl, lauryl radicals or the like, these radicals

can be straight-chain or branched. Particularly A combination of 1-hexyl-3,7-dimethylxanthine and nicotinic acid and / or their is advantageous here therapeutically effective equivalents, such as nicotinic acid salts, nicotinic acid esters and amides.

The stabilization effected according to the invention applies, for example, to oxidative influences and Influences of light. It applies to both water-soluble and fat-soluble vitamins as such and to their therapeutically effective equivalents, e.g. B. Salts, Esters or provitamins, e.g. B. Vitamins A, C and E. and especially the group of B vitamins. Of course, mixtures of several vitamins can also be used in are stabilized in the manner according to the invention.

The stabilization according to the invention is practically not impaired by customary, therapeutically ineffective processing aids For example, lactose, mannitol, talc or swelling can be used as processing agents active substances, e.g. milk protein, starch, gelatin, cellulose or their derivatives, such as methyiceiiuiose, Hydroxyethyl cellulose or suitable swelling or non-swelling copolymers are present be. Of course, preparations containing vitamins stabilized according to the invention can also be used with a physiologically compatible cover, e.g. B. coat with a varnish made from a polymerisation or condensation resin.

According to the invention stabilized vitamins or preparations which contain such can be known per se Way granulated v:, rden. The granules can be used as such administered or in other medicament forms, e.g. B. be processed into capsules, tablets, coated tablets, coated tablets or the like.

example 1

100 g of l-hexyl-3,7-dimethylxanthine (compare DBP 8 60217) are melted at about 85 ° C. In the 20 g of magnesium nicotinate, 10 g of sodium ascorbate and 2 g of vitamin Bi are suspended in the melt. Suspension is then made to solidify immediately. The solid mass is known according to Process processed into granules. This can be used as such after filling into capsules or after Compressing to solid formations are administered. The briquettes show practically none after 6 months Loss of vitamins. The preparation is suitable as a geriatric medicine.

Example 2

100 g of l-hexyl-3,7-dimethylxanthine are melted at approx. 85 ° C. 2 g are suspended in the melt Vitamin A palmitate. The further processing takes place analogously to Example I. The vitamin A palmitate is also shown in FIG the application forms produced have considerable stability. After months of storage, a clear Vitamin A loss cannot be ascertained. The preparation is suitable as a remedy for circulatory disorders of the eyes.

Example 3

100 g l-hexyl-3,7-dimethylxanthine are melted at 85 ⁰ C. Suspended in the melt 10 g of magnesium nicotinate, 2 g of vitamin B bat ₆ .5 g of sodium and 5 g of dl-Ascor <x-tocopherol succinate. The further processing takes place as in Example I. After 6 months, no decrease in the vitamin content could be determined.

will be presented. The preparation is suitable as a remedy for age-related circulatory disorders.

Example 4

200 g of 1-hexyl-3,7-dimethylxanthine are melted until clear. In the melt it becomes a solid Mixture of vitamin C, vitamin A, vitamin E, vitamin B |, vitamin Ββ, vitamin B2 and vitamin B12 in ».inern such a weight ratio that 1 g of the total melt distributes the proportions below Contains vitamins After the melt has cooled down, the solid-phase mixture turns into granules processed The granules show a good stabilization of the vitamins. The preparation is suitable as Geriatricum.

Check of stability

The results of the analysis of the starting mixture and the mixture after a storage period of 10 Months at room temperature are summarized below:

Analysis of the Follow-up examination Starting mixture 74, £ mg / g vitamin C 76.9 mg / g 6990 I.U. Vitamin A 6160 i.E7g 74.6 mg / g Vitamin E. 74.2 mg / g 4.25 mg / g Vitamin bi 4.2 mg / g 7.03 mg / g Vitamin B ₆ 7.2 nig / g 638 mg / g Vitamin B2 648 mg / g 6.90 mcg / g Vitamin Bu 7.03 mcg / g meg = micrograms.

Example 5

In the melt of 100 g of 1-hexyl-3,7-dimethylxanthine a mixture of vitamin Ri, vitamin E and vitamin A is entered and the mixture as after Example 4 processed further The proportion of vitamins per g of total melt is given below Tabel. The remedy is suitable as a remedy for circulatory disorders, especially for the eye area.

