DK149482B - ADDITIONAL SUPPLEMENTS WHICH ARE ABLE TO PASS THE WAVE OF DRUGS, AND ITS USE FOR FEEDING OF DRUGS - Google Patents

Description

in 149482

The invention relates to a gastric feed supplement for ruminants in particulate form in which 30-50% by weight of at least one biologically active substance is provided with a coating containing an aliphatic monocarboxylic acid having 5 to 22 to 22 carbon atoms or ricinoleic acid or a mixture of several of said acid rf as well as the use of this feed supplement for feeding ruminants.

DE-PS 22 12 568 already discloses a gastric feeding supplement for ruminants in particulate form, at 10 of which at least one biologically active substance is provided with a coating which is resistant to the ambient conditions of the stomach, but which, after passage into the intestine, dissolves under influence. from bile and pancreatic juice. The coating consists of an aliphatic monocarboxylic acid having 15 to 22 carbon atoms or ricinoleic acid or a mixture of such acids, or is a salt of such an acid or a mixture of such acids. However, because the dissolution of the coating of the known feed supplement requires the influence of bile and pancreatic juice, the 20 available for digestion and resorption is considerably shortened.

The feed supplement according to the invention is characterized in that the coating relative to the total weight consists of a) 10 to 35% by weight of at least one sodium, potassium or calcium salt of an aliphatic monocarboxylic acid having 14 to 22 carbon atoms or ricinoleic acid, b) the balance up to 100 wt.%, but at least 30 wt.% At least one aliphatic monocarboxylic acid 30 having 14 to 22 carbon atoms and / or ricinoleic acid and / or a hardened plant or animal fat.

Surprisingly, it has been found that, unlike those in which the coating consists either of only fatty acid or of fatty acid salts, the particles of the feed supplement are already attacked in the acidic environment of the running stomach and the biologically active substances are released , without requiring any additional influence from bile and pancreatic juice. But on the other hand, the particles of the present feed supplement also withstand an attack from an environment of gastric juice pH and microbial degradation in the rumen. As the following examples show, the dissolved proportion of the feed supplement according to the invention is generally somewhat higher. than 10 in the corresponding comparison experiments using the test conditions described in the Examples. Thus, the particles of the present feed supplement can pass through the rumen as well as the particles known from DE-PS 22 12 568, but, however, begin to dissolve already in the running stomach, thereby extending the time available for digestion and resorption.

The feed supplement according to the invention consists in relation to the total weight of 30 to 50% by weight of at least one biologically active substance. Such biologically active substances are e.g. amino acids such as methionine or lysine; derivatives of amino acids such as N-acylamino acids, e.g. N-stearoylmethionine or N-oleoylmethionine, the calcium salt of N-hydroxymethylmethionine or lysine monohydrochloride; hydroxy analogues of amino acids such as 2-hydroxy-4-methylmercapto butyric acid or their calcium salts; proteins such as poultry flour (Federmehl), fish meal, casein or potato protein; vitamins such as vitamin A, vitamin A acetate, vitamin A palmitate, vitamin, vitamin E, nicotinic acid or nicotinic amide, calcium panthotenate; (3-carotene; enzymes such as acidic proteases; carbohydrates such as glucose; veterinary pharmaceuticals, e.g. Of [(2,2,2, -trichloro-1-hydroxy-ethyl) -phosphoric acid methyl ester] Of course, mixtures of two or more biologically active substances can also be used.

The coating protecting the biologically active substances in the rumen also contains, in relation to the total weight of the feed supplement, 10 to 35% by weight of at least one sodium, potassium or calcium salt of an aliphatic monocarboxylic acid having 14 to 22 carbon atoms or ricinolic acid 5 and for filling up to 100% by weight, but at least 30% by weight relative to the total weight of the feed supplement of at least one aliphatic monocarboxylic acid having 14 to 22 carbon atoms and / or ricinolic acid and / or a cured plant or animal fat, e.g. . cured soybean oil or cured 10 beef tallow.

The aliphatic monocarboxylic acids of 14 to 22 carbon atoms present in the protective coating as free fatty acids or in the form of sodium, potassium or alkaline salts can be saturated or unsaturated, branched or branched chain. The fatty acids present in natural fats, such as myristic acid, palmitic acid, stearic acid, arachic acid or behenic acid, or mixtures of such acids are preferred.

Conveniently, the feed supplement of the invention can be prepared such that first a homogeneous melt is prepared from the components that make up the protective coating. Thereafter, the biologically active substance or a mixture of such substances to be protected is dispersed with stirring in this melt. Then the liquid dispersion, which is vibrated through nozzles, is fed through high frequency vibrations. Thereby, the jet emanating from each nozzle is divided into discrete droplets of defined size which, after forming a spherical shape, solidify upon free fall. In this way, 30 spherical particles with any cross section between 50 and 2500 μπι can be produced.

A particularly important biologically active substance in the form of the feed supplement is methionine. Since numerous studies show that of all amino acids 35, methionine is generally the most essential α-minoic acid for ruminants. Thus, infusion of methionine into the running stomach of sheep leads to an increase in wool growth [P.J. Reis, P.G. Schinkel, Aust. J. Biol. Sci. 16, 218 4 149432 (1963)]. In Holstein oxen, the infusion of methionine in the running stomach leads to an elevated N balance [C.R.Richardson, E.E.Hatfield, J. Anim. Sci. 4, 740 (1978)]. Studies on lactating cows are cited by W. Kaufmann 5 and W. Lupping in "Z. Tierphysiol., Tierernåhrg. U. Futter Middle Chain." 41, 202 (1979). Results of tests have also been reported showing that methionine protected during the passage of the stomach, whereby the methionine is released into the running stomach, as a supplement to the usual force-feeding ration in dairy cows produces an increase in milk yield. in the protein and fat content of the milk, in the persistence and in the fertility after the onset of lactation.

The invention further relates to the use of the present feed supplement, at a daily dose of from 1 to 100 g, for feeding ruminants.

The feed supplement of the invention is preferably used with methionine as a biologically active substance and especially for feeding dairy cows, to improve milk yield, protein and fat content of milk, persistence and / or fertility after the beginning of lactation.

Other important biologically active compounds are the vitamins. Thus, e.g. Vitamin A deficiency in bulls for poor appetite and therefore for poor weight gain. In pregnant cows it can cause calf throwing or stillborn calves. β-Carotene has a specific effect on the fertility of oxen [Dt. Tierårztl. Wschr. J32, 444 (1975)].

Energetic malnutrition of high-performance animals can lead to impaired milk protein performance. Addition of carbohydrates, such as glucose, in protected form thereby leads to a very favorable energy supply.

In the case of orally administered drugs, a release of the active substance is generally desired only after passage of the stomach. The feed supplement in question is then particularly suitable if a release in the running stomach is desired.

149482 5

The invention is further illustrated by the following examples and comparative experiments. Unless otherwise stated, parts represent parts by weight and percentages by weight.

Example 1 a) (Comparative Experiment) .70 parts of stearic acid were melted at 80 ° C. 30 parts of methionine were suspended with stirring and the melt was dripped from nozzles to give uniform spherical particles with a cross section of 1 to 2 mm.

B) From a mixture of 60 parts of stearic acid and 10 parts of sodium stearate, upon heating to 80 ° C, a homogeneous melt was prepared in which 30 parts of methionine were also stirred. The particles were prepared as in (a).

By analogy, particles were prepared from: c) 30 parts of methionine, 55 parts of stearic acid and 15 parts of sodium tea arate, d) 30 parts of methionine, 50 parts of stearic acid and 20 parts of sodium tearate, 20 e) 30 parts of methionine, 50 parts of stearic acid and 20 parts potassium tearate, f) 30 parts methionine, 45 parts stearic acid and 25 parts sodium tear, g) 30 parts methionine, 35 parts stearic acid and 35 parts sodium stearate.

To find the specific pH-dependent release using the pH difference between gastric juice and running gastric juice, the particles were incubated in a shaker in each case for 2 hours at 37 ° C in 50 ml of a buffered pH system. corresponded to the stomach mildew and still moving. The buffer system consisted of a solution of 74.77 g of potassium dihydrogen phosphate, 103.03 g of disodium hydrogen phosphate trihydrate and 13.5 g of potassium iodide in 1 liter of water. The pH of the buffer system was 6.5. At the same time, the particles were incubated for 2 hours at 37 ° C in 50 ml of buffer system that was pH-equivalent to the running stomach environment. This system consisted of a solution of 6.5 ml of 0.2 N hydrochloric acid and 25.0 ml of 0.2 N potassium chloride solution in 100 ml of water. The pH of this buffer system was 2.0.

Then, the dissolved particles were filtered off and the solution in each case added 100 ml of pH 6.5 phosphate buffer, resulting in a pH of 6.5 in each case. The proportion of the methionine transferred from the particles in solution was then determined iodometrically.

The results are given in the following Table 1.

149482 7 die P (1)

• H <H

m GO • Η Λ β Φ r ·· σι σι ro in oo vo 0t> τΐίιΐ, β g ffl β \ ¢ 0 rl (Ί ΙΟ · Φ • ρ φ 0) Λ ss ιΗ α> ___ τ3 --- G Ρ Π) Φ U-ι to 'ί 1ί) Η t' (Ν Ιίΐ 4J <4-1 *. S ». ·· ν · * ^ m3 σι ro ιη νο ιη αο γ ~ φ (¼ co eo oo oo oo οο .-) φ 04>

Ο m D S

rH ....... 1 1 * pH - · - '"-—« »^ φ -Ρ tf <0 (ti ^ -ν Φ <0 Λ π3 3 3 3« Ζ! 3 (d Ρ _ µ -Pm ΦΦ omoomm +) +) I η η cm cs cm η

XrJi 0_____ Ό ο Φ Ρ U CU> i ία

Ρ G

Φ · Η οοηοοηιη Μ ΐ '«ιη λ λ μ tnm G Φ • Η-Ρ G in p (g - σι ω G' S · G Ή Μ

Φ G P

go o g -ri OOOOOOO 4-1 id r · n m m ro m ro m to co +> O '

Φ G

S -H

G

__________________ Cn

• H

f "l

G

Cn W g w ΐ S ”o m ai ίί o i p lu 0 i — JrHrHrHrHrHrH C /}, _fe ____ * 149482 8

The 20% stearate product shows a very wide release of methionine at pH conditions in the running stomach without enzymatic activity being required. A smaller or greater proportion of stearate leads to a less efficient release of methionine during the incubation time of only 2 hours.

This effect can also be seen with the eyes. While the particles of a) after incubation in the acidic buffer showed no external change, the particles of 10 d) and e) were cracked in several places. The particles of b), f) and g) showed a slight softening of the outer layer.

Example 2 Similarly, particles having a net hionine content of 40% relative to the final product were prepared.

The sodium stearate fraction was adjusted to 10, 15 and 20%.

In comparison, a product without stearate addition was manufactured and tested.

The composition and results are listed in Table 2.

149482 9 <*> µ

<D

-Hm 44 P P • H ft p q) ο> Η Π H σι • H id - - '* · ο! Ξ m οι σι a \ -P <u σι σι ^ n ΟΛ e «.

PI

H

Q) __ 'd

S M

id <u

M-ι r ~> o οι H

4-1 Ή * «* · * · * · in p ri m co

• Q. ft h CO CO OO

H a) ft> 04 0 id H __ Q) -—- -—-, q 4-1 id id id id id 2 2 3

Eh S4 w w id {D o in o

+) 44 I Η H CM

a) ω 44 44 P--

Ό <U

0 M

> 4> 1 ft to p ιμ -Η ο o in ο id 5η νο m ^ 'a * <d Cn <DP +> H 05 5 —_ U> «-awpwp -η ua> po so ή 1 · Η ο ο ο Ο 01 3 ο! vf <ί ^ vf Φ 05 4J ρ a) ή S & cn _ Ή f — j Ρ σ <»ο W id Λ 0 Ό 1 Μ 3 0 04 ΟΙ ΟΙ ΟΙ 05 la _ Μ 149482 10

A larger proportion of stearate as described in the examples leads to an increase in the viscosity of the melt, so that the preparation of larger particles is also complicated. By completely replacing the fatty acid with a salt of the fatty acid, a melt cannot be prepared, even using temperatures of 180 ° C. This also leads to a significantly greater thermal load on the fabric to be protected.

Example 3 For comparison of the above-described tests with results using physiological solutions, the product, after Experiment 1 d), is incubated with 50 ml of running stomach juice obtained from freshly slaughtered oxen at 37 ° C for 2 hours. The determination happened in the same way. The result is shown in Table 3.

