DE1795067A1 - Collagen hydrolyzate and depolymerized product and process for its production - Google Patents

Description

96-13.

Patent attorney ..., Df pi. -Ing. R. Beetz U. Dipl.-Ing. Lamprecht

llünchen 22, Stelnidorfrtr. It

ORSYMONDE, PARIS (France)

Collagen hydrolyzate and decomposition as well as process for its manufacture

The invention relates to a collagen hydrolyzate and »Depolymerizate with no adhesive or gel-forming properties a content of $ 4 to $ 15 of free amino acid ^ that through Breakdown of natural collagen is preserved.

According to a modification, the new contains collagen hydrolyzate and ° depolymerizate additionally calcium and possibly phosphorus, which have been added in ionic form.

Natural collagen, or ossein, is a natural polypeptide that occurs in bones and by direct chemical and ionogenic compounds between amino acid molecules, in particular Proline and oxyproline is formed, with a substantial part of the amino acids involved in the structure containing sulfur in the molecule.

Apply natural collagen as it is Patients, it represents a stimulatory effect of growth or the increase in horn-like Beatand parts (such as nails,

(Q)
109884/1470

Hair does analog), but JedGoh has not been able to exploit this effect so far because of serious defects in this product, such as an extremely unpleasant odor, which rules out its possible additions to dietetics. In addition, it is extremely sticky when dissolved, which - for administration by the buccal route - starting from a powder or granulate is very disruptive or obstructive. the optimal effect ^ one might expect given its composition? and it is assumed that poor assimilation, owing to its heavy and excessively polymerized proteins, is to blame for this.

According to an essential feature of the invention, a process for the production of a new product (see above) "has been found which is free from the above-mentioned deficiencies and has new properties" which open up a versatile and variable field of application possibilities.

The process according to the invention for the preparation of the new collagen hydrolyzate and depolyzerizate by breaking down collagen is characterized in that the natural collagen is added with an acidic or alkaline pH agent alone or with the addition of a puff paste ei a plWdGVb vpn; 3 to 3 * 5 or from 8 to 8 _a 5 bgi {Bäß | gen Teriiperatu "ren of about 100 to 110 ⁰ C, which can also F'lO reach 15Q ^P _C. treated under pressure for a period of 45 to 90 minutes, and the reaction was finally neutralized, with the collagen concentration of the treated reading on a half

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1785067

$ 5 to $ 20 is capped.

Purely the setting or determination of the pH value can you use different means and either one (weakly acidic or basic) organic compound or a mineral component (a strong acid or base in the presence of a buffer formed by the collagen itself can be)..

The method according to the invention therefore consists in degradation of natural collagen to its partial hydrolysis and depolymerization up to the loss of its adhesive and gelling properties.

This procedure leads to a limited decomposition or

Splitting of the polypeptide chains _a which is sufficient for splitting or releasing (fractional) these chains from one another, the degradation being up to '. operated at a point at which the product has lost its disruptive physical properties and has reached a sufficient degree of assimilation by the organism. regardless of the route of administration and the desired effect; This release of the chains is accompanied by a breakdown of the polypeptide chains with reduction in chain lengths by partial hydrolysis, which is the reason for the presence of a limited proportion of some single molecules of various amino acids involved in the structure of collagen.

This precise limitation of the depolymerization and hydrolysis

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- yy. -

grades requires very precisely defined working conditions the characteristics of the method according to the invention form and cause for the product received and its properties are »

Only through this modification or combination of the agents used, the natural collagen can be converted into a partially depolymerized and hydrolyzed product according to the invention, which then no longer has an adhesive or gel-forming effect, and a content γόη h up to 15 $ has free individual amino acids? this new product is applicable in the following areas:

1) In dietetics as assimilable in digestive administration Source of sulfur-containing amino acids as well as proline and oxyproline;

2) in cosmetics as a source of the same substances * which, however, can be absorbed percutaneously)

© 3) in therapy with medicines containing sulfur, such as in gynecology, dermatology and "ORL ¹¹ (ORL) as well as in rheumatology.

The new calcium and phosphate already mentioned above containing medicinal products for calcium therapy (ealcitherapy) are compositions which, in addition to the collagen broken down according to the invention, form sources of phosphate and calcium ions, and in any suitable form, solid or liquid, as well as in any suitable chemical form, as detailed below is specified.

109884/1470

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It has recently been found that calcium for adequate assimilation by the bones, given in rather massive doses, is rough _? which are in the region of 1 g / day (calculated for elemental calcium). The ^{agents currently available on the MaX 1} ICt / -. which are generally made on the basis of phosphates, only allow the administration of doses of a few Deka-Milligranmi and zviar mainly because of the low calcium content of their molecules.

