CH574247A5 - Oily, injectable peptide/aluminium alkanoate compsns - - with prolonged duration of activity - Google Patents

Abstract

Oily, injectable compsns. of peptides in which (A) the peptide or its salt is adsorbed on an Al salt of a fatty acid, the absorbate being suspended in the oil or (b) the peptide or its salt is suspended in a gel formed from an Al salt of a fatty acid and an oil. The compsns. are for i.m. or s.c. injection or may be given intranasally. They have greatly prolonged duration of activity compared with known compsns. which may be of 7-8 days. Pref. peptide/Al salt ratio is 1:5-1:10. The gels pref. contain 0.5-2% w/v of Al salt in the oil. The pref. Al salt is aluminium stearate and the pref. oil is arachis oil.

Description

  

  
 



   In the therapeutic use of physiologically active peptides, e.g. B. corticotropins, MSH, calcitonins, hypertensins, insulin, growth hormone, glucagons, thyrotropins, LHRH, TRH, vasopressins, bradykinins and the like. a., a problem that has not yet been satisfactorily resolved is that the peptides in the body are inactivated too quickly. Attempts have been made in various ways to extend the effectiveness, e.g. B. in ACTH by forming complexes of the peptides with inorganic substances such as sparingly soluble zinc compounds, for example zinc hydroxide or zinc phosphate, or with organic substances such as gelatin, polyvinylpyrrolidone, phosphoric acid esters of polyphenols or polyalcohols, for example polyphloretin phosphate or alkaline or acidic polyamino acids, for example protamine or polyglutamic acids.

  Apart from the fact that the prolonged effect achieved is not fully satisfactory, certain of the preparations produced also have the disadvantage that they can cause allergies.



   It has now been found that a much greater prolongation of activity than before can be achieved if a gel made of a fatty acid aluminum salt and a fatty acid ester, in particular a vegetable oil, which is liquid at room temperature, is used as the carrier material for the peptide. The present invention therefore relates to a carrier especially suitable for the production of injectable oily peptide preparations, which consists of a gel containing a mixture of 0.1 to 10% (w / v) fatty acid aluminum salt and a fatty acid ester which is liquid at room temperature.



   The gel used as the carrier consists of a mixture of approx. 0.1 to 10%, preferably 1-3 (weight: volume) fatty acid aluminum and a liquid long-chain fatty acid ester. The fatty acid aluminum salt mainly contains stearic acid as fatty acid, but other long-chain saturated or unsaturated fatty acids with 12 to 22 carbon atoms, e.g. B. the above can be used. The fatty acid aluminum salt is preferably a mono fatty acid salt, e.g. B. monostearate, contains one mole of fatty acid per gram atom of aluminum. But you can also use di or tri-fatty acid salts of aluminum, especially the commercially available products that do not always correspond exactly to the chemical name, but rather according to their aluminum hydroxide content, e.g.

  B. according to the formula Al (OH) n (Cl7H3sCOoH) 3-ns where n is 0, 1 or 2, can be named. According to U.S. Pharmacopeia XVIII, for example, aluminum monostearate contains 14.5 to 16.0% Al2O3 and correspondingly varying amounts of stearic acid or other fatty acids, especially palmitic acid.



   The liquid fatty acid ester contains a long-chain fatty acid with 8-22, especially 12-22 carbon atoms, such as. B. the above-mentioned fatty acids. The alcohol component has a maximum of 6 carbon atoms and is a mono- or polyvalent, z. B. mono-, di- or trihydric alcohol, e.g. B. methanol, ethanol, propanol, butanol or pentanol or their isomers, but especially glycol or glycerine. Examples of fatty acid esters are: ethyl oleate, isopropyl myristate, isopropyl palmitate, Labrafil M 2735 (polyoxyethylene glycerol trioleate from Gattefosse, Paris), Miglyol 812 (triglyceride of saturated fatty acids or chain length C8 to C12 from Chemische Werke Witten / Ruhr, Germany) vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, rapeseed oil, especially peanut oil.



   The gel is prepared in a known manner, e.g. B. by slowly heating the ester together with the aluminum salt to approx. 140 ° C. while stirring. A clear gel forms at approx. 115-125 "C. When the temperature of approx.



     140 C is reached, the heat source is removed and the gel is allowed to cool to 1200 C with stirring and from this temperature to room temperature without stirring. The gel should preferably have a viscosity of 20-250 cP, preferably 50-100 cP, at 20.



   The preparations made with the carrier according to the invention, for. B. ACTH preparations, have a prolongation of the effect of several days, z. B. 7-8 days. According to the state of the art, this could by no means be foreseen. It is especially surprising that this long-term effect can be achieved with the usual extremely small doses of peptide, e.g. B. with fractions of a milligram can be achieved.



   The peptides mentioned at the beginning can be considered as physiologically active peptides, especially calcitonins and peptides with MSH and ACTH effects. The latter include the peptides with the structure of the natural MSH and ACTH peptides and synthetic peptides or peptide amides with a shorter amino acid sequence and / or with a modified amino acid sequence. As ACTH-effective peptides or peptide amides z. B. those with an N-terminal sequence up to the 16th to 39th amino acid of the natural corticotropins. In this sequence, one or more of the amino acids, especially amino acids 1 to 4, can be missing, e.g. B. in Angew.



  Chemie 83, 155 (1971), or one or more amino acids, e.g. B. in positions 1-5, 11, 15-18 and 25-33 by other amino acids, amino acid 1 can also be replaced by a deaminocarboxylic acid. For example, the serine residues serine and / or serine3 by glycine or alanine, tyrosine2 by phenylalanine, methionine4 by α-amino-lower alkyl acetic acid, in which lower alkyl has 2-4 carbon atoms, e.g. B. norvaline, valine, norieucine, leucine, isoleucine, α-aminobutyric acid, glutamic acid through glutamine, lysine11 and / or lysine15,16 through ornithine, arginine17,18 through lysine or ornithine, amino acid25 through valine. Serin1 can also e.g.

  B. by proline, a- orerss-alanine, threonine, propionic acid, β-aminopropionic acid, β-hydroxypropionic acid, butyric acid, y aminobutyric acid, α-aminoisobutyric acid, valeric acid, caprionic acid, E-aminocaproic acid or phenylglycine. All amino acids, except those in the N-terminal 1-position, necessarily have the L-configuration.



  The new preparations preferably contain ACTH-effective peptides whose first amino acid has the D configuration, especially D-serine; Furthermore, peptides with a chain length of 18-24 amino acids, especially with 18-19 amino acids, are preferably used. Also to be emphasized are preparations which contain C-terminal N-unsubstituted amides of the named ACTH-effective peptides, especially those of peptides with a sequence of 18 amino acids, primarily D-Ser1-Lysl7> 8-ss118-corticotropine- Lysl8-amide. Peptides with 25-39 amino acids in the range 25-33 preferably have the sequence determined for human ACTH (cf. Nature New Biology 235, 114 [1927]).



   ACTH-effective peptides suitable for the preparations are, for example, D-Ser1-corticotropin-Arg18- amide, D-Ser1-Om11-Lys17, 1s-ssl¯l8-corticotropin-Lysl8-amide, D-Ser1-Orn11, '5-1B¯pl-18¯CortiCotropin-Ornl8-amide, the a-AminoisobutynS ll-ssl-18-Corticotropin-Argl8-amide, the D-Ser1-Orn17, 18-ss 118-Corticotropin-Om> 8-amide , the D-ser1-GIy3-Lys17s18-ss1-18-corticotropin-Lys18-amide, the D Ser1-Nle4-Lys17 18-ss '-' 8-corticotropin-lysl8-amide, the D-Ser1 Lys17,

   18-ss119-corticotropin, the ss9-corticotropin, the D Ser1-ss 1-l9-corticotropin, the ss 1-l9-corticotropin-prol9-amide, the Glu (NH2) 5-ss119-corticotropin, the D-Ser ' -Lys17,18- Val19-ss1-l9-Corticotropin-Val9-amid, the D-Ser1-Nle4-Lysl7118¯ Val19-ss1-19-Corticotropin-Val9-amide, the ss l-20-Corticotropin-Val20-amide, the D-SerÚ-ss120-Corticotropin-Val20-amide, the D-SerÚ-Lysl7918-ss1-20-Corticotropin-Val20-amide, the a-Amino butyryl4-Glu (NH2) s-ss1-2 -Corticotropin-Val20- amide, the D Serl-Lysl 16-ssÚ-19-corticotropin-Pro19-amide, the a-aminobutyryl4-ss l-20-corticotropin-Val20-amide, the ss Ú-21-corticotropin,

   the D-SerÚ-Lys17,18-ss1-21-corticotropin-Lys21-amide, the D-Ser1 Lys -ss 22-corticotropin-Val22-amide, the 23-corticotropine, the ss1-23-corticoropin-Tyr23-amide , (fas ss-Ala1-ss 1-23 Corticotropin-Tyr23-amide, the D-Serl-ss 3-Corticotropin-TyI23 amide, the D-SerÚ-Ala3-ssÚ-23-Corticotropin-Tyr23-amide, the Glyl- ss 3-Corticotropin-Tyr23-amid, the D-Ser1-Lysa7 18 ssl-23 Corticotropin-Tyr23-amid, the ss124-Corticotrnpin, the Glu (NH2) 5-ss1-24-Corticotropin, the D-SerÚ-Orn17, 1s-ssl-24-corticotropin, the Glyls3-ssl-24-corticotropin, the Orn17, 18-ss124-corticotropin,

