JPH07118166A - Insulin composition - Google Patents

Abstract

PURPOSE:To obtain an intranasal administration composition having good nasal absorbability and giving little stimulation to the mucosa by using an alginic acid propylene glycol ester as a specific carrier for improving the problem of insulin difficult to administer by oral administration. CONSTITUTION:This insulin composition is produced by uniformly dispersing an active amount of insulin in a carrier consisting of alginic acid propylene glycol ester to effect the bonding of insulin to the ester. The composition is used as a powdery composition for nasal administration. As an alternative, the insulin composition contains alginic acid propylene glycol ester as an absorbefacient and the composition is used as an aqueous solution for nasal administration or a composition for rectal administration.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an insulin composition, and more particularly to an insulin composition having excellent pharmaceutical stability and absorbability into the body when administered intranasally (nasally).

[0002]

BACKGROUND OF THE INVENTION Insulin is a hormone secreted from β cells of the islets of Langerhans in the spleen of vertebrates such as bovine or pig, and is a specific bioactive peptide that lowers blood glucose. Insulin also plays an important role in regulating substance metabolism, promotes glucose uptake / oxidation in tissues and its conversion to glycogen / fat, and consequently lowers blood glucose. Is a type of drug used in. However, insulin is degraded by proteases in the digestive tract, has a high molecular weight and is highly polar, and is hardly absorbed as it is from the intestinal mucosa. Therefore, it is difficult to administer it orally by injection. Is limited to. Such an administration method causes pain at the injection site to the patient, is not preferable, and causes considerable pain to the patient when the administration is performed at regular intervals. Therefore, it is desired to develop a non-injection administration method that is safe and convenient for frequent administration and is self-administerable. As one of such administration methods, insulin has been studied for absorption through the nasal mucosa by dissolving it in a relatively acidic solvent or mixing with bile salts or other surfactants. Studies have been conducted on rectal absorption by administering the drug as a suppository together with a drug for rectal administration. Among them, when considering the nasal administration method, which has been actively studied recently, the venous plexus has developed in the nasal mucosa lamina propria of the nasal cavity, which is the administration site, and the drug is used for this nasal mucosa. Since it is absorbed through and enters the systemic circulatory system, it is an excellent method of administering insulin, which is a drug that is difficult to administer orally.Although various formulation application examples have been proposed, it is not However, it cannot be said that it is sufficient in terms of drug absorption or local irritation, and there is still no practical application.

[0003]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The present inventor has conducted studies to develop a nasal administration preparation which has good absorption and is not irritating to insulin, which has been difficult to administer orally. That is, it is an object of the present invention to provide a composition for intranasal administration, which is superior in bioavailability to the nasal administration preparations proposed so far. As a result of diligent studies to solve the above problems, the present inventors have found that insulin is uniformly dispersed in a specific carrier, which has not been studied as a carrier for nasal administration preparations, and a composition in which it is adhered and bonded to the nasal cavity. It was found that effective clinical treatment is possible by administration by the route, that is, application to the nasal mucosa. That is, the present inventors have completed the present invention by discovering that the technique of dispersing and adhering insulin to a special carrier proposed by the present invention can obtain bioavailability equal to or higher than that obtained by standard injection administration. Came to let. The present inventor has newly found that the special carrier used in the composition of the present invention not only acts as a carrier for nasal administration of insulin, but also exerts a particularly remarkable effect of promoting absorption in vivo. ,
The present invention has been completed.

[0004]

According to the present invention, however, there is provided a composition in which an effective dose of insulin is uniformly dispersed and adhered to a carrier which is a propylene glycol alginate ester. That is, the first object of the present invention is to provide an insulin composition that can be administered intranasally, and specifically, an effective dose of insulin is uniformly dispersed in propylene glycol alginate ester, which is adhesively bonded. , Intranasal compositions are provided, and such compositions are preferably provided as powder formulations. A second object of the present invention is to provide a composition containing an absorption enhancer for improving the absorbability of insulin into a living body, and specifically, it contains propylene glycol alginate as an absorption enhancer. A composition is provided which is applied as an aqueous solution for intranasal administration or as a preparation for rectal administration.

Propylene glycol alginate ether as a carrier for uniformly dispersing, adhering and binding insulin in the present invention has been used as an emulsifier, a thickener, etc. for pharmaceuticals, but it is administered intranasally. The application of the formulation as a carrier has never been considered. It has now been found by the present inventor for the first time that it can be a carrier for drug delivery via the nasal route. The propylene glycol alginate used in the present invention is KIMILOIDO-.
(Registered trademark). Furthermore, the present inventor has newly found that the special carrier used in the composition of the present invention not only acts as a carrier for intranasal administration of insulin, but also has an effect of promoting bioabsorption. Therefore, another preferred object of the present invention is
It is to provide a composition comprising an effective dose of insulin in combination with a propylene glycol alginate which is an absorption enhancer. In a more specific embodiment, the composition is intranasally administered as an aqueous preparation. , Or for use as a rectal preparation.

[0006]

The amount of insulin contained in the composition of the present invention as an effective dose depends on the degree of the target disease to be treated, the desired frequency of administration, the individual therapeutic effect required, and the like. When the composition of the present invention is used by intranasal administration, it can be determined, for example, in comparison with bioavailability with known injections. Specifically, when the composition according to the present invention is administered by nasal administration, insulin is administered at a dose of about 1 to about 100 insulin units, more preferably about 2 to about 50 insulin units, if necessary, in divided doses. It is appropriate to treat. It is convenient to administer the above doses in a single application, ie, a single intranasal dose consisting of about 2 to about 50 insulin units, preferably about 4 to about 30 insulin units of insulin. is there. Therefore, when the composition of the present invention is produced, the insulin content is, for example, 10% by weight of the formulation.
0.005 to 20% per 0%, preferably 0.01 to
It is preferable to add 10%, more preferably 0.02 to 5.0%. The amount of propylene glycol alginate forming the composition of the present invention is, for example, 80 to 99.995%, preferably 85 to 99.99%, and more preferably 95 to 99.9% per 100% by weight of the preparation.
%, It was found that good nasal absorption can be obtained. On the other hand, in the case of obtaining an aqueous solution for nasal administration using the propylene glycol alginate of the present invention as an absorption enhancer, for example, the effective dose of insulin described above is, for example, pH 4.5 to 5.5, preferably pH 5.0. To about 1% gelatin as an insulin stabilizer and aspartic acid for example 0.1 to 1%, preferably 0.2 to
About 0.4% may be added, and the propylene glycol alginate of the present invention may be added as an absorption promoter.
In this case, the compounding amount of the propylene glycol alginate which is the absorption promoter of the present invention is, for example, 0.01 to 20%, preferably 0.
It is 1 to 10%, more preferably 0.5 to 5.0%.

The insulin powder composition of the present invention can be obtained by mixing the carrier propylene glycol alginate and insulin. For example, this mixing is performed while applying pressure or shearing force, like mixing with a mortar. The propylene glycol alginate used in the production of the composition of the present invention has an average particle size of 20 to 250 μm, preferably 30 to 60 μm. On the other hand, the physiologically active peptide is preferably as fine powder as possible, and the average particle diameter thereof is usually 20 μm or less, preferably 10 μm or less. The insulin composition for intranasal administration using the composition of the present invention can be produced, for example, as follows. That is, aspartic acid is added as a stabilizer to an effective amount of insulin, for example, 0.1 to
0.5%, preferably 0.38% is added and mixed for 30 minutes in an agate mortar. Then, the dried powder is kneaded with propylene glycol alginate in order of about 2 to 3 times and kneaded at a kneading humidity of 60% or less, and a fine powder in which insulin is uniformly adhered and bonded to a target carrier ( Intranasal composition) is obtained. The thus-obtained intranasal composition has a low-grease content in order to prevent the loss of the active substance before use (for example, before intranasal administration).
After filling the ase type capsule, appropriate packaging,
It is preferably hermetically sealed. As such an airtight package,
Blister packaging-aluminum packaging is a good combination.

The specific effects of the composition of the present invention will be shown below in test examples.

[Test example]

Test Example: A composition comprising insulin-propylene glycol alginate, which is the composition of the present invention, was used. As the insulin content, the intranasally administered composition of the present invention having a ratio of 2.4 mg / animal (5 insulin units (IU) / animal was used. Male New Zealand rabbits were used in groups of 6 and the composition described above was used. Nasal administration (single dose), 0 hours, 15, 30, 60, 120 after administration
And the decrease in mean blood glucose level after 180 minutes was measured. The blood glucose level at 0 hours after administration was defined as 100%, and the decrease in blood glucose level at each measurement time was calculated as a percentage. As a target group, 2 IU of insulin / animal dose was subcutaneously injected,
The decrease in blood glucose level 0 hour, 1, 2, 4, 6 hours after administration was measured in the same manner. The results are summarized in Table 1.

[0009]

[Table 1]

As is clear from the results in the table, the use of propylene glycol alginate as a carrier resulted in excellent absorption of insulin into blood by intranasal administration, resulting in a significant increase in blood glucose (blood glucose level). It turns out that it is decreasing.

The following is an example of the composition of the present invention. Powder composition: 80 mg insulin (2080 units)
Then, using an agate mortar, mix with 200 mg of propylene glycol alginate for 10 minutes. Add propylene glycol alginate 300 to this mixture.
mg, and mixed for 20 minutes at a humidity of 60% or less, and further 420 mg of propylene glycol alginate
Was added and mixed at a humidity of 60% or less for 30 minutes to obtain 1,000 mg of the powder composition of the present invention.

Aqueous solution composition: In 100 ml of purified water, hydrochloric acid was added to adjust the pH to 5.0, and insulin 2 was added thereto.
00 units, gelatin 1%, aspartic acid 0.38%,
Add 2% alginate propylene glycol ester,
The mixture was uniformly dissolved and mixed to obtain the intended aqueous solution composition of the present invention.

Composition for rectal administration (suppository): Prescription 1: 200 units of insulin Purified water (pH 4.0 with 0.1N-HCl) Appropriate amount (containing aspartic acid 0.38% gelatin 1.00%) propylene glycol alginate Ester 10 mg Hydrophilic base Residual amount ─────────── Total 2-4 g Glyceogelatin is used as the hydrophilic base, and the rectal administration composition of the present invention (suppository is used) by a conventional suppository manufacturing technique. ) Got. When the blood concentration of insulin was measured using the suppositories thus obtained, the maximum blood concentration was reached 10 to 20 minutes after administration, and an effective decrease in blood glucose level was observed. The propylene glycol alginate of the present invention is It was found to show a good absorption promoting effect. It should be noted that other hydrophilic bases such as macrogol, gelatin capsules and emulsifying bases were used for the same production.

Formulation 2: When a lipophilic base is used as a base, it may be formulated by combining a surfactant having a good compatibility and having an HLB value of about 4 to 6. Insulin 200 units Purified water (pH 4.0 with 0.1N-HCl) Appropriate amount (containing aspartic acid 0.38% gelatin 1.00%) Alginic acid propylene glycol ester 10-25 mg Surfactant Appropriate lipophilic base residue Amount ─────────── Total 2-4g Witepsol is used as lipophilic base, dipotassium glycyrrhizinate is used as surfactant, and the rectal administration of the present invention is carried out by a conventional suppository manufacturing technique. A composition (suppository) was obtained. Other lipophilic bases include Estarium A,
B, C, D, E, TV Novata A, AB, B
C, Suppocire A, B, C, AM, BM, natural cocoa butter, and other surfactants were also used.

[0015]

INDUSTRIAL APPLICABILITY As described above, according to the present invention, insulin, which has hitherto been difficult to administer orally, is well absorbed by nasal administration and is not irritating, that is, a composition for intranasal administration. Will be provided. In particular, the powder composition of the present invention in which insulin is dispersed in a specific carrier, propylene glycol alginate, is administered by the nasal route, that is, applied to the nasal mucosa, so that its absorbability in the body is good, It is suggested that effective clinical treatment is possible. Further, the propylene glycol alginate of the present invention has an insulin absorption-promoting effect, and the water-soluble composition of the present invention containing the same is administered by the nasal route or by rectal administration as a suppository. It was found that insulin absorbability in vivo was increased, and its medical effect was enormous.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical indication location A61K 9/14 47/16 J 47/36 BE A61K 9/14 U

Claims (9)

[Claims] 1. A composition in which an effective dose of insulin is uniformly dispersed and adhered to a carrier which is a propylene glycol alginate ester. 2. The composition according to claim 1, which contains aspartic acid as a stabilizer. 3. A composition according to claim 1 or 2 in the form of a powder formulation for intranasal administration. 4. The composition for intranasal administration according to claim 3, wherein insulin is uniformly dispersed and adhered to propylene glycol alginate ester. 5. A composition in which an effective dose of insulin is blended with propylene glycol alginate which is an absorption enhancer. 6. The composition according to claim 5, which contains aspartic acid as a stabilizer. 7. A composition according to claim 5, which is in the form of an aqueous solution. 8. In the form of an aqueous solution formulation for intranasal administration,
The composition according to claim 5 or 6. 9. A composition according to claim 5 or 6 in the form of a preparation for rectal administration.