KR930002093B1 - Protein drug mixture for oral administration - Google Patents

Abstract

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Description

Composition for oral administration of protein medicine

1 is a graph showing a change in blood glucose concentration with time when the insulin composition of the present invention prepared according to Examples 1 to 4 is administered,

Figure 2 is a graph showing the change in blood glucose concentration with time when the insulin injection is injected subcutaneously while changing the dosage of insulin,

FIG. 3 is a graph showing the correlation between the log [dose] and the area under the curve in the percentage-time graph of the initial blood glucose concentration in FIG.

4 is a graph showing a change in blood glucose concentration over time when the insulin composition prepared according to Comparative Example 1 to Vegyo 4 is administered,

5 is a graph showing a change in blood glucose concentration with time when the insulin composition prepared according to Example 5 to Example 8 is administered,

6 is a graph showing a change in blood glucose concentration over time when the insulin composition prepared according to Examples 9 to 12 is administered,

7 is a graph showing a change in blood glucose concentration over time when the insulin composition prepared according to Examples 13 to 16 is administered,

8 is a graph showing a change in blood glucose concentration over time when the insulin composition prepared according to Examples 17 to 20 is administered,

9 is a graph showing a change in blood glucose concentration with time when the insulin composition prepared according to Examples 21 to 24 is administered,

10 is a graph showing a change in blood glucose concentration over time when the insulin composition prepared according to Examples 25 to 28 is administered,

11 is a graph showing a change in blood glucose concentration over time when the insulin composition prepared according to Examples 29 to 32 is administered,

Figure 12 is a graph showing the change in blood concentration with time when the human growth hormone composition of the present invention prepared according to Example 37,

Figure 13 is a graph showing the change in blood concentration with time when the human growth hormone composition of the present invention prepared according to Example 38,

Figure 14 is a graph showing the change in blood concentration with time when the human growth hormone composition of the present invention prepared according to Example 39,

FIG. 15 is a graph showing changes in blood glucose concentration over time when the insulin composition prepared according to Example 41 is administered.

The present invention relates to a composition for oral administration of protein pharmaceuticals, and more particularly, to a composition containing tocopherol acetate (Vitamin E Acetate), an absorption accelerator and a therapeutically effective amount of protein pharmaceuticals.

Many kinds of medicines have not been properly absorbed by the gastrointestinal tract and have been administered by parenteral methods such as injection. In particular, protein medicines have been administered by intravenous injection, intramuscular injection or subcutaneous injection because they are not easily degraded in the gastrointestinal tract and do not pass through the intestinal membrane. For example, insulin is administered primarily subcutaneously.

However, it is very inconvenient to administer by injection, it is accompanied by pain, there is a fear of necrosis of the tissue at the injection site, and also there are many defects such as side effects, short duration of action and frequent administration Because of these various drawbacks, improved methods for administering protein medicines in place of injections have been studied.

Galinsky (Alvin M Galinsky) described in US Pat. No. 4,164,573 a method for preparing and administering insulin as a challenge. That is, insulin suppositories were prepared by adding cottonseed oil or peanut oil to a substance such as wax and including surfactant and insulin, and the bioavailability of these suppositories was 5.1% compared to subcutaneous injection. It was found to be relatively high. In addition, insulin suppositories using various kinds of components such as saponin, corn oil, polyoxyethylene lauryl ether, and fatty acids are known in this field. However, even though the method of rectal administration of insulin has been shown to be possible, it has not yet been established in a good way, because the suppository itself is not a convenient method of administration and bioavailability is not excellent.

Ishida et al. (M. Ishida et al., Chem. Pharm. Bu1l 29, 810-816 (1981)) reported that insulin could be administered through the buccal mucosa of the oral cavity. Insulin, cocoa butter and sodium choline were added to the mixture of hydroxypropyl cellulose and Carbopol-934 so that they could stick to the buccal mucosa of the oral cavity. Experiments with dogs showed that insulin was not absorbed through the buccal mucosa of the oral cavity. However, it showed poor bioavailability of 0.5% compared to intramuscular injection.

(John P. Longenecker et al., J. Pharm. Sci. 76, 2 (1987)) studied how to administer insulin to the nasal passages. Intranasal administration resulted in relatively high bioavailability. However, the nasal administration method is not only a convenient method but also severe irritation to the nasal mucosa may cause side effects such as damage to the nasal mucosa when administered over a long period of time.

In addition, methods for oral administration of protein medicines have been actively studied. Oral administration can compensate for the shortcomings of the above-mentioned formulations, and in particular, the method of administration is very convenient, while the bioavailability is low.

The low bioavailability of such protein drugs is due to the fact that, first, proteins are easily degraded by intestinal protease and thus lose their activity. To solve this problem, Henry M. Christensen, in British Patent No. 957,020, describes a method for preventing the breakdown of insulin in the intestine using trypsin inhibitors. Several protease inhibitors have been known so far, and it is known in the art that they inhibit the action of proteases represented by trypsin and chymotrypsin to some extent prevent proteolysis.

The second reason for poor bioavailability of protein drugs is that protein molecules are so large that they do not pass through the intestinal mucosa. To address this problem, M. Kidron et al., In US Pat. No. 4,579,730, describe the fact that oral administration of insulin compositions using bile acids and bile salts as absorption promoters reduce blood sugar levels. have. This can be seen that bile acids and bile salts reduce the blood sugar by promoting the absorption of insulin.

Bile salt derivatives, salicylic acid derivatives, surfactants and many substances are known to be used as absorption accelerators.

In addition to absorption accelerators, studies have been made to ensure that the composition of the dosage form itself has a suitable form for absorption.Sezaki et al. Have disclosed that Japanese Patent Publication No. 53-50316 contains bile salts and fatty acid monoglycerides or higher fatty acid salts. A pharmaceutical composition for oral administration using a composition prepared in the form of micelles is described. This mixed micelle composition showed better bioavailability than aqueous solution, but commercial use is still difficult. In addition, Cho Young-won describes oral protein pharmaceutical compositions for binding insulin to the particle surface consisting of a solid emulsifier and a surfactant and coating the fat thereon again in Korean Patent Publication No. 87-8587. Since the composition is a solid, it is advantageous to prepare it in the form of a solid preparation such as granules or capsules, but since an excipient is excessively used in the composition compared to the active ingredient, it is necessary to administer a considerable amount of granules or capsules in order to obtain efficacy. It is impractical because it is an impractical formulation, the manufacturing process is complicated, and the excessive use of excipients is uneconomical, and furthermore, the bioavailability is uncertain, and it is still difficult to be used commercially.

Accordingly, the present inventors have intensively researched to provide a composition suitable for oral dosage form of a protein medicine and having excellent bioavailability of the protein medicine, and as a result, a protein medicine containing togoferol acetate and a small amount of an absorption accelerator and a protein medicine Has developed a composition for oral administration.

That is, an object of the present invention is to provide a composition for oral administration of protein pharmaceuticals, which is suitable for the preparation of the oral dosage form which is the most convenient and ideal dosage form, and has excellent bioavailability.

Hereinafter, the present invention will be described in detail.

In the composition for oral administration of a medicament, the composition for oral administration of a protein medicament containing tocopherol acetate, an absorption accelerator, and a protein medicament having biological activity is characterized by its composition.

Referring to the present invention in more detail as follows.

Tocopherol acetate is very similar in physical properties such as viscosity and tocopherol, but unlike tocopherol, tocopherol acetate itself is very difficult to absorb the biodegradation in the form of tocopherol in vivo, and its bioavailability is lower than tocopherol. Known. However, the present inventors have observed the properties of tocopherol acetate, and the effect of togopherol acetate on the bioavailability of protein drugs is not a big problem, but when combined with an appropriate absorption accelerator, it creates an environment suitable for promoting water absorption. The help of the accelerators has been shown to be synergistic.

In other words, tocopherol acetate itself has little bioabsorbability, but in the state of the composition containing a small amount of the absorption promoter exhibits a completely new physical properties, which acts to greatly increase the bioavailability of protein drugs, which is the kind of composition Tocopherol acetate is the main component of the most ideal composition due to the characteristics of the absorption accelerator that the absorption promoting action is significantly changed depending on the state.

In particular, according to the results shown through animal experiments, oral administration of the composition of the present invention containing tocopherol acetate as a main ingredient, oral administration of a composition containing tocopherol as a main ingredient similar to physical properties of tocopherol as well as general oral compositions Compared with the case, the absorption rate was much higher. Moreover, the composition of the present invention was absorbed in a significant amount even when no protease inhibitor was added at all, which resulted in the addition of a protease inhibitor in the case of a composition for oral administration of a conventional general protein medicine under the same conditions. When the protein drug in the composition is broken down by the protease secreted in the intestine is hardly absorbed considering the fact that it can be said.

Therefore, the composition for oral administration of a protein drug product according to the present invention is characterized in that it contains tocopherol acetate as a main ingredient, and contains a small amount of the absorption accelerator, and the protein drug drug is highly suspended therein.

Absorption accelerator according to the present invention, polyoxyethylene derivatives, salicylic acid and its derivatives, bile acids and their derivatives, sodium lauryl sulfate known to have an absorption promoting action by changing the structure of the urethral membrane or the permeability of the mucosa , One or two or more selected from sodium taurodihydrofusidate, a chelating agent and a surfactant can be used. Among these, polyoxyethylene derivatives, in particular polyoxyethylene 20 cetyl ether or polyoxyethylene 20 oleyl ether, Most preferred. Such an absorption accelerator is used in an amount of 0.1 to 20 parts by weight based on 100 parts by weight of tocopherol acetate, and particularly preferably 1 to 5 parts by weight.

On the other hand, protein drugs that can be applied to the composition of the present invention may be any protein drug having biological activity, in particular, including insulin, α-interferon, β-interferon, γ-interferon, growth hormone, interleukin-2, tumor necrosis Factors, colony stimulating factors or the like are suitable.

Such protein pharmaceuticals are used in their therapeutically effective amounts.

The composition of the present invention exhibits very good bioavailability without containing protease inhibitors, but may further contain protease inhibitors, in particular protease inhibitors such as afpotinin, to further enhance the effect.

The composition for oral administration of protein medicines as described above can be prepared by completely dissolving or highly dispersing the absorption promoter in tocopherol acetate as a main component and finely suspending the protein medicines.

The composition of the present invention can be prepared in an oral dosage form such as capsules, pills, tablets, and the like, and in particular, a coating agent can be appropriately selected according to the site to be absorbed by the medicine, which is very preferable.

Hereinafter, the present invention will be described based on Examples. The following examples illustrate the invention and do not limit the scope of the invention. In particular, in the following examples, only the example of using insulin, human growth hormone, and γ-interferon as protein drugs in consideration of the ease of assay for animal test results, etc., it is preferable to apply any of the above-mentioned drugs It will be apparent to those skilled in the art that the effect can be obtained.

Example 1

Tocopherol acetate and polyoxyethylene 20 cetyl ether were placed in an organic container and mixed while slowly raising the temperature to about 60 ° C. The mixture is then cooled to room temperature, crystalline Zn-insulin (24.5 IU / mg, Sigma) is added to 49 IU / 9 and evenly dispersed in a strong stirrer in an ice bath containing the insulin composition. Was prepared.

In order to evaluate the absorbency of the insulin composition prepared as described above was tested as follows.

SD rats were used as test animals. For 24 hours before starting the test, water was freely eaten and not fed. More rats than the rats to be used for the test were prepared and weighed in the range of 180-250g, and only blood sugar concentrations within the normal range were selected for the test. Test rats were randomly divided into three to five animals to form one test group.

Under the anesthesia, the abdominal centerline of the rat was incised to remove the intestine, and then 0.5 g / kg.rat (474 mg / kg + polyoxyacetic acid) was injected into the insulin composition through a syringe with an 18G needle in the ileum located about 10 cm distant from the cecum. Ethylene 20 cetyl ether 25 mg / kg + insulin 24.5 IU / kg). The administration site was closed after the administration solution was prevented from leaking with a surgical adhesive. The sutured rats were placed in a fasting cage for free activity and water was freely eaten.

