JPH0684299B2 - Method for producing sustained release preparation of isosorbide dinitrate - Google Patents

Description

The present invention relates to a simple method for producing an excellent sustained-release preparation of isosorbide dinitrate.

[Conventional technology]

 Isosorbide dinitrate has long been used to treat angina.
However, the usual formulation (eg Nitorol ) Oral
It has a short duration of action after administration and is not suitable for the prevention of angina attacks.
Since it is suitable, a sustained-release formulation is proposed for the purpose of sustained action.
Has been done. Several iso-nitrates with different elution rates
Sustained-release preparations in which sorbido mini granules are filled in capsules (commercial
Product name, Nitorol R ) Is one of them (clinical drug
S., Vol. 11, No. 4, p. 343, 1980).

[Problems to be solved by the invention]

 Nitorol R above Are several types of nitric acid with different elution rates.
Since it consists of isosorbide mini granules,
As for the manufacturing method, several types of isosorbide dinitrate mini-granules were individually
Due to the complexity of the manufacturing process
In addition, these isosorbide dinitrate mini granules
That they must always mix in exactly the same proportions
It is complicated and difficult.

An object of the present invention is to provide a simple method for producing an excellent sustained-release preparation of isosorbide dinitrate.

[Means for solving problems]

As a result of various studies, the present inventors obtained an isosorbide nitrate sustained-release preparation extremely easily by spray-coating a composition in which isosorbide nitrate was attached to a granular carrier with a spray solution in which ethyl cellulose and macrogol were dissolved. Then, the present invention was completed.

First, a composition in which isosorbide nitrate is adhered to a granular carrier (hereinafter referred to as elementary granules) is prepared by, for example, sucrose, lactose or starch to a granular carrier produced from a conventional pharmaceutical excipient, hydroxypropyl cellulose, Methylcellulose, while spraying an aqueous solution of a binder such as polyvinylpyrrolidone, with isosorbide nitrate, for example, lactose, sucrose,
It can be produced by adding a mixed powder consisting of excipients such as starch and crystalline cellulose little by little. This operation can be easily performed using a fluidized coating apparatus such as a centrifugal fluidized coating granulator.
The particle size of the granular carrier is 14 to 42 mesh, preferably 20 to 32 mesh.
It is a mesh. The ratio of isosorbide dinitrate in the mixed powder consisting of isosorbide dinitrate and an excipient is usually 20-
50% by weight. The amount of the mixed powder attached to the granular carrier is preferably 40 to 120% by weight.

Next, spray coating of elementary granules with a spray liquid in which ethyl cellulose and macrogol are dissolved can be easily performed by a normal operation using a coating device such as a centrifugal fluidized coating granulator, a fluidized bed coating device, and a pan coating device. You can do it.

Ethyl cellulose is preferably water-insoluble, and therefore, one having an ethoxy group content of 44 to 51% is preferably used.

The macrogol preferably has an average molecular weight in the range of 2600 to 9300, and particularly preferably 7300 to 9300 (for example, Macrogol 6000).

As the solvent of the spray liquid, an organic solvent capable of dissolving both ethyl cellulose and macrogol is used, and for example, a mixed solvent of ethanol and methylene chloride is preferable.

Now, first of all, the weight ratio of ethyl cellulose to macrogol affects the sustained release of the formulation. That is,
When the ratio of ethyl cellulose to macrogol is increased, the dissolution rate of isosorbide nitrate is suppressed, and the obtained preparation becomes more sustained release. A preferred weight ratio (ethyl cellulose: macrogol) is 40:60 to 60:40.

Secondly, the coating rate on elementary granules also affects the sustained release of the formulation. That is, when the weight% of both ethyl cellulose and macrogol relative to the elementary granules [100 x (ethyl cellulose weight + macrogol weight) / elementary granule weight, that is, coating rate] is large, the dissolution rate of isosorbide dinitrate is suppressed and the obtained formulation is , More sustained release. The preferred coating rate is 3 to 50% by weight.

