NO146044B - PROCEDURE FOR PREPARING A PHARMACEUTICAL INSULIN PREPARATION FOR RECTAL USE - Google Patents

Description

The invention relates to a method for producing a pharmaceutical insulin preparation for rectal use

which essentially contains insulin, a preparation base for rectal use and a special absorption accelerator.

Insulin is a drug that is particularly suitable as a hypoglycemic agent and is widely used. In practice, insulin is only given by injection and since the majority of people who have diabetes mellitus and who must take insulin, have to take a syringe of insulin every day throughout their lives, this administration of insulin is very problematic both for doctors and patients and the patients are exposed to heavy loads of a mental and physical nature.

To avoid these difficulties in connection

with the injection of insulin, pharmaceutical preparations of insulin for rectal administration have recently been developed.

However, in order to achieve the desired hypoglycemic effect by rectal use of the pharmaceutical insulin preparations, the insulin dose must be much greater than by injection, which will be explained in more detail below. As the required amount of insulin to be taken varies greatly in each case of diabetes mellitus, it is unsuitable in each case to give a pharmaceutical insulin preparation of high potency, and such a method of use is dangerous as hypoglycemia may occur when a larger amount of insulin is taken of the body in unexpected cases. Furthermore, the insulin itself is very expensive and the known pharmaceutical insulin preparations, which must be used in large quantities, are therefore disadvantageous in terms of price.

For these reasons, the known farnuiseutic insulin preparations for rectal use have not been used in practice. For example, Y. Matsubara has done an experiment to determine the hypoglycemic effect by administering per rabbit rectum a pharmaceutical preparation prepared by mixing insulin, water, olive oil and a polyoxyethylene oleic acid ester (Tokyo Idai Zasshi, 21, 135

(1963) and Y. Nishioka et al. did an experiment to

find the hypoglycemic effect by administering per rabbit rectum a pharmaceutical mixture of insulin, water, olive oil (or a water-soluble or oil-soluble preparation base), and a pqlyoxyethylene-hydrogenated castor oil derivative (Lecture Summar6; Vol. IV,

196 (1975) of the 95th Annual Meeting of the Nippon Yakugaku Kai). First- . the aforementioned author reported that when insulin was administered in a dose of 30 I.U./kg a lowering of "blood glucose of 30 - 40% was found in rabbits and the last author states that when insulin was administered in a dose of 100 I.U./kg was the reduction in blood glucose 50% in rabbits. On the other hand, it is emphasized that when insulin is injected into rabbits in a dose of 0.1 to 1 I.U./kg, the reduction in blood glucose was 40 - 60% in rabbits. This means that the insulin dose for rectal administration must amount to 30-300 times the injection dose in the former case and 100 - 1000 times the injection dose in the latter case.

As a result of various investigations on a technical basis, it has been discovered that when a pharmaceutical preparation of insulin, an oily or aqueous base for rectal use and a specific nonionic surfactant is administered per rectum with an insulin dose that is practically the same as the dose used by injection, the insulin is quickly absorbed in the body through the rectum and produces a high insulin concentration in the blood equal to or higher than when the insulin is administered by injection, and will thereby significantly reduce the blood sugar content. When a pharmaceutical preparation produced according to the invention is given through the rectum of a rabbit with an insulin dose of 0.5 - 1 I.U./kg, a reduction in blood sugar of 40 - 60% is found in the rabbit, which shows that the present pharmaceutical preparation for rectal use can produce a noticeable hypoglycaemic effect approximately equivalent to the same dose of insulin given by injection.

Thus, the main purpose of the invention is to provide a pharmaceutical insulin preparation for rectal use which can be used in practice without the disadvantages associated with the injection of insulin.

The invention thus relates to a method for producing insulin-containing preparations for rectal use, by mixing

(1) insulin

(2) an oily or aqueous preparation base for rectal use, and

(3) at least one absorption accelerating agent,

which method is characterized by the fact that a polyoxyethylene-higher alcohol ether or polyoxyethylene-higher alkylphenol ether is used as an absorption-accelerating agent, which has an HLB value of 6 - 19, and where the average number of polyoxyethylene units is 4 - 10, in an amount of 0.001 - 0.5 times the weight of the preparation base layer.

The polyoxyethylene oleic acid ester and the polyoxyethylene hydrogenated castor oil derivative which were used as absorption-accelerating agents in the aforementioned reports to Y. Matsubara and Y. Nishioka are a type of non-ionic surface-active agents, but according to the present invention other special nonionic surfactants.

The special non-ionic surfactants used in the preparation of the preparation are polyoxyethylene-higher alcohol and polyoxyethylene-higher alkylphenol ethers with HLB numbers equal to 6 - 19, and with average polyoxyethylene numbers equal to 4 - 30, and the specific non-ionic surfactants agents can produce the desired effect, but other than the non-ionic surfactants defined, cannot produce the desired effect (see experiment 1 below).

Any insulin that exhibits hypoglycaemic action when administered parenterally, e.g. insulin from guinea pigs, pigs, whales, etc., can be used. Furthermore, a metal complex of insulin can be used, e.g. zinc complex of ipsulin, as well as protamine zinc insulin and globin zinc insulin.

The preparation base for rectal use that is used in the method according to the present invention is such base that is usually used for the production of pharmaceutical rectal preparations, such as oil- or fat-based, or water-based.

An oil or fat base can be sesame oil, olive oil, soybean oil, rapeseed oil, cottonseed oil, rice bran oil, tsubaki oil (from Camellia japonica L), corn oil, peanut oil, coke nut oil, cocoa butter, "Isocacao MO-5": (higher saturated fatty acid -triglyceride), lauric butter, beef tallow, lard, wool fat, substances formed by modification of most of the oils mentioned above, by e.g. hydrogenation, inter-esterification, acetylation, fractional extraction, mineral oils such as vaseline, paraffin, silicone oils etc, esters of fatty acids with 6-30 carbon atoms with glycerol, such as glyceryl palmitate, glyceryl laurate, glyceryl stearate, glyceryl myristate, waxes like natural waxes, e.g. e.g. beeswax, carnauba wax, esters of fatty acids with 6-30 carbon atoms with alcohols with 2-8 carbon atoms, e.g. isopropyl myristate, higher fatty acids with 6-30 carbon atoms, e.g. stearic acid,

oleic acid, artificial suppository base (e.g. "Witepsol": tri-....= glyceride of saturated vegetable fatty acid with monoglycerides).

Said oil or fat base can be used either separately or J as mixtures of two or more. Particularly favorable oil and fat bases are corn oil, olive oil. An aqueous base is e.g. polyethylene glycol 300, 400, 1000, 1500, 4000 and 6000, methylcellulose, sodium carboxymethylcellulose, glycerogelatin. These aqueous preparation bases can be used either separately or as mixtures. Particularly favorable water bases are mixtures of polyethylene glycol 1500 and 6000. Water as a preparation base can also be used as mixtures of water and oil-fat bases or other aqueous bases. There are also no special indications regarding the amount of preparation base that can be used in the method according to the invention, but the amount is usually 0.5 - 4 g, preferably 1 - 3 g per administration for adults.

Practical examples of polyoxyethylene (POE) higher alcohol ethers in which the higher alcohol has 6-22 carbon atoms are POE lauryl ether (HLB = 8, n = 4.2), POE lauryl ether (HLB = 9.5, n = 6 ), POE lauryl ether (HLB = 11.5, n = 9), POE lauryl ether

(HLB = 15.5, n = 21), POE lauryl ether (HLB = 16.5, n = 25), POE cetyl ether (HLB = 10.5, n = 5.5), POE cetyl ether (HLB = 11.5,

n = 7), POE cetyl ether (HLB = 13.5, n = 10), POE cetyl ether (HLB = 15.5, n = 15), POE cetyl ether (HLB = 17.7, n = 20), POE stearyl ether (HLB = 7.5, n = 4), POE stearyl ether (HLB = 11.5,

n = 10), POE stearyl ether (HLB = 18, n = 20), POE oleyl ether (HLB = 10.5, n = 7), POE oleyl ether (HLB = 14, n = 10), POE oleyl ether ( HLB = 16, n = 15), POE oleyl ether (HLB = 17, n = 20), POE octyl ether (HLB = 15.8, n = 15). Practical examples of POE higher alkyl phenol ethers in which the higher alkyl group has 6 - 22 carbon atoms are POE nonyl phenyl ether (HLB = 8, n = 5), POE nonyl phenyl ether (HLB = 14, n = 7.5), POE nonyl phenyl ether (HLB = 16.5, n = 10), POE nonyl phenyl ether (HLB = 18.0, n = 15), POE nonyl phenyl ether (HLB = 19.0, n = 18), POE octyl phenyl ether (HLB = 11.5 , n = 10), POE-octylphenyl ether (HLB = 13.5, n = 15), POE-octylphenyl ether (HLB = 17.0, n = 30), where n denotes the average number of POE units.

The amount of specific, nonionic surfactant to be used is 0.001 - 0.5 times, preferably 0.005t - 0.1 times the weight of the preparation weight basis.

You can also incorporate one or more additional ingredients such as antioxidants (e.g. butylated hydroxytoluene), complexing agents (e.g. ethylenediaminetetraacetic acid), preservatives (e.g. paraben, propylparaben) and the like in a suitable amount .

Suitable dosage forms in connection with the present invention are suppositories which are solid at room temperature, but melt at body temperature. Furthermore, ointments or enema preparations containing insulin and the relevant absorption-accelerating agent can be dispersed in a liquid liquid base and administered in soft capsules for rectal use or for rectal injection. Such dosage forms can be prepared as usual

for ointments, suppositories and the like by melting or dissolving the preparation base and the absorption-accelerating agent and distributing the insulin evenly in the mixture or solution and, if necessary, casting the preparation in molds.

The amount of insulin in the pharmaceutical preparations is 2-200 I.U., and preferably 5-150 I.U. per gram total amount of absorption accelerator and oily or aqueous base for rectal use.

The following examples shall illustrate practical examples of the production of pharmaceutical insulin preparations for rectal use according to the invention, where the stated insulin doses are intended for humans.

Experiment 1 Serum I.R.I. content and percent reduction of blood sugar;

1. Test method:

Male rabbits that were fasted for 28 hours, weighing approx. 2 kg (one group consisted of 5 rabbits), was used to determine the content of immunoreactive insulin in serum, the serum I.R.I., and the blood sugar content after rectal administration as well as intramuscular or intravenous administration of insulin. Guinea pig crystalline insulin (activity 24 I.U. per mg) was supplied by Sigma Chemical Company. The first examination consisted of giving the insulin in the form of a rectal preparation by injection into the rectum approx. 3 cm deep from the anus with a small syringe. The later investigation was done by injecting insulin intramuscularly in the hip or intravenously in the ear of rabbits. Blood samples were taken from the ear at regular intervals. The serum insulin content was measured radiologically by radiation immunity using the double-antibody f system described by Morgan and Lazarow [Morgan, CR. = Lazarow, A. Diabetes, 12, 115 (1963)]. The blood sugar content was assessed according to the glucose oxidase method [Schmidt F.H. Internist., 4, 554 (1963)]. Each number represents the mean value for percent reduction in blood sugar. The results appear in Tables I and II.

2. Preparations used in the experiment: dispersions

of rectal-based insulin containing nonionic surfactant; According to the invention, experiments No. 1-3, 5-9. Dispersions of insulin in rectal preparation base and nonionic surfactant (eg POE fatty acid esters and hydrogenated castor oil POE) other than the specific nonionic,

surfactants used in the preparation of the preparations according to the present invention (comparative tests: no. 11 - 17), solution prepared by adding insulin to distilled water (comparative tests no. 4, 18, 19). The preparations in trials no. 1 - 3 and 5 - 17 were ointments or enema preparations.

As can be seen from table I, serum IRI (immunoreactive insulin) in rabbits after administration of pharmaceutical preparations manufactured according to the invention (experiments no. 1 - 3) given rectally in insulin doses of 0.5-2 I.U./kg were approximately equally high or higher than when the insulin was given to rabbits intramuscularly as an injection at a dose of 0.5 I.U./kg. That is to say that pharmaceutical preparations for rectal use produced according to the present invention can give a high insulin concentration in the blood just as well as with intramuscular insulin injection with insulin doses that are approximately as large as with intramuscular injection.

As further appears from table II, the percentage reduction of the blood sugar level by administration of pharmaceutical preparations prepared according to the present invention (experiment no. 5-9) in the rectum of rabbits in insulin doses of 1 - 5 I.U./kg was approximately as good as when the insulin was given to rabbits by intramuscular injection and intravenous injection in doses of 0.5 I.U./kg (experiments no. 18 and 19). That is that pharmaceutical preparations for rectal use produced according to the invention substantially reduce the blood sugar level in the same way as by giving insulin by injection and in insulin doses that are almost as low as by injection.

On the other hand, experiments with pharmaceutical rectal preparations (experiments no. 10-17) which do not contain absorption-accelerating agents (containing other non-ionic surfactants than the absorption-accelerating agents used in the preparation of the preparations according to the invention) show no able to sufficiently reduce the blood sugar content with insulin doses approximately as large as by injection.

Example 1

4.5 g of POE lauryl ether (HLB = 11.5, n = 9) was dissolved in 145.5 g of corn oil with stirring, and 8000 I.U. insulin in the solution while stirring, after which 1.5 g samples of the dispersion were filled into tubes for rectal use.

Example 2

After melting 45.5 g of polyethylene glycol 1500

and 100 g of polyethylene glycol 6000 and thoroughly dispersing 4.5 g of POE nonylphenyl ether (HLB = 16.5, n = 10) and 15,000 I.U. insulin that was stirred into the molten mixture, 1.5 g portions of the dispersion were poured into suppository forms. The solidified molding compounds were then released from the mold.

Example 3

In 142.5 g of corn oil, 7.5 g of POE-nonylphenyl ether (HLB = 16.5, n = 10) were dissolved with stirring. After dispersing 12,000 I.U. insulin in the solution while stirring, 1.5 g samples of the dispersion were held up in container tubes for rectal use.

Example 4

6 g of POE lauryl ether were dissolved in 94 g of corn oil

(HLB =11.5, n = 9) under stirring. After dispersion of 4000 I.U. insulin in the solution while stirring, 1 g samples of the dispersion were filled into soft capsules for rectal use.

Example 5

In 76 g of corn oil, 1 g of POE lauryl ether (HLB = 11.5, n = 9), 9 g of white beeswax and 14 g of isopropyl myristate were dissolved at 60°C with stirring. After cooling to 35°C, 8000 IU of insulin was dispersed in the solution with stirring, and then 1 g samples of the dispersion were filled into soft capsules for rectal administration.

Example 6

In 81.8 g of corn oil, 1 g of POE lauryl ether (HLB= 11.5, n = 9), 10.4 g of white beeswax, 0.8 g of carnauba wax and 6.0 g of isopropyl myristate were dissolved at 60°C with stirring. After cooling to 35°C, 8000 IU insulin was dispersed in the solution with stirring, and then 1 g samples of the dispersion were filled into soft capsules for rectal administration.

Claims (3)

1. Method for the production of insulin-containing preparations for rectal use, by mixing m.an (1) , insulin (2) an oily or aqueous preparation base for rectal use, and (3) at least one absorption-accelerating agent, characterized in that a polyoxyethylene-higher alcohol ether or polyoxyethylene-higher alkylphenol ether is used as an absorption-accelerating agent, which has an HLB value of 6 - 19, and where the average number of polyoxyethylene units is 4 - 30, in a amount of 0.001 - 0.5 times the weight of the preparation base layer. 2. Process according to claim 1, characterized in that the polyoxyethylene higher alcohol ether is polyoxyethylene lauryl ether with an HLB value of 11.5. 3. Process according to claim 1, characterized in that the polyoxyethylene-higher alkylphenol ether is polyoxyethylene-nonylphenyl ether with an HLB value of 16.5.