149482 11 +> d? m <o

ri CO

O) CN

G> • H (0 vo g s oi O 0) • Η Λ Λ «ι +> P5 I_— rH 0)

O) VH fd M-J

g 3 3ft cn

CD

-P> VO

to 3 H

«V S r-» a) ft Λ O -Sv D PI

n H »- * φ +> 3 λ nj a (0 H w free (0 tu o

+) +) <N

<u m +> fd φ 0 in u> t ft ω

G

m -a o to M in 3 tn a) G +> • Htfl

G

+> __

fB

to G G -H Ο) G

1 o E -Η o 3 Λ to W + J 0) a O) εη o • s to - ^ M 3 Λ

ISLAND

fa n 149482

Example 4 12

To assess whether the product obtained after Experiment 1 b) with a sodium stearate content of 10% can also be observed by prolonged incubation in running gastric juice 5 an increased release compared to the product after Experiment 1 a) (without stearate proportion), both products were each incubated for 16 hours at 37 ° C in running gastric juice. In doing so, they presented the following results (Table 4).

dP

• Η P

<D fi S

• ri -ri

β -P O

• ri 40

-5

e Ή r- ro ι-i (ύ - * Φ t n n in Ό d) Γ "CM fi>

(tf (tf, S

+ J φ tn Λ H J ft'—

ISLAND

D

iH __ r-T "φ +> (tf Λ-, <tf 2 (tf +» P ~ E-t 0) (tf +> Φ o X +> I Ή β W Ό O —- P Φ ftp

m tn (tf β • H

O 'P o o

β (tf t- UD

-ri φ · β +1 04 +> to -a æ tn in —- p β β Ο Φ · Η <Η S β ιη go tn (tf -Η Ο Ο β οι Λ η η · Η +> β Φ 04 --β 04 * Φ

tn "(tf Λ S

ρ ίο 0 t Ί1 01 fa _ * 149482 13

Example 5 In a similar manner to Examples 1 and 2, a product of a) 30% lysine hydrochloride and 70% stearic acid was prepared, and b) 30% lysine hydrochloride, 50% stearic acid and 20% sodium stearate.

After incubation in running stomach buffer for 2 hours at 37 ° C, the particles were filtered off and the solutions were column-chromatographically examined on the amino acid analyzer LKB 3201 for the lysine content.

10 Thereby, the following differences were found in the release rate (Table 5).

149482 14 dp

HM

<u T3 g • P -P P + »0 H CN Λ 0 - Ο P P Q)

Ό ip i- (O

> i4H '^

Λ 3 P * <N

β Q. t "(N

• h a) w>> 1 (0 Ή S a) Η Λ (!) · & T3 P] β- "β

-P

in s 1-1 in a »0

H D

a) - - J3 -P β

Kj -p (0 s B O) P - -P (0

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Ή p β> t 0) O 'β β · Η Ο Ο • HP r- ρ * β β + ι 0) (Β * Ρ tn cn β Ο) οι 1 --- ο.

εη ω <3 υ Ρ w ® ο ο ο ή • mm ω Οι m β t * i · Ρ Ρ! β θ 'Ή

r-In

θ 'λ β - & Ο) W β Λ 6

Ρ S

0 in β

IP CQ

___ * ·

Example 6

In accordance with Example 1, particles of a) 30% nicotinic acid amide and 70% stearic acid were prepared, and b) 30% nicotinic acid amide, 50% stearic acid and 20% sodium stearate.

After incubation in running gastric juice for 2 hours at 37 ° C, the particles were filtered off and the N content determined by the Kjeldahl method. By comparison with the N content analyzed before the incubation, the extent of release was determined. The result is shown in Table 6..

---

• H

d • ri Φ Φ µ s

> l * rl M -P S

• rH CM +> Ο · ϋ µ • µ φ fim Η η m - * rH fi σι Ο Οι Ό Φ ΰ> td id, ε -Ρ φ ι »Λ Η ι-3 Ό ft— 'Ο

Η D

Φ - .. - Λ ««% id +> Φ

Eh Φ I 3 -Ρ fd - Μ Φ +> fi 4-) id ο τΙ οι Ρ ι cm ο μ.,. -

ft I

s m · μ id Μ id φ tji® μ ο ο οι C 4-1> 1 r * in Ό.

-µ οι in to Α μ + j ——- ο (Β ι φ m οι fi -μ ω C3 Ή fi Ο · Φ 4-1 id Ο Ο fi fo Φ ro η · μ Ο μ fi id · μ> ι 0> ca 2 οι · μ Η "Π — ι- c ΰ> * φ Ό π Φ Id λ 1 μ id Ο" Φ 01, Yes __ #

Example 7 Particles were prepared in a similar manner to Examples 1 and 2 using hardened soybean oil in the protective layer.