In addition, the concentration of ethyl cellulose and macrogol [100
Also, x (weight of ethyl cellulose + weight of macrogol) ÷ weight of spray liquid, that is, concentration of spray liquid] also affects the sustained release property of the preparation. That is, when the concentration of the spray liquid is lowered, the dissolution rate of isosorbide nitrate is suppressed, and the obtained preparation becomes more sustained-released. A preferable spray liquid concentration is 3 to 20% by weight,
It is more preferably 9 to 15% by weight.

The preparation obtained as described above is in the form of granules, and if necessary, further dried and sized. The sustained-release preparation obtained by the present invention is administered to humans mainly as a granule or as a capsule by filling it into a capsule for the purpose of preventing an attack of angina. The dose is usually for adults per day,
It is an amount corresponding to 20 to 240 mg as isosorbide dinitrate, and this amount is orally administered once or in 2 to 4 divided doses.

〔The invention's effect〕

 The method of the present invention provides excellent sustained release of isosorbide dinitrate.
Sex preparations can be manufactured very easily. From conventional mini granules
Sustained release formulation (Nitorol R ) In the production of
Several kinds of mini-granules with different dissolution rate of isosorbide dinitrate
The operation of preparing each separately and these mini granules
Requires a complicated operation of mixing the
It Compared with this, in the present invention, it is
With normal operation using the equipment used,
Since it is only necessary to prepare seed granules, the operation is easy.
It is simple and can be done in a short time.

In addition, a sustained-release formulation consisting of conventional mini granules (nitrol
R ), The quality is constant due to natural products.
Not shellac (edited by Tetsuo Inoue, pharmaceutical additives, Nanzan)
Do, p. 34, 1972).
(See Hospital Pharmacy, Volume 10, Issue 3, p. 201, 1984)
In Ming, we use materials with such inconsistent quality
The advantage is that you don't have to

Furthermore, the elution rate of isosorbide dinitrate can be adjusted very easily and freely by changing the weight ratio of macrogol, the coating rate, or the concentration of the spray solution, and a sustained-release formulation with the desired elution rate can be obtained. There is an advantage that it can be obtained, and a preparation having an elution rate similar to that of a conventional sustained-release preparation can be manufactured very easily (see Test Examples 1 to 3 below).

When the preparation obtained by the method of the present invention is orally administered, the blood concentration of isosorbide nitrate lasts for a long time (see Test Example 4 described below).

Hereinafter, the sustained release property and sustainability of the preparation obtained by the method of the present invention will be described with reference to test examples.

[Test Example 1] The coating rate and the spray liquid concentration were kept constant (each 26
Wt%, 11.1 wt%) and ethyl cellulose and mac
Iso-nitrate from formulations prepared with varying weight ratios of logol
The dissolution rate of sorbide was measured at regular intervals,
And Nitorol R Compared with the case of.

1. Test preparation A; Granules of Example 1 [ethyl cellulose: macrogol
6000 = 50: 50 (weight ratio)] B; Granules of Example 2 [ethyl cellulose: macrogol
6000 = 45: 55 (weight ratio)] X; Nitorol (Commercial regular tablet) Y; Nitorol R (Conventional sustained-release capsule formulation) 2. Test method Using 900 ml of distilled water as a test solution, add isosol nitrate.
Add each test formulation in an amount equivalent to 20 mg bid
Test according to the second dissolution test method (paddle method) described in the positive
I tried The rotation speed of the stirring blade is 100 rpm. Trial test formulation
After adding to the test solution, collect 1 ml of the test solution at regular intervals.
High-performance liquid chromatography under the conditions
Quantify the elution amount of rubid and calculate the elution rate based on this value
did.

High performance liquid chromatography measurement conditions: column, NOVA PA
KC ₁₈ 3.9mm × 15cm (Nippon Waters Limited); eluent, methanol / water (45/55, v / v); flow rate, 0.
7 ml / min; detection, UV (220 nm) absorbance.

3. Test results Figure 1 shows. In the figure, A and B are the example 1 and the actual example, respectively.
Elution of isosorbide dinitrate from the granules obtained in Example 2
Shows the rate transition, X is nitorol , Y is Nitorol R
The change in dissolution rate in the case of is shown.

