JPS61148114A - Nifedipine granule - Google Patents

Abstract

PURPOSE:A rapid-acting and easily absorbable granule consisting of a spherial core agent and fine powder of nifedipine sticking to the surface thereof and a sustained release compound granule of nifedipine using same. CONSTITUTION:A sustained release compound granule of nifedipine consisting of rapid-acting spherical granules consisting of a spherical core agent and fine powder of nifedipine sticking to the surface thereof and slow-acting spherical granules obtained by coating the above-mentioned rapid-acting spherical granules with an enteric substance and/or slightly soluble substance, and containing 10-90wt% preferably 10-50wt%, based on the total granules, rapid-acting spherical granules. The final grain size of the above-mentioned granules is preferably 12-150 mesh, particularly 12-80 mesh. The above-mentioned rapid- acting spherical granules are very easily absorbable and rapid acting and therefore may be formulated into a capsule, etc. Stick packages or packs divided into sachets as one unit can be easily and smoothly put into and administered to the interior of the mouth.

Description

[Detailed description of the invention] The present invention provides easily absorbable granules of nifedipine.

and a long-lasting composite granule using the same.

Nifedipine, 4-(2'-ditophenyl)-2,
G-dimethyl-3,5-dicarbomethoxy-1.4-dihydropyridine is an extremely potent calcium antagonist and is widely used as a therapeutic agent for angina pectoris due to its excellent coronal duct dilation effect. Also.

It also acts on other peripheral vascular smooth muscles and has a surface pressure-lowering effect, so it is also used as an antihypertensive agent.

However, since nifedipine is sparingly soluble in water, when it is made into a solid form such as a single powder tablet or granules, there is a problem with its absorbability.

In addition, in the case of highly absorbable soft capsules, although the effect is fast-acting, there is a drawback that the duration is short.

The present inventors have arrived at the present invention as a result of intensive research to develop a solid form of nifedipine that is easily absorbed and a solid form of nifedipine that has a long-lasting effect.

Moreover, the present invention has a spherical nucleating agent and NJ'? 3L
an easily absorbable, fast-acting spherical granule of nifedipine, which is made of a fine powder of nifedipine; It consists of highly effective spherical granules,
This is a long-acting composite granule of nifedipine in which 10 to 90% by weight of the entire granules are fast-acting spherical granules.

The spherical core agent used in the present invention is lactose.

Crystals or fine powders (nucleating agents) of non-medicinal ingredients consisting of carbohydrates such as granulated sugar and sucrose or inorganic substances such as calcium phosphate and soft anhydrous silicic acid are processed by centrifugal force and jet air using a centrifugal fluid coating granulator, for example. It can be obtained by coating or coating a coating component thereon while transferring the coating material. As a nucleating agent, it is preferable to use one that has been sieved and has as uniform a particle size as possible.

As the coating component, the same material as the above-mentioned nucleating agent in finer powder, or a polymer such as starch or starch is used, and it is sufficient to use 1 to 3 times as much of the coating component as the nucleating agent. During covering or coating, the nucleating agent is sprayed with a binder solution such as an aqueous solution of polyvinylpyrrolidone or an isopropyl alcohol solution of hydroxypropyl cellulose, and the coating component is adhered thereon, and by drying, a spherical nucleating agent is formed. 1q is received. Thus 1
The spherical nucleating agent mentioned above has a relatively uniform particle size, and because of its spherical shape, subsequent drug coating is performed uniformly and efficiently.

The final particle size of the granules of the present invention is preferably about 12 to 150 mesh, particularly preferably in the range of 12 to 80 mesh, so the particle size of the spherical nucleating agent should be appropriately determined accordingly. It is.

The particle size of nifedipine fine powder is approximately 10μ.
The following refers to nifedipine, which can be obtained by grinding nifedipine alone or a mixture of nifedipine and an excipient such as corn starch, crystalline cellulose, or sucrose, in a ball mill, hammer mill, or agglomerator, for example.