Check of stability

The results of the analysis of the starting mixture and the mixture after storage for 6 months at room temperature are summarized below:

Analysis of the
Starting mixture

Follow-up examination

Vitamin bi
Vitamin E.
Vitamin A

5.87 mg / g
66.8 mg / g
9525 I.Eyg

5.92 mg / g
67.6 mg / g
9070 IU / g

Example 6

1-Hexyl-3,7-dimethylxanthine is melted at 85 ° C. In this melt enough vitamin C, Bi, B ₂ and magnesium nicotinate are suspended that each capsule of the finally produced granulate contains the amounts given in the table below. After the melt has solidified and processed further to form granules, these are filled into capsules which, in addition to the usual auxiliaries silicic acid and magnesium stearate, are listed in the table below

Contains the quantities of active ingredients specified under "Starting mixture", Pas preparation is intended as a means against Circulatory disorders suitable.

Check of stability

The results of the analysis of the starting material and the mixture after storage for 7 months at room temperature are summarized below:

which melted at around 75 ° C. A mixture of 2 g of vitamin Bi and is suspended in the melt 2 g of vitamin A-PalmitaL After cooling to room temperature, the solid mass turns into granules processed (remedy for circulatory disorders).

10

IO

l-hexyl-3,7-dimethyl-

xanthine

Vitamin C 343 mg

Vitamin Bi 1.54 mg

Vitamin B ₂ 2.17 mg

Magnesium nicotinate 52.7 mg

example

100 g of 1- (5-oxohexyl) -3,7-dimethylxanthine according to DBP 12 35 320, are melted at 110 ° C. 15 g of magnesium nicotinate are suspended in the melt, 2 g of vitamin B ι-chlorohydrate and 5 g of vitamin A palminate, solidified and granulated. The granules is processed into pharmaceutical forms. The remedy is suitable

201.6 mg 219.0 mg **) 15 are suitable for use in cerebral, peripheral and

for circulatory disorders of the eye, also age-related.

Analysis of the
Starting mixture *)

Follow-up examination *)

34.6 mg **) 1.54 mg
2 ^ 0 mg **)

50.7 mg

each in the capsule.

The differences in numerical values between the initial mixture and the follow-up examination are within the scope of the analytical error range.

As can be seen from Examples 4 to 6, there is good stabilization of the vitamins in all cases achieved.

Example 7

150 g of l-isoamyl-3,7-dimethylxanthine (melting point UO ⁰ C), made from isoamyibromide and l-sodium-3,7-dimethylxanthine, are melted in an oil bath at about 120 ° C. and contain 2 g of vitamin B ₆ and 5 g of sodium ascorbate distributed. The mixture is poured out in blocks or in a thin layer above the solidification point and, after solidification, granulated in a manner known per se. The preparation obtained can be applied directly. It is a blood circulation-promoting preparation that is also effective as a geriatric.

Example 8

70 g of 1-hexyl-3,7-dimethylxanthine are melted at 80 ° C. 15 g of 7- (5-oxohexyl) -1,3-dimethylxanthine are added to the melt (manufactured according to DBP 12 33 405). A clear melt is obtained, in which 2 g of vitamin Bi, 5 g of sodium ascorbate and 2 g of vitamin A palmitate are suspended. After solidification The mass is processed zt-.m granules, which are used to treat peripheral and cerebral circulatory disorders is useful.

Example 9

100 g of l-Lai'ryl-3,7-dimethylxanthine, made from Lauryl bromide and l-sodium-3,7-dimethylxanthine, wer-Example 11

10 g! - (5-Hydroxyhexy!) - 3,? - il'methy! Xanth! N (m.p. 125 ° C) (produced in accordance with the »Archives of Pharmacy« 299 (1966) page 455) are melted. 2.0 g of vitamin B2 and 14 g are suspended in this melt Vitamin Bi-chlorohydrate is obtained after cooling a solid mass that granulates and, optionally after the addition of appropriate auxiliaries, becomes solid Pharmaceutical forms is processed. The agent is suitable for use in circulatory disorders and in of geriatrics.

Example 12

100g l-Hexy! -3,7-dimethylxanthine are melted at 8O ⁰ C. 2 g of vitamin B2 and 1.5 g of vitamin Bi-chlorohydrate are suspended in the melt. After cooling, the melt is granulated and processed further. The agent is suitable for use against circulatory disorders and in geriatrics.

