DE2202176A1 - Complexes of biologically active natural or synthetic peptides and / or polypeptides and / or protein substances and / or their derivatives or salts, pharmaceutical preparations containing these and processes for producing the same - Google Patents

Description

DR. STEPHAN G. BESZEDES
PATENT ADVOCATE

806 DACHAU near MÖNCHEN

BOX 1168

AM HEIDEWEG 2

TELEPHONE: DACHAU 4371

Postal checking account Munich 1368 71 Bank account no. 90 637 at the Kreis- und Stadtsparkasse Dachau-lndersdorf

P 404

description

for patent application

JUDGE GEDEON VEGYESZETI GYAR R.T.

Budapest, Hungary

concerning

Complexes of biologically active natural or synthetic peptides and / or polypeptides and / or proteins and / or their derivatives or salts, pharmaceutical preparations containing them and processes for their production

The invention relates to new complexes of biologically active peptides and / or polypeptides and / or proteins and / or their derivatives or salts with prolonged and / or increased effect, pharmaceutical preparations containing these and methods of making the same.

In accordance with the therapeutic and clinical requirements, there is a worldwide effort to combine individual medicinal products into one to produce extended effect forms. In particular, this applies to the peptides, polypeptides and proteins as well

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such as their derivatives or preparations containing salts, in the majority of which the rapid inactivation of the active ingredient in the organism meant an unsolved or hitherto unsatisfactory problem. So they had to. introduced into the organism often or constantly so that the therapeutic effect lasts for a considerable period of time. This made their therapeutic application, in spite of their undoubtedly advantageous biological effect, practically impossible in certain cases and extremely difficult in other cases. There is therefore a need for such preparations which withstand the inactivating effect of the organism for a certain period of time and thus have a prolonged effect.

There are numerous drug process techniques for extension the. Duration of action of individual peptides and polypeptides known. These procedures are based on the principle that the peptides or polypeptides, for example, with sparingly soluble zinc compounds, such as zinc hydroxide, zinc phosphate, zinc polyphosphates or their salts, or also with high molecular weight organic materials, such as gelatin, poly- * saccharide derivatives, polyvinylpyrrolidone, phospharic acid polyphenol or phosphoric acid polyalcohol esters, protamines or polyglutamic acids, are reacted or certain Derivatives (for example tannic acid salts) of the peptides or polypeptides brought into an oily base material will. This slowly soaks up the active compound from the point of application. The listed procedures are limited to adrenocorticotropin, insulin and vasopressin only. The duration of the effect of the preparations produced in this way However, they cannot be controlled and so they do not always meet the therapeutic requirements.

The applicant's attempts were therefore directed towards the provision of biologically active peptides and / or polypeptides and / or proteins and / or their derivatives

209832/1

or preparations containing salts with extended and / or increased effect, which withstand the inactivating effect of the organism for a long time, whereby possibly moreover, their effect is stronger than that of the active peptides. It is also an object of the invention to delay the effect to solve from such biologically active materials, which were previously unknown in such a form.

In the course of the tests, it was found by the applicant that that a very effective delay can be achieved that the biologically active peptides and / or polypeptides and / or proteins and / or their derivatives or salts with hydrated and condensed natural or artificial silicon dioxide, silicic acid or any polysilicic acid or their salts, silicates, polysilicates or their mixtures are brought into contact; It was also surprisingly found that in some Peptides, polypeptides and proteins as well as derivatives and salts thereof are not only significant in this way controllable delay or retard effect occurs, but in a striking way even a biological one Increased effectiveness shows.

The complexes according to the invention, which can be referred to as adsorption complexes, are all new. A strange advantage it is also that from the greater part of the raw materials used peptides, polypeptides and proteins as well Derivatives and salts thereof (for example from hypertensin, oxytocin or its derivatives, gonadotropic hormones, Bacitracin, Polymyxin, Various Actinomycins, Valomycin, Thyrotropic Hormone, Somatotropic Hormone, 1-asparaginase, streptokinase, streptodornase, urokinase, Trypsin and of-kinotrypsin [<* - Kimotrypsin]) not yet a preparation with delayed effect and / or increased effect

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and / or controllable duration of effect was known.

