DE2620446A1 - Aqueous INSULIN PREPARATION - Google Patents

Description

AvK / Ax 5 COLOGNE! 7.5.1976

DEICHMANNHAUS AT THE MAIN RAILWAY STATION

27, Doshomachi 2-chome, Higashi-ku, Osaka (Japan).

Aqueous insulin preparation

The invention relates to a new insulin preparation which is clinically suitable for nasal administration as well a new method of administering insulin.

It is known that insulin is valuable as a drug for the treatment of diabetes mellitus, for shock therapy mental disorders and for the treatment of malnutrition, i.e. chronic nutritional disorders.

So far, insulin has only been given by injection. Other ways of administering insulin, e.g., sublingual, oral, intratracheal, and rectal studied since the discovery of insulin. However, since insulin is a polypeptide that contains about 50 amino acids and has a molecular weight of about 6,000, it has heretofore been recognized that little or no pharmacological Effect of the insulin is achieved with all administration methods except injection (see "Insulin Monogatari ", p. 86, edited by Iwanami-shoten, Japan 1965) "

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Telephone: (0221) 23454! - 4 · Telex: 8882307 dopa d ■ Telegram: Dompalent Cologne

There were also insulin supplements containing zinc or protamine and have a long duration of action. With these preparations, however, occurs during a significant amount of insulin in the bloodstream at all times, causing dangerous hypoglycemic i.v. Shock can occur when a patient with diabetes, mellitus is hungry or asleep. It is thus assumed that insulin will be injected after the meal * - must to avoid hypoglycemic shock (The Journal of Practical Pharmacy 25 (1974) 505). It is however difficult to take insulin because of the physical! Pain and the associated emotional stress to be administered by injection according to the above dosage regimen.

Extensive investigations were carried out by the applicant with the aim of finding a new method of administration for insulin and an insulin preparation which does not have the disadvantages mentioned. First, that when an aqueous insulin solution or suspension is brought 'having a pH above 4.7 with the nasal mucosa in'<touch has been found, a practically useful insulin-J linmenge is not absorbed. It was then surprisingly found that insulin is quickly absorbed by the ' nasal mucosa and passes into the bloodstream when an aqueous solution or suspension with a pH of more than 4.7 and water, insulin and a substance with surface activity (hereinafter referred to as i surface-active compound for short) contains, with which ι nasal mucosa is brought into contact. This phenomenon was confirmed by the fact that the blood sugar level is remarkably lowered after the nasal administration of insulin.

It has thus been found that nasal administration of an aqueous preparation having a pH greater than 4.7 has and water, insulin and a surfactant

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Compound contains, enables a new self-treatment with insulin and this treatment the disadvantages of previously known insulin therapy switches off.

It has also been found that insulin is advantageously absorbed when the aqueous insulin preparation \ in the form of a spray or mist is brought into contact with the nasal mucous membrane. ;

• · - ι—

It was also found that the insulin dose required for nasal administration to bring about the same drop in blood sugar level as for intramuscular injection is 4 to 6 times the insulin dose required for intramuscular administration. ^:

It is also known that insulin is very unstable in aqueous preparations (Journal of Biological Chemistry 237, 3406). Thorough research in this regard has revealed that an aqueous insulin preparation, j which has a pH in the range from 4.7 to 9.0 and j water, insulin and a surface-active compound ' does not have this instability of the insulin. ■

The invention accordingly provides a new aqueous' insulin preparation that enables self-treatment with insulin \ by nasal administration, wherein this pre- '' ready a pH of more than 4.7 (preferably a pH in the range of 4, 7 to 9.0) and contains water, insulin and a surface-active compound.

The insulin used for the purposes of the invention can be j

from natural sources, e.g. from mammals (e.g. ι Pig or cattle), birds or fish, or by chemical reactions using known methods

the. The insulin suitable for the purposes of the invention i

can contain a small amount of harmless impurities

included, but of course there is also a highly purified \

Insulin, a so-called "monocomponent", is suitable. ■

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The insulin content in the aqueous preparation according to the invention is usually in the range from 0.1 to 10% by weight, preferably in the range from 0.2 to 5% by weight. If the insulin content is below 0.1% by weight, the absorption is of insulin through the nasal mucosa is lower. An insulin content of more than 10% by weight is uneconomical.

