JPS5976024A - Composition for preventing adsorption of insulin and method therefor - Google Patents

Abstract

PURPOSE:The titled composition containing an additive, e.g. lecithin or ethylene oxide-propylene oxide copolymer, etc. in direct coexistence or in combination with insulin. CONSTITUTION:A composition for preventing adsorption of insulin obtained by adding one or two or more selected from the group consisting of lecithin, ethylene oxide-propylene oxide copolymer, hydroxypropyl cellulose, methyl cellulose, ethylene oxide adduct of castor oil, polyethylene glycol sorbitan oleate, methylcyclodextrin and sorbitan ester of fatty acids to an aqueous solution or suspension or freeze-dried powder of insulin. The amount of the additive is 0.0001- 1% in the aqueous solution or suspension. The above-mentioned composition is capable of preventing the adsorption of the insulin on contact with a wall of glass or plastic of various vessels.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a composition for preventing insulin adsorption and a method for preventing insulin adsorption.

As is well known, insulin is a peptide hormone that is widely used as a treatment for diabetes and exhibits an excellent hypoglycemic effect, but the amount administered at a time is only a few micrograms, and this dosage must be strictly observed. Must be. In other words, there is a special situation in which the minute amount of the substance formulated in a pharmaceutical formulation must be administered accurately as is.

However, on the other hand, proteins and peptides that are generally present in aqueous solutions adhere to glass.

As a result, it is well known that the amount of the drug to be added in the formulation is considerably reduced from the original amount.

For example, when insulin is injected into an infusion container, a considerable amount of insulin is instantly adsorbed onto the glass surface of the container, and it is known that this adsorption is more likely to occur when the insulin concentration is low (Pharmacology Vol. .39
, 107-111 (1979)). Namely.

Peptide hormones such as insulin are originally administered in a very small amount, so they are easily adsorbed to glass containers, and the loss rate due to adsorption is high because the initial amount of the compound is small. , resulting in a significantly reduced dose.

For example, even if strict precautions are taken during manufacturing to prevent adsorption to containers and other materials, and the required amount is accurately prepared, if the required amount is transferred to a syringe during actual administration, or when an infusion is When injected into an infusion container for co-infusion with a syringe, a considerable amount is adsorbed to the glass wall of the syringe or the glass wall of the infusion container, respectively.9
This results in serious consequences.

By the way, recently, along with glass products, plastic syringes (made by polypropylene), infusion bottles (made by polypropylene, polyethylene), 9 drip lead-out tubes (vinyl chloride), etc. have become widely used, and they absorb insulin. Opportunities are now even greater. In view of these circumstances, the inventors of the present invention have investigated technical means to prevent insulin from being adsorbed even when it comes into contact with the plastic walls of various utensils, and as a result, lecithin, ethylene oxide propylene oxide copolymer, hydroxypropyl cellulose, Methylcellulose.

The desired purpose can be achieved by adding one or two selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyethylene glycol sorbitan oleate, methyl cyclodextrin, and sorbitan fatty acid ester to an aqueous insulin solution or suspension. Knowing that this can be achieved, we have completed the present invention.

The present invention will be explained in detail below.

In the present invention, insulin may be produced by any method (generally extracted from the pancreas of mammals, particularly cows, pigs, etc.) by various methods.

Separated and purified products are used. Although the dosage of insulin varies depending on the purpose of diagnosis or treatment.

For example, 201. It is not limited by the content of 1,000 units including U units of insulin.

Next, the additive for preventing adsorption according to the present invention.

As shown in the experimental examples below, lecithin, ethylene oxide propylene oxide copolymer, hydroxypropyl cellulose, and methyl cellulose.

One or two members selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyethylene glycol sorbitan oleate, methyl cyclodextrin, and sorbitan fatty acid ester.

The effect of these substances was accidentally discovered among a large number of substances as a result of an experiment conducted to determine the effect of preventing insulin adsorption, and therefore there is no generic concept that uniquely generalizes only these substances. Moreover, the mechanism leading to prevention of adsorption is not clear. However, we have found that these substances are specifically selected for the purpose of preventing secretin adsorption, and that these substances exhibit almost complete adsorption prevention effects at extremely low concentrations. The novelty and inventive step of the present invention can be recognized in this respect. The amount of the additive selected from these substance groups is such that when the insulin-containing composition is made into an aqueous solution or suspension, the amount is 0.00019/) or more in the aqueous solution or suspension. This is desirable. Also, when these substances are administered in vivo.

It is desirable that the amount is so low that it does not exhibit any pharmacological effects by itself, and in this sense, the concentration in the insulin aqueous solution or aqueous suspension is preferably 1% or less. However, the present invention is not particularly limited to this concentration range. In the first place, the mechanism by which the additive according to the present invention exhibits the adsorption prevention effect is as described above (although it is not clear).
The result of some action on the container contact surface is
This is clear from the fact that the same effect can be obtained even if the additive according to the present invention is added later to the insulin aqueous solution.

As a result, the minimum required amount of the additive according to the present invention is determined not by the insulin content but by the surface area of the inner surface of the container. Therefore, if the maximum surface area of the contactor during use is known, the amount of the additive according to the invention to be added to the insulin-containing composition of the invention can be determined accordingly. However, in reality, since the surface area cannot be determined from the beginning, the amounts of these components in the nine compositions cannot be determined accurately. However, as shown in the experimental examples below, when the insulin-containing composition is made into an aqueous solution or an aqueous suspension, if the amount is in the above concentration range in the aqueous solution, that is, 0.0001% to 196%, the 9 Appropriate to achieve the purpose.

Next, there are several types of pharmaceutical forms of the composition of the present invention. In other words, insulin and the additive according to the present invention do not necessarily need to be given together in the same composition from the beginning, but they can be prepared separately and mixed together before use. Composition forms are also possible. Therefore, specific examples of the two compositions include the following pharmaceutical forms.

1) A composition in which insulin and the additive according to the present invention are formulated so as to coexist directly in the same aqueous solution or suspension; 11) A composition in which insulin and the additive according to the present invention are formulated in separate aqueous solutions or aqueous suspensions, respectively. 11) A composition in which insulin and the additive according to the present invention are blended so that they coexist directly in the same lyophilized powder 1v) Insulin and the additive according to the present invention are present as separate freeze-dried powders, to which a separately prepared solution for dissolution or suspension is added at the time of use.

Insulin is provided as a lyophilized powder, and the additive according to the present invention is provided as an aqueous solution thereof. The various aqueous solutions, aqueous suspensions, and lyophilized powders mentioned herein can be easily prepared according to conventional methods.

For example, for an aqueous solution, the manufacturing method described in the Japanese Pharmacopoeia section on insulin injections can be applied mutatis mutandis, and an appropriate stabilizer can be added to the aqueous solution or suspension.

In the present invention, it is possible to freely add a buffer, etc., and to add a buffer or a suitable excipient for lyophilization to the lyophilized powder.

The present invention is also a method of preventing adsorption of insulin to the contact wall of an instrument in an insulin-containing aqueous solution or suspension. That is, a method of adding an aqueous solution of the additive according to the present invention prepared separately to an insulin-containing infusion solution or an insulin-containing ampoule solution for the purpose of preventing adsorption of insulin to the container contact wall, or a method according to the present invention that has already been prepared. The method of adding insulin to an additive-containing infusion solution or an additive-containing ampoule solution according to the present invention achieves the same object as in the invention of the anti-adsorption composition detailed above.

The effects of the present invention will be explained using the following experimental examples.

Example sample 0.9% NaCl aqueous solution containing methylcellulose, polyoxyethylene hydrogenated castor oil, lecithin, hydroxypropylcellulose, ethylene oxide propylene oxide copolymer, polyethylene glycol sorbitan oleate, methyl cyclodextrin, and sorbitan fatty acid ester additives. 0.196.0.01%, 0.
001%, 0.0001%, and 0.00001% were prepared and used as specimen samples.

In addition, only 0.9% NaCl aqueous solution was prepared as a control sample.

Method Insulin 5. Prepare a solution with a concentration of OLU/ml.

This was used as an insulin stock solution. 2 m of each sample solution was added to a polyethylene test tube and a glass test tube, and 8 μ of insulin stock solution was added thereto using a microsyringe. After shaking vigorously, 50 μL was taken into the microsyringe and injected into a high performance liquid chromatography column.

The amount of non-adsorbed insulin was measured by high performance liquid chromatography to determine the recovery rate.

In high-performance liquid chromatography, the measurement wavelength is 2
10 nm, mobile phase was 1.4 L96HCIO4-C
H, ON = 65:35.

Results The results are shown in FIGS. 1 and 2. FIG. 1 is a graph showing the results in polyethylene test tubes. FIG. 2 is a graph showing the results in glass test tubes.

In the figure, Cont indicates the case of only 0.9% NaCl aqueous solution.

MO is methyl cellulose, HCO is polyoxyethylene hydrogenated castor oil, Lecithin is lecithin, R
PC is hydroxypropyl cellulose, Pluron
IC is ethylene oxide propylene oxide copolymer.

Tween is polyethylene glycol sorbitan oleate, and 5PAN is sorbitan fatty acid ester.

Me-CyD indicates the recovery rate when each additive of methylcyclodextrin is added to a 0.9% NaCl aqueous solution.

In addition, A, B, C and D each contain 0.1% additive.
, 0.01%, 0.001%, and 0.0001%.

It is clear from FIGS. 1 and 2 that the additive according to the present invention acts as an anti-adsorption agent. Moreover, the additive according to the present invention is
When added at 0.0001% or more.

It has been found to be effective in preventing the adsorption of insulin to objects.

The present invention will be specifically explained with reference to Examples described below.

Example 1 2000 units of insulin and 0.10 units of polyoxyethylene hydrogenated castor oil in a total volume of 100 ml. , An aqueous solution containing phenol O, xog, and 1.8 g of glycerin and adjusted to pH 2.5 to 3.5 with hydrochloric acid was prepared aseptically.

Dispense 1 ml into ampoules and melt.

Example 2 2000 units of insulin in a total volume of 100 ml, 0.50 g of polyethylene glycol sorbitan oleate,
Ethylene oxide propylene oxide copolymer 0
．． 50g, 7 enol 0.10g and NaC1O
, 8 g, adjusted to pH 2.5 to 3.5 with hydrochloric acid, is aseptically prepared, dispensed into ampoules in 1 mL portions, and melted.

Example 3 An aqueous solution containing 1 w/v 96 polyoxyethylene hydrogenated castor oil was prepared aseptically, dispensed into ampoules of 5 mL each, and melted to prevent insulin adsorption when injectable insulin preparations were co-injected with infusions, etc. Use as additive liquid.

[Brief explanation of the drawing]

Figures 1 and 2 correspond to Figures 1 and 2 described in the Results section of Experimental Example 1. 2 Figure 1 shows insulin in contact with a polyethylene test tube 9 Figure 2 shows insulin in contact with a glass test tube It is a bar graph showing the relationship between the insulin recovery rate and the type and addition concentration of the additive according to the present invention at each time. Patent applicant. Eisai Co., Ltd. 15th Token

Claims (1)

[Scope of Claims] (1) Selected from the group consisting of lecithin, ethylene oxide propylene oxide copolymer, hydroxypropyl cellulose, methyl cellulose, polyoxyethylene hydrogenated castor oil, polyethylene glycol sorbitan oleate, methyl cyclodextrin, and sorbitan fatty acid ester. (2) Insulin-containing composition in which insulin and an additive on one or two sides coexist directly or in combination (2) The amount of the additive is such that the insulin-containing composition is made into an aqueous solution or an aqueous suspension. In case. In the aqueous solution or suspension, o, oooi~
1% (3) Insulin-containing composition (4) Insulin-containing composition (4) Insulin-containing composition according to Claim 1 or 2, wherein the insulin-containing composition is an aqueous solution (5) An insulin-containing composition according to claim 1 or 2, wherein the composition comprises a freeze-dried powder of insulin. Ethylene oxide propylene oxide copolymer according to item 1 or 2, hydroxypropyl cellulose, methyl cellulose, polyoxyethylene hydrogenated castor oil, polyethylene glycol sorbitan oleate, methyl cyclodextrin, and sorbitan fatty acid ester. A method for preventing insulin adsorption characterized in that one or two additives are added (7) The amount of the additive is 0.0001 to 1% in the insulin-containing aqueous solution or suspension. Method for preventing insulin adsorption according to claim 6