The method for coating the surface of the spherical core agent with nifedipine powder is not particularly limited, and a known spray coating method or the like may be employed, but the centrifugal fluid coating method is preferred. Specifically, a predetermined amount of the spherical nucleating agent is put into a centrifugal fluid coating granulator, and while the spherical nucleating agent is rotated by centrifugal force (due to the rotation of the rotor), it is simultaneously attached to the side wall of the granulator. The air is blown up to a height controlled by the air flow blown out from the slit between the rotor and the rotating body.
From a spray gun located above, for example, a syrup solution made by appropriately mixing sucrose and water, or a low boiling point organic solvent such as ethanol, isopropyl alcohol, acetone, methyl ethyl ketone, etc., or water, etc. For example, a solution (binder) in which an organic polymer such as methylcellulose, ethylcellulose, hydroxypropylcellulose, human oxypropylmethylcellulose, polyvinylpyrrolidone, or polyvinyl alcohol is dissolved is sprayed to wet the spherical nucleating agent, and then granulated. By introducing nifedipine or a composition containing nifedipine into the coated powder through the coating powder inlet located above the machine and allowing it to adhere to the wet spherical core agent and avoid drying for a certain period of time, the desired resultant can be obtained. Fast-acting spherical granules of particle size can be obtained.

Alternatively, 1q of fast-acting spherical granules to which fine powder of nifedipine is attached can be obtained by dissolving nifedipine in the solution, spraying the solution onto a spherical nucleating agent, and removing the solvent. You can also do it.

In this way, the fast-acting spherical granules of the present invention are obtained, but these fast-acting spherical granules can be prepared by simply mixing fine powder of diphthodivin with various excipients, such as ordinary powders, tablets, or granules. Since it is very easily absorbed and fast-acting, it can be made into fast-acting nifedipine capsules by, for example, filling it in hard capsules and injecting it into hard capsules.

In addition, the fast-acting spherical granules of the present invention may be further coated with a protective coating such as sugar coating or other gastric-soluble polymer on the surface, as long as the fast-acting granule satisfies the condition of being fast-acting, that is, quickly dissolving in the stomach or upper small intestine. Good too.

The slow-acting spherical granules of nifedipine in the present invention can be obtained by further coating the surface of the fast-acting spherical granules obtained as described above with an enteric substance and/or a poorly soluble substance. Examples of enteric substances include cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, methyl hydroxycellulose phthalate, h]roxybrobyl methylcell (cose phthalate, methyl methacrylate-methacrylic acid copolymer (trade name) ; Eudragit), etc. As enteric substances, those that dissolve at l1l-1 = 5.5 or more are preferred, and those that dissolve at l1l-1 = 6.0 or more are particularly preferred because they have a long duration. Examples of poorly soluble substances include hydrogenated oils such as fish oil and soybean oil, fatty acid esters of glycerin such as glycerin monostearate, cellulose acetate, and ethyl cellulose.

The method of coating the enteric substance and/or the poorly soluble substance is not particularly limited, and any known method can be adopted. A preferred method is to spray-coat a solution or suspension of an enteric substance and/or poorly soluble substance using a centrifugal fluid coating method and then dry it. As the solvent, in addition to water, organic solvents such as ethanol, isopropanol, methylene chloride, acetone, etc. can be used either alone or in combination. The coating level is 1 to 20% by weight, preferably 3 to 15% by weight of the fast-acting spherical granules. Another advantage of the present invention is that because the granules are spherical, less coating is required.

The long-acting composite granules of nifedipine of the present invention are a mixture of the fast-acting spherical granules obtained as described above and one or more types of slow-acting spherical granules.
~90% by weight, preferably 10-50% by weight, should be fast-acting spherical granules and the remainder should be slow-acting spherical granules.

With this ratio, a good initial blood concentration of nifedipine is achieved and an effective blood concentration is maintained for a long time.

There may be one type of slow-release spherical granule or two or more types. For example, if two types of delayed-release spherical granules each using two types of enteric substances with different dissolution pHs are used together, the durability of the drug's efficacy can be further varied.

Furthermore, similar effects can be expected by combining the use of enteric-coated substances and the use of poorly soluble substances.

The granule in the present invention is a concept that includes so-called granules and trickles, and is approximately 12
-150 meshes, preferably 12-80 meshes. Particles smaller than about 150 particles are not only inconvenient to handle during preparation operations, but also because there is little difference in dispersion and disintegration in the body, regardless of the difference in the properties of the fine particles. Contains are unsuitable as long-acting preparations. If the size is larger than about 12 grammes, - When dividing into packaging units, variations in the blending ratio of fast-acting spherical granules and slow-acting spherical granules are likely to occur, so it is undesirable to contain large amounts of these. .

As for the method of blending fast-acting and slow-acting granules, accuracy can be ensured by weighing and blending each granule for each packaging unit, but preferably, a large amount of both granules are mixed in advance, and then - A method of dividing into individual packaging units is adopted.

The composite granules of the present invention have a sharp particle size distribution and consist of spherical granules, so they are very suitable for this method.

The composite granules of the present invention can be packaged into stick packages or sachets to form one package. Since the composite granules of the present invention are spherical granules of approximately constant size, they can be easily and smoothly administered into the mouth from such packaging.

Hereinafter, the present invention will be explained in detail with reference to Examples.

Note that "mesh" means Tyler mesh, and "%" and "parts" mean percent by weight and parts by weight.

Example 1 C) 60 g of nifedipine (average particle size 30μ or more) and corn starch 1,8 K9 were put into a ball mill with an internal capacity of about 2SQ, and rotated for about 30 hours to mix and finely pulverize Nifedipine. Nifedipine particle meter 1-8
μ).

(b) 2.5K per granule with a particle size of 24 to 48 mesh
g, using a centrifugal flow type coating granulator (inner volume approx. 109
), and while rotating the rotor at 150-170r, p, m, blow air through the slit (air♀150U
, min, air temperature 50-70℃), 1- The granulated sugar (nucleating agent) is blown up with air and the whole is ゛C.
Transfer by centrifugal force, then spray a 3% aqueous solution of polyvinylpyrrolidone from a spray gun at a rate of approximately 0.05 min. The pellets were then coated with a nucleating agent to enlarge the pellets, and then transferred for 30 minutes to dry. As a result, although the granulated sugar (nucleating agent) had sharp angular parts due to its crystals, more than 90% of the obtained coating was spherical nucleating agent with 20 to 30 meshes.

＼) The spherical nucleating agent obtained as described above was sieved, and 20 to 30 meshes of 2K were transferred to a centrifugal flow type coating granulator, and a 5% isopropyl alcohol solution of hydroxypropyl cellulose was added to this. Then, 1.7 kg of the mixed finely pulverized product of nifedipine obtained in (a) was gradually added to make the nifedipine adhere to the spherical core agent. The rotational speed, air amount, and spray Φ were the same as in the case of VJ production of the spherical nucleating agent. After that, blow air at 70°C for 60 minutes and dry with v/v.
[Spherical granules were obtained.

The content of nifedipine contained in these granules was 1.33% as a result of UV absorbance measurement.

(d) Using the finely pulverized mixture of nifedipine and cornstarch obtained in (a) above and the fast-acting spherical granules of the present invention obtained in (c) above, nifedipine for the second liquid described in the Japanese Pharmacopoeia is prepared. When the solubility of the former was measured (at a temperature of 37°C for 2 hours), it was 10 μg/IIfl, while the latter was 18 μg/IIf! Met.

Example 2 (a) 2 kg of fast-acting spherical granules obtained as in (c) of Example 1 were placed in a centrifugal fluid coating granulator,
While rotating the rotor at 150-170r, p, m, air is blown through the slit (air filoO9,/1n
, air temperature 30°C), the granules were blown up with air and transferred as a whole by centrifugal force, and then Eudragit L, -100-55 (manufactured by Rohm Pharma, methacrylic acid-ethyl methacrylate copolymer) was added to the granules. 10
After rotating for 40 minutes while spraying a 5% isopropanol solution of a mixture of 0 parts of acetylated monoglyceride, 10 parts of acetylated monoglyceride, and 1 part of light anhydrous silicic acid from a spray gun (spray 90,031 parts min), the mixture was heated to 60°C. It was dried by blowing air for 60 minutes to obtain slow-release spherical granules.

The content of nifedipine in these granules is 1.2
There was 8%r.

(○) The fast-acting spherical granules obtained in (c) of Example 1 and the slow-acting spherical granules obtained in (a) above were weighed to 3.
= 7 to obtain a long-lasting composite granule of the present invention.

This composite granule was divided into Sudeikku packaging so that each package weighed about 1.5 g, and was hung in a fujibin for about 20η.
). Since the granules were spherical and uniform in size, the packaging operation was easy, and there was very little variation between the middle portions of each packaging.

(c) As a result of oral administration of the composite granule 1.57 obtained in (b) above to adult males (average size of 5 persons), blood concentrations as shown in Table 1 were obtained.

For comparison, the results obtained when the fast-acting spherical granules (0.75 g) obtained in (c) of Example 1 were orally administered are also shown.

It can be seen that the composite granules of the present invention have sufficient initial concentration and persistence.

In Table 1, the surface concentration was determined by adding medium-hydrogenated noedivin to serum as an internal standard substance, benzene-extracted image, Na NO
After conversion into a 1,4-dihydropyridine compound by oxidation treatment with 2, it was fixed by the G C-Mass fragment method.

Example 3 Nifedipine 0.44Kg, cornstarch 5.55K
g and hydroxypropyl cellulose 0, 315 K
The mixed powder consisting of nifedipine was mixed and pulverized twice using a hammer mill (Sample Mill Kff-1 type, manufactured by Fuji Paudal Co., Ltd.).

5.5 kg of this mixed and pulverized material and (○
) using the spherical nucleating agent 6.121 (g) obtained by the method of
Thereafter, a long-acting composite granule of nifedipine was obtained using the same method C as in Example 1.

Example 4 21.54 kg of corn starch and 1.38 kg of hydroxypropyl cellulose were mixed with 9 in a machine (Asahi Kako K-35)
0 type), and while rotating and stirring, add 6.52 kg of 10% methylene chloride solution of Nifujibin.
was added dropwise to obtain a mixture in which microcrystals of nifedipine were formed on the surface of the excipient.
).

Using 13.97 kg of this mixture (fine powder) and the spherical nucleating agents e and esKg obtained by the method of Example 1, the persistence of nifedipine was determined in the same manner as in Example 1. A composite granule was obtained.

Example 5 A mixture of Eudragid L-100-55 and ethyl cellulose (
4:6) in 5% ethanol-methylene chloride (1:1) solution to obtain slow-release spherical granules.

1. Then, the fast-acting spherical granules and the slow-acting spherical granules were mixed at a ratio of 5:5 to form a long-acting composite granule of the present invention.

Claims (1)

[Scope of Claims] 1. An easily absorbable, fast-acting spherical granule of nifedipine comprising a spherical core and fine powder of nifedipine adhered to the surface of the spherical core. 2. Fast-acting spherical granules consisting of a spherical core agent and fine powder of nifedipine attached to the surface thereof, and slow-acting spherical granules formed by coating the fast-acting spherical granules with an enteric substance and/or a poorly soluble substance. A long-acting composite granule of nifedipine consisting of 10 to 90% by weight of the total granules being fast-acting spherical granules.