The invention therefore relates to complexes of biological active natural or synthetic peptides and / or polypeptides and / or proteins and / or their derivatives, respectively Salts with a structure corresponding to or deviating from the natural structure with at least inorganic, partly composed of silicon / oxygen bonds Silicon compounds.

Furthermore, pharmaceutical preparations according to the invention are which contain or contain 1 or more of the above complexes as an active ingredient or active ingredients consist of this or these, provided.

The invention also relates to a process for the preparation of the complexes according to the invention, which is characterized is that 1 or more biologically active natural or synthetic feptides and / or polypeptides and / or proteins and / or their derivatives or salts with 1 or more at least partially made of silicon / Inorganic silicon compounds built up / oxygen bonds be brought into contact.

Biologically active peptides, polypeptides and proteins include not only natural substances, but also theirs synthetic equivalents and / or synthetic structures that are not identical to the natural molecules

Understand molecules.

According to the invention, the effect of all can be biological active peptides, polypeptides and proteins, as well as derivatives and salts thereof, which contain at least 1 amino acid have an acyl bond formed with another (the same or different from the former) amino acid, be extended and / or reinforced.

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Among the salts of biologically active peptides, polypeptides, proteins and their derivatives are to understand the therapeutically useful salts formed with inorganic or organic acids.

In this description, complexes are those whose structure has not yet been fully elucidated Compounds understood, which result from the peptides, polypeptides and protein substances and their derivatives and salts form in such a way that these with the specified at least inorganic silicon compounds partially having silicon / oxygen bonds are brought into contact.

Of the inorganic compounds having silicon / oxygen bonds, various silicon * dioxides, silicic acid and polysilicic acids and their salts, preferably silicates and polysilicates as retardants used; In particular, all inorganic silicon compounds built up at least partially from silicon / oxygen bonds, those made up of finite open silicon / oxygen chains and / or silicon / oxygen rings and / or endless silicon / oxygen chains and / or silicon / oxygen Layers or three-dimensional silicon / oxygen networks are built up and in which, if necessary, im characteristic silicon / oxygen molecular structure as well Framework components that are less electronegative than silicon occur and / or such elements with the framework can be connected.

As the retarding agent, the following can advantageously be used inorganic silicon compounds are used: synthetic silicon dioxides as well as naturally occurring Diatomaceous earths containing silica, respectively

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Kieselguhr types, for example various celites, silicic acid or polysilicic acids, which optionally in the Solution prepared in situ can include various natural and man-made silicates and polysilicates, for example Clays (such as kaolins, bentonites and montmorillonites), mica (such as muscovite, hydrous muscovite [HydromuskoviteJ and Biotite) feldspar (such as orthoclase, albite and anorthite), zeolites (such as heulandite, natrolite and clinoptilolite as well natural and synthetic molecular sieves) as well as expediently selected modifications of all obtained by ion exchange these materials.

The retardants used in the present invention are Commercial products (for example Attapulgit, Attasorb, Pharmasorb, Veegum, Bentone WS and Tonsil) and on the other hand from the applicant in the literature products which have been purified in a known manner and comminuted to colloidal fineness.

The complexes according to the invention are expediently prepared in such a way that aqueous solutions of peptides and / or polypeptides and / or proteins and / or their Derivatives or salts brought into contact with colloidal suspensions of inorganic silicon compounds will. The amount of the retarding agent to achieve the desired controllable retarding effect can be 0.1 up to 100 times based on the weight of the agent to be delayed.

The complexes according to the invention can be used therapeutically in the form of the customary pharmaceutical preparations. Such pharmaceutical preparations can be those according to the invention Contain complexes along with known auxiliaries. If necessary, the preparations can also be used in other

«209832/1065

contain active substances in the therapeutic relationship.

The pharmaceutical preparations can be, for example, injection solutions, lyophilisates or preparations, suspensions, suppositories, tablets,
Be coated tablets and capsules.

