JP2892858B2 - Controlled release formulation and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a controlled release preparation and a method for producing the same. More specifically, the present invention relates to a controlled release preparation suitable as a powder or fine granule having a sigmoid-type elution pattern, and a method for producing the same.

[0002]

2. Description of the Related Art In recent oral preparations, sustained-release preparations capable of maintaining an effective blood concentration for 24 hours by administering once or twice a day are preferred. As such a sustained release preparation, a granule having a different time (lag time) until the active ingredient starts dissolving after administration so as to reach a desired effective blood concentration after a desired time has been taken. Are variously combined and are often configured as one agent.

[0003] In a preparation comprising such a combination of various particles, a so-called sigmoid which rapidly elutes a pharmaceutically active ingredient after a certain lag time and reaches an effective blood concentration in a short period of time. It is required to have a mold elution pattern.

[0004] However, development of such preparations is difficult, and at present there is no satisfactory product. For example, as a preparation eluted after lag time, a preparation using an acrylic emulsion is disclosed in
Although disclosed in the specification of Japanese Patent No. 3322, this method uses an acrylic polymer, so there is a concern that the monomer remains, and the safety remains unclear. Also, JP-A-1-068
No. 17 proposes an inclusion body in which pores of a porous substance such as chitin or cellulose are filled with a pharmaceutical compound and then coated with a polymer membrane, lipid or a mixture thereof. However, in this preparation, although the encapsulated active ingredient gradually elutes from the pores of the carrier, the elution rate is slow, it takes a very long time to reach the desired blood concentration, and a sigmoid-type elution pattern is obtained. There is no problem. Further, Japanese Patent Application Laid-Open No. Sho 62-30709 discloses a membrane-bursting type sustained-release preparation in which a pharmaceutical compound is attached together with a swelling substance around core particles and the mixture is coated with a mixture of ethyl cellulose and talc. I have. In this method, a swelling pressure is generated, so that a preparation having a sigmoid-type elution pattern can be obtained, but in this method, when small core particles are used to obtain a preparation of small particles, a swelling substance may be used. In the coating process, agglomeration of particles occurs.In addition, in the coating process of the elution control film, when a macromolecular substance such as ethyl cellulose is coated on small particles, static electricity and agglomerates are generated. It has technical problems such as easiness.

[0005]

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned problems, and provides a controlled-release preparation having a so-called sigmoid-type elution pattern, which rapidly elutes an active ingredient after a certain lag time and has a so-called sigmoid-type elution pattern. It is intended to provide a manufacturing method.

Further, the present invention aims to provide a controlled-release preparation having a sigmoid-type elution pattern suitable as a powder or a fine granule, and a method for producing the same.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object, and as a result, formed an active ingredient layer containing a pharmaceutical compound around a water-swellable carrier. By adhering a water-insoluble non-melting substance to the surroundings using a melting substance as a binder to form a coating layer, the time until the start of elution of the active ingredient is delayed, and a lag time is obtained. It has been found that the time (lag time) can be controlled by the coating amount of the coating layer, and that the active ingredient is rapidly eluted by the coating film of the coating layer exploding after a certain period of time due to the swelling pressure of the water-swellable carrier. Was completed.

That is, the present invention provides a water-swellable carrier, an active ingredient layer containing a pharmaceutical compound formed around the carrier,
And a controlled release formulation comprising a coating layer containing a water-insoluble and non-meltable substance formed around the active ingredient layer using a fusible substance as a binder.

In the present invention, a core substance is prepared by forming an active ingredient layer containing a pharmaceutical compound around a water-swellable carrier, and then a water-insoluble substance is formed around the core substance using a meltable substance as a binder. The present invention relates to a method for producing a controlled release preparation, which comprises providing a coating layer containing a non-meltable substance.

[0010]

FIG. 1 is a schematic diagram of a controlled release preparation of the present invention.

In the present invention, a core substance is prepared by using particles of a water-swellable substance as a carrier and forming an active ingredient layer containing a pharmaceutical compound around the carrier. A substance in which a pharmaceutical compound is attached around a water-swellable carrier using a fusible substance as a binder to form an active ingredient layer is particularly suitable as a core substance. As the water-swellable carrier (hereinafter referred to as a carrier), the ratio of pores in the carrier is about 5 to 50%, and the rate of volume increase when immersed in water at room temperature is about 10% or more. Is not particularly limited.

