JPH0441421A - Pulmonary absorption composition - Google Patents

Abstract

PURPOSE:To obtain a pulmonary absorbable composition, capable of rapidly absorbing proteins or peptides into bodies and quickly increasing blood level by containing the proteins or peptides and regulating the pH within a specific range or blending a surfactant therewith. CONSTITUTION:A pulmonary absorbable composition, containing one or two or more compounds (e.g. insulin) selected from proteins, peptides and derivatives thereof and prepared by regulating the pH of an aqueous solution to 3-4 with a pH adjuster, preferably a citric acid buffer solution or, in the case of powder, regulating the pH to 3-4 when dissolved in water and/or blending 0.1-5 wt.% surfactant, preferably sorbitan trioleate therewith. The administration form thereof is preferably an aerosol composition containing the proteins, peptides or derivatives thereof, a dispersing agent or an aqueous solution and a propellant.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a pulmonary absorption composition containing a protein or peptide or a derivative thereof.

[Prior art and problems to be solved by the invention] In recent years, with the progress of genetic preprogramming methods and peptide synthesis methods, a large number of physiologically active peptides, proteins, or their derivatives have been mass-produced, and they have not been able to be used clinically as peptide-based or protein-based drugs. It's coming.

However, these peptides and proteins have extremely low biopermeability and are easily susceptible to enzymatic degradation, so with some exceptions, administration methods to living organisms are limited to subcutaneous, intramuscular, and intravenous injections. Therefore,
In order to spread these new fields of pharmaceuticals widely into the future, there is a strong desire to develop dosage forms other than injections.

[Means for Solving the Problems] As a result of intensive research into forms of pulmonary administration of proteins and peptides that are simple and have rapid effects, the present inventors have found that proteins, peptides, or derivatives thereof are capable of absorbing glycofluoric acid salts. When coexisting with a patented surfactant, or pH
It was discovered that when administered as an aqueous solution of 3 to 4, the protein or peptide or its derivative is quickly absorbed into the body, and the protein or peptide concentration in the blood increases rapidly, and based on this finding, the present invention was completed. did.

That is, the present invention provides (A) one or more compounds selected from the group consisting of proteins, peptides, and derivatives thereof, and (B) an aqueous solution with a pH of 3 to 4 or dissolved in water in the case of powder. It is an aqueous or powdered lung absorption composition that is sometimes adjusted to a pH of 3 to 4 and/or contains a surfactant.

Proteins, peptides, or derivatives thereof in the present invention include those extracted from animals, those obtained by synthesis or genetic engineering techniques, and derivatives chemically derived therefrom. The administration form of the pulmonary absorption composition in the present invention is preferably an aerosol composition containing a protein or peptide or a derivative thereof, a dispersant or aqueous solution, and a propellant.

The surfactant used in the present invention may be any surfactant as long as it does not adversely affect the herbal medicine, and surfactants used in aerosol formulations of various pharmaceuticals can be used. Preferred surfactants include, for example, sorbitan monooleate, glyceryl monostearate, sorbitan monopalmitate, sorbitan monolaurate, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monooleate. A particularly preferred surfactant is sorbitan trioleate (Span 85).

As the pH 3 to 4 regulator, any pH regulator that does not have an adverse effect on the crude drug may be used, and any pH regulator that is used in general pharmaceutical compositions can be used, but particularly preferred pH regulators are Examples include citrate buffer.

When using water, purified water, distilled water for injection, etc. can be used. In this case, the resulting composition is an aqueous aerosol formulation.

This may contain 0.1 to 5% by weight of a surfactant as described above.

As the propellant, various physiologically acceptable gases can be used, but preferred propellants include trichloromonofluoromethane, dichlorotetrafluoroethane, dichlorodifluoromethane, or mixtures thereof. .

[Effects of the Invention] According to the present invention, peptides or derivatives thereof can be rapidly absorbed into the body in the form of pulmonary administration, and the peptide concentration in the blood can be rapidly increased. This has made it possible to administer peptides, which were previously limited to subcutaneous, intramuscular, and intravenous injections, without the need for patients to go to the hospital or suffer the pain of injections.

[Example] Next, the present invention will be specifically described with reference to Examples and Test Examples.

Example 1 Under a stream of dry nitrogen, 5rrg of human insulin, 40.7cm of citric acid, and 4.3ng of sodium citrate were ground in an agate mortar to a size of 1 to 5 pieces, and then 1100n of sorbitan trioleate was added. Mixed evenly.

This was filled into a pressure-resistant container with 6 g of a 2:3 mixed solution of trichloromonofluoromethane and dichlorofluoromethane, and the metered injection valve was tightened to obtain an aerosol preparation.

Example 2 Human insulin was dissolved in a citric acid-sodium citrate buffer solution of pH 3 to give a total volume of 4rd.

This was filled into a pressure-resistant container together with 1.4 g of a 3:2 mixed solution of dichlorodifluoromethane and dichlorotetrafluoroethane, and the metered injection valve was closed to obtain an aerosol preparation.

Test Example 1 An aqueous insulin solution (3 U/kg) was administered to a rat under anesthesia through an exposed tracheostomy, and the blood insulin concentration at each time was measured by EIA method.

(result) The results are shown in Figure 1.

As shown in FIG. 1, the bioavailability was significantly increased by coexisting the surfactant Span 85 and glycocholic acid.

Test Example 2 A test was conducted according to the method described in Test Example 1. At this time, the pH of the aqueous solution was allowed to change and insulin absorption from the lungs was measured.

(Results) As shown in FIG. 2, by adjusting the pH of the administered insulin aqueous solution to pH 3, the bioavailability increased to more than three times that of pH 7.

However, if the pH is less than 3, the acidic aqueous solution will damage the lung tissue, which is not preferable.

[Brief explanation of drawings]

FIG. 1 shows a comparison of the effects of various absorption enhancers on the pulmonary absorption of insulin with that of subcutaneous injection. FIG. 2 shows the observation of blood insulin concentration when the pH of the administered insulin aqueous solution was changed.

Claims (1)

[Claims] 1) (A) one or more compounds selected from the group consisting of proteins, peptides, and derivatives thereof and (B) an aqueous solution at pH 3 to 4 or in water in the case of powder. An aqueous or powdered lung absorption composition characterized by adjusting the pH to 3 to 4 when dissolved and/or incorporating a surfactant. 2) The pulmonary absorption composition according to claim 1, which contains insulin as the peptide. 3) The pulmonary absorption composition according to claim 1 or 2, wherein the aqueous solution is adjusted to pH 3 to 4 using citric acid, or in the case of a powder, the pH is adjusted to pH 3 to 4 when dissolved in water.