It has been shown that the surface-active compound promotes the absorption of insulin through the nasal mucosa into the bloodstream. As a surface-active compound

fertilizer can use natural or synthetic surfactants will. For example, saponin, salts of bile acids, the product "Surfaction" are preferred (Agricultural and Biological Chemistry 33 (1969) 1669), anionic surfactants, amphoteric surfactants and nonionic Surfactants. The surface-active substances used in the context of the invention Compounds are expediently selected from compounds known per se.

Saponin is the so-called saponin glucoside, which is made up of saponin and a sugar, e.g. glucose, galactose, pentose, Methylpentose, arabinose or glucuronic acid.

Suitable salts of bile acids are, for example, alkali salts of cholic acid, glycolic acid, taurocholic acid, cholanic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid and dehydrocholic acid. \

Preferred anionic surfactants are, for example

1 1 salts of carboxylic acids with the formula R COOM, where R is a hydrocarbon radical with 7 to 17 carbon atoms and

1 '

M is an alkali metal, salts of sulfonic acid esters;

2 2 2
of the formula R -0-SO ₇ M, where R is a hydrocarbon- '

2 '

rest with 8 to 18 carbon atoms and M is an alkali metal or an organic ammonium ion, sulfonic acid salts of formula

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wherein R is a hydrocarbon radical with 8 to 16 carbon atoms and M is an alkali metal.

Preferred amphoteric surfactants are, for example: Surface-active compounds belonging to the type of amino

4 4

acids and have the formula R CO-NH-A-COOM,

4th
wherein R is a hydrocarbon radical with 7 to 17 carbon atoms,

4 -NH-A-COO- is an amino acid residue and M is an alkali metal, surface-active compounds of the betaine type with the formula *

CH,

1 y

-CO ₀ COO ^θ

CH-, 3

wherein R is a hydrocarbon radical with 8 to 18 carbon atoms and imidazole type surface active compounds with the formula

E ⁶ _

CH, OH

wherein R is a hydrocarbon radical having 2 to 17 carbon atoms, Y is hydrogen, an alkali metal or a radical of the formula -CHpCOOM, wherein M is hydrogen, an alkali metal or an organic ammonium ion, and Z is a radical of the formula -COOM ⁵ , -CH ₂ Is COOM ⁵ or -CH-CH ₂ SO ₃ M ⁵ , wherein

5

M is hydrogen, an alkali metal, or an organic; Is ammonium ion.

Preferred nonionic surfactants are, for example; Polyoxyethylene alcohol ether (with higher alcohols) of | Formula;

) H m

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7th
in which R is a saturated or unsaturated alkyl radical having 4 to 18 carbon atoms and m is an integer from 3 to 60, polyoxyethylene alkylphenyl ether of the formula

where R is a saturated or unsaturated alkyl radical having 8 to 10 carbon atoms and η is an integer from 8 to 70 is, polyoxyethylene lanolin alcohol ether of the formula

R ⁹ -0- (C ₂ H ₅ O) ^ H

9
where R is a steroid alcohol radical or a triterpene alcohol radical and 1 is an integer from 5 to 40, polyoxyethylene polyoxypropylene alcohol ether (with higher alcohols) of the formula in

10
where R is a saturated or unsaturated alkyl radical having 12 to 18 carbon atoms, ρ is an integer from 10 to 40 and q is an integer from 1 to 10; Polyoxyethylene fatty acid esters of the formula

E ¹¹ COO (CpHcO) H

11
where R is a saturated or unsaturated alkyl radical having 7 to 17 carbon atoms and s is an integer from 5 to 50, and esters of polyhydric alcohols with fatty acids

with the formula

12 13

12 13

where R is a radical of a polyhydric alcohol and R is a hydrocarbon radical having 7 to 17 carbon atoms. from Among the nonionic surfactants, those having an HLB value in the range of 6 to 20 (i.e. 6: 1 to 20: 1) are preferred and those having an HLB value in the range from 8 to 16 (i.e. from 8: 1 to 16: 1) are particularly preferred. If two or more nonionic surfactants are to be used, they are preferably mixed so that the HLB value of the Mixture of surfactants is in the above ranges.

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In the above formulas, the hydrocarbon radicals R, R, R, R, R, R and R can be, for example, straight-chain, branched or cyclic, saturated or unsaturated alkyl radicals, aryl radicals, for example phenyl radicals and. Naphthyl residues, and aralkyl residues, for example benzyl residues or phenethyl residues, be. The organic ammonium ion, for ^:

2 5
M and M are an organic ammonium ion which is formed by adding a proton to an organic amine, preferably a tertiary organic amine, for example pyridine, trialkylamine, which is optionally substituted by a hydroxy group (for example triethanolamine). The amino acid residue -NH-A-COO- is elimination j of a hydrogen atom from an amino group, a ^tion: amino acid, and at the same time a hydrogen atom from a carboxyl group of the same amino acid formed. Glutamic acid, for example, can be used as amino acids,

Alanine and ß-aminopropionic acid in question. The steroid

9 alcohol residue and the triterpene alcohol residue, for the R

are the steroid alcohol residue or triterpene alcohol-i

rest that form lanolin. The rest of the polyvalent

12th
Alcohol, for which R stands, is a residue that goes through ^!

Elimination of a hydroxyl group from a polyhydric alcohol, e.g. glycerin, sorbitol and sucrose, formed: will. ;

These surface active compounds can be used alone or in combinations of two or more surface-active ' Connections are used. The level of surfactant or surfactants is usually in the range of about 0.1 to

20% by weight, preferably in the range from about 0.2 to 10 % By weight, based on the total preparation. A content of less than 0.1% by weight is not sufficient for absorption of insulin into the bloodstream. A content of more than 20 wt .-% also leads to a good effect, however, it is inexpedient from an economic point of view.

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The pH of the aqueous insulin preparation according to the invention is usually above 4.7, in particular in the range of more than 4.7 to 9.0. The aqueous preparation according to the invention can be a solution or a suspension. If a solution or suspension with high stability is desired, the preparation is adjusted to a pH in the range from about 6.0 to 8.5 is preferably set in the range from about 7.0 to 8.0.

The aqueous insulin preparation according to the invention can be prepared by mixing the constituents in any order according to the usual borrowed methods. In general, the preparation by dissolving or suspending Insulin and one or more surface-active compounds in water is carried out, preferably in water, the hydroxide, a base, for example sodium ^1, or contains an acid, for example hydrochloric acid, and adjusting the mixture to a pH -Value in the above range with a base (e.g. an aqueous sodium hydroxide solution) or with an acid (e.g. hydrochloric acid).

Furthermore, the insulin preparation according to the invention can be other

common additives for aqueous medicaments, e.g. an isotonic agent, an aseptic agent, a preservative. agent or a buffer.

For administration, the aqueous insulin preparation according to the invention can be in the form of a spray using a A nebulizer, a fogger or a spray device are introduced into the nasal cavities, the nebulized; Insulin preparation is brought into contact with the nasal mucosa.

The outstanding advantage of nasal administration according to the invention is that it can be used by all patients (even Children) who have to be treated with insulin, it is possible to easily supply insulin to any desired

i th point in time without any inconvenience such as pain etc.

to take.

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The insulin dose for nasal administration according to the
Invention is approximately 4 to 6 times that of
amount given by intramuscular injection.

The invention is further illustrated by the following examples
explained. ^:

example 1

40 mg porcine insulin (25 units / mg) are in 7 ml
a mixture of 100 mg of polyoxyethylene (9) lauryl ether, 1 ml of aqueous 0.1 ln sodium hydroxide solution, 90 mg of NaCl,
Dissolve 1 ml of pH 7.0 phosphate buffer and water. the
Solution, In-HCl to pH 7.4 adjusted to 0 and ^diluted to 10 ml distilled water. The received
Solution has an activity of 100 insulin units each
ml.

Example 2

200 mg porcine insulin (25 units / mg) are in 7 ml j of a mixture of 2 ml 0, In hydrochloric acid, 500 mg saponin
and dissolved in water. The solution is adjusted to pH 7.6 with aqueous 0.1 n sodium hydroxide solution and with
distilled water diluted to 10 ml. The received _; Solution has an activity of 500 insulin units: per ml.

Example 3

500 mg high purity porcine insulin (25 units / mg) are in 7 ml of a mixture of 1 ml of aqueous 0.1N sodium hydroxide solution, Dissolve 1 ml of borate buffer of pH 7.0, 300 mg of sodium glycocholate, 160 mg of glycerine and water. j The solution is adjusted to pH 7.3 with 0, In-HCl and ' diluted to 10 ml with distilled water. The received

Solution has an activity of 1250 insulin units

per ml. i

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Example 4 ;

40 mg porcine insulin (25 units / mg) are in 6 ml
a mixture of 100 mg polyoxyethylene (9) lauryl ether,
1 ml of aqueous 0.1 ln sodium hydroxide solution, 500 mg of glucose and water dissolved. 1 ml of acetate buffer is added to the solution
pH 5.0 added. The suspension obtained is adjusted to pH 5.5 with 0.1N HCl and diluted to 10 ml with distilled water. This suspension has an activity
of 100 insulin units per ml.

Example 5 *

200 mg porcine insulin (25 units / mg) are in 7 ml; of a mixture dissolved from 2 ml of 0.1N hydrochloric acid,! Consists of 500 mg of "surfactin" and water. The solution will be
adjusted to pH 7.6 with aqueous 0.1n sodium hydroxide solution and diluted to 10 ml with distilled water.
The solution obtained has an activity of 500 insulin units per ml.

Attempt 1 j

Influence of resorption promoting agents on the nasal
Absorption of insulin in rats ;

The insulin preparations for this study were produced in the manner described in Example 1, with
however, various absorption promoting agents have been used.

Male rats (SD-JCL, weight 200-300 g) were with; Sodium pentobarbital by intraperitoneal injection
anesthetized at a dose of 5 mg / 100 g. A micropipette was used to inject 0.1 ml / kg of the insulin prepa- i into the nasal cavity

council introduced. At certain time intervals after the I.

Administration of the drug were blood samples from the!

Taken from tail vein. The blood sugar level was to \

a method using o-toluidine determined.

(Clin. Chem. 8 (1962) 215). '■

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The results are given in the table below and show the change in the glucose concentration in the Piadma. Each value represents the average for two to nine animals.

For comparison, insulin was given in an amount of 2 inputs, units / kg injected intramuscularly.

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Influence of absorption-promoting agents on nasal absorption of insulin in rats Dose: 10 units / kg (pH 7.4)

OO O CO

O CO CO

I. Comparison
sample Re sorptionsförderndes \ nchanges in the glucose level in the 0.5 1 2 Plasma,% 4 hours ittel (content 1%) O 102.6
I. 92.7 88.2 3 98.8 Saponin - 100 94.2
98.7 81.7
95.3 80.7
93.8 92.2 85.3
96.4 Salt from
Bile acids Propylene glycol
Polyethylene glycol 2000 100
100 99.1 93.1 95.3 90.1
98.3 90.7 Lecithin 100 76.0 43.7 35.0 91.4 41.2 Anion-active Saponin from tea leaves 100 72.3
80.5 44.5
54.8 27.7
29.3 32.2 53.0
50.3 Surfactant Sodium glycocholate
Sodium taurocholate 100
100 79.6 52.1 38.1 38.5
33.5 60.1 Sodium cholate 100 68.5 44.3 28.7 48.1 60.1 Sodium lauryl sulfate 100 75 .4 47.2 30.3 45.5 29.4 Potassium laurate 100 78.5 57.0 39.8 27.2 50.8 Amisoft CT-12 100 43.6

-P-CD

Resorption Change of the < 0.5 31 sugar level 2 in plasma,% 54.3 changing means
(Content 1%) 0 64.5 1 27.3 3 4 hours 31.9 Amphoteric
Surfactant Miranol C2M-
concentration '100 75.1 44.3 26.0 42.5 24.6 P.O.E. 9-lauryl ether 100 80.7 39.7 37.0 21.5 15.1 P.O.E. 10 stearyl ether 100 71.7 60.8 20.2 26.1 57.4 P.O.E. 10 cetyl ether ¹ 100 71.0 39.5 37.7 17.8 40.9 P.0.E.5-octyl ether . 100 60.7 44.2 31.5 46.1 34.8
42.9 P.Ο.Ε.ΊΟ-octylphenyl ether 100 74.0
80.1 38.4 30.2
40.9 31.4 52.1 Non-ionic
nogenes
Surfactant POElO-nonylphenyl ether
POE24 cholesteryl ether ι 100
1100 86.8 50.8
55.6 53.4 24.2
39.9 56.5 POE24 P.0.P.8-cetyl-
ether 100 76.7 69.3 39.9 53.8 72.0 P.O.E. 10 monolaurate 100 86.4 44.4 62.7 47.7 52.4 Sucrose ester DK-FIlO 100 64.8 70.0 31.6 64.8 59.8 Surfactin Surfactin 100 40.0 39.5 28.1 38.1 Intramuscular injection
2 units / kq 100 38.4 43.2

U)

Comments: P.O.E. = Polyoxyethylene P.O.P. = Polyoxypropylene

to cn

ro

O -F- -P-- CD

Claims (17)

Claims 1. Aqueous insulin preparation for nasal administration with a pH above 4.7, containing water, insulin and a connection with surface activity. 2. Aqueous insulin preparation according to claim 1, characterized in that it has a pH of more than 4.7 to 9.0. 3. Aqueous insulin preparation according to claim 1 and 2, characterized in that it has a pH in the range; from 6.0 to 8.5 and contains water, insulin and a substance with surface activity. 4. Aqueous insulin preparation according to claim 1 to 3, characterized in that it has a pH in the range from 6.0 to 8.5 and water, 0.1 to 10% by weight Contains insulin and 0.1 to 20% by weight of a substance with surface activity. : 5. Aqueous insulin solution for nasal administration, characterized in that it has a pH in the range from 7.0 to 8.0 and having water, 0.2 to 5% by weight of insulin and 0.2 to 10% by weight of a substance Contains surface activity. 6. Aqueous insulin preparation according to claim 1 to 5, characterized in that it is used as a substance with surface activity Contains saponin. 7. Aqueous insulin preparation according to claim 1 to 5, characterized in that it is used as a substance with surface activity contains a salt of bile acids. 8. Aqueous insulin preparation according to claim 1 to 5, characterized in that it is used as a substance with surface activity contains an anion-active surface-active compound. ^ 09809/0987 9. Aqueous insulin preparation according to claim 1 to 5, characterized in that it is used as a substance with surface activity contains an amphoteric surfactant compound. 10. Aqueous insulin preparation according to claim 1 to 5, characterized in that it is used as a substance with upper- surface activity a non-ionic surface-active Connection contains. 11. Aqueous insulin preparation according to claim 1 to 5, characterized in that it is used as. Substance with surface activity contains surfactin. ^! 12. Aqueous. Insulin solution according to claim 5, characterized indicates that it is a substance with surface | activity contains sodium glycocholate. 13. Aqueous insulin solution according to claim 5, characterized in that that it contains sodium taurocholate as a substance with surface activity. 14. Aqueous insulin solution according to claim 5, characterized in that indicates that it is a substance with surface] activity contains sodium cholate. > 15. Aqueous insulin solution according to claim 5, characterized in that it is used as a substance with surfaces. activity contains surfactin. 16. A method for the administration of insulin, characterized in that that an aqueous insulin preparation according to claim 1 to 15 with the nasal mucosa in Brings touch. 17. Process for the manufacture of aqueous insulin preparations according to claims 1 to 15, characterized in that one insulin and a substance with surface activity dissolves in water and adjusts the pH of the aqueous solution. $ 09809/0987 ^, ORIGINAL INSPECTED