Blood was collected from the tail vein every hour up to 4 hours after administration and the glucose concentration in the blood was measured by glucose oxidase method, and the results are shown in Table I below. This concentration is expressed as a percentage of the initial blood glucose concentration (measured by averaging the glucose concentration in the blood twice at an hour before administration of the insulin composition) and the results are shown in FIG.

On the other hand, insulin injections were injected subcutaneously with varying dosages (0, 0.2, 0.5, 1.5, 2.0 IU / kg), and the change in blood glucose concentration over time was measured for each, and the results are shown in FIG. Indicated.

In addition, the relationship between the log (dose) and the area under the curve (AUC) in the percentage-time graph of the initial blood glucose concentration in FIG. 2 is shown in FIG. 3, and the correlation expressed by the following equation was obtained. .

Log [Dose] = 0.004669 (AUC) -1.035

r = 0.9986

Where AUC is the area between the curve and the straight line X = 100% in the percentage-time graph for initial blood glucose concentration (FIG. 2).

By comparing the blood glucose change of the oral administration insulin composition prepared in this example with the above results, the bioavailability compared to subcutaneous injection was obtained, and the results are shown in Table 1 below.

Example 2

Insulin composition was prepared in the same manner as in Example 1 using polyoxyethylene 2-cetyl ether as the absorption promoter, and the absorbency thereof was tested (dosage: 474 mg / kg + polyoxyethylene 2-cetyl ether 25 mg / tocopherol acetate). kg + insulin 24.5 IU / kg).

The test results are shown in Table 1 and FIG.

Example 3

Insulin composition was prepared in the same manner as in Example 1 using sodium choline as an absorption promoter, and its absorbency was tested (dosage: tocopherol acetate 474 mg / kg + sodium choline 25 mg / kg + insulin 24.5 IU / kg). ).

The test results are shown in Table 1 and FIG.

Example 4

Insulin compositions were prepared in the same manner as in Example 1 above using sodium salicylate as the absorption promoter, and their hydrophilicities were tested. (Dose: Tocopherol Acetate 474 mg / kg + Sodium Salicylate 25 mg / kg + Insulin 24.5 IU / kg).

The test results are shown in Table 1 and FIG.

Comparative Example 1

Tocopherol was used in place of initial tocopherol to prepare an insulin composition in the same manner as in Example 1 above, and its absorbency was tested (dosage: tocopherol 474 mg / kg + polyoxyethylene 20 cetyl ether 25 mg / kg + insulin 24.5 IU / kg).

The test results are shown in Tables 1 and 4 below.

Comparative Example 2

Insulin compositions were prepared in the same manner as in Example 1 using tocopherol instead of tocopherol acetate and using polyoxyethylene 2 cetyl ether as the absorption promoter, and the absorbency thereof was tested (dosage: tocopherol 474 mg / kg + poly Oxyethylene 2 cetyl ether 25 mg / kg + insulin 24.5 IU / kg).

The test results are shown in Tables 1 and 4 below.

Comparative Example 3

Insulin compositions were prepared in the same manner as in Example 1 above using tocopherol instead of tocopherol acetate and sodium choline as an absorption promoter, and their absorbency was tested (dose: tocopherol 474 mg / kg + sodium choline 25 mg). / kg + insulin 24.5 IU / kg).

The test results are shown in Tables 1 and 4 below.

[Comparative Example 4]

Insulin compositions were prepared in the same manner as in Example 1 using tocopherol instead of tocopherol acetate and sodium taurodihydrofucidinate as the absorption promoter, and the absorbency thereof was tested (dosage: tocopherol 474 mg / kg + Sodium taurodihydrofusidate 25 mg / kg + insulin 24.5 IU / kg).

The test results are shown in Tables 1 and 4 below.

Example 5

Tocopherol acetate and polyoxyethylene 20 cetyl ether, an absorption promoter, were placed in a glass container and mixed while slowly increasing the temperature to about 60 ° C. The mixture was then cooled to room temperature and then dispersed well by adding aprotinin to 3,000 KIU / g and crystalline Zn-insulin (24.5 IU / mg, Sigma) to 24.5 IU / g In this water bath, an evenly dispersed stirrer was used to prepare an insulin composition.

To evaluate the absorbency of the insulin composition prepared as described above was tested as in Example 1 (dosage: tocopherol acetate 474 mg / kg + polyoxyethylene 20 cetyl ether 25 mg / kg + aprotinin 1500 KIU / kg + insulin 12.3 IU / kg).

The test results are shown in Tables 1 and 5 below.

Example 6

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 2 cetyl ether as the absorption accelerator, and its absorbency was tested (dosage: 474 mg / kg of polycoethylene 2 cetyl ether 25 mg / kg + aprotinin 1500 KIU / kg + insulin 12.3 IU / kg).

The test results are shown in Tables 1 and 5 below.

Example 7

An insulin composition was prepared in the same manner as in Example 5 using sodium choline as an absorption promoter, and its absorbency was tested (dosage: tocopherol acetate 474 mg / kg + sodium choline 25 mg / kg + aprotinin 1500 KIU / kg + insulin 12.3 IU / kg).

The test results are shown in Tables 2 and 5 below.

Example 8

An insulin composition was prepared in the same manner as in Example 5 using sodium salicylate as an absorption accelerator, and its absorbency was tested (dosage: tocopherol acetate 474 mg / kg + sodium salicylate 25 mg / kg + aprotinin 1500 KIU / kg + insulin 12.3 IU / kg).

The test results are shown in Tables 2 and 5 below.

Example 9

Insulin composition was prepared in the same manner as in Example 1 by adding insulin to 30 IU / ml using polyoxyethylene 20 cetyl ether as an absorption promoter, and the absorbency thereof was tested (dosage: 474 mg of tocopherol acetate). kg / polyoxyethylene 20 cetyl ether 25 mg / kg insulin 15 IU / kg).

The test results are shown in Tables 2 and 6 below.

Example 10

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 60 cured castor oil as the absorption promoter, and the absorbency thereof was tested (dosage: tocopherol acetate 474 mg / kg + polyoxyethylene 60 cured castor oil). 25 mg / kg + aprotinin 1500 KIU / kg + insulin 12.3 IU / kg).

The test results are shown in Tables 2 and 5 below.

Example 11

Insulin composition was prepared in the same manner as in Example 5 using disodium ethylenediaminetetraacetate as an absorption promoter, and the absorbency thereof was tested (dosage: 474 mg / kg + sodium ethylenediamine tetraacetate 25 mg / tocopherol acetate). kg + aprotinin 1500 KIU / kg + insulin 12.3 IU / kg).

The test results are shown in Tables 2 and 6 below.

Example 12

Insulin composition was prepared in the same manner as in Example 5 using sodium lauryl sulfate as an absorption accelerator, and its absorbency was tested (dosage: 474 mg / kg of sodium lauryl sulfate + 25 mg / kg of sodium lauryl sulfate + aprotinine). 1500 KIU / kg + insulin 12.3 IU / kg).

The test results are shown in Tables 2 and 6 below.

Example 13

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 23 lauryl ether as the absorption promoter, and its absorption was tested (dosage: tocopherol acetate 474 mg / kg + polyoxyethylene 23 lauryl ether 25 mg / kg + aprotinin 1500 KIU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 2 and FIG.

Example 14

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 20 oleyl ether as the absorption promoter, and its absorbency was tested (dosage: tocopherol acetate 474 mg / kg + polyoxyethylene 20 oleyl ether 25 mg / kg + aprotinin 1500 KIU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 2 and FIG.

Example 15

Insulin composition was prepared in the same manner as in Example 5 using sodium taurodihydrofusidate as the absorption promoter, and the absorbency thereof was tested (dosage: 474 mg / kg + sodium taurodihydrofusidate 25 mg / tocopherol acetate). kg + aprotinin 1500 KIU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 2 and FIG.

Example 16

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 20 stearyl ether as the absorption promoter, and the absorbency thereof was tested (dosage: tocopherol acetate 474 mg / kg + polyoxyethylene 20 stearyl ether 25 mg / kg + aprotinin 1500 KIU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 2 and FIG.