The pharmakologischeη investigations of different
Preparations prepared as above were carried out as follows:

The studies relating to hypertensin were carried out on rats weighing 250 to 400 g. The rats' blood pressure was sustained by ganglia-blocking agents
Effect reduced and then the blood pressure of the animals was recorded by means of an electromanometer arranged in the carotid artery. The sensitivity of animals to
Hypertensin was determined by intravenous administration of 0.1 ng
Hypertensin / kg body weight examined and then that was
Hypertensin is injected intramuscularly partly in solution in an isotonic sodium chloride solution, partly in the form of magnesium / aluminum silicate complexes of colloidal fineness and various concentrations. It was found that
with administration of 25 US hypertensin / kg body weight in
an isotonic solution practically no hypertensive
Effect occurs. The 25 mg hypertensin / kg body weight, from which a complex was generated with 3 »5 times the amount by weight of magnesium / aluminum silicate, based on the active ingredient, showed a 5 to minute duration and 20 to 20 minutes in each of the animals examined 50% increase in blood pressure, based on the susceptibility test. When using 7 times the weight of the delay agent, ä.ch extended the
Duration of the increase in blood pressure to 20 to 60 minutes and the
maximum increase in blood pressure, based on the susceptibility test, increased to 50 to 100%. From the measurement results it can be determined that the hypertensin according to the invention

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can be delayed and it was also found that with an appropriate choice of the ratio of delay agent to the peptide to be delayed under the test conditions an optimum with regard to the proportion of the delayed agent is to be observed.

Those concerned with delaying the effect of oxytocin Investigations were carried out on anesthetized or anesthetized rats and after opening the abdominal wall the tone and contractions of the uterus were registered in an isotonic way. So was the observation of the Strength and duration of the effect of the oxytocine possible. It was found that when administered intramuscularly of 0.1 IU oxytocin / kg body weight (0.1 U oxytocin / kg body weight) in an isotonic sodium chloride solution no effect was detectable on the uterus. If the oxytocin complex contains 0.1 or 0.2 mg magnesium / aluminum silicate, based on 1 I.E. active ingredient, and of the preparation delayed in this way intramuscularly an identical dose was administered, an extremely evaluable contraction and increase in tone were found, which in the case of the lower concentration took an average of 39 minutes. From the above it can be seen that the oxytocin can also be delayed according to the invention.

Delayed preparations produced according to the invention from insulin were tested according to VI. Magyar Gyogyszerkönyv, Volume I, page 164 examined on hares. For comparison, a isotonic sodium chloride solution and insulin delayed with zinc / / protamine are used. During the examinations it was established in accordance with the information in the literature that the duration of action of the in an isotonic · Sodium chloride solution of dissolved insulin for less than 4 hours ibt. When using zinc / protamine delayed insulin, blood sugar levels reached even after 7 hours

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80% of the initial value is not. After 8 to 12 hours, however, the blood sugar levels went down in those with zinc / protamine delayed insulin-treated animals return to the initial value in each case. If 40 I.E. insulin with 3 mg polysilicate was delayed according to the invention, the blood sugar level remained in the case of the administration of an identical dose even for a period of up to 24 to 36 hours 80% of the initial value. The first 7 hour segment of the blood sugar curve is the one with the zinc / protamine delayed Insulin obtained curve similar. On the basis of the tests it can be established that according to the invention a significantly longer one permanent even reduction of the blood sugar level can be achieved than with the use of zinc / protamine.

The first delayed preparation of coriogonadotropic hormone was produced according to the invention. Since the administration of

human coriogonadotropic hormone in therapy is done by intramuscular route, which is a high molecular weight containing protein-like compound exposed to the action of the tissue ferments. Because of the decomposition of the hormone , exceptionally high volumes (1,500 to 4,500 international Units £ l. E.J) administered so that the desired therapeutic Effect comes about. When the delayed preparation according to the invention is used, the desired results are achieved Effect also became possible by administering a smaller amount. The experiments were carried out in an isotonic Coriogonadotropic hormone dissolved in sodium chloride solution, as well as complexes formed with polysilicates of various concentrations ▼ on human coriogonadotropic hormone administered. The investigations were partly on adolescent males, partly performed on juvenile female rats. In the male rats, the weight change of the prostate + seminal vesicle measured (Magyar Gyogyszerkönyv, VIth edition, Volume I, Page 160) and also the weight gain of the prostate (Lorain: J. Endocrinol. 6, 319, 1950) was investigated. Both

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juvenile female rats were gaining weight of the uterine horns measured. It was found that during a 1 week observation period using 9 mg of retarder to 130 I.E. active ingredient both in the male animals and in the female animals one in comparison the effect of the active ingredient diluted with the isotonic sodium chloride solution occurred 2.4 times as great. Likewise During a 1-week observation, a 3 × 6-fold increase in activity was observed when using twice the amount of the delay agent. Similar results were also obtained for Obtain observation times of 2 and 3 weeks, respectively. From the above results it is clear that the complex of the present invention has the effect of human coriogonadotropic hormones prolonged and strengthened and furthermore by changing the quantitative ratio of the retarding agent sum hormone the degree of delay can be changed.

For the pharmacological investigation of the delayed peptides according to the invention with adrenocorticotropin action, the known method based on the increase in blood corticoid level was used (Hedner, F., Acta pharmacol. Toxicol. 18, 65 [1961J? Rerup, C ₁ Hedner, P., Acta endocr., Jfö, 527 [1962] J; Rerup, 0., Hedner, P., Acta endocr., 46, 279 [19643). The experimental rats were injected intramuscularly and subcutaneously with the prolonged-action preparations prepared with retardants of various concentrations. The corticosterone levels were measured on peripheral blood samples taken at different times from the administration. AT ₁ . For comparison, adrenocorticotropin in the same amount, but in a non-delayed form, ie in solution in an isotonic sodium chloride solution and the synthetic best-known delayed adrenocorticotropin preparation formed with zinc phosphate were examined in the same amount. The time-dependent investigation of the blood corticoid level clearly demonstrated that the various adrenocorticotropically active peptides

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2098324 & 065

Complexes obtained according to the invention have a greatly prolonged effect ensure which duration of action can also be influenced by the concentration of the delay agent in the case of intramuscular administration, the effect is prolonged compared to that of the comparative preparation, the advantage of the invention delayed preparations is more pronounced when administered subcutaneously. When administered intramuscularly one made from 100 I.E. of active ingredient with 4 mg of delay agent Complex in a dose of 10 I.U./kg body weight was tested in a 24-hour study in the case of the invention Sample obtained a corticosterone level of 27 »4 ug / 100 cm * in the blood sample taken after 24 hours, while with the identical amount of the zinc phosphate delayed synthetic adrenocorticotropin preparation used for comparison this value was only 12.4 µg / 100 cnr. In the above way, for example, the corticotropin preparations 1-24 H, 1-28 H, 1-32 H, 1-39H, 1-23 amide and natural, lichee porcine can be delayed.

The activity of the vasopressin was increased with a% The amount of water hydrated perorally hydrated rats was investigated according to their body weight (J. H. Burn: "Biological Standardization ", 1950, Oxford University Press, page 187). The test animals were placed in metabolic vessels and the time was measured during which they emptied 50% of the amount of water introduced. This was 80 to 90 minutes for the control animals. In the case of subcutaneous injection of 0.008 I. E. vasopressin in aqueous Solution increased the duration of the 50% evacuation to 130 minutes. When using one of the peptide with 1 mg hydrous aluminum silicate (aluminum hydrosilicate) per 1 I.E. produced complex extended with an "identical Dose the duration of the water evacuation in comparison «by only about 2 times the peptide dissolved in water, which proves the retarding effect of the complex.

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The invention is not intended to be limiting in light of the following Examples to be understood are explained in more detail.