   Lysl7, ls-ssl-24-corticotropin, D-Serl-Nle4 ss1-24-corticotropin, D-Serl-ssl-24-corticotropin, D Ala1-ssl-24-corticotropin, D-Serl-Gly3 -Lysl7 18-ssl-24-Corticotropin, das D-SerÚ-Nle4-Lys17,18-ssÚ-24-Corticotropin-Pro24 amid, D-SerÚ-Orn17,18-ss1-24-Corticotropin-Pro24-amid, das D Serl-Nle4-Ornl7 jl8-ss 1-24-Corticotropin-Pro24-amid, the D SerÚ-GIy -Lys17,18-ssÚ-24 corticotropin-Pro24-amid das D SerÚ-Lys17,18-ssÚ-24- Corticotropin, the D-Ser1-Lys17,18-ss 1-24 corticotropin-Pro24-amide,

   the D-Ser1-Nle4-Val2s-ssl-2s-corticotropin-Val25-amide, the D-Serl-Nle4-D-Val2s-ssl-2s-corticotropin-D-Val25-amide, the D-SerÚ -Nva4-Lys17,18-Val25-ssÚ-25 Corticotropin-Val25-amid, dasssÚ-25-Corticotropin-Val254-amid- das D-Ser'Nle4-Lys'7''8-VaPS-P 5-Corticotropin-Val25 -amid, the Nle4-Val25-ssÚ-25-corticotropin-Val25-amid, the Nva4 Val25-ssÚ-25-corticotropin-Val25-amide, the Nle4-Lys17 18-Val25- ss1-25-corticotropin-Val25-amide, the ss6-corticotropin, the ssÚ-28-corticotropin, thatsl-30-corticotropin, the, B1-3l-corticotropin, thats1-39-corticotropin, the D-Ser1-ssl-39-corticotropin,

   the Gly1-ssl-39-corticotropin.



   Synthetic α-MSH peptides, which, as described in US Pat. No. 3,803,309, have a regulating effect on the release of growth hormone and can also be used in the new preparations, are the peptides mentioned in the above patent, especially those with the sequence of the first 11-16 amino acids of ACTH, in which the above-mentioned replacement amino acids for ACTH can be present, and in which the first amino acid is preferably acylated, especially acetylated, primarily α-MSH and D-Ser1-α-MSH.



   Calcitonins to be used in the preparations are the known natural calcitonins such as pig calcitonin, human calcitonin, salmon calcitonin, bovine calcitonin, sheep calcitonin, and synthetic analogs in which one or more amino acids are replaced by others, e.g. B.



  Methionine by norleucine, or in which the first amino acid has been replaced by a deamino acid or an acyl amino acid.



   In the preparations, the peptide is used in free form or in the form of a therapeutically useful acid addition salt. Such salts are derived from z. B. of inorganic acids such as hydrohalic acids, for example hydrochloric acid or hydrobromic acid, perchloric acid, nitric acid or thiocyanic acid, sulfuric or phosphoric acid, or organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, hydroxymaleic acid, dihydroxymaleic acid, benzoic acid, phenylacetic acid, 4-aminobenzoic acid, 4-hydroxybenzoic acid, anthranilic acid, room acid, mandelic acid, salicylic acid, pamoic acid, methanoic acid, 2-phenoxy acid, acetylenic acid, 2-aminosulphonic acid, acetic acid, 2-aminosulphonic acid, phenyl-phenoxyacid, dihydroxymaleic acid, dihydroxymaleic acid , Hydroxyethanesulfonic acid,

   Benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid or sulfanilic acid. Salts with long-chain fatty acids, e.g. B. those with 12-22 carbon atoms such as lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, eicosacarboxylic acid (1), behenic acid, and corresponding unsaturated acids such. B. oleic acid, elaidic acid, erucic acid, brasidic acid, linoleic acid.



   The preparations are made by mixing the peptide or peptide salt with the gel. One can proceed, for example, that the required dose of the peptide or peptide salt is micronized, e.g. B. to a particle size of at most 50, preferably below 20, and rubbed with a small amount of the gel and then diluted the concentrate obtained with the remaining gel, or you can micronize the peptide or peptide salt with a small amount of the ester and then with mix with the gel. There is also the possibility of the peptides in a solvent, e.g. B. a preservative such as benzyl alcohol to dissolve and then mix with an appropriate amount of the previously prepared gel.