Examples of such a carrier include, for example, crystalline cellulose, chitosan, corn starch, low-substituted hydroxypropylcellulose, carboxymethylcellulose, sodium polyacrylate, isobutylene maleic anhydride, and the like. Avicel SP made of cellulose spherical and porous
(Trade name, manufactured by Asahi Kasei Kogyo Co., Ltd.) and the like are convenient.
The carrier is preferably one having relatively small particles, for example, having an average particle size of about 500 μm or less, especially about 100 to 300 μm.
μm is preferred.

The pharmaceutical compound that can be contained in the active ingredient layer is not particularly limited as long as it is an orally administrable drug, and it is not limited to a water-soluble drug and a compound having low solubility in water can be used. Such pharmaceutical compounds include, for example, chemotherapeutic agents, antibiotics, respiratory stimulants, antitussive expectorants, antineoplastic agents, drugs for autonomic nerves, drugs for mental nerves,
Local anesthetics, muscle relaxants, drugs for digestive organs, antihistamines, addiction treatments, hypnotics, antiepileptics, antipyretic analgesics and anti-inflammatory agents, inotropic agents, arrhythmia treatment agents, diuretics, vasodilators,
Examples include antilipidemic agents, nutritive tonic altering agents, anticoagulants, hepatic agents, hypoglycemic agents, and antihypertensive agents. The particle size of these pharmaceutical compounds is in the range of 0.1 to 100 μm,
Preferably, it is in the range of 0.1 to 10 μm.

The active ingredient layer can be formed by various known methods, but is preferably formed by attaching a pharmaceutical compound to carrier particles using a fusible substance as a binder.

In the preparation of the present invention, the coating layer is formed by using a fusible substance as a binder and adhering a water-insoluble non-fusible substance, that is, a release controlling agent, around the core substance to form a layer. is there. Examples of the release controlling agent include silicic acid such as calcium silicate, magnesium silicate, calcium stearate, and magnesium stearate, or alkaline earth metal salts of stearic acid, titanium oxide, and light silicic anhydride. Of these, preferred is magnesium silicate, but it may be a synthetic product or a natural product, so-called talc. The particle size of these release controlling agents is 0.1 to 100 μm.
m, preferably in the range of 0.1 to 10 μm.

The fusible substance serving as a binder in the active ingredient layer and the coating layer is preferably about 30 ° C. or higher, especially about 30 ° C.
Any lipid-like substance that melts at a temperature of 40 to 100 ° C. can be used. For example, higher fatty acids, higher fatty alcohols, higher fatty acid esters, higher hydrocarbons, and the like can be suitably used. .

The higher fatty acids include, for example, those having 10 to 10 carbon atoms.
There are 32 saturated or unsaturated fatty acids. Specific higher fatty acids include, for example, capric acid, undecylic acid,
Lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid,
Nonadecanoic acid, arachinic acid, behenic acid, lignoceric acid, cerotic acid, heptacosanoic acid, montanic acid, melicic acid, laccelic acid, elaidic acid, brassic acid, and the like. Of these, myristic acid, palmitic acid, stearic acid, Nonadecanoic acid, behenic acid and the like are preferred, and palmitic acid, stearic acid and behenic acid are particularly preferred.

Examples of the higher aliphatic alcohol include aliphatic monohydric alcohols having 12 to 30 carbon atoms. Specific higher aliphatic alcohols include, for example, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, sertyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, eicosyl alcohol, seryl alcohol, merisyl alcohol, and the like. Is raised. Of these, cetyl alcohol, stearyl alcohol, eicosyl alcohol, and the like are preferable, and cetyl alcohol and stearyl alcohol are particularly preferable.

As the higher fatty acid ester, for example,
(1) Saturated or unsaturated fatty acids having 10 to 32 carbon atoms and 14 carbon atoms
Esters with aliphatic monohydric alcohols of up to 32, (2) carbon number
Esters of 10 to 22 saturated or unsaturated fatty acids with glycerin or hydrogenated products thereof.Specifically, for example, (1) myristyl palmitate, stearyl stearate, myristyl myristate, ceryl lignocerate, serotin Fatty acid esters such as lacceryl acid and lacceryl laccelate; natural waxes derived from animals such as lanolin, beeswax, spermaceti and shellac wax; and natural waxes derived from plants such as carnauba wax and candelilla wax. Further, as (2) glyceryl monolaurate, glyceryl monomyristylate, glyceryl monostearate, glyceryl dilaurylate, glyceryl dimyristylate, glyceryl distearate, glyceryl trilaurate, glyceryl trimyristylate,
In addition to glyceryl tristearate, beef tallow, lard,
Hardened tallow, hardened rape oil, hardened castor oil, hardened coconut oil,
And hardened soybean oil. Among them, carnauba wax, hardened rapeseed oil, hardened castor oil, shellac wax, glyceryl tristearate, glyceryl tripalmitate and the like are preferable, and hardened rapeseed oil, hardened castor oil and carnauba wax are particularly preferable.