[Test Example 2] Weight ratio of ethyl cellulose and macrogol, and spray
Keep the fog concentration constant (50:50, 11.1% by weight, respectively)
Isosodium nitrate from formulations manufactured with varying coating rates
Measure the dissolution rate of rubid at regular intervals to
And Nitorol R Compared with the case of.

1. Test formulation A: Granules of Example 1 (coating rate 26% by weight) C: Granules of Example 3 (coating rate 4% by weight) D: Granules of Example 4 (coating rate 15% by weight) E : Granules of Example 5 (coating rate 40% by weight) X: Nitorol  Y: Nitorol R  2. Test method The same as in Test Example 1.

3. Test results Figure 2 shows. In the figure, A, C, D, and E are Example 1 and Example, respectively.
3, Nitric acid from the granules obtained in Examples 4 and 5
Shows the change in the dissolution rate of isosorbide, where X is nitrol ,
Y is Nitrole R The change in dissolution rate in the case of is shown.

[Test Example 3] Weight ratio of ethyl cellulose and macrogol and coat
Spraying with a constant loading rate (50:50, 26% by weight, respectively)
Of isosorbide dinitrate from formulations manufactured with varying liquid concentrations
Dissolution rate is measured at regular intervals to and
Nitorol R Compared with the case of.

1. Test preparation A; Granules of Example 1 (spray solution concentration 11.1% by weight) F; Granules of Example 6 (spray solution concentration 13% by weight) X; Nitorol  Y; Nitorol R  2. Test method The same as in Test Example 1.

3. Test results Figure 3 shows. In the figure, A and F are Example 1 and Example 6, respectively.
Of the dissolution rate of isosorbide dinitrate from the granules obtained in
, And X is nitorol , Y is Nitorol R in the case of
The change in the dissolution rate of is shown.

[Test Example 4] Measurement of blood concentration 1. Test drug F; Granule Y of Example 6; Nitorol R  2. Test method A healthy adult male fasted overnight (weight 50-73 kg, 6 per group)
20mg equivalent isosorbide dinitrate to name crossover method)
Each of the test agents of was administered orally with 100 ml of water. In addition,
The granules of Example 6 were filled in No. 4 capsules for administration.
After that, for a certain time (0.5,1,2,3.5,6,10,14 o'clock respectively
Each time), blood is collected (3 ml each) and immediately centrifuged (2500rp).
m, 10 minutes) to obtain plasma. 9-fluores as internal standard
Using non-gas chromatography as follows.
The isosorbide dinitrate concentration in plasma was determined from the above. Ie
A solution of 9-fluorenone in n-hexane (concentration 1
0 ng / ml) 0.5 ml, and then add n-hexane 1.5 ml
Shake vigorously for 5 minutes, then centrifuge (3000 rpm,
10 minutes) to separate the n-hexane layer and aqueous layer
The isosorbide dinitrate and 9-fluorenone to n-
Extracted into the xane layer. Furthermore, n-hexane 2.
0 ml was added and the same extraction operation was performed twice. All extraction
Combine the effluent (n-hexane layer) and n-
The xane was evaporated and concentrated to about 2 ml. Obtained concentration
Add 1 ml of acetonitrile to the solution and shake vigorously for 30 seconds.
After centrifugation, centrifuge (2000 rpm, 5 minutes) and acetonitrile
Layers were obtained. Evaporate acetonitrile under a nitrogen stream and leave
The residue was dissolved in 0.2 ml of ethyl acetate to prepare a measurement sample solution.
Gas chromatograph this solution (7 μl) under the following conditions
The isosorbide nitrate and 9-fluorenone pigment.
The peak area was measured to determine the area ratio of the two. This area
The ratio and the calibration curve created in advance
Obtain the amount of acid isosorbide, and from this value
The sorbide concentration was calculated.

Gas chromatography analysis conditions Equipment: Shimadzu GC-7A; Detector, ECD (⁶³Ni); Sample injection device
Oki, Shimadzu AOC-7 (autosampler) column and packing material: 2.6mm × 0.5m glass column, Silicon
e OV-7 20% (Gas Chrom Q), 100-120 mesh Column temperature: 148 ℃ Injector temperature: 190 ℃ Carrier and flow rate: Nitrogen, 60ml Peak area calculation: Shimadzu Chromatopack C-R3A 3. Test results It is shown in FIG. In the figure, F represents the granules obtained in Example 6.
The time course of blood concentration after oral administration is shown.
Troll R Changes in Blood Concentrations after Oral Administration
Indicates.

〔Example〕

 Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1 Using a centrifugal fluidized coating granulator (manufactured by Freund Sangyo Co., Ltd., Model CF-360), a granular carrier made of sucrose at a rotation speed of 150 rpm (Non-pareillou 103, 24-32 mesh, manufactured by Freund Sangyo Co., Ltd.) 640 g was made to flow, and while spraying 150 ml of 6.7 (W / W)% hydroxypropylcellulose aqueous solution at 40 ° C at a spraying rate of 5 to 7 ml / min, a mixed powder of 200 g of isosorbide nitrate and 300 g of lactose was added little by little. Isosorbide dinitrate was applied. This was dried at 40 ° C. and then sieved to obtain 1120 g of elementary granules having a particle size of 16 to 32 mesh. Next, 500 g of the elementary granules are put into the centrifugal fluidized coating granulator described above, and 65 g of ethyl cellulose and 6000,65 g of macrogol (weight ratio 50:50) are mixed with equal weight of ethanol and methylene chloride while flowing at a rotation speed of 150 rpm. Spray liquid dissolved in 1040 g of solvent (spray liquid concentration, 11.1% by weight)
Was spray-coated at a spray rate of 10 ml / min and a temperature of 40 ° C. (coating rate: 26% by weight). Then, it was dried at 40 ° C. and passed through a 16-32 mesh sieve to obtain 590 g of granules.

Example 2 58.5 g of ethyl cellulose in the spray liquid, macrogol
Example 1 except that the amount of 6000 was 71.5 g (weight ratio 45:55)
Granules (587 g) were obtained in the same manner as in.

Examples 3 to 5 Example 1 except that the spray liquid having the same composition ratio and the same concentration as used in Example 1 was sprayed at 180 g, 675 g or 1800 g, respectively.
Coating rate of 4% by weight
502 g of granules (Example 3), 560 g of granules with a coating rate of 15% by weight (Example 4), or 665 g of granules with a coating rate of 40% by weight (Example 5) were obtained.

Example 6 The spray liquid concentration was changed to 13% by weight (solvent amount was 870 g)
Granules (605 g) were obtained in the same manner as in Example 1 except for the above.

[Brief description of drawings]

 Figure 1 shows the spray liquid of ethyl cellulose: macrogol
It is a figure for explaining the relationship between the weight ratio and the dissolution rate.
It In the figure, A is the first embodiment, B is the second embodiment, respectively.
Elution of isosorbide dinitrate from the obtained granules over time
The rate transition is shown. X is nitorol , Y is Nitorol R
The changes in the dissolution rate in each case are shown. FIG. 2 illustrates the relationship between coating rate and elution rate.
FIG. In the figure, A is Example 1, C is Example 3,
D is the granule obtained in Example 4 and E is the granule obtained in Example 5.
Shows the change over time of the dissolution rate of isosorbide nitrate from
X is nitorol , Y is Nitorol R That's the case
The change in elution rate is shown below. FIG. 3 illustrates the relationship between the spray liquid concentration and the elution rate.
It is a figure. In the figure, A is the first embodiment and F is the sixth embodiment.
Time course of isosorbide dinitrate from the obtained granules.
Shows a high elution rate, and X is nitrol , Y is Nitorol R
The changes in the dissolution rate in each case are shown. FIG. 4 shows that when the preparation obtained by the present invention is orally administered, nitric acid is added.
To explain persistent blood levels of isosorbide
FIG. F is the oral administration of the preparation obtained in Example 6 to humans.
The change in blood concentration of isosorbide nitrate after administration is shown.
In addition, Y is Nitorol R Isosol nitrate when administered
The change of blood level of bid is shown.

Claims (1)

[Claims] 1. A method for producing a sustained release preparation of isosorbide nitrate, which comprises spray-coating a composition in which isosorbide nitrate is adhered to a granular carrier with a spray liquid in which ethyl cellulose and macrogol are dissolved.