Example 17

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 10 tridecyl ether as the absorption promoter, and the absorbency thereof was tested (dosage: tocopherol acetate 474 mg / kg + polyoxyethylene 10 tridecyl ether 25 mg / kg + aprotinin 1500KIU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 3 and FIG.

Example 18

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 4 lauryl ether as the absorption promoter, and its absorption was tested (dosage: tocopherol acetate 474 mg / kg + polyoxyethylene 4 lauryl ether 25 mg / kg + aprotinin 1500KIU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 3 and FIG.

Example 19

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 10 cetyl ether as the absorption accelerator, and its absorbency was tested (dosage: 474 mg / kg of polycoethylene 10 cetyl ether 25 mg / kg + aprotinin 1500KIU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 3 and FIG.

Example 20

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 10 stearyl ether as an absorption accelerator, and the absorbency thereof was tested (dosage: 474 mg / kg + polyoxyethylene 10 stearyl ether tocopherol acetate). 25 mg / kg + aprotinin 1500KIU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 3 and FIG.

Example 21

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 2 stearyl ether as the absorption promoter, and the absorbency thereof was tested (dosage: 474 mg / kg + polyoxyethylene 2 stearyl ether tocopherol acetate). 25 mg / kg + aprotinin 1500KIU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 3 and FIG.

Example 22

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 2 oleyl ether as the absorption promoter, and its absorbency was tested (dosage: 474 mg / kg + polyoxyethylene 2 oleyl ether tocopherol acetate). 25 mg / kg + aprotinin 1500KIU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 3 and FIG.

Example 23

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 10 oleyl ether as the absorption promoter, and its absorbency was tested (dosage: 474 mg / kg + polyoxyethylene 10 oleyl ether tocopherol acetate). 25 mg / kg + aprotinin 1500KIU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 3 and FIG.

Example 24

Insulin compositions were prepared in the same manner as in Example 5 using polyoxyethylene 20 oleyl ether as the absorption promoter, and their absorbency was tested (dosage: 474 mg / kg + polyoxyethylene 20 oleyl ether tocopherol acetate). 25 mg / kg + aprotinin 1500KlU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 3 and FIG.

Example 25

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 21 stearyl ether as an absorption accelerator, and its absorbency was tested (dosage: 474 mg / kg + polyoxyethylene 21 stearyl ether of tocopherol acetate). 25 mg / kg + aprotinin 1500KIU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 3 and FIG.

Example 26

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 9 lauryl ether as the absorption promoter, and its absorbency was tested (dosage: tocopherol acetate 474 mg / kg + polyoxyethylene 9 lauryl ether 25 mg / kg + aprotinin 1500KlU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 3 and FIG.

Example 27

Insulin composition was prepared in the same manner as in Example 5 using polyoxyethylene 10 lauryl ether as the absorption promoter, and the absorbency thereof was tested (dosage: 474 mg / kg + polyoxyethylene 10 lauryl ether tocopherol acetate). 25 mg / kg + aprotinin 1500KIU / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 4 and FIG.

Example 28

Insulin compositions were prepared in the same manner as in Example 5 using polyoxyethylene 2 cetyl ether and polyoxyethylene 20 cetyl ether as absorption promoters, and their absorbency was tested (dosage: 474 mg / kg of polytocopherol acetate) Oxyethylene 2 cetyl ether 12.5 mg / kg + polyoxyethylene 20 cetyl ether 12.5 mg / kg + aprotinin 1500 KUI / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 4 and FIG.

Example 29

Insulin compositions were prepared in the same manner as in Example 5 using polyoxyethylene 20 cetyl ether and polyoxyethylene 20 oleyl ether as absorption promoters, and their absorbency was tested (dosage: tocopherol acetate 474 mg / kg + Polyoxyethylene 20 cetyl ether 12.5 mg / kg + polyoxyethylene 20 oleyl ether 12.5 mg / kg + aprotinin 1500 KUI / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 4 and FIG.

Example 30

Insulin compositions were prepared in the same manner as in Example 5 using polyoxyethylene 20 cetyl ether and polyoxyethylene 10 stearyl ether as absorption promoters, and their absorbency was tested (dosage: 474 mg / kg + of tocopherol acetate). Polyoxyethylene 20 cetyl ether 12.5 mg / kg + polyoxyethylene 10 stearyl ether 12.5 mg / kg + aprotinin 1500 KUI / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 4 and FIG.

Example 31

Insulin compositions were prepared in the same manner as in Example 5 using polyoxyethylene 2 cetyl ether and polyoxyethylene 20 oleyl ether as absorption accelerators, and their absorbency was tested (dosage: tocopherol acetate 474 mg / kg + Polyoxyethylene 2 cetyl ether 12.5 mg / kg + polyoxyethylene 20 oleyl ether l2.5 mg / kg + aprotinin 1500 KUI / kg + insulin 12.3 IU / kg).

The test results are shown in the following Table 4 and FIG.

Example 32

Insulin compositions were prepared in the same manner as in Example 5 using polyoxyethylene 20 cetyl ether and biotin as absorption promoters, and their absorbency was tested (dose: tocopherol acetate 474 mg / kg + polyoxyethylene 20 cetyl ether). 25mg / kg + biotin 25mg / kg + aprotinin 1500KIU / kg + insulin 12.3IU / kg).

The test results are shown in the following Table 4 and FIG.

Example 33

Insulin compositions were prepared in the same manner as in Example 5 using sodium glycolate as the absorption promoter.

Rx. Tocopherol Acetate 9477mg

Sodium Glycocholine 500mg

Aprotinin 3mg (≒ 30000KIU)

20 mg of insulin (490 IU)

Example 34

Insulin compositions were prepared in the same manner as in Example 5 using sodium glycocholate and polyoxyethylene 20 cetyl ether as absorption promoters.

Rx. Tocopherol Acetate 8977mg

Sodium Glycocholine 500mg

Polyoxyethylene 20 Cetyl Ether 500mg

Aprotinin 3mg (≒ 30000KIU)

20 mg of insulin (490 IU)

Example 35

Insulin compositions were prepared in the same manner as in Example 5, using polyoxyethylene 20 cetyl ether as the absorption promoter.

Rx. Tocopherol Acetate 9300mg

500 mg polyoxyethylene 20 cetyl ether

Aprotinin 3mg (≒ 30000KlU)

200 mg insulin (490 IU)

The composition was filled in hard gelatin capsule No. 1 and enteric coating with a coater (Hi-coater, Freund, Japan) using Eudragit S 100 as a coating material.

Rx. Eudranet S 90g

Acetone 180 g

Isopropanol 360g

Di-n-butyl phthalate 18g

Example 36

Insulin compositions were prepared in the same manner as in Example 5, using polyoxyethylene 20 cetyl ether as the absorption promoter.

Rx. Tocopherol Acetate 9457mg

Polyoxyethylene 20 Cetyl Ether 500mg

Aprotinin 3mg (≒ 30000KIU)

Insulin 40 mg (980 IU)

The composition was filled in hard gelatin capsule No. 1, and enteric coating with a coater (Hi-coater, Freund, Japan) using Eudragit L100 as a coating material.

Rx. Eudragit L 90g

Acetone 180 g

Isopropanol 360g

18 g dibutyl phthalate

Example 37

Tocopherol acetate and polyoxyethylene 20 cetyl ether were placed in a glass vessel and mixed while slowly raising the temperature to about 60 ° C. The mixture is then cooled to room temperature, and then added with aprotinin, glycine, sodium glycocholate, and human growth hormone, and evenly dispersed in a water-containing water bath with a powerful stirrer to prepare the human growth hormone composition. Prepared.

Rx. Tocopherol Acetate 5069mg

Polyoxyethylene 20 Cetyl Ether 300mg

Sodium Glycocholine 300mg

Aprotinin 1mg (≒ 10000KIU)

Glycine 300mg

Human Growth Hormone 30mg (60IU)

Human growth hormone composition prepared as described above was administered to four rats according to the method of Example 1 (dosage: human growth hormone 1mg / rat).

The test results are shown in FIG.

Example 38

Tocopherol acetate and polyoxyethylene 20 cetyl ether were placed in a glass vessel and mixed while slowly raising the temperature to about 60 ° C. Then, the mixture was cooled to room temperature, and then aprotinin, glycine, and human growth hormone were added thereto, and the human growth hormone composition was prepared by uniformly dispersing in a water-containing water bath using a strong stirrer.

Rx. Tocopherol Acetate 4474mg

Polyoxyethylene 20 Cetyl Ether 250mg

Aprotinin 1mg (≒ 10000KIU)

Glycine 250mg

Human Growth Hormone 25mg (50IU)

Human growth hormone composition prepared as described above was administered to four rats according to the method of Example 1 (dosage: human growth hormone 1mg / rat).

The test results are shown in FIG.

Example 39

Tocopherol acetate and polyoxyethylene 20 cetyl ether were placed in a glass vessel and mixed while slowly raising the temperature to about 60 ° C. Then, after lowering the temperature of the mixture to room temperature, the human growth hormone composition was prepared by adding a human growth hormone free of glycine and evenly dispersing in a water-containing water bath with a powerful stirrer.

Rx. Tocopherol Acetate 5669mg

Polyoxyethylene 20 Cetyl Ether 300mg

Aprotinin 1mg (≒ 10000KIU)

Human Growth Hormone 30mg (60IU)

Human growth hormone composition prepared as described above was administered to six rats according to the method of Example 1 (dosage: human growth hormone 1mg / rat).

The test results are shown in FIG.

Example 40

A gamma interferon composition was prepared in the same manner as in Example 37 using gamma interferon as a protein drug.

Rx. Tocopherol Acetate 4946mg

Polyoxyethylene 20 Cetyl Ether 300mg

Aprotinin 1mg

Dextrose 150mg

Phosphorus Serum Albumin 300mg

Glycine 300mg

Gamma Interferon 3 mg (75 million IU)

Example 41

Tocopherol acetate and polyoxyethylene 20 cetyl ether were placed in a glass container and mixed while slowly raising the temperature to about 60 ° C. Then, the temperature of the mixture was lowered to room temperature, and sodium glycocholate was added thereto to disperse well. In a water bath containing ice, it is well dispersed by adding aprotinin to 1500 Kiu / g and crystalline Zn-insulin (24.4 IU / mg, Sigma) to 49 IU / g, evenly with a powerful stirrer. The insulin composition was prepared by dispersing.

In order to evaluate the absorbency of the insulin composition prepared as described above, 1 g / kg · rat (tocopherol acetate 898 mg / kg + polyoxyethylene 20 cetyl ether 50 mg / kg + sodium glycolate) 50 mg / kg + aprotinin 1500 Kiu / kg + insulin 49 IU / kg) orally. The subsequent test was the same as the method after administration in Example 1, the test results are shown in Table 4 and FIG.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

Claims (8)

A composition for oral administration of a medicament, wherein the composition for oral administration of a protein medicament comprises tocopherol acetate, an absorption accelerator and a protein medicament having biological activity. The method of claim 1, wherein the absorption promoter is one or two or more selected from polyoxyethylene derivatives, salicylic acid and derivatives thereof, bile acids and derivatives thereof, sodium lauryl sulfate, sodium taurodihydrofusidate, chelating agents and surfactants. Composition for oral administration of protein pharmaceuticals, characterized in that the mixture. According to claim 2, wherein the polyoxyethylene derivative is a composition for oral administration of protein pharmaceuticals, characterized in that polyoxyethylene 20 cetyl ether or polyoxyethylene 20 oleyl ether. The composition for oral administration of protein pharmaceuticals according to claim 1 or 2, wherein the absorption accelerator is contained in an amount of 0.1 to 20 parts by weight based on 100 parts by weight of tocopherol acetate. The method of claim 1, wherein the protein drug is oral administration of the protein drug, characterized in that insulin, interferon, growth hormone, interleukin-2, tumor necrosis factor, colony stimulating factor or the like. The composition for oral administration of protein pharmaceuticals according to claim 5, wherein the interferon is γ-interferon. The composition for oral administration of protein pharmaceuticals according to claim 1, wherein the composition contains a protease inhibitor. 8. The composition for oral administration of protein pharmaceuticals according to claim 7, wherein the protease inhibitor is aprotinin.