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example 1

A sterile filtered aqueous solution of hypertensin was mixed under aseptic or aseptic conditions with a colloidal suspension of hydrous aluminum silicate (aluminum hydrosilicate) and mannitol, the solution was acidified with 0.1 η hydrochloric acid to a pH of 6 and filled into ampoules and lyophilized. Dry ampoules containing the following ingredients were thus obtained:

Hypertensin 0.5 mg

Hydrous aluminum silicate (bentonite) 4.0 mg mannitol 25.0 mg

Before use, the contents of the dry ampoule were mixed with 2 cm of an isotonic sodium chloride solution in a solvent ampoule.

Example 2

50 I.U. corresponding oxytocin was dissolved in 6 cm * of an iaotonic sodium chloride solution, 100 mg of sodium silicate and 1 g of glycerol were added and the suspension was then brought to a pH of 4.5 with 0.1 η hydrochloric acid acidified. It was then diluted to 10 cm with distilled water, filled into ampoules and sterilized at 100 ° C. for 30 minutes.

Example 3

There was dissolved 50 IU oxytocin appropriate under aseptic conditions in 7 cnr an isotonic sodium chloride solution, 9 mg of magnesium / aluminum-silicon-cate and 0.1 mg merthiolate added and then the

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Suspension acidified to pH 5 with 0.1 η hydrochloric acid. After that, it was turned on with distilled water 10 cm * filled and the whole thing under aseptic conditions filled in ampoules.

Example 4

It was 2,000 I.U. corresponding crystalline insulin with the help of 10 (drops of 0.1 η hydrochloric acid in 2.5 cnr Dissolved in water. The solution was 25 cnr of a suspension of Magnesium / aluminum silicate, which per cm * 4 mg magnesium / Aluminum silicate and 0.03 mg glycerol was added. To the solution thus obtained, 20 cnr of a solvent containing 115 mg of methyl p-oxybenzoate, 36 mg citric acid and 290 mg

^ .2 HoO contained, added. The pH of the on a Total volume of 50 cnr replenished solution was 6.8.

The composition of the solution thus prepared was as follows:

Insulin (crystallized) 40.0 I.U / cm ⁵

Magnesium / aluminum silicate ("Veegum") 2.0 mg / cnr

p-Oxybenzoic acid methyl ester (nipagin) 1.0 mg / cm * Citric Acid 0.33mg / cm ^

Disodium phosphate. 2 HpO 5 »8 mg / cnr

Glycerin 15 »0 mg / cnr

Example 5

It was made up of the following components (the amounts given relate to 1 ampoule) in dry ampoules filled preparation produced:

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Coripgonadotropic Hormone 500 I.E.

Magnesium / aluminum silicate ("Veegum") 35 »O mg

Merthiolate 0.02 mg

Glycocolla 15 »0 mg

The sterile filtered aqueous solution of the coriogonadotropic hormones was mixed under aseptic conditions with the magnesium / aluminum silicate, merthiolate and glycocoll, the solution was _{acidified with 0.1 η hydrochloric acid to a pH of S 1} ^, filled into ampoules and lyophilized. Before use, the contents of the drying ampoule were mixed with 2 cnr of 0.9 # sodium chloride solution filled in a solvent ampoule.

Example 6

Ee, a peptide corresponding to 2500 IU with AOTH activity 1-28 H was dissolved in 2 cm ^{5 of} water. 10 cm of a suspension of magnesium / aluminum silicate containing 15 mg of magnesium / aluminum silicate was added to the solution, and then 4 cm of buffer solution, the _{Na.HPO 1} , .2 HpO content of 45 mg / cm and the citric acid content of which was 25 mg / cm. The mixture was made up to a total volume of 25 cm. The pH of the mixture was 5-5. The solution thus obtained contained the following materials in each case:

. Peptide ACTH _{1-28 H} 50 1. E. '

Magnesium / aluminum silicate ("Veegum") 3.0 mg

Citric acid 2.5 mg

Disodium phosphate. ₂ H 2 O 3.6 mg

Benzyl alcohol 10.0 mg

Sodium chloride 8.0 mg

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Example 7

It was made up of the following components (the amounts given relate to 1 ampoule) in dry ampoules filled preparation produced:

ACTH (obtained from the pituitary gland of the pig) IO I. E. Sodium silicate 5 mg

Mannitol 20 mg

It was added to a sodium silicate solution acidified to pH 4.5 with 0.1 M hydrochloric acid the ACTH and the mannitol were added under aseptic conditions and the whole was filled into ampoules and with stirring lyophilized. Before use, the contents of the desiccant vial were filled with 2 cnr in a solvent vial distilled water containing 0.9% benzyl alcohol and 0.7% sodium chloride, mixed.

Example 8

Fecal suppositories were obtained from the following constituents (the amounts given relate to 1 fecal suppository) manufactured:

Peptide ₁ ^ _{28 R}

Magnesium / aluminum silicate ("Veegum") ^ Distilled water

Semi-solid, paraffin-like polyethylene glycol (Carbowax 15OO)

Polyoxyethylene sorbitan monofatty acid ester (Tween 61)

The peptide ACTH ,, p "π was prescribed in the

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1 mg 5 mg 95 mg 100 mg 800 mg

The amount of water dissolved, the magnesium / aluminum silicate was added, the whole was mixed and the suspension was acidified to a pH value of 6 with _{an O t 1 η hydrochloric acid.} The polyethylene glycol and the polyoxyethylene sorbitan monofatty acid ester were liquefied at a temperature of 35 to 40 ° C., the aqueous peptide suspension was added in smaller portions with stirring and suppositories of 1 g were produced by a casting process.

Example 9

Fecal suppositories were obtained from the following constituents (the amounts given relate to 1 fecal suppository) manufactured:

Peptide ACTH ^ _{-28 H} 1 mg

Kieselguhr (Gelite). 5 mg

Distilled water 46 mg semi-solid, paraffin-like polyethylene glycol

(Carbowax 1500) ^ ^{48 mg} White, hard, translucent,

water soluble polyethylene glycol (Carbowax 6000) ^mg

Mirj 52 100 mg

The peptide ACTH * or η ^ ^{WUR e} i ⁿ ^ ^he prescribed · amount of water released. The kieselguhr was added, the whole thing was mixed and the suspension was acidified to a pH of 6 with 0.1 η hydrochloric acid. The polyethylene glycols and the Mirj 52 were ^{liquefied at a temperature of 35 to 40 0} C and then was under. Stirring in smaller portions, the aqueous peptide suspension was added and suppositories of 1 g were produced by a pouring method.

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5 I. E. 20th mg 2 mg 17th mg 20th mg

- 18 -

Example 10

A vasopressin suspension was made from the following ingredients manufactured:

Vasopressin

Magnesium / aluminum silicate ("Veegum") methyl p-oxybenzoate (nipagin) sodium chloride

Glycerin

Acetic acid to pH 4.5 hit distilled water made up to 2.0 cnr

Example 11

50 I.E. of the corresponding vasopressin was dissolved in 6 cm * of an isotonic sodium chloride solution, 40 mg of magnesium silicate ("Bentone WS") and 74 g of glycol were added and the suspension was then made up with 0.1 η hydrochloric acid. acidified to a pH of 4.5. Thereafter, the whole was filled cnr with distilled water to 10, filled into ampoules and sterilized for 30 minutes at 10O ⁰ C.

Example 12

It was a sterile filtered aqueous solution of Polymyxin B under aseptic conditions with a silica ("Aerosil") and sodium chloride containing sterile suspension mixed and filled into ampoules and then lyophilized. So were dry ampoules, which the contained the following ingredients:

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Polymyxin B 10 mg

Silica ("Aerosil") 10 mg

Sodium chloride 12 mg

Before use, the contents of the dry ampoule were mixed with 2 cm of a 1% procaine solution in a solvent ampoule.

