JPS62267238A - Production of insulin suppository - Google Patents

Abstract

PURPOSE:To obtain the titled suppository, rich in elution property and having high safety and blood concentration level, by dissolving insulin, an absorption accelerator and/or water-soluble saccharide at a specific blending ratio in water, drying the resultant solution, blending the obtained powder with a base and forming the blend. CONSTITUTION:An insulin suppository obtained by dissolving insulin in an amount of 0.1-1wt% based on the suppository, an absorption accelerator, e.g. a compound expressed by formula I (R is H, OH, etc.) or a compound expressed by formula II (X is Cl, Br) in an amount of 2-5wt% based on the suppository and/or a water-soluble saccharide, e.g. lactose or mannitol, in an amount of 0.5-30wt% based on the suppository in water, drying the resultant solution, blending the resultant powder with a base and forming the blend. The above- mentioned method provides a high dissolution rate of the insulin from the suppos itory and good safety. Furthermore, the content is uniform and release of the absorption accelerator can be controlled to sustain the insulin concentration in blood serum at a high level.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to suppositories containing half-open insulin-containing capsules, such as phthalate capsules, which reduce the concentration of sugar in serum.

[Conventional technology]

Recent research issues in pharmaceutical science include the development of methods for effectively transporting drugs to the site of action and simpler administration methods for drugs.

As one example, attempts to incorporate peptide hormones into living organisms by methods other than injection have recently been actively researched.

In particular, the development of Ink 51J suppositories is one of the central issues. Needless to say, administration of insulin is essential for diabetic patients. Therefore,
It is desirable that the administration method be as inconvenient to the patient as possible.

By the way, insulin is hardly absorbed from the gastrointestinal tract. Therefore, in order to maximize the amount of insulin absorbed after rectal administration, it is necessary to use absorption enhancers that increase the permeability of the rectal mucosa. For example, it has been demonstrated in rats, rabbits, dogs, and humans that the presence of sodium salicylate increases its absorption [T.N. (
1980) (T, N15hihata et al.
, :Bnhancement ofrectal a
bsorption of drug by adju
vant J, Pharm, Sci, 69.74
4 (1980))].

However, there have been various problems regarding clinical use, such as the following.

(i) The elution rate of insulin from the formulation is slow.

(ii) The stability of insulin in the formulation is poor.

6■) The insulin content in each formulation is not constant.

■ In order to expect clinical efficacy, it is necessary to maintain a high blood insulin concentration after administration to keep blood sugar levels at a low level.

Although the first problem was solved by adding an acidic aqueous solution of insulin to the base in a laboratory setting, the second problem could not be solved. That is, when an aqueous solution is added, there is a problem in that the stability of insulin is impaired.

The third point can be solved by carefully preparing suppositories or phthalate capsules one by one, but large-scale production has been relatively difficult.

The fourth point could be solved to some extent by using an absorption enhancer, but it was still not sufficient.

The method for producing a preparation for rectal administration of insulin according to the present invention includes:
It was developed to improve or solve the various problems mentioned above.

[Problem that the invention seeks to solve]

Therefore, in view of the above-mentioned problems in clinical use, it is an object of the present invention to ensure that the dissolution rate from the preparation is sufficiently fast and stable, that the insulin content does not vary much between preparations, and that after administration, To provide a method for producing an insulin half-open product that can maintain a high level of blood insulin concentration.

[Means for solving problems]

The present inventors have discovered that (1) by dissolving insulin together with an absorption enhancer or a water-soluble additive and then drying it, it is possible to prepare an insulin powder containing insulin uniformly; therefore, when it is made into a suppository, the same (2) A constant concentration of absorption enhancer can be maintained at the site of action at all times. We have discovered that by producing suppositories that control the release of absorption enhancers, it is possible to maintain high insulin levels in serum and keep blood sugar levels low.

That is, the present invention provides suppositories with insulin of 0.1 to
1% by weight, 2 to 5% by weight of absorption enhancer, and/or 0.5 to 30% by weight of water-soluble saccharide are uniformly dispersed and dissolved in an aqueous solution, and then dried. Provided is a method for producing an insulin suppository, which comprises mixing an insulin suppository with an agent and/or an absorption enhancer, and a base, followed by molding.

As the absorption enhancer used in the present invention, one group selected from [I] Formula % Formula % is shown. ) Sodium salicylate and sodium salicylate derivatives having the structure can be used, and furthermore, benzoic acid or benzoic acid derivatives having the structure of formula (II) can be used.

(X represents -α or -Br.) The water-soluble saccharides used in the present invention include lactose, mannitol, D-erythrose, L-arabinose, D-
-ribose, D-xylose, D-glucose, D-mannose, D-galactose, D-fructose, L-
Sorbose, trehalose, sucrose, maltose, cellobiose, gentiobiose, melibiose, raffinose, gentianose, meletitose, stachyose, and the like can be used.

As the surfactant, in addition to soybean lecithin, nonionic surfactants such as polyoxyethylene ether surfactant or polyoxyethylene sorbicun ester surfactant can be used.

If an absorption enhancer is not used at the stage of preparing the insulin fine powder, the required amount of absorption enhancer (2 to 5% by weight relative to the suppository) is mixed in at the subsequent stage of mixing with the base and molding.

As the base, it is possible to use, for example, lipophilic suppositories such as semi-synthetic oleaginous bases or bases used for making phthalate capsules.

In addition, when used as a lefkuru capsule, it can be manufactured, for example, by the following method (Japanese Patent Application Laid-Open No. 61-5853'7).

That is, the powder containing insulin or the like prepared according to the present invention and a base are mixed with a stirrer and then defoamed under vacuum to obtain a capsule contents solution. Next, the sol solution for forming the soft capsule shell is flowed down onto the casting drum of a soft capsule manufacturing machine using a rotary die punching method while adjusting the thickness uniformly using an applicator to prepare a film of a constant thickness, and then cooled and Gel it while blowing dry air to form a film of uniform thickness. Two sheets of gelled film are sandwiched between symmetrical rotating metal molds and molded to form a soft capsule outer shell, while the liquid inside the capsule is pressurized and filled into the soft capsule outer shell using a drug injection pump. By rotating the mold, the outer shell of the soft capsule is welded and closed to form a punched soft capsule. It is produced by drying it in a hot air rotary dryer.

Example 1 Preparation of uniform insulin powder Insulin lg (27U/mg) was mixed with 0.001N
Hα (or 0.005 M-citric acid) and 0.001%
500me including Tween 3 Q
81 g of sodium salicylate dissolved in an aqueous solution
was dissolved. Considering the stability of the insulin aqueous solution, the preparation was carried out at a temperature range of 10° C. or lower and 4° C. or higher.

Next, after drying by vacuum drying method or freeze drying method,
The particles whose particle size was adjusted to 350 μm or less using No. mesh were used for the production of the base material. The reason for choosing the particle size is
This is to sufficiently disperse the particles in the base.

Table 1 shows the component ratios when insulin powder was prepared using salicylic acid according to this example.

The base of the suppository in Table 1 is soybean lecithin, a semi-synthetic oil-based base (manufactured by Dynamit Nobel, West Germany, coconut oil/palm), in order to control the release of salicylate from the suppository. It was prepared by mixing it with kernel oil (higher fatty acid di-triglyceride composition).

The content of soybean lecithin in the base was 10% by weight.

Production of single rectal insulin tablet Mixed powder of insulin and sodium salicylate mentioned above 3
'OOmg was mixed with 700 mg of the above-mentioned base at 45°C, poured into a mold, solidified, and then stored at 4°C.

According to this document, a suppository containing about 100 U of insulin can be made when half opened.

If it is desired to reduce the amount of insulin administered, for example, half of insulin can be prepared using 0.1 g of insulin by the method described in Example 1 above, resulting in a suppository containing about 10 U of insulin per suppository.

Amount of insulin in suppositories When examining the insulin content using 20 suppositories,
49.1±2. It was IU/g (suppositories).

On the other hand, when a suppository is produced by mixing 40 g of insulin bulk powder with 20 g of a semi-synthetic oil-based base (Uitepsol H-35), the insulin content is 51.4 ± 19.7 L]/g
(suppository).

Q Comparative Example 1 The conventional suppository used in the comparative experiment of manufacturing halved insulin is about 60 μp of an acidic aqueous solution containing 50 U (1,95 μ) of insulin dissolved in 30
It was prepared by mixing with 700+ ng of a molten semi-synthetic oleaginous base (Witepzol H-15) containing 0 mg sodium salicylate.

Elution of insulin and sodium salicylate Japanese Pharmacopoeia 2nd solution 2ml! Or 3ml/1l! (37°C) and collect the aqueous layer over time. The aqueous layer was collected using a Millipore filter, the amount of insulin was determined by radioimmunoassay, and the amount of salicylic acid was determined by high performance liquid chromatography (HPLC).

As shown in FIG. 1, insulin was eluted relatively quickly from the suppositories (◯) prepared by the method of the present invention compared to the conventional suppositories (·). More than 70% of the insulin was released within 30 minutes.

The effects of administering half of the insulin to three large male peagles were confirmed. Insulin dosage is 5-50U
/ head. For each of the three animals, changes in serum glucose concentration over time after administration were measured, and the results are shown in FIGS. 2 to 4.

Serum glucose concentration before suppository administration was large N.

1 is 91.2±6.7mg/dj! , 88.4g±3.9mg/dA for large No. 2, 8 for large No. 3
It was 9.2±7.4 mg/d1.

As shown in Figures 2 to 4, when the new suppository was administered at an insulin dose of 10 U/head or more, the serum glucose concentration decreased significantly in all dogs.

In these figures, the solid lines indicate when the new insulin suppositories were administered at 5U/head (b), 10U/head (mu), 20U/head (△), 300/head (・), and 50U/head (○), respectively. The dashed line shows the case where 50 U/head of a conventional suppository was administered.

A comparison at 50 U/head administration shows that the new suppository effectively lowers the glucose concentration compared to the conventional suppository. Also, when the new suppository is administered IO or 20 U/head, a decrease in glucose concentration equivalent to that of the conventional suppository 50 U/head is observed. In addition, with the new suppository, serum glucose levels were reduced by administering only 5 U/head.

Stability of insulin during half-opening A new suppository containing 100 insulin per suppository was prepared and stored at 4° C. for 4 weeks, and then similarly administered to Peagle-sized animals to measure the serum glucose concentration.

The changes in glucose concentration over time showed no significant difference from those shown in FIGS. 2 to 4. Therefore, it can be stably stored under the above conditions.

Example 2 Preparation of homogeneous insulin powder 1 g of insulin is dissolved by the method shown in Example 1, and 27 g of mannitol is dissolved therein.

Thereafter, a uniform insulin powder was obtained by the same operation as in Example 1.

Preparation of half insulin 100mg of the above powder and 300LI of sodium salicylate
1 g was mixed with the base of Example 1 to give a dosage of 10 per suppository.
Suppositories containing 0 U of insulin were prepared.

Example 3 Preparation of homogeneous insulin powder 0.72 mg of insulin was mixed with 299.28 mg of 5
- Sodium methoxysalicylate (Sodium 5
-methoxysalicylate) with 0
．． 0OINHα - 0.3 of 0,001% Tween 80
After dissolving in 6 me and drying under reduced pressure, a fine powder was obtained.

Preparation of insulin halves 300 mg of the above fine powder was weighed, and the base prepared in Example 1 (Witepsol H-35: Witepsol H-42
= 65:35 mixture containing 210% by weight of soybean wrench) and prepared as a suppository at 40°C according to the method of Example 1.

Each suppository contained 19.5 J of insulin.

The elution rate of insulin and sodium 5-medoxysalicylate was monitored using 5 samples (n=5). The results were good at 78.5±6.2% and 96.4±5.1%, respectively, after 30 minutes.

FIG. 5 shows the change in serum glucose concentration when the suppository prepared in Example 3 was administered to a normal person in the same manner as in Example 1.

The serum glucose concentration significantly decreased, indicating that insulin was well eluted.

Example 4 Insulin 108 mg and mannitol or lactose Log were dissolved in 30 mff of the aqueous solution of Example 1 and dried under reduced pressure to form a powder (74 μm or less).

10 g of this powder and 30 g of sodium salicylate were mixed at 40° C. with the base prepared in Example 1 to form a suppository.

One half-open piece (1g) produced in Example 4 contained about 30
It contained U insulin.

FIG. 5 shows the results of comparing the elution rates of the insulin halves prepared in Example 4 using mannitol (◯) and lactose (·). The number of samples is 5
And so.

FIG. 6 shows the changes in serum glucose when the suppository was administered to normal subjects for two types of sugars in the same manner as above. The number of samples was 3.

Example 5 Suppositories were manufactured by varying the blending ratio of soybean lecithin used in the base to 0%, 20%, and 30%, and the effects were tracked in the same manner as in Example 1. .

The base is Witepsol H-35 and Witepsol H-4.
Add soybean lecithin to a 65:35 mixture of 2, 0% (
It was prepared by mixing ○), 20% (・), and 30% (△).

Insulin powder is 108mg insulin and 29,8
92 g of sodium salicylate was prepared by dissolving it in an aqueous solution and drying it under reduced pressure in the same manner as in Example 1.

A suppository is prepared by mixing 300 mg of the insulin powder dried under reduced pressure with 700 kg of the base at 40 tons. The prepared material was assimilated at room temperature and then stored at 4°C.

Figure 8 shows the elution rate of insulin and sodium salicylate from the suppositories containing soybean lecithin, and Figure 9 shows the glucose concentration in serum when each of the suppositories mentioned above was administered to a normal person. Show change.

〔Effect of the invention〕

Since the absorption enhancer or saccharide contained in the insulin rectal suppository produced by the method of the present invention is water-soluble, the insulin is eluted relatively more quickly than in conventional suppositories. Furthermore, these additions do not impair the stability of the preparations, and have the effect of equalizing the amount of insulin contained in each preparation.

A surfactant such as soybean lecithin in the mixed base gradually releases the absorption enhancer (such as IJ), allowing a certain amount of the absorption enhancer to be absorbed for the period required for sustained medicinal efficacy. This shows changes in the glucose concentration in the serum when insulin is absorbed continuously and has the effect of lowering the glucose concentration in the serum.

do.

[Brief explanation of drawings]

Figure 1 (A) shows the suppository (○) prepared by the method of the present invention.
) and a conventional suppository (·), and (B) shows the elution of sodium salicylate. Figures 2 to 4 show the glucose concentration in serum after half-open administration of insulin according to the present invention and conventionally. FIG. 5 shows the change in serum glucose concentration when the suppository molded in Example 3 was administered to a normal person. FIG. 6 shows the elution rate of mannitol (0) and lactose (.) in the Inter-51J suppository molded in Example 4. FIG. 7 shows changes in serum glucose when the suppository of Example 4 was administered to normal subjects. FIG. 8 shows the elution rate of insulin and sodium salicylate from the suppository containing soybean lecithin of Example 5. Figure 9 shows the 2,0 hours after each suppository of Example 5 was administered to a normal person.
Time Figure 5 Time Figure 6 Figure 7 (A) (8) Time Time Time

Claims (4)

[Claims] (1) 0.1 to 1% by weight of insulin, 2 to 5% by weight of absorption enhancer, and/or 0.5 to 30% of water-soluble saccharide based on the suppository
A method for producing an insulin suppository, which comprises dissolving % by weight in water, then drying, mixing the obtained powder with a base, and further molding to produce a suppository. (2) The method according to claim (1), wherein the absorption enhancer is a compound having the structure of formula [I]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] (R represents one group selected from -H, -OH, -OCH_3, -Cl, and -Br.) (3) The method according to claim (1), wherein the absorption enhancer is a compound having the structure of formula [II]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[II] (X indicates -Cl or -Br.) (4) Water-soluble sugars include lactose, mannitol, D-
Erythrose, L-arabinose, D-ribose, D-
Xylose, D-glucose, D-mannose, D-galactose, D-fructose, L-sorbose, trehalose, sucrose, maltose, cellobiose,
Claims (1) to (3), which are at least one water-soluble saccharide selected from the group consisting of gentiobiose, melibiose, raffinose, gentianose, meletitose, and stachyose. Method.