Test report

In each case, the same amounts of different batches are processed into medicament preparations, and once in the melt according to the process according to the invention somewhat above the melting temperature the xanthine compound and at the other time by mixing the component in a suitable one Mixing device. For the rest of the first procedure, the same procedure was used as in Example 1 (samples Ia, Ha, IHa and IHc) or 10 (sample IVa), while in the other way of working, care was taken to ensure that a homogeneous -, -, Mixture has been achieved, the results are in the the following overview table summarized:

Sample I.

a) melt: 1-hexyltheobromine and Vit. + 0.8 A-pa | mjtat (encapsulated) b) mixture; Components like a) % Vit. A-palm. Vo storage time I-hexyl theobromine + 3.0 Vit. A-palm. I -hexyl theobromine I.E. < mg + 1.8 I.E.% mg -0.8 5000 -17.6 Intended to 50.0 5000 50.0 + 1.6 4120 -11.6 Initial 50.4 4060 - 18.8 49.6 + 1.0 4420 27.0 6 months 51.5 3820 -23.6 50.8 3650 1 year M), 9 3800 -24.0 50.5

continuation

a) Melt: 1-hexyltheobromine and Vit. A-palmitai (encapsulated) Storage time I-hexyltheobromine ViI. Λ -palm.

mg% i.r :. %

Loss of homogeneity

total

+ 3.0 + 0.8

2.2

-24.0%

-18.8 -24.0

b) Mixture: Ingredients such as a) I-hexyltheobromine Vit. A-palm.

mg%!. [■ :.

+ 1.6 -0.8

2.4

- 27.0%

-11.6 -27.0

15.4

Sample Il

a) melt: l- (lexyltheohri imine and Vit. A-palmitate (encapsulated) Vii. Λ-μϋϊιΐι. % b) mixture : Components like a) Vo Vit. Ä-paim % Lsgcrzcii J -I! CAV! IMCULM IfIIIIM I.E. i-hexyiiheobromine I.E. mg % 5000 -21.4 mg ' + 4.6 5000 -21.4 Theor. Baseline 50.0 3930 -27.8 50.0 -3.0 3930 -14.4 Value immediate η. Manuf. 51.0 + 2.0 3610 -29.2 52.3 + 1.8 4280 -26.0 6 months 48.3 -3.4 3540 48.5 -2.8 3700 1 year 51.1 + 2.2 not 50.9 not 2 years 49.0 -2.0 certainly - 29.2% 48.6 -2.8% certainly 26.0% -21.4 + 4.6 -14.4 loss - 2.0% -29.2 -3.0 -26.0 Fluctuation range + 2.2 7.8 7.6 11.6 -3.4 total ~ 5.6 ~

Sample III

a) Preparations as a melt, containing 1-hexyltheobromine. Magnesium nicotinate, Na ascorbate. Vitamins Bi, B ₂ , B ₆ HCI. dU tocophero succinate and vitamin A palmitate (encapsulated)

storage time

Initial value 6 months

1 year

2 years

loss

Fluctuation range

total

I -Hcwltheobromine + 0.8 Magnesium nicotinate % Na-ascorb. % Vit. BiHCI % mg + 9.5 mg mg mg 200 + 8.0 50.0 + 5.4 35.0 -2.0 1.50 + 2.67 201.6 + 1.5 52.7 + 1.4 34.3 -1.1 1.54 + 2.67 219.0 50.7 -8.4 34.6 - 7.42 1.54 ■ J-10.65 216 + 9.5 45.8 -5.8 32.4 -3.7 1.66 - 2.00 203 + 0.8 47.1 -5.8% 33.7 - 3.7% 1.47 - 2.0% + 5.4 -3.7 + 10.65 -8.4 -7.42 - 2.00

8.7

13.8

3.72

12.65

continuation

storage time

Vit. B ₂ mg

Vit. B ₆ HCI

mg%

dla-Tocoph.-succinate mg%

ViL A-palm. LE%

Initial value 6 months

1 year

2 years

loss

Fluctuation range

total

2.20 -136 2.40 + 231 20.0 - 3.0 2500 -18.7 2.17 2.47 -11.70 19.4 -173 2032 -33.6 £ 20 -1.82 2.12 + 9.16 16 3 -21.0 1660 -533 2.16 -031 2.62 + 7.92 153 -213 1160 -57.6 2.18 -031% 2.59 15.7 -213% 1060 -57.6% -031 + 9.16 - 3.0 -18.7 -1.82 -11.70 -213 -57.6

031

20.86

183

385

ίο

Sample HI

b) Preparations as a mixture containing I-hexyl theobromine, magnesium nicotinate, Na ascorbate, vitamins Bi, B2,
dla-tocophtrol succinate and vitamin A palmitate (encapsulated)

storage time

I-hexyltheobromine mg %

Magnesium nicotinate
mg%

Na ascorbate
mg%

Vit.BiHCl mg%

Initial value 6 months 9 months

1 year

2 years

loss

Fluctuation * width

200 + 10.0 50.0 - 2.6 35.0 + 60.0 , 50 - 2.0 220 + 15.0 48.7 + 14.4 56.0 -31.1 , 47 -15.3 230 + 0.5 57.2 - 1.0 24.1 -43.8 .27 ± 0 201 - 7.5 50.5 ± 0 19.7 -67.71 , 50 - 1,3Y 185 + 3.5 50.0 - 3.2 12.0 -31.1 , 48 -13.9 207 48.4 - 3.2% 24.1 -31.1% , 31 -13.9% + 15.0 + 14.4 + 60.00 - 1.33 - 7.5 - 3.2 -67.71 -13.9

continuation Vit. B, % ViI. B "H" : i % dla-tocoph ■ succinate Vit. A palmitate % Storage row mg mg mg % I.E. 2.20 -51.0 2.40 -59.9 20.0 2500 -28.3 Intended to 1.08 -31.4 1.06 -50.5 19.0 - 5.0 1792 + 6.0 Initial value 1.56 -46.4 1.19 -25.4 14.7 -26.5 2650 -19.6 6 months 1.18 -10.45 1.79 -23.7 13.5 -32.5 2010 -32.8 9 months 1.97 -13.2 1.83 -32.5 8.1 - 9.5 1680 -63.5 1 year 1.91 -13.2% 1.62 - 32.5% 14.0 -30.0 914 -63.5% _ Years -10.45 -23.7 - 30% + 6.0 loss -51.0 -59.9 - 5.0 -63.5 Fluctuation 40.55 36.2 -32.5 69.5 broad 27.5 total

Sample IH

c) Preparations with an increased proportion (stab.) of I-hexyl theobromine as a melt, containing I-hexyl theobromine, magnesium nicotinate, sodium ascorbate, vitamins Bi, B ₂ , Bf ,, dlm-tocopherol succinate and vit. A- palmitate (encapsulated)

storage time 1-hexyl theobromine
mg% + 2.67
+ 6.67 % Magnesium nicotinate
mg% -9.65
-1.09
-5.09 % Na ascorbate
mg % -1Z72
+ 136 Vit. BiHCI
mg% -1.2
-1.2
-1.8 Vit A palmitate
IE% + 20.2
+ 93
+ 103 Intended to
Initial value
6 months
2 years, 9 months 300
308
320
not
certainly ± 0
-3.3 55.0
49.7
54.4
52.2 - 5.09% -132
+ 2 ^ 7
-I3O 42.0
44.7
38.1
37.7 + 6.43
- 930
-10.22 1.65
1.63
1.63
1.62 -1.8% 4000
4810
4380
4420 loss + 2.67
+ 6.67 -1.09
-9.65 -10.22% -U
-13 Fluctuation
broad 4.00 8.56 + 6.43
-10.22 0.6 total 16.65 continuation storage time VitB ₂
mg ViLB ₆
mg dlflc-Tocoph.-succinate
mg% Intended to
Initial value
I 6 months
I 2 years, 9 months 2.42
2.42
234
not
certainly 2.64
Z60
2.70
239 22.0
19.2
223
not
certainly

continuation Il ViI. B ₂
mg % Vii.
mg 1 8th 1 0 705 12th Vit.
IE A-palmitate
% Storage row -3.3%
0
-3.3 B ₆ % dlrt-TocopH.-succinate
mg% + 20.2
+ 9.5 loss
Fluctuation
broad -1.9%
+ 2.27
-1.90 + 136
-12.72