In the above, natural wax, beef tallow, lard, and various hardened oils contain various components, and any of them can be suitably used. For example, shellac wax contains ceryl lignocerate as a main component and contains a mixture of ceryl serotinate and lacceryl lacceryl, and also contains components such as free alcohols, hydrocarbons, and resin components, and can be suitably used.

As higher hydrocarbons, for example, those having 12 to 12 carbon atoms
32 hydrocarbons, specifically, solid paraffin which is a mixture of various hydrocarbons.

The particle size of these fusible substances is 0.1
The range is preferably from 500 to 500 μm, preferably from 0.1 to 50 μm.

The content of the fusible substance in the active ingredient layer and the coating layer slightly varies depending on the kind of the fusible substance to be used and the kind of the pharmaceutical compound or the release controlling agent combined therewith, but it is usually 40% (W). / W, and so on)
Preferably, 30 to 10% is appropriate. The amount of the fusible substance used is suitably 10 to 40 parts by weight based on 100 parts by weight of the pharmaceutical compound or the release controlling agent. For example, when K3 wax (a fat obtained by hydrogenating various animal and vegetable fatty oils) is used as a melting substance and talc is used as a release controlling agent to form a coating layer, K3 wax is used.
It is preferred to use about 10 to 80 parts by weight of talc for 10 parts by weight.

In the active ingredient layer and the coating layer, various additives usually used in this field, such as excipients and binders, may be added.

Examples of the excipient include sugars such as sucrose, lactose, mannitol, and glucose, starch, crystalline cellulose, calcium phosphate, calcium sulfate, and the like. As the binder, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, Polyvinylpyrrolidone, glucose, sucrose, lactose, maltose, dextrin, sorbitol, mannitol, hydroxyethylcellulose,
Examples include hydroxypropylmethylcellulose, hydroxypropylcellulose, macrogol, gum arabic, gelatin, agar, starch and the like.

The particle size of these compounding agents is usually 0.1 to 10
0 μm, preferably in the range of 0.1 to 30 μm is suitable.

In the preparation of the present invention, a core substance is prepared by first forming an active ingredient layer containing a pharmaceutical compound around a carrier, and then a coating layer containing a release controlling agent is provided around the core substance. It is manufactured by

The method of the present invention is carried out using a granulating and coating apparatus used in ordinary granulation and coating operations by those skilled in the art, such as a rolling granulator, a centrifugal fluidized-type granulating and coating apparatus, and a fluidized bed granulator. can do.

The formation of the active ingredient layer may be carried out by any conventional method such as a spray drying method and a melt coating method. However, when a fusible substance is formed as a binder, the following will be described. It can be carried out continuously with the formation of a suitable coating layer.

The formation of the coating layer can be carried out, for example, by (A) rolling the core material under a temperature condition at which the meltable material is melted or softened while rolling the meltable material, the release controlling agent and, if necessary, the ordinary pharmaceutical preparation. Spray and adhere the mixture of the ingredients, or (B) suspend the meltable substance, release controlling agent and, if necessary, the ingredients of the usual pharmaceutical preparation in a suitable solvent, and apply it to the core substance. It is carried out by spraying and drying. Preferred methods (A) and (B) are described below.

In the method (A), the core material is previously heated, for example, by centrifugal flow, at a temperature about 5 ° C. higher than the melting point of the fusible substance to be used. However, in this case, the heating temperature may be a temperature at which the fusible substance is melted or softened, and strict temperature control is not required. To this, a mixed powder containing a release controlling agent and a fusible substance is gradually added to adhere to a carrier or a core substance.

In the method (B), first, a suspension containing a release controlling agent and a fusible substance is prepared. In this case, examples of the solvent used for the suspension include a hydrophilic organic solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, acetonitrile, and acetone, and a mixed solvent thereof with water. Then, after spraying the suspension on the core substance in the above-described appropriate device,
Dry at a temperature at which the fusible material melts or softens.

In the methods (A) and (B), the "core substance" is replaced with "carrier particles", and the "meltable substance, release controlling agent and, if necessary, a conventional pharmaceutical compounding agent" are replaced by " It is also used in the formation of an active ingredient layer using a fusible substance as a binder in the case of switching to "compounds for pharmaceutical compounds, fusible substances and, if necessary, ordinary pharmaceutical preparations".

In the present invention, the active ingredient layer accounts for 5 to 900%, preferably 5 to 100%, of the carrier.
The coating layer is at least about 20% based on the core material, preferably about 30 to
It is preferable to adjust to be 300%. If the coating layer is less than 20% relative to the core material, dissolution of the pharmaceutical compound cannot be controlled, and if it is more than 300%, there is no rupture of the membrane and no pharmaceutical compound is released.

The thickness of each layer thus obtained varies depending on the compounding amount of the pharmaceutical compound for the active ingredient layer, but is usually 10 to 150 μm, and for the coating layer, it is usually 20 to 150 μm. is there. Further, the preparation of the present invention
Those having a relatively small particle size are preferred, and those having an average particle size of about 500 μm or less are particularly preferred. This is to facilitate control of the effective blood concentration.

The manufacturability of the controlled-release preparation by the above-mentioned method is good, and the agglomeration of particles is very small.

In the controlled-release preparation thus obtained, since the coating layer is dense and strong, water penetrating into the inside is retained by the swelling carrier and the water is applied to the coating layer until an appropriate swelling pressure is applied. It retains its form, does not release the internal pharmaceutical compound (ie, can maintain a constant lag time), and when the swelling pressure is sufficiently increased, the coating layer bursts at once, so after a certain lag time, Can elute the pharmaceutically active ingredient. That is, the elution curve becomes a sigmoid type.

Further, the lag time of the controlled release preparation of the present invention can be changed to a desired value by changing the type and the amount of the release controlling agent in the coating layer or the amount of the film.

The release controlling agent of the present invention thus obtained is
A single release or a combination of preparations having various lag times may be used to prepare a sustained-release tablet, for example, by appropriately adding excipients, lubricants, disintegrants, and the like. It can be a release capsule,
In order to appropriately adjust the dose according to the situation of the user such as age, sex, symptoms, etc., powders, fine granules or granules whose dose can be adjusted by the weighed amount are preferable.

Example 1 Avicel SP having a particle diameter of 200 to 300 μm as a swellable carrier
(Granular Avicel) 500 g is placed in a centrifugal flow type granulation coating apparatus CF and rolled while keeping the temperature at 90 ° C., and 20 parts by weight of K3 wax (particle diameter 1 to 50 μm) and diltiazem hydrochloride (particle diameter 1 to 30 μm) 80 100 g of the mixture by weight was gradually added under heating and allowed to adhere to the carrier to produce a core substance. Further, a mixture of 15 parts by weight of K3 wax and 85 parts by weight of talc
00g was gradually added under heating to adhere to the core substance to obtain coated granules 1 (yield 99%).

Example 2 Diltiazem hydrochloride was treated with trimebutine maleate (particle size: 1).
The same operation as in Example 1 was carried out except that the coating ratio (weight ratio (%) of the coating layer to the weight of the core material (%)) was 160% and 200%, respectively. 2 (99.2% yield each)
And 99.0%).

Example 3 Diltiazem hydrochloride was converted to bromhexine hydrochloride (particle size: 1 to 30).
μm) to obtain coated granules 3-1 and 3-2 having a coating ratio of 160% and 200%, respectively (yield 9%).
9.4% and 98.9%).

Example 4 The same operation as in Example 1 was carried out except that diltiazem hydrochloride was replaced by theophrine, to give coated granules 4 (yield 98.8%).

Example 5 The same operation as in Example 1 was carried out except that diltiazem hydrochloride was replaced with afloqualone to obtain coated granules 5 (yield 99.5%).

In the preparation of all the coated granules described above, the productivity was good and no agglomeration of the granules was observed.

Example 6 A controlled release preparation was obtained in the same manner as in Example 1 except that the controlled release layer was replaced with 20 parts by weight of carnauba wax and 80 parts by weight of talc.

Example 7 A controlled release formulation was obtained in the same manner as in Example 2 except that the controlled release layer was replaced with 20 parts by weight of stearic acid and 80 parts by weight of titanium oxide.

Example 8 A controlled release preparation was obtained in the same manner as in Example 3 except that the controlled release layer was replaced with 20 parts by weight of palmitic acid and 80 parts by weight of calcium stearate.

Example 9 The controlled release layer was composed of 20 parts by weight of stearyl alcohol and talc 60
The same procedure as in Example 4 was carried out except that the weight parts were replaced with 20 parts by weight of ethylcellulose to obtain a controlled release preparation.

Example 10 The following Example 5 was repeated, except that the controlled release layer was replaced with 20 parts by weight of stearic acid, 60 parts by weight of talc and 20 parts by weight of Eudragit RS.
And a controlled release formulation was obtained.

Example 11 A controlled release preparation was obtained in the same manner as in Example 3 except that the controlled release layer was replaced with 20 parts by weight of palmitic acid and 80 parts by weight of magnesium stearate.

Example 12 A composition in which 200 g of the core substance prepared in the same manner as in Example 1 was placed in a flow coater mini, and 380 g of an equal mixture of carnauba wax and magnesium stearate was suspended in 4 times the volume of 80% ethanol. Spraying and drying at 80 ° C. for about 16 hours gave 560 g of controlled release formulation.

Example 13 200 g of the core substance prepared in the same manner as in Example 1 was placed in a centrifugal fluidizer, and 380 g of a mixture of 80 parts by weight of stearic acid and 20 parts by weight of calcium stearate was suspended in 4 times the volume of 50% ethanol. The obtained composition was sprayed and then dried at 80 ° C. for about 16 hours to obtain 560 g of a controlled release preparation.

Test Example 1 The coated granules 1 to 5 prepared in Examples 1 to 5 were subjected to a dissolution test (JP, paddle method, eluate water: 100 rpm). The results are shown in FIGS.

As is apparent from the figure, a good sigmoid-type elution curve can be obtained not only when a water-soluble pharmaceutical compound but also a poorly water-soluble pharmaceutical compound such as bromhexine hydrochloride or theophylline is used. Was. Further, with respect to trimegtin maleate and bromhexine hydrochloride, the lag time can be controlled by changing the coating rate to 160% or 200% (see FIGS. 3 and 4), and the desired elution pattern depends on the thickness of the coating layer. It has been shown that a controlled release formulation having

[0056]

The controlled-release preparation of the present invention is excellent as a preparation having a sigmoid-type elution pattern in which an active ingredient is rapidly eluted after a sufficient lag time. Further, it is possible to obtain a preparation having a desired lag time by changing the thickness of the coating layer. In addition, the controlled-release preparation of the present invention has very small agglomeration of particles during the coating operation, has good productivity, and has a particle size suitable for powders, fine granules and the like. By using this formulation alone or by combining formulations with various lag times,
Time control of the effective blood concentration suitable for diseases, symptoms, ages, etc., becomes possible.

[Brief description of the drawings]

FIG. 1 is a view showing the structure of a controlled release preparation of the present invention.

FIG. 2 is a graph showing the results of a dissolution test of coated granules 1 in Test Example 1.

FIG. 3 shows coated granules 2-1 in Test Example 1 and
It is a graph which shows the result of the dissolution test of 2-2.

FIG. 4 shows coated granules 3-1 in Test Example 1 and
It is a graph which shows the result of the dissolution test of 3-2.

FIG. 5 is a graph showing the results of a dissolution test of coated granules 4 in Test Example 1.

FIG. 6 is a graph showing the results of a dissolution test of coated granules 5 in Test Example 1.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI A61K 47/14 A61K 47/14 D 47/38 47/38 B (56) References JP-A-4-313524 (JP, A) (58) Field surveyed (Int.Cl. ⁶ , DB name) A61K 9/52 A61K 9/56

Claims (3)

(57) [Claims] 1. A water-swellable carrier, an active ingredient layer containing a pharmaceutical compound formed around the carrier, and a water-insoluble, non-melting substance formed around the active ingredient layer using a fusible substance as a binder. Controlled release preparation comprising a coating layer containing a substance. 2. The water-swellable carrier is a spherical porous crystalline cellulose, the fusible substance is a higher fatty acid, a higher aliphatic alcohol, a higher hydrocarbon or a higher fatty acid ester, and the water-insoluble, non-meltable substance is silicic acid. The controlled release preparation according to claim 1, which is an alkaline earth metal salt, an alkaline earth metal stearate, titanium oxide or light anhydrous silicic acid. 3. A core substance is prepared by forming an active ingredient layer containing a pharmaceutical compound around a water-swellable carrier, and then a water-insoluble non-melting substance is formed around the core substance using a meltable substance as a binder. A method for producing a controlled-release preparation, comprising providing a coating layer containing: