JPH04360826A - Controlled release pharmaceutical preparation - Google Patents

Abstract

PURPOSE:To obtain the title preparation, a three-layer tablet pharmaceutical preparation capable of releasing at a constant rate for a long time pharmaceutically active substance(s), by sandwiching a matrix-type medicine-stored interlayer with release-controlling layers predominant in water-soluble polymer(s). CONSTITUTION:The objective pharmaceutical preparation, a three-layer tablet pharmaceutical preparation, made up of (A) a medicine-stored interlayer containing at least one kind of water-soluble polymer (pref. water-soluble cellulose alkyl ether derivative) and at least one kind of pharmaceutically active substance and (B) release-controlling layers predominant in at least one kind of water-soluble polymer. The release-controlling layers B act in such a fashion that they prevent both the surfaces of the interlayer from direct contact with the body fluid to prevent the initial bursting release and they themselves are gelled and gradually eroded by the body fluid and the medicine is gradually permeated and migrate from the interlayer into them to effect increase in the medicine-releasing area along with advancing said erosion and they will disappear toward the later period for the release so as to disperse the interlayer as a whole into the body fluid. The present pharmaceutical preparation is especially effective for the zero-order release control for water-soluble medicine(s).

Description

[Detailed description of the invention]

0001

[Field of Industrial Application] The present invention relates to a novel controlled-release formulation, and more particularly, a three-layer tablet formulation that allows a pharmaceutically useful pharmacologically active substance to be released at a constant rate (zero-order) over a long period of time. Regarding.

0002

[Prior Art and Problems] Is it possible to keep the effective blood concentration of a pharmaceutically useful pharmacologically active substance (hereinafter sometimes referred to as a drug) constant for a long period of time to maintain its efficacy and to reduce the number of administrations to reduce the burden on patients? In order to prevent side effects by suppressing the rapid rise in blood concentration in the initial period after administration, various so-called zero-order controlled release preparations have been developed that release drugs at a constant rate over a long period of time. ing.

[0003] Among these, the one most widely used today is the so-called matrix type preparation. This is a preparation in which a drug is dissolved or dispersed uniformly or non-uniformly in a matrix forming a continuous layer consisting of water-soluble or insoluble formulation adjuvants, which prevents erosion of the matrix phase by body fluids. Drug release is controlled by the drug diffusion mechanism through the matrix phase. This type of formulation is relatively easy to manufacture;
When the active ingredient is a poorly soluble drug, a relatively good constant rate of release can be obtained; however, when the active ingredient is a water-soluble drug,
Since the dissolution and diffusion rate of the drug itself is high, the release rate is actually large in the early stage and decreases in the late stage (first-order rate).
Sufficient release control effect cannot be obtained.

[0004] In order to improve these drawbacks of matrix-type preparations, attempts have been made to partially coat the matrix phase with a water-insoluble polymer to define the contact area with body fluids and control drug release. There is. For example, JP-A-62-155211 discloses that a storage core consisting of an active substance and a water-swellable polymeric material, a gelling polymeric material, or a polymeric material with swelling and gelling properties is coated with a water-insoluble polymeric material, Controlled release formulations are disclosed in which the release of the active substance is controlled by the swelling pressure and duration of the swelling of the storage core that occurs upon contact with the storage core. However, in this formulation,
Because the coating layer is water-insoluble/active substance impermeable and the release of the active ingredient is limited to the externally exposed parts of the storage core that are not coated with the water-insoluble polymer, the storage core loses its ability to control release when it reaches its swelling limit. This may lead to a decrease in the release rate.

[0005] Therefore, there is a strong demand for the development of an economical formulation that is capable of stable zero-order release control over a long period of time, is easy to manufacture, and is free from such fluctuations in release behavior.

[0006]

[Means for Solving the Problems] The present inventors investigated the possibility of zero-order release control of drugs, especially water-soluble drugs, for solid preparations in various dosage forms, and found that a matrix-type drug storage intermediate layer was used. The present invention was completed based on the discovery that a three-layer tablet in which a release control layer mainly composed of a water-soluble polymer is laminated on the top and bottom of the tablet solves the above-mentioned problems, and is easy and economical to manufacture.

Thus, according to the invention, at least one
a drug storage intermediate layer containing a water-soluble polymer substance and at least one pharmacologically active substance; and a release control layer mainly composed of at least one water-soluble polymer substance laminated on both sides of the drug intermediate layer. A three-layer tablet formulation is provided, characterized in that it consists of:

[0008] The "drug storage intermediate layer" in the three-layer tablet formulation of the present invention is a matrix made of a water-soluble polymer material in which the drug is finely dispersed uniformly or non-uniformly, preferably uniformly, and then compression molded. It is a so-called matrix-type formulation component, located between the release control layer described below, and the surface exposed to the outside is limited to the side surface of the tablet due to the presence of the release control layer. When this exposed surface comes into contact with body fluids (for example, digestive fluids), it absorbs water and becomes a gel, gradually being eroded and acting to release the drug into the body fluids.

[0009] The water-soluble polymeric material used as the matrix in the drug storage intermediate layer is a pharmaceutically acceptable material that is gelatinous and soluble upon contact with water, preferably whose gelatinous solubility does not vary significantly with pH. Specifically, water-soluble cellulose alkyl ether derivatives such as hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC) are suitable, and among these, particularly 2%
HP with an aqueous solution viscosity of 6 to 10 centipoise at 20°C
C and 150-400 centipoise HPC are preferred. These water-soluble polymers can be used alone or in combination, and the type, amount, and mixing ratio of them when combined are determined depending on the type, amount, and desired release rate of the pharmacologically active substance used. Just adjust it. Materials that are easily affected by pH, such as sodium carboxymethylcellulose and carboxyvinyl polymers, or materials that disintegrate quickly, such as polyvinylpyrrolidone, are not suitable for use alone, but the gelation/dissolution properties of the above water-soluble cellulose alkyl ether derivatives For the purpose of modification, necessary amounts can be mixed and used as appropriate. The amount of the water-soluble polymer used can be adjusted appropriately depending on the type, amount, and desired release rate of the pharmacologically active substance used, but is generally 10 to 97% by weight based on the weight of the drug storage intermediate layer. Preferably, it can be within the range of 50 to 97% by weight.

[0010] There are no particular restrictions on the type of pharmacologically active substance that can be included in the drug storage intermediate layer, and both water-soluble and slightly water-soluble substances can be used. The effects of the present invention tend to be more pronounced for water-soluble drugs for which a sufficient zero-order release effect cannot be obtained, for example, those whose solubility in water at 20° C. is about 1 g/100 ml or more.

[0011] Examples of pharmacologically active substances used in the present invention include drugs that are absorbed from the gastrointestinal tract, such as various central nervous system drugs, circulatory system drugs, gastrointestinal drugs, metabolic drugs, and antibacterial substances. Among them, one with a single dose of 750 mg or less, preferably 100 mg or less is desirable.

[0012] Further, if necessary, conventional auxiliary agents such as lubricants, excipients, and pH adjusters may be appropriately blended into the drug storage intermediate layer.

[0013] The drug storage intermediate layer is generally 50 to 1000 m long.
It can have a weight within the range of g.

On the other hand, the "release control layer" in the three-layer tablet formulation of the present invention is laminated on both sides of the drug storage intermediate layer, and prevents both sides of the drug storage intermediate layer from coming into direct contact with body fluids. This prevents the burst release of the drug immediately after the tablet comes into contact with body fluids, and then gels itself and is gradually eroded by body fluids, and the drug gradually permeates through the intermediate layer and is released. As erosion of the control layer progresses, it acts to increase the drug release area, and further acts to disappear in the late stage of release, releasing the entire drug storage intermediate layer into the body fluid.

The release control layer that plays such a role is mainly composed of a water-soluble polymeric substance, and the water-soluble polymeric substance may be the same or a different type from those mentioned above for the drug storage intermediate layer. However, since those with too low viscosity will not provide a sufficient sustained release effect, it is appropriate to choose one with relatively high viscosity. The controlled release layer may generally contain such a water-soluble polymeric material in an amount of 50 to 100% by weight, preferably 80 to 100% by weight, based on the weight of the layer.

[0016] The release control layer may optionally contain a lubricant,
Auxiliary agents such as pH adjusters may be included, and at least one drug that is the same or different from that in the drug storage intermediate layer may be contained in a small amount, for example, about 20% by weight or less of the amount to be contained in the drug storage intermediate layer. It can also be included in the proportion of

The controlled release layer generally has a thickness of 10 to 25 per side.
It can have a weight in the range of 0 mg.

[0018] When the three-layer tablet of the present invention is intended to obtain a controlled release effect for a longer period of time, or when applied to a pharmacologically active substance with higher water solubility, the drug storage intermediate layer and the controlled release layer are added. It is advantageous to increase the proportion of the highly viscous water-soluble polymer contained in the composition, or to increase the amount of the release-controlling layer within the above-mentioned range.

[0019] The three-layer tablet of the present invention has a
That is, the tablet can have a diameter of about 2 to 15 mm, preferably about 5 to 10 mm, and can be manufactured according to a conventional three-layer tablet manufacturing method. That is, it can be prepared by physically mixing the raw materials for the drug storage intermediate layer and the controlled release layer, respectively, introducing and filling the mixture into a three-layer tablet machine, and compressing the mixture at an arbitrary pressure. Moreover, if necessary, the mixture of the above-mentioned layers may be once granulated and then introduced into a three-layer tablet press for production.

[0020]

[Operation and Effect] In the three-layer tablet formulation of the present invention described above, the drug storage intermediate layer acts as a good dissolution-controlled matrix with an effective surface limited by the release-controlling layer at the initial stage of release, and is absorbed by body fluids. It gradually releases pharmacologically active substances at a constant rate while undergoing gelation and erosion. In parallel with this, the release control layer is similarly gelled and eroded, and as the erosion progresses, the pharmacologically active substance gradually penetrates into the release control layer from the intermediate layer side, and the release of the pharmacologically active substance also occurs from the surface of the release control layer. It begins. This, in effect, acts to compensate for the effective surface area of the drug storage intermediate layer, which is reduced by erosion, and prevents a decrease in the release rate. This balance between the gelation/erosion rates of both the drug storage intermediate layer and the controlled release layer keeps the release rate constant. As the erosion progresses further, the release control layer disappears, the pharmacologically active substance-containing layer is exposed to body fluids, and disappears while releasing the pharmacologically active substance from its entire surface.

[0021] According to the zero-order release three-layer tablet formulation of the present invention, when a water-soluble drug is used as the main drug, the initial burst release that can occur with a simple matrix formulation can be prevented, and the blood concentration can be reduced. It is possible to effectively prevent the occurrence of side effects caused by a sudden increase in . In addition, the formulation of the present invention is unlikely to cause a decrease in release rate in the late stage of release, and is capable of stable zero-order release control over a long period of time.

[0022]

[Examples] The present invention will be explained in more detail with reference to Examples below.

Example 1 Ipsapirone hydrochloride 200gHPC
-L (Nisso) * 129.7gHPC-M
(Nisso) ** 2464.3g fumaric acid
After uniformly mixing 200 g, granulating and sizing, magnesium stearate was added at a ratio of 0.2% by weight based on the sized powder, and the mixture was uniformly mixed to obtain a composition for a drug storage intermediate layer.

HPC-L (Nisso)* 299.4gHP
C-M (Nisso)** 199.6g Magnesium stearate 1g was uniformly mixed to prepare a composition for a release control layer.

Both compositions were filled into respective hoppers of a multi-layer tablet press, and tableted in a mortar with a diameter of 8 mm at a compression pressure of 1 ton to form 3 disk-shaped layers containing 10 mg of ipsapirone hydrochloride in each tablet. Got the tablets.

The dissolution curve of the obtained three-layer tablet of ipsapirone hydrochloride is shown in FIG. For comparison, FIG. 1 also shows the dissolution curve of a single-layer tablet of ipsapirone hydrochloride obtained by compressing only the drug storage intermediate layer composition as described above. The elution method was the rