JPS603286B2 - Constant-dissolution formulation - Google Patents

Description

[Detailed description of the invention] The present invention relates to constant rate dissolution formulations.

Sustained-release preparations have numerous medical advantages, such as reducing the number of drug administrations, reducing side effects, and maintaining effective blood concentrations. Conventionally, sustained-release preparations include those based on coating membrane permeability of the drug, those that dissolve and elute depending on the absorption Q anqin, those that absorb water and swell in the gastrointestinal tract and gradually dissolve, and those that dissolve in the gastrointestinal tract. It is known that there are drugs that elute depending on plaques, but sustained-release preparations based on membrane permeability of the drug have a delay in the start of elution of the drug, and furthermore, the elution is not at a constant rate but in a primary elution. However, there are disadvantages such as the fact that it is difficult to apply to drugs that are soluble in water and have a large body mass.

Further, sustained-release preparations based on other principles have the disadvantage that sustained-release properties are largely influenced by the environment within the gastrointestinal tract. For these reasons, it has been difficult to maintain a constant effective blood concentration of the drug with conventional sustained-release preparations. The present inventors have developed a new formulation that eliminates the above-mentioned drawbacks.As a result of various studies,
When coating a formulation containing a water-soluble substance and having recesses on its surface with a coating agent that is insoluble in water and has water permeability, an extremely small gap is created between the coating film and the recesses. It was completely unexpectedly discovered that the active ingredient elutes at a constant rate.

The present invention was completed based on this knowledge.

The size of the concave portion of the preparation of the present invention is 0.1 to 1.0 medium,
It is desirable that the fence has a depth of 0.1 to 0.4 and a length of 0.1 or more.

In this case, if the medium, depth, and length are all 0.1 mm or less, the recesses will be completely covered with the coating film, and the active ingredient will not be eluted from the recesses, resulting in so-called primary elution. Ru.

Mata middle school 1. At a depth of 0.4 or more and at a depth of 0.4 or more, the recesses are completely covered, similar to a formulation without recesses, and dissolution is of the primary type, and constant rate dissolution is not performed. The shape of the recesses may be any shape as long as it satisfies the above requirements, and the size, number, etc. of the recesses are arbitrarily determined in consideration of the size of the preparation, the desired dissolution rate of the active ingredient, etc. be able to.

The coating agent for the preparation of the present invention is preferably one that is insoluble in water, has water permeability, and is soluble in organic solvents or water-containing organic solvents, such as methacrylic acid and methacrylic acid esters such as Eudragit Retard S■ and Eudragit LS■. Examples include copolymers, methyl acrylate such as MPM-06■, methyl methacrylate copolymers, ethyl cellulose, cellulose acetate, polyvinyl acetate, cellulose acetate phthalate, hydroxypropyl cellulose phthalate, and the like.

There are no particular restrictions on the water-soluble substance as long as it is easily soluble in water, and not only water-soluble excipients but also water-soluble active ingredients may be used. If the active ingredient used in this preparation is well soluble in water, no particularly water-soluble excipients are required. , use excipients that are easily soluble in water, such as glucose.
The active ingredient of the preparation of the present invention may be either a water-soluble or water-impossible drug, as long as it remains in the gastrointestinal tract for a long time. For example, antibiotics such as penicillin, cephalosporin antibiotics, erythromycins, tetracyclines, macrolide antibiotics,
Antipyretics and analgesics such as aspirin, sulpirin, para-aminoacetophenol, diclofenac sodium, d-chlorpheniramine maleate, diphenylpyraline,
Antihistamines such as diphenhydramine, psychotropic drugs such as diazepam, chlorpromazine, lithium carbonate clothiapine, vitamins, antidiabetic agents such as tolbutamide, cardiac drugs such as pregolamine lactate and digitoxin, sleeping pills such as barbiturates, Examples include diuretics such as furosemide, sodium salicylate and theobromine, and anti-malignant tumor agents such as 5-FU, bleomycin and its derivatives. Note that the drugs used in the present invention are not limited to the above examples. It is necessary to select the method for coating the tablet and the operation method as appropriate depending on the purpose. Coating base solvents include alcohols such as methanol, ethanol, and inpropyl alcohol, methylene chloride, and methyl chloride. Chlorinated hydrocarbons such as form and chloroform, mixtures thereof, or mixtures thereof with water are preferably used, and those having a boiling point of 100° C. or lower are preferable. The thickness of the coating may be any thickness depending on the purpose, but if damage due to handling is taken into consideration, it may be 30 mm or more. The constant-rate dissolution tablet of the present invention may further be made into an inner-core compressed tablet (commonly known as an inner-core tablet), a water-soluble film-coated tablet, or a sugar-coated tablet using this tablet as a core, if necessary.

In this case, by formulating the active ingredient in the components of the outer layer, it becomes possible to provide the initial dosage as defined in the design theory of sustained-release preparations. The present invention will be specifically explained below using examples.

Example 1 6 parts of d-chlorpheniramine maleate, 1 part of lactose, 1 part of corn starch, and 2 parts of polyvinylpyrrolidone were mixed, and ethanol was added thereto, kneaded, granulated, and dried to form grains. do.

Thereafter, 1.2 hours of magnesium stearate was added and mixed. A single tableting punch with a diameter of 7 and a curvature of 11 with a convex part of 0.5 ribs in the middle, a depth of 0.2 side, and a length of 3 sides, and a single tableting punch of the same size without a convex part were used. Used 1500±50k
Compress into 9 tablets with a weight of 120 per tablet using a molding pressure of 9/9.

Next, 5 parts of ethylcellulose with a viscosity of 1 centipoise, 0.5 part of stearic acid, 1 part of triacetin, 4 parts of inpropyl alcohol, and 43 parts of chloroform are added.
The 5 parts coating solution is used to coat the tablets placed in the test film coating pan, and the coating is terminated when each tablet weighs an average of 12 ridges and 9 ridges. When this tablet was tested using the Japanese Pharmacopoeia's disintegration tester and the first liquid (plaque 1.2) according to the Japanese Pharmacopoeia's enteric tablet test standards, d-chlorpheniramine maleate was gradually determined. It eluted rapidly (1.003%/min).

On the other hand, as a control, uncoated tablets (control product 1
) Tablets without recesses (control product 2) were tested, and the former completed ejection in about 3 minutes, while the latter clearly showed a delay in the start of elution. was incomplete.

The relationship between elution time and elution rate is shown below.

Time Inventive product Control product 1 Control product 22 minutes 2 miscellaneous 92 purple 0 many 5 minutes 4% 100 grandchildren 1 grandchild 10 minutes 9* - 2% 30 minutes 31* - 4* 60 minutes 62% - 12% 90 minutes 95 Point by point 20% 120 minutes 100* - 37*180 minutes
- - 78% This relationship is shown in Figure 1.

As is clear from this figure, in the product of the present invention, the drug is released at a constant rate, but in the control product 1, the elution rate is too fast, and in the control product 2, the elution pattern is linear, and the elution rate is too fast. It turns out that it is incomplete. Example 2 Grains consisting of 50 parts of tolverisone hydrochloride, 45 parts of lactose, 12 parts of corn starch and 2 parts of polyvinylpyrrolidone were prepared in the same manner as in Example 1, and 1.1 parts of magnesium stearate was added and mixed.

This is made of a single tableting punch with a medium diameter of 0.2 willow, a depth of 0.2 ribs, a length of 3.5 sides, a diameter of 7 sides with a V-shaped protrusion of an acute angle of 60 degrees, a curvature of 11 skin, and no protrusions. 1350±50k with pestle
Compress into 9 tablets with a weight of 120 per tablet using a molding pressure of 9/2. Next, the tablets placed in a test film coating pan were coated with a coating solution consisting of 5 parts of Eudragit Retard S (manufactured by Rohm and Haas), 1 part of Myverset, 74 parts of inpropyl alcohol, and 24 parts of acetone. , the coaching ends when the average weight of one tablet reaches 128 9. A test similar to that in Example 1 was conducted using one tablet of this tablet.

As a result, the product of the present invention not only gradually eluted, but also eluted at a constant rate (0.683%/min). On the other hand, bare tablets (
Control product 1) dissolves extremely quickly, and tablets without recesses (control product 2) have incomplete dissolution and are not constant.
A delay in the start of elution was observed. The above results are shown below.

Time Invention product Control product 1 Control product 22 minutes 1
% 79 males 0 grandchildren 5 minutes 3 * 100% 0 * 10 minutes 7 many - 1 * 30 minutes 19% - 2 purple 60 minutes 41 grandchildren " 8 grandchildren 90 minutes 63% - 16% 120 minutes 81 one by one 27 sides 150 minutes 97 points 39 phosphorus 180 minutes 100 points - 58% This relationship is shown in Figure 2.

Example 3 Griseofulvin powdered product (specific surface area: 1.52 mm/average body surface area: approximately 2.7 mm): 125 mm, lactose: 40 mm, corn starch: 7 mm, and polyvinyl pyrrolidone: 2 mm
After granulating the grains made of grains using distilled water, drying and sizing them, 1.7 grains of magnesium stearate are added and mixed.

Next, a single tableting punch with a diameter of 8 skin and a curvature of 12 side, which had orthogonal cross-shaped convex portions on the middle 0.4 side, depth 0.25 side, and length 4 side, and a punch without a convex portion were used. 1100±50k9/
Compress into 9 tablets with a weight of 175 per tablet using normal molding pressure.

Next, using the coating solution used in Example 2, coating was completed when the weight of one tablet reached 183:9. When the same test as in Example 1 was conducted using this tablet, it was found that the product of the present invention gradually expanded due to subsequent penetration, and the contents were observed to flow out from the recesses, and when the amount of elution was measured, elution started. Although it was slightly delayed compared to Examples 1 and 2, it eluted at a constant rate (0.533%/min).

On the other hand, the plain tablet (Control Product 1) dissolved relatively quickly, while the tablet without convex portions (Control Product 2) showed almost no dissolution even after 300 minutes.

The above relationship is shown below.

Time Inventive product Control product 1 Control product 210 minutes 1
Grandchildren 5 grandchildren 0 grandchildren 20 minutes 6% 9% 0% 30 minutes 11% 15* 0% 60 minutes 26% 39* 1 answer 120 minutes 60 many 82% 1ゑ180 minutes 92% 100* 2% 240 minutes
100 * - 2 grandchildren 300 minutes - - 4 rare examples 4 Grains consisting of 25 minutes of diclofenac sodium, 80 minutes of mannitol, 17 hours of corn starch and 2 hours of hydroxypropyl cellulose were granulated using distilled water and dried. After sizing, one night of magnesium stearate is added and mixed.

Next, a single tableting punch with a diameter of 8 legs with a circular convex portion of 0.3 diameter side and a depth of 0.3 mm and a curvature of 12 ribs and a punch without a convex portion were used at a molding pressure of 1,300 kg and 50 k9/base. lock 12
Compress into 5 to 9 tablets.

The tablets were then coated using the coating solution used in Example 1 until the weight of one tablet reached 133 mm. When the same test as in Example 1 was conducted using this tablet, it was observed that the contents of the present invention were observed to flow out from the recesses, and at a constant rate (1
467%/min) was eluted. In contrast, the naked tablet (control product 1
) dissolution was fast, whereas tablets without recesses (control product 2)
) had a dissolution rate of 20% even after 24 min.

The above relationship is shown below.

Time Inventive product Control product 1 Control product 2 10 minutes 13% 32 males - 20 minutes 29% 88% - 30 minutes 45 scales 100% 40 minutes 58% - 15 minutes 74 grandchildren - 160 minutes 88% - 4% 90 minutes 100 minutes - 120 minutes after 5 - - 8% 180 minutes - - 14% 240 minutes - - 20 minutes Example 5 A mixed powder consisting of 9 parts of bleomycin hydrochloride, 158.15 parts of lactose, and 2 parts of hydroxypropylcellulose was prepared. Granulate, dry, and size particles using ethanol.

Next, 0.85 parts of magnesium stearate was added, and the mixture had a diameter of 8 ribs with a V-shaped protrusion of 0.2 ribs in the middle, 0.2 ribs in depth, 0.5 ribs in length, and a V-shaped convex portion with an acute angle of 60 degrees, and a curvature of 1 square rib. Using a single-shot tableting punch, each tablet is compressed into 170.9 tablets at a molding pressure of 1180 k9/50 k9/base. Next, the coating liquid of Example 1 is used to coat the tablets placed in a test coating pan until the weight of one tablet becomes 9 of 190.

Place this tablet in a test tube containing 10 minutes of Ringer's solution.
When the tablet was stored at 370° C. and the amount eluted was measured, the drug gradually oozed out from the tablet at a constant rate (0.23 titer/hour), and the entire amount eluted in about 7 hours. Next, the tablets were implanted into the thigh muscles of five rats (male 170-190, 9 weeks old), the daily excretion amount in urine was measured, and the recovery rate of pleomycin was determined. The results are shown in FIG. As can be seen from this figure, the recovery rate of bleomycin is almost the same from day 1 to day 3, and it is clear that it is eluted at a constant rate even in the body.

5 After 6 days, the thighs of the rats were opened and observed, and only the coating film remained.

Just to be sure, we conducted a test to confirm that bleomycin remained, but no trace of it remained.

[Brief explanation of the drawing]

0 Figures 1 and 2 show constant-rate dissolution tablets of the present invention, plain tablets (control product 1), and tablets without recesses (control product 2).
FIG. 3 shows the relationship between the elapsed time and the recovery rate of bleomycin after the fixed-rate tablet of the present invention was implanted into the body of a rat. 1 spear, 2 spears, 3 spears

Claims (1)

[Claims] 1 Contains water-soluble substances and has a surface width of 0.1 to 1.0 mm
A preparation having a small concave portion with a depth of 0.1 to 0.4 mm and a length of 0.1 mm or more is coated with a coating agent that is insoluble in water and has water permeability, so that the active ingredient is eluted at a constant rate. Constant rate dissolution formulation.