It has now been found that fixed connections or Compositions of the collagen and calcium phosphate degraded according to the invention can be produced or separately phosphory = Generate lated or phosphated collagens and then combine them with a calcium salt such as calcium lactate or phosphate or combine or at the same time the degraded collagen, a phosphate-containing compound and a calcium salt in solution can bring, whereby the result remains practically always the same., namely on the basic side functions of the polypeptide chains of the degraded collagen fixed ions derived from phosphorus and by neutralizing the remaining acidic functions of the calcium ions attached to fixed phosphorus-containing ions. *

By administering the above-mentioned composition

_ »Settlements can have both massive calcium doses in the '' area of ο '

"> iöOO wg / day as well as phosphatioiien are supplied, which are common co ■ '.- ■■

° ^ come into effect, whereby the oversupply can be achieved _fc can that for the new therapeutic applications in the lime « -J therapy is required. This administration is done in high doses

possible through the use of the collagen degraded according to the invention, which is more assimilable and convenient to ingest

179506?

Serves as a carrier for calcium and phosphate ions,

The inventive products based on partially depolyzed and hydrolysed collagen are particularly well-suited for use as components in pharmaceutical soup kits for the use of calcium *

™ Eb was developed as part of the development of the present 'iSrfindimg found * that the collagen obtained was eaten.pvoduk'to as a basis for a composition containing phosphate and calcium ions can be used, since the amino acids obtained acid chains in the outer layer, considerable amounts of phosphabions ai'iaiilager, which then again-un; neutralized by Calciurriionor without the solubility and assimilation problems that exist with known products

The following are examples to illustrate the Er2 ^like iT) _dung; which ό-- ™ should not restrict their scope in any lf-3ise.

Example 1 "

Add 10 g of collagen in a dilute solution of O ^{Γ ί} ifl pure HCl in water and made up to 100 g with water. The pH value of this mixture is about 3.5, it can also be close to 3 ^ v.stxi the amount of HOl 'used is reduced / ^ t =, Mg is then continuously heated to 110 ⁰ G and maintains this temperature for 3/4 hour, then allowed to cool down to 60 ° C and neutralized with sodium hydroxide solution to a pH of 7

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All of these operations should be carried out aseptically. The received Solution can then be evaporated in vacuo.

It can be "nebulized" bsw after dilution. a spray drying be subjected. The powder obtained should be stored in closed containers in a completely dry atmosphere, which are still provided with drying agents.

Obtained as a white _a most up rehbraunes powder is very hygroscopic and has lost all his 6elbildungs \ ^r Property Assets "

The product obtained is very soluble in water and gives a pseudocolloidal solution "

It also dissolves in glycerine and acetic acid. In other it is insoluble in organic solvents.

It has the following chemical properties:

Arrears 1,

Free amino acids (expressed in glycocolla): Amino acids in a polypeptide bond:

Glycine -109884/1 approximately lo $ Il Alanine BATH ORIGINAL H 8th% I! Proline " 14 *, " Oxyproline Π 10 * Leuein not determined Cystine and cysteine Tyrosine A 70

Aspartic acid, for example

Glutamic acid ^w $

Iron (expressed in FpO ,,) 1 * 3 $ der Verasehungsruc5kstan.de Nitrogen 17,

Sulfur 0,

Example 2

There was a disposition from the following starting materials manufactured:

Collagen 10 g

Lactic acid Ig

Citric acid 0.20 g

Na benzoate 0.02 g

Water q.s.p. 100 g,

whose pH was around 3.6.

Using the same hydrolysis process as in Example 1, neutralization with sodium hydroxide solution up to a pH value of 7 or with calcium carbonate or calcium hydroxide up to a pH value of 6.7 to 6.8, an ealcium-containing one is obtained (in the latter case) depolymerizeda collagen _t

Example 3

Using the following raw materials:

Collagen 10 g HCl pure 5 ml

Water qsp ο 10p F. "'

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BADORtQlNAt,

a dispersion as in Example 1 with a pH of about 3 made.

This dispersion is under pressure for one hour 140/150 ° C heated. It is neutralized with calcium carbonate and thus receives a CaClg «series mixture,

Example 4

From the following substances:

Collagen 10 g Lactic acid 2 g Calcium carbonate 1.50 g Water q.B.p. 100 g

a dispersion is prepared that takes 1 1/2 hours to boil is heated and a solution with a pH value of 6.7 -7 with a calcium content is obtained after filtering, which is above the theoretical value, whereby the calcium over · » shot is fixed by the acidic fraction of albura roses and free amino acids *

Example 5

From the following substances:

Collagen 10 g Ca carbonate 2g or gdleiuinhydroxyä 1 * 5 g Water q.a.p « 200 g

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a dispersion is prepared; the pH-lewt which is i $ «rig at 8 to 8.5 * depending on the basisefesia used

One hour at 10O ⁰ C and then neutralized up to pH 7 by the gradual addition of lactic acid while maintaining the hot effect this lewtralisaMom takes minutes,

After filtration, a solution is obtained with a Caloium content which is above the theoretical value, where ier Calolum excess in the acidic fraction of the albumopes and amino acids is fixed.