Total 3.3 4.17 14.08 10.7

Sample IV

a) Preparations as a melt, containing 1-oxohexyltheobromine, magnesium nicotinate, Na-ascorbate, vitamins B ₂ , B ₆ HCI. dla-tocopherol succinate, Vit. Α-palm, (encapsulated)

storage time 1 -oxohexyl theobromine % Magnesium nicotinate % Na ascorbate dlrt-Tocoph.-succinate % 13.7 Vit. B ₂ % Vit. A palmitate % mg mg mg% mg 4.0 mg I.E. Intended to 200 + 0.5 50.0 + 1.8 35.0 20.0 - 1 1.43 2.20 -13.62 2500 -23.6 Initial value 201 + 8.0 50.9 -4.2 39.8 + 19.8 -29.5 4.57 1.90 -10.00 1910 -20.8 6 months 216 + 3.5 47.9 -3.2 36.2 + 14.1 -22 1.14 1.98 - 20.50 1980 -16.4 9 months 207 + 0.5 48.4 + 0.2 35.5 + 15.6 -11 0 1.75 -17.25 2090 - 34.6 1 year 201 + 1.0 50.1 0 36.6 + 17.8 -21 13.70 1.82 - 27.30 1635 -54.0 2 years 202 0 50.0 0 35.4 + 15.8 -21% 1.14 1.60 -27.30% 1150 -54% loss + 8.0 + 1.8 - 1.0 12.56 - 10.00 -16.4 Fluctuation + 1.0 -4.2 + -293 - 27.30 -54.0 broad 7.0 6.0 + 283 17.30 37.6 total continuation ViLB ₆ HCI storage time mg 2.40 ο / ο Intended to 233 Initial value 1.99 - 2.91 6 months 2.32 - 17.05 9 months 1.83 - 3.33 1 year 2.J3 -23.70 2 years - 2.91 loss - 2.91% Fluctuation range - 2.91 - 23.70 total 20.79 Sample IV

b) Preparations as a mixture containing 1-oxohexyltheobromine, magnesium nicotinate, sodium ascorbate, vitamins B ₂ . BeHCl, dla-tocopherol succinate, Vit Α-palm, (encapsulated)

storage time

1 -oxohexyltheobromine mg%

Magnesium nicotinate mg%

Na ascorbate mg

Intended to 200 + 5.5 50.0 -4.6 35.0 - 1.71 Initial value 211 + 11.5 47.7 -3.0 34.4 -2030 6 months 233 + 2.5 483 -2.4 273 -1235 9 months 205 + 2.0 48.8 +03 30.6 -36.60 1 year 204 + 3.0 50.4 -7.0 22.2 -19.12 2 years 206 - 463 -7.0% 283 -19, i2% loss + 113 +0.8 - 1.71 Fluctuation range + 2.0 -7.0 -36.60 9.5 7.8 34.89 total

total

13th

14th

continuation Vit. B ₂ % Vit. B ₆ IIC! % dla-tocoph. -succinate Vit. A palmitate % Camp? time mg mg mg % I.E. 2.20 -14.55 2.40 - 4.58 20.0 2500 -23.6 Intended to 1.88 -13.19 2.29 - 4.71 20.8 + 4.0 1910 -23.2 Initially 1.91 -1932 2.30 -50.00 18.0 -10.0 1920 -15.2 6 months 1.77 -20.45 1.20 -38.30 16.5 -17.5 2120 - 2.4 9 months 1.75 - 35.40 1.48 -37.50 17.8 -11.0 2440 -61.5 1 year 1.42 - 35.40% 1.50 - 37.50% 17.6 -12.0 965 -61.5% 2 years -13.19 - 4.58 - 12.0% - 2.4 loss -35.40 -50.00 + 4.0 -61.5 Fluctuating -17.5 broad

22.21

45.42

21.5

59.1

Sample V

a) Competitive preparations: Presumably stabilizers are used in their manufacture

Capsules with 7- (j9-hydroxylethyl) -theophylline, buphenine HCl, vitamin A, vitamin B _r nitrate, vitamin B ₂ . Vitamin B ₆ HCl, nicotinic acid amide. Vitamin C and Vitamin E Acetate

storage time Examined became: Vitamin B | nitrate o / o Vit. B ₂ % Vit. C mg mg mg % 0.70 -10.00 0.80 -13.75 Intended to 25.0 0.63 + 7.15 0.69 -13.75 Initial value 25.8 + 3.2 0.75 ± 0 0.69 -13.75 3 months 24.8 -0.8 0.70 + 11.42 0.69 - 4.00 6 months 26.0 + 4.0 0.78 -11.42 0.77 -13.75 1 year 26.5 + 6.0 0.62 -11.42% 0.69 -13.75% 2 years 24.4 -2.4 + 11.42 - 4.00 loss -2.4% -11.42 -13.75 Fluctuation range + 6.0 22.84 9.75 -2.4 total 8.4

continuation

storage time

The following were examined:

mg

Tocopherol acetate mg%

Vit. A I.E

rope 0.70 -14.29 8.0 -IW Ί500 - 3.6 Initial value 0.60 + 12.85 7.00 -25 ^ 1555 -11.0 3 months 0.79 -143 535 -413 1335 - 6.0 6 months 0.60 -18.55 4.70 -123 1410 + 9.2 1 year 0.57 -143 7.00 -373 1638 + 33 2 years 0.60 -143% 5.00 -373% 1550 loss + 1235 -123 + 9.2 Fluctuation range -1835 -413 -11.0

total

31.40

28.8

Sample V

b) Competitor preparation without xanthine bodies

(Presumably stabilizers are used in manufacture.)

storage time vitamin C % ViLB ₁ % Vitamin bi % mg mg mg Intended to 50.0 + 3.4 1.00 - 8th UO + 6.00 3 months 51.7 + 1.4 032 + 7 1.59 -20.0 6 months 50.7 + 5.6 1.07 + 14 UO + 2.0 1 year 52.8 + 5.4 1.14 -20 1.53 - 1.34 2 years 52.7 0.80 -20% 1.48 - 134 °; loss + 5.6 + 14 + 6.0 Fluctuation range + 1.4 -20 -20.0

total

4.2

34

26.0

continuation Vitamin B ₆
mg % Tocopherol acelate
mg o / o Viiamin A
IE % storage time 2.00
2.15
2.01
1.75
1.98 + 7.5
+ 0.5
-12.5
- 1.0 2.00
1.49
1.57
1.88
1.54 -25.5
-21.5
- 6.0
-23.0 2000
2680
2170
1890
2260 + 32.0
+ 8.5
- 5.5
+ 13.0 So!!
3 months
6 months
1 year
2 years - 1.0% - 23.0% loss + 7.5
-12.5 - 6.0
-25.5 + 32.0
- 5.5 Fluctuation range

total

20.0

Further stabilization experiments were carried out with a preparation which, according to Example 11 under Use of l- (5-hydroxyhexyl) -3.7-dimethylxan-

19.5

thin was made. The results can be found in the following table:

37.5

are de

1) Experiment 1
1- (5-Hydroxyhexyl) -3,7-dimethylxanthine

Initial Down analysis search for 4 years Storage at Room temperature per 13.5 g per 13.5 g

1- (5'-Hydroxyhexyl) - 9.91g 10.0g 3.7-dimethylxanthine

Vitamin B ₂ 1.86 g 1.99 g

Vitamin Bi-HCI 1.56 g 1.36 g

As the table shows, the granules have practically proven themselves after four years of storage at room temperature not changed, only for vitamin Bi a loss of approx. 12% is found. However, this loss is likely to occur in The limits of the analysis fluctuations are so that the stability of the melt according to the invention is very good

is to be designated.

Another stabilization experiment was carried out with I-Oc tyl-3,7-dimethylxanthine in the melt The follow-up examinations were carried out after 3 or 6 months of storage at room temperature. Tuesday The results can be found in the table below:

030 113/1

Setpoint 18 10 705 18th 6 months 17th ED mg composition mg Initial analysis 209.1 200.0 per 283.8 mg Follow-up examinations mg 3 months 30.4 l-OctyI-3.7-d ^: methyl- 30.0 195.0 ED mg \ m xanthine 1.6 193.0 2.01 Ascorbic acid 22nd 30.2 50.4 Vitamin Bi-nitrate 50.0 1.75 32.6 Vitamin B2 1.98 1.80 Magnesium nicotinate 51.5 2.10

As the table shows, after 3 months and after 6 months of storage, the granules practically did not develop changed Only with magnesium nicotinate there is a loss of 3.1 mg. However, this value is within the error limit of the analysis. The stability of the melt according to the invention can therefore be described as very good.

Claims (1)

Claim: Use of at least one 1,3- or 3,7-dimethylxanthine in the 7- or 1-position an alkyl radical with 5-15 carbon atoms or by a hydroxyalkyl or oxoalkyl radical with 6 C atoms is substituted, to stabilize one or more vitamins of the series A, B, C and E up to an amount of 30% by weight with suspending in the melt of the substituted Xanthine, which is processed into granules after solidification. IO