  Injection preparations produced in this way are characterized by a particularly fine degree of distribution of the preparations.



   The injection preparations are manufactured under antimicrobial conditions. One can proceed in such a way that the active ingredients and auxiliary substances are subjected to a suitable antimicrobial treatment prior to filling. The aseptic oily preparations are filled into suitable containers and sealed under antimicrobial conditions.



   The effective dose of the peptide to be used in the preparations is that single dose which is administered when the peptide is used in aqueous suspension or solutions. This dose, which depends on the type of peptide, is known. In the case of ACTH peptides, it is e.g. B. at 0.03 to 3.0 mg / ml. Preservatives, e.g. B. Benzyl alcohol can be added.



   The following examples serve to illustrate the invention. The temperatures are given in degrees Celsius.



   example 1
2.0 g of powdered aluminum monostearate are added to 100 ml of peanut oil. This suspension is mixed thoroughly and heated to 1.40 "C with stirring and slow heating (2-3" per minute) (a clear gel forms at approx. 115-125 "). The heating is then switched off and stirring continues until the Temperature has dropped to 1200 C. From this temperature on, the gel is allowed to cool to room temperature without stirring.



   This carrier can be used for the production of injectable ACTH peptide preparations as follows: a) 2.0 ml of the gel is heated to approx. 30-40 and mixed with 0.6 mg of finely ground (grain size below 20, u) D-SerÚ -Lys17,18-ss1-18-corticotropin-Lys18-amide hexaacetate. This mixture is diluted from room temperature to 20.0 ml with further gel, while stirring, so that 0.03 mg of peptide amide salt are contained in 1.0 ml of gel.

 

   b) 2.0 ml of the gel is heated to approx. 30-40 "and mixed with a solution of 0.6 mg D-Ser1-Lys17 18 ssl-18¯ corticotropin-Lys18-amide-hexastearate in 0.4 g Benzyl alcohol.



  The mixture is diluted to 20.0 ml by adding further gel with stirring so that 0.03 mg of peptide amide salt are contained per ml of gel.



   c) 2.0 ml of the gel is heated to approx. 30-40 and mixed with 6.0 mg of finely ground (grain size below 20) D-SerÚ-Lys17,18-ssÚ-18-corticotropin-Lys18-amide. The mixture is diluted to 20.0 ml by adding further gel with stirring, so that 0.3 mg of peptide amide per ml of gel are obtained.



   d) 2.0 ml of the gel is heated to 30-40 "and mixed with 20.0 mg of finely ground (grain size below 20) Synathen 6 (ssl-24-corticotropin-hexaacetate). It is diluted with further gel while stirring to 20.0 ml, so that 1.0 mg of peptide salt are contained per ml of gel.



   Example 2
For 100 ml of Miglyol <&commat; 812 are given 3.5 g of powdered aluminum monostearate. This suspension is mixed thoroughly and heated to approx. 140 ° C. while stirring and slowly heating (2-3> per minute) (a clear gel forms at approx. 115 to 125 ° C.). The heating is then switched off and cooled to 1200 with stirring. From this temperature on, the gel is allowed to cool to room temperature without stirring.

 

   The gel can be used to make injectable ACTH peptide preparations as follows:
2.0 ml of the gel is heated to approx. 30-40 "and mixed with 10.0 mg of finely ground (grain size below 20C") D-serÚ-Lys17,18-ss1-18-corticotropin-Lys18-amide The mixture is diluted to 20.0 ml with further gel while stirring, so that 0.5 mg of peptide amide are present per ml of gel.

 

Claims (1)

PATENT CLAIM Carrier for peptides, which is intended for the production of injectable oily peptide preparations, characterized in that it consists of a gel containing a mixture of 0.1 to 10% (w / v) fatty acid aluminum salt and a fatty acid ester that is liquid at room temperature. SUBCLAIMS 1. Carrier according to claim, characterized in that the gel contains the aluminum salt of one or more saturated or unsaturated fatty acids with 12-22 carbon atoms. 2. Carrier according to claim, characterized in that the gel contains aluminum monostearate. 3. Carrier according to claim, characterized in that the gel contains 1-3% (w / v) aluminum salt. 4. Carrier according to claim, characterized in that the gel contains a fatty acid ester which is derived from a saturated or unsaturated fatty acid with 8-22 carbon atoms. 5. Carrier according to claim, characterized in that the gel contains peanut oil as the fatty acid ester.