The physifcalisehen properties \ mm * AEE the product obtained are in wesentl ^ iÄeJi SUe §ΐ € ϊ | .οίΐβ; η as those of the product according Beisptel 1,

The content of free amino acids of -generated ΐ is lower than that of the product just at item 1 and though; 9 #.

Calcium aitell
Milk turkey

Example 6

Production of a calcium-containing depolylated colamite 1OJi calcium.

To this end, the following swbs will dance:

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BAD ORlG ^ ^ ₀

Collagen 10 β

Calcium hydroxide 1

or calcium carbonate 2

Water q.s.pV 100 g

Äitspergiertj the pH of the mixture is about 8.5

This mixture is heated for one hour at 110 ⁰ C and ^ nit Milohsäure neutra3-ielert.

Example 7

Production of a celium-containing depolymerized collagen with 10 $ calcium »

The following raw materials:

,! Collagen 10 g

Lactic acid 4.5 g

Water Q.s "p * 100 g

are dispersedi the pH value is about>.

This dispersion is heated to 110 ° C. for half an hour heated and gradually neutralized with calcium carbonate while boiling.

Example 8

Production of a phosphorus and calciura containing depolyaieri =. sized collagen.

The following substances:

Collagen 10 g
Phosphoric acid 3 # 5 g water qsp 100 g

are dispersedj the pH of the solution is close to 3.5j it is ^{heated to HO 0} C for one hour and then neutralized with 6.5 g of dicalcium phosphate to a pH of 6.5.

The product obtained is dried without filtering and has the following properties:

Phosphorus content:
Calcium content

The products of the invention have been pharmacological and clinically examined.

In rats and dogs, even after administration in higher doses or over longer periods of time (doses prolongees) as a substitute for common protein foods Toxicity noted.

In humans, clinical studies have shown good results in the treatment of osteoporosis and in others Cases of difficulty with calcium assimilation. In addition, interesting results were obtained in terms of treatment of osteoarthritis achieved.

109884/1470

The following are examples of pharmaceutical compositions indicated with the product according to the invention,

Composition A

Product according to the invention 50 g Strength 58

Sodium alginate ig

Sugar 50 g

Chocolate mass 10 g sodium saccharinate 0.1 g

Solution for granulating
Polyvinylpyrrolidone (polyvinyl
pyrroiidore) 2 g

Glyoerin. Ig

Glyoiii 0.1g 5% alcohol

The granulated composition thus obtained can be used without further administered by the bulk route without inconvenience will. Babel will be doses of 2.50 g of the active ingredient applied per boais; this composition can be packed in bags or offer bags «

Composition B

Product according to the invention 50 β Mannitol 5 G Sodium alginate 109884/1470 1 'G BAD0RK3INAI

sugar 30 g cocoa 10 & NatriUBS saccharinate 0 * 1.g Solution for granulating Polyvinyl pyrrolidone 2 tf 50 pounds alcohol

This composition can be used like the Zirsamraene-etspng £

Product g < ooäB the invention 1 g Lactose Mannitol Excipient q.s .p. I. Tablet gu

The tablets are chewed before a meal; ibhe

summarized clinical failures received the itrans? Ms 4 tablets per day.

Claims (4)

■. ■ »■ 15 - 'claims 1. Collagen hydrolyzate and -depclymerisat, characterized. that it is neither gelling nor sticky and has a content of free amino acids between b and 15 $. 2. collagen hydrolyzate and -depclyraerisat according to claim 1, characterized by an additional content of calcium and optionally phosphate, which has been added in ionogenic form are ο 35 .. 'Process Eur production of the collagen hydrolyzate and "depolymerization" by degradation of collagen, characterized in that the natural collagen -n with an acidic or alkaline pH-changing agent alone or with the addition of a Buffernd.li'eus at a pH from 3 to 3.5 or from 8 to 8.5 at moderate temperatures of about 100 to 110 ⁰ C, which can also reach 140 to 150 ⁰ C, treated under pressure over a period of from 5 to 90 minutes and the reaction mixture then neutralized «whereby the collagen concentration of the treated solution is limited to about 5 to 2Q #. 4. The method according to claim 3, dadurch.'gekisiert ,, that one the acidic pH word with weak acids or buffered strong acids and the basic pH value with weak bases or buffered strong bases, the collagen itself being used as a buffer in particular. 109884/1470 17950R7 - KS - 5ρ Local or oral anvienafare compositions with non-toxic and beneficial for the treatment under consideration. Exsipients »geke: onseiclinst through a content of KollGgenbyarolyEat rmö -d ^ polymoriaat; nash Anspn.'c? h 1 or 2, 10988A / U70 ORIGINAL BATHROOM