5 The composition and results of the study as in Example 1 are shown in Table 7.

u dP d)

Ή -H IH

3 C ft -H <s) vo σ> r- β> * · - * · 0 (d -s · f '· σι • Hg σ \ m

X <D -p X Φ e · g X

H

<D ~ - Ό β U (C d) ih +> m i "o o * H ia 3 · ^ · 0) a & vo σι X Η φ σ σ vo X ft>

Ed O 3 s a

P -P

tin ~ + »y w« X 3 w - 3 0) Ό -P o o

O 01 I H CM

M

ft- - 0)

Ή · Η Id -P Η O O

& i'U id ooo fi Η · η Is id ifl ¢ 1 • H fB O -a β SU ΙΑ Ρ, Μ «73 0 w · η m β β ΙΑ ο ο σι Β · η ο ο ο gg X η η η · Η id −Ρ β οι φ σι a · η ________ Η _ β σ> ο

a * I

Ο ΐ Λ Ο I

Ρ 'οι ϋι f »Ρ. Κ U9482 17

Example 8 Similarly, as described above, products were prepared in which methionine and protein in combination were protected. As a protein, 5 poultry flour (Federmehl) was used.

After conducting the incubation in gastric and placebo buffer as in Example 1, the solutions were examined column chromatographically for the amino acid content. In addition to methionine, other amino acids could only be detected in trace-10 amounts.

The composition and result are shown in Table 8.

Example 9 a) {Comparative Experiment) 70 parts of stearic acid were melted at 80 ° C. Thirty parts of methionine were suspended therein with stirring and the melt was dripped from nozzles to give uniform spherical particles of 1 to 2 mm cross-section.

b) From a mixture of 60 parts of stearic acid and 10 parts of calcium stearate, upon heating to 80 ° C a homogeneous melt was prepared in which 30 parts of methionine were also suspended. The melt was dripped from nozzles to produce uniform spherical particles with a diameter of 1 to 2 mm.

Similarly, particles were prepared from: 25 c) 30 parts methionine, 50 parts stearic acid and 20 parts calcium stearate, d) 30 parts methionine, 35 parts stearic acid and 35 parts calcium stearate.

The particles prepared were examined each time in the manner described in Example 1. The results are shown in the following Table 9.

149482 18 η - o Ή ϋ9 U Ή α) d Η ή ρ, r ~ m ιο co IH α) - *. ·. »S3 ί c * p> to tn ro γί Ο ft θ '(Ί (0 m a ^ a β α) - - - -Hg. Ο> m oo co µ <d 5S" g S' U ^

s3 I

ω —-- 5 S3 in I —— I-

(3)

W n, +) ih r- ^ vo ^ to β - «* Ό. & o σι i i.

H g VS) VD t- φ Q) S 's Ό «Η

2 $ β * H

3¾ (¾ D CO OJ VD CD

- - -. O J ·. '. »-« ·. +) <d σ \ <-t in vs η 0 7? to> r- co oo as 2 SS 5l »S„ §-s 4J oo 2 H CO I i — I ΓΊ _j ^ ® <u - Λ ---, £) JJ ^ „2nu 2« β β β 64 e & B J3, ϋ uo -P co ® I ~ ~ ^, Μ β Ο Ο Ο ^ ® αοιη 3Ή m vf η. * i> 5 ^ · ηµ r ~> cm m p (3 --- MO) rtl

ft +> S

to z m 73 <u o & 5 S '8 g, | j I ft -Η Ο Ο O in 3H ΗΓ'-νοιηη -PA! O O O 3J Π5 RJ H m <N cn "'α» tn M Q) fr, +> «.

β-η · S1 W W

gft § -H ___ M

«^ R1 n g - CO R C £ Φ fi M cu * H (/} CQ * H O S C £ β Ή 2 ο« Q to ϊί · Ηθσοο .j • hooo 0) e-β m m m m g jincnnG g -Ρ &

• P -H S 0) -H

3 & m 2 H

- —-- 3 Γ 0)

0 »* fig, I

two ΒΛΟ § g ---— - CO

M 5 H S 32 U 73 0 CO 00 OO 55 g ft tO? 3 3 31 *