HK1098954B - Solid pharmaceutical preparation containing sparingly water-soluble drug - Google Patents

Description

Solid preparation containing poorly water-soluble drug

Technical Field

The present invention relates to a solid preparation containing a poorly water-soluble drug, and more particularly, to a solid preparation containing bisacodyl.

Background

Bisacodyl acts directly on the mucosa of the large intestine and acts as a laxative, mainly in the form of an oral formulation, to stimulate laxation by enhancing intestinal peristalsis. This drug is known to be extremely insoluble in water.

The problem is that bisacodyl repeats its action due to enterohepatic circulation when absorbed at a position before the upper part of the small intestine. Therefore, bisacodyl is preferably allowed to act in the region from the lower small intestine to the large intestine.

Dioctyl sodium sulfosuccinate is a known laxative. It acts directly on the dry hard stools in the intestines and allows water to permeate therein to soften and swell them, and then facilitates excretion.

A technique for improving the stability of a formulation in which bisacodyl and dioctyl sodium sulfosuccinate are combined together has been conventionally described (patent reference 1).

In some documents, it is reported that bisacodyl is coated with various coatings (coating) to release bisacodyl in a region from the lower small intestine to the large intestine (patent references 2 to 4).

However, there has not been any technique that enables the simultaneous release of bisacodyl and dioctyl sodium sulfosuccinate in the region from the lower small intestine to the large intestine.

Patent reference 1: japanese laid-open patent publication S57-99,521.

Patent reference 2: japanese laid-open patent publication H10-203,983.

Patent reference 3: published Japanese translation of patent application PCT International H11-506,432.

Patent reference 4: published Japanese translation of patent application PCT International H11-506,433.

Disclosure of Invention

Even by applying various coatings for release in the region from the lower small intestine to the large intestine, bisacodyl is not effective enough due to its low solubility, and thus satisfactory excretion cannot be obtained.

It is an object of the present invention to provide a formulation containing bisacodyl sufficiently effective.

After intensive studies to solve the above problems, the present inventors have found that a core material (core) in which bisacodyl and dioctyl sodium sulfosuccinate are combined may be coated with an enteric coating which allows the core material to be released in a region from a lower portion of a small intestine to a large intestine, thereby improving the solubility of bisacodyl at its site of action and synergistically providing higher drug efficacy for the same drug dose, thereby finally achieving the present invention.

The present invention provides:

a solid preparation comprising a core material containing bisacodyl and dioctyl sodium sulfosuccinate coated with an enteric coating which allows the drug to be released in the region from the lower small intestine to the large intestine;

the solid preparation according to [1], wherein the core material contains light anhydrous silicic acid; and

the solid preparation according to [1] or [2], wherein the preparation is insoluble in the first fluid for 2 hours and has a Disintegration time of more than 60 minutes in the second fluid according to a Disintegration Test (Disintegration Test) in the Japanese pharmacopoeia.

In the present invention, the core material means an object coated with an enteric coating, and includes granules, plain tablets (tablet tablets), and powders and gels prepared by granulating powders comprising dioctyl sodium sulfosuccinate and bisacodyl.

In this context, enteric coatings include films for granules or plain tablets, and capsules that dissolve in the intestine. When capsules are used, particles as a core material are filled in an enteric capsule material to produce capsules.

In the present invention, the enteric coating which releases the drug in the region from the lower small intestine to the large intestine means a coating which is insoluble in the first fluid for 2 hours and has a disintegration time of more than 60 minutes in the second fluid according to the disintegration test in the japanese pharmacopoeia. The enteric film used in the present invention may be any material capable of releasing a drug in the region from the lower small intestine to the large intestine. For example, a multilayer coating including an enteric polymer (e.g., cellulose acetate phthalate described in patent references 2 to 4) can be used to achieve the object of the present invention.

In view of excretory effects, bisacodyl is preferably contained in the present invention in an amount of 0.75 to 45 mg, more preferably 5 to 15 mg per dose. When the dosage form is a tablet, the content is preferably 0.75

In the present invention, the content of dioctyl sodium sulfosuccinate is preferably 3 to 360 mg, more preferably 8 to 30 mg per dose of a bisacodyl-containing preparation, in view of synergistic effect with bisacodyl. When the dosage form is a tablet, the content is preferably 3 to 120 mg, more preferably 5 to 30 mg per tablet.

In the present invention, when the core material is directly coated with the enteric coating, the amount of the coating is preferably 1 to 30% by mass of the core material.

The core material for use in the present invention is preferably prepared as follows:

sodium dioctyl sulfosuccinate is dissolved in a solvent such as water and ethanol to prepare a solution. The solution is added to and mixed with an excipient (e.g., light anhydrous silicic acid) by spray coating or one-time coating, and the powder thus obtained is granulated into a granulated powder.

To the resulting granulated powder is added bisacodyl, if necessary, and another pharmaceutical ingredient or additive commonly used for the preparation of pharmaceutical products is added thereto, followed by mixing, pulverizing or granulating the mixture as usual to provide a core material in the form of granules, tablets or the like.

The core material thus obtained may be coated with an enteric coating which enables the drug to be released in the region from the lower small intestine to the large intestine by a known method to provide the solid preparation of the present invention.

For the preparation of the core material of the present invention, the powder preferably contains a water-soluble polymer which is commonly used as a binder.

Examples of the water-soluble polymer include hydroxypropyl cellulose, polyvinylpyrrolidone and hydroxypropylmethyl cellulose. The content of the water-soluble polymer is preferably about 10 wt% of the total amount of the core material particles.

For preparing the solid preparation of the present invention, the core material preferably contains light anhydrous silicic acid in view of its properties. The content of the light anhydrous silicic acid is preferably 0.5 to 1.5 parts by mass, more preferably 0.6 to 1.3 parts by mass, for 1 part by mass of dioctyl sodium sulfosuccinate.

The lower small intestine, which is the drug release site of the preparation of the present invention, corresponds to the entrance of the large intestine and thus to the gastrointestinal tract which secretes a small amount of digestive juice. For the amount of digestive fluid in the human gastrointestinal tract, it generally decreases from the small intestine to the large intestine. Thus, when a drug is released in the region from the lower small intestine to the large intestine, the solubility of the drug itself often has an effect on its efficacy. The dioctyl sodium sulfosuccinate contained in the formulation of the present invention also functions as a surfactant, and thus can improve drug solubility when combined with a drug. In particular, low solubility drugs can be very effectively dissolved at a site that secretes a small amount of digestive juice.

In the present invention, bisacodyl and dioctyl sodium sulfosuccinate are simultaneously released in the region from the lower small intestine to the large intestine to exhibit a synergistic effect. With a conventional coating (which is not a coating capable of releasing a drug in the region from the lower small intestine to the large intestine), even if the two components are orally administered at the same time, no synergistic effect can be expected because each component cannot be utilized in a sufficient amount at the target site.

It has been found that the solid formulations of the present invention improve the solubility of bisacodyl at its site of action, thereby providing a synergistic improvement in excretory (catharsis) effect.

Drawings

FIG. 1 shows the results of a flow-through cell dissolution test (flow-through cell dissolution test) on DSS and bisacodyl.

Fig. 2 shows the results of a flow-through cell dissolution test (flow-through cell dissolution test) on bisacodyl.

Figure 3 shows the effect of excretion when DSS and bisacodyl were administered simultaneously, with the ordinate and abscissa being incidence of excretion (catharsis excretion rates) and samples, respectively.

Detailed Description

The present invention will be described in more detail with reference to examples, comparative examples and test examples.

Example 1

The formulation was prepared according to the composition shown in table 1. Which is a composition prepared by mixing bisacodyl as an active ingredient with lactose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose and light anhydrous silicic acid. In addition, another active ingredient, dioctyl sodium sulfosuccinate, was dissolved in a mixture of ethanol and purified water, and the resulting granulated solution was sprayed onto the composition to prepare granules. After drying, the resulting granules were combined with light anhydrous silicic acid, magnesium stearate and granulated lactose in powder form to prepare mixed granules, which were then tabletted to prepare tablets having a mass of 50 mg/tablet. Which may be used as core material particles.

Next, methacrylic acid copolymer (S, L blend), magnesium stearate, and castor oil were dispersed and dissolved in ethanol and acetone to prepare a coating solution, which was used to coat the core material particles in an amount of 8 mg/tablet to prepare the solid formulation of the present invention.

Comparative example 1

Core material particles without coating were prepared as described in example 1 and used as comparative example 1.

TABLE 1

Test example 1

The formulations in example 1 and comparative example 1 were evaluated by dissolution testing. Test method the amount of dioctyl sodium sulfosuccinate eluted was measured by HPLC in accordance with method 3 (flow cell method) of the japanese pharmacopoeia. This test is a reproduction of the performance of the formulation in the human gastrointestinal tract, since in this test the acidity and basicity of the test solution added to the bath changes over time and is therefore suitable for evaluating the elution performance of a targeted (site-targeting) formulation. Table 2 shows the acidity and basicity of the test solution properties and the elution time.

TABLE 2

Elution time [2]Minute (min)]	PH	In the gastrointestinal tract of a human
			0 to 30	1.2	Stomach (stomach)
30 to 90	6.55	Upper part of small intestine
			90 to 210	7.21	Lower part of small intestine
210 to 360	6.71	Large intestine

Figure 1 shows the dissolution profile of dioctyl sodium sulfosuccinate.

As can be seen from the figure, the formulation of example 1 triggered drug release in the high pH region simulating the lower part of the small intestine, whereas the formulation of comparative example 1 containing only core particles triggered drug release in the region simulating the pH of the stomach at 1.2.

In addition, a similar evaluation of bisacodyl dissolution from the formulation of example 1 showed that it triggered drug release in the lower small intestine as did dioctyl sodium sulfosuccinate.

Test example 2

The formulation is characterized by triggering drug release in the lower gastrointestinal tract, unlike conventional enteric formulations, and is therefore a more effective laxative. To illustrate this, the disintegration and dissolution properties were compared between this formulation and a common (commercially available) enteric formulation containing bisacodyl.

The disintegration time of the formulation in example 1 was measured by a disintegration method and a shaking method (shake method) in japanese pharmacopoeia. In the shaking method, approximately 10 ml of the test solution and one tablet are placed in a 50 ml measuring flask. The mixture was shaken with a shaker at a speed of about 100 rpm and an amplitude of 3 cm while the time to tablet disintegration was recorded. In this test, a first fluid J.P, (pH1.2), a second fluid J.P, (pH6.8) and a test solution having a pH of 8.3 were used, and for each solution, the disintegration time was determined. As a comparative example, a commercially available formulation was evaluated by the shaking method.

Table 3 shows the disintegration time of each test solution.

TABLE 3

Test solutions	Example 1		Commercially available formulations
					Disintegration method, J.P.	Oscillation method	Oscillation method
A first fluid; pH1.2	Not disintegrated within 120 min test period	Not disintegrated within 120 min test period	Not disintegrated within 120 min test period
				A second fluid; pH6.8	Does not disintegrate within 60 minutes	Not disintegrated within 120 min test period	31 minutes
pH8.3	43 minutes	70 minutes	41 minutes

As can be seen from the table, the test results in the shaking method showed that the formulation did not disintegrate within 120 minutes in the test solution having pH of 6.8, unlike the conventional enteric formulation. It was also shown that in the disintegration method of the japanese pharmacopoeia, the formulation did not disintegrate in the second fluid at pH6.8, but only in the test solution at pH 8.3. As used herein, "disintegrate" means that the enteric coating dissolves and thereby initiates release of the inner drug.

Test example 3

The drug release performance of example 1 and the commercial formulation was evaluated by the flow cell method using bisacodyl as a reference. The results are shown in fig. 2.

As shown in the figure, the formulation failed to induce dissolution of bisacodyl in the pH range corresponding to the stomach and upper small intestine, but induced dissolution in the high pH range corresponding to the lower small intestine.

The above disintegration and dissolution test results show that the formulation disintegrates and initiates drug release in a higher pH range (i.e., lower small intestine) than ordinary enteral formulations.

Test example 4

The change in bisacodyl solubility was studied in the presence of bisacodyl and dioctyl sodium sulfosuccinate. Bisacodyl was dispersed in purified water, and the dispersion was shaken under given conditions for 5 hours. The resulting liquid was allowed to stand for 3000 minutes^-1Centrifuge for 5 minutes. Then, the supernatant was collected and the amount of dissolved bisacodyl was determined by HPLC.

In a similar manner, bisacodyl was dispersed in solutions containing 0.07%, 0.14%, and 0.35% dioctyl sodium sulfosuccinate. Each dispersion was run at 3000 minutes^-1Shaken and centrifuged for 5 minutes. Then, the supernatant was collected and the amount of dissolved bisacodyl was determined by HPLC. The results are shown in table 4.

TABLE 4

Sample (I)		Concentration of DSS [% ]]	Solubility of bisacodyl [ mg/ml ]]	The ratio with the control [% ]]
					Control 1	Bisacodyl + purified water	0％	0.00189	-
Sample 1	Bisacodyl + 0.07% DSS aq.	0.07％	0.00362	191.5％
					Sample 2	Bisacodyl + 0.14% DSS aq.	0.14％	0.00451	238.6％
Sample 3	Bisacodyl + 0.35% DSS aq.	0.35％	0.0127	672.0％

As can be seen from table 4, in the case of the coexistence of bisacodyl and dioctyl sodium sulfosuccinate, the solubility of bisacodyl was found to be higher than that in the case of the presence of bisacodyl alone. In addition, the solubility increased with increasing concentration of dioctyl sodium sulfosuccinate in the solution. The results show that when core particles are prepared in this formulation, the content of dioctyl sodium sulfosuccinate in the core particles can be increased to improve the solubility of bisacodyl and thus increase its excretion effect.

Test example 5: action of combination of bisacodyl and DSS

1. Test procedure

SD males were used, 10 animals per group. The test substances used were bisacodyl (2 mg/kg) alone, DSS (3.2 mg/kg) alone, and bisacodyl (2 mg/kg) + DSS (3.2 mg/kg).

1) Internal ileal dosing test

The rats underwent laparotomy under ether anesthesia, and the test substance was injected into the ileum at a dose of 1 ml/kg of body weight of the rats by syringe at a distance of 20 cm from the ileum to the oral cavity. After abdominal suturing, the animals recovered from anesthesia and were observed for 24 hour episodes of voiding.

2) Oral test

The test substance was administered to rats at a dose of 5 ml/kg body weight, and 24-hour excretion onset was observed.

The results are shown in fig. 3. Among the two routes of administration, no excretion was observed with DSS alone (3.2 mg/kg).

When administered internally in the ileum, bisacodyl in combination with DSS showed a synergistic enhancement in excretion. In contrast, in normal oral administration, binding to DSS did not show an enhancement compared to the excretion of bisacodyl.

These results indicate that the formulations of the present invention release higher concentrations of the drugs (bisacodyl and DSS) in the region from the lower small intestine to the large intestine, thus synergistically enhancing their excretion compared to the effects of each drug alone.

Industrial applicability

The present invention can deliver a poorly water-soluble drug (e.g., bisacodyl) to the site of action of the drug at a high concentration efficiently and synergistically improve the action thereof, and thus can be used for pharmaceutical products and the like.

Claims (2)

1. A solid preparation comprising core particles containing bisacodyl and dioctyl sodium sulfosuccinate coated with a coating solution comprising S, L mixture of methacrylic acid copolymer, magnesium stearate and castor oil dispersed and dissolved in ethanol and acetone,

wherein the formulation is insoluble in a first fluid for 2 hours and has a disintegration time of more than 60 minutes in a second fluid according to the disintegration test of the japanese pharmacopoeia.

2. The solid preparation according to claim 1, wherein the core material contains light anhydrous silicic acid.