Example 15

It was made up of the following components (the amounts given relate to 1 ampoule) in dry ampoules filled preparation produced:

Ergotamine tartrate 0.5 mg

Fuller's earth ("Tonsil") 2.0 mg

methyl p-oxybenzoate (nipagin) 1.0 mg

Glycocolla 20.0 mg

A sterile filtered aqueous solution of the ergotamine tartrate was added under aseptic conditions to a suspension containing the bleaching earth, the p-oxybenzoic acid methyl ester and the glycocol, which had previously been acidified to a pH of 5 with 0.1 η hydrochloric acid , and then the whole was filled into ampoules and lyophilized. Before use, the contents of the drying vial were mixed with 2 cnr of an isotonic sodium chloride solution filled in a solvent vial.

example

It was made using the peptide ACTH / j * q ^ the following ingredients are made into a suspension:

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Peptide ACTH _{1-59 H}

Magnesium / aluminum silicate ("Veegum")

Benzyl alcohol sodium chloride

0.1 η hydrochloric acid up to a pH value of 6.5 Made up with distilled water

Example 15

2202176 I. E. 50 mg 2 mg 10 mg 8th cm* 1

A peptide corresponding to 1,250 IU with ACTH activity 1-24 H was dissolved in 2 cm ^ V / water. The solution was given 10 cm of a suspension of magnesium / aluminum silicate, each containing 15 mg of magnesium / aluminum silicate, and then 8 cm of a buffer solution, the content of which was NaH ₂ PO ₄ ^ H ₂ O 132 mg, the content of Na ₂ HPO ₄ 320 mg and the sodium chloride content of which was 205 mg. The mixture was made up to a total volume of 25 cm with distilled water and then the suspension thus obtained was added in smaller portions with stirring to 25 cm of an aqueous solution which contained 2% benzyl alcohol. The pH of the suspension was 6.4. The suspension thus obtained contained the following materials per cm *:

Peptide ACTH _1-2 ^ _H 25 IU

Magnesium / aluminum silicate ("Veegum") 3 _m g

_t sodium dihydrogen phosphate. ₂ H 2 O 2.6 mg

Disodium phosphate 6.4 mg

Benzyl alcohol 10 mg

Sodium chloride 4 x mg

According to Examples 1 to 15, Bacitracin, various actinomycins, valomycin, thyrotropic hormone,

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Streptodornase, urokinase, trypsin and o (-kinotrypsin (0 (-Kimotrypsin) drug preparations manufactured.

Claims

Claims (1)

Claims 1.) Complexes of biologically active natural or synthetic peptides and / or polypeptides and / or proteins and / or their derivatives, respectively Salts with a structure corresponding to or deviating from the natural structure with at least Inorganic silicon compounds partly built up from silicon / oxygen bonds. 2.) Complexes according to claim 1, characterized in that the or at least 1 peptide and / or polypeptide hypertensin, vasopressin or respectively Angiotension or one of the main biological effects is the hormone inducing compound. 3.) Complexes according to claim 1 or 2, characterized in that the or at least 1 peptide and / or Polypeptide oxytocin or a compound that triggers the main biological effect of the hormone is. 4.) Complexes according to claim 1 to 3 »characterized in that the or at least Λ polypeptide and / or derivative thereof is an adrenocorticotropic hormone-active material. Complexes according to claim 1 to 4 _t characterized in that the or at least 1 polypeptide is a compound having insulin action. 6.) Complexes according to claim 1 to 5, characterized in that the or at least 1 protein is a gonadotropic hormone-active material. - 23 - 209832/1066 7.) Complexes according to claim 1 to 6, characterized in that that the or at least 1 peptide and / or polypeptide and / or derivative thereof is antibiotic, antimycotic or cytostatic material. 8.) Complexes according to claim 1 to 7 »characterized in that the or at least 1 protein is a thyrotropic hormone or thyrotropic hormone-active material. 9) Complexes according to claim 1 to 8, characterized in that that the or at least 1 protein is a somatotropic hormone or somatotropic is hormone-active material. 10.) Complexes according to claim 1 to 9, characterized in that the or at least 1 peptide and / or polypeptide is a therapeutically useful enzyme. 11.) Complexes according to claim 1 to 10, characterized in that • that the or at least 1 inorganic silicon compound is one of finite open silicon / / oxygen chains and / or silicon / oxygen rings and / or endless silicon / oxygen chains and / or silicon / oxygen layers and / or dreidimensiona _t len silicon / oxygen networks constructed, possibly also a lower electronegativity than silicon possessing scaffolding element and / or having associated with the scaffold element compound. 12.) Complexes according to claim 1 to 11, characterized in that the or at least 1 inorganic Silicon compound a natural or sy η the- - 24 - 209832/1066 2202178 bexlohvrssvtlet sin n? -7Ur »τη ?;» Λ -. Tprosh 1 fci13 , 4fi <fare2i gtfcftttnfttleh * a r ^ l »dtmtlbtn 1» * · ? * 1 Me 13 _f d «<! Iurch flnfl dlf> Π1 ^ · ΡΐΐΓ'Γ« Γ · » tr} Vo <J * r Γοΐχ kit β ti β H ure urvS / odtr dt« r «n UnIr ^ itf> i? i? o _$ r3 loht in solution in fltu trhalttn who · ) Complex "nnch Aniipruch 1 to 11 * deduroh e" ktnaMlehfit% | Λ ^ Ο di # i b ^ eirlnr '^ rfip' »mii ^?, ^« T «nn 1 tnorstnlioht Olliciunrtrbln'irr ^ ojn colloidel · · Silicate bvtithttoe ·· "Ties M" Gnt "ittn //. Lu" iniu "-illik" t lit. 16.) Ko9pXf> x9 nich Arnprnch 1 am 15, thus gtktanet wages, d ^ ß die beti ^ h ^^ rrnTralPe nindftotena 1 tnugtnltoht OilioiuavtrbinduTin «in Ton uad / or Olisatr bteithungewelst tine BweokmKQlg ßewfthlte duroh Iontnauetauaoh modified modification of the same. 17) Complexes according to Annpruoh 1 to 16, thereby gtktnnetlch- net, that the hunger-free aindeatena 1 inorganic " Silicon compound, a feldspar and / or zeolite, has a size selected by ionic precision. »Is a modification of the same received in exchange. 1Θ.) Complexes according to claim 1 to 13 or 15 to 17 »characterized in that the clay is a kaolin and / or Bentonite and / or montmorillonite or tine appropriately chosen modification of the same obtained by ion exchange is. COPY - 25 - BATH ORIGINAL 209832/1085 19 ·) Koaplojte according to claim 1 to 13 or 15 to 17 »thereby Marked that dor Gliciror üuokovit and / or uasrorhnltiger Uuskovlt (hydrorauakovite) and / or Illlt or rather a "badly rooted one." Ion exchange obtained modification thereof. 20.) Complexes according to claim 1 to 13 or 15 to 17, characterized in that the feldspar and / or orthoclase Albite and / or Anorthlt or a purposefully digested modification of the same obtained by ion exchange. 21 ·) Eonplexe according to claim 1 to 13 or 15 to 17 «thereby characterized in that the zeolite is a natural and / or artificial zeolite or an appropriate one perceived modification of the same obtained by ion exchange 22.) Pharmaceutical preparations, characterized by a Content of 1 or more complexes according to Claims 1 to 21 as active ingredient or ingredients. 23 ·) Pharmaceutical preparations according to claim 22, characterized by a content of customary formulation agents, preferably carriers, binders or lubricants, and / or other active ingredients with a similar effect. ) Process for the preparation of the complexes according to claim 21, characterized in that 1 or more biologically active natural or synthetic peptides and / or polypeptides and / or proteins and / or their derivatives or salts with 1 or more at least partially of silicon / oxygen - -Bonds built up inorganic silver silicon compound- COPY. 26 - - 2ο - brings bonds into contact. 25.) Method according to claim 24, characterized in that the bringing into contact of the peptides and / or polypeptides and / or proteins and / or their derivatives or salts with the inorganic silicon compound or the inorganic Silicon compounds in an aqueous medium, expediently at room temperature. 26) The method of claim 24 or 25, characterized in that the inorganic silicon compound or inorganic silicon compounds in the 0.1 to 100-fold amount, based on the weight of the peptides and / or polypeptides and / or proteins and / or their Derivatives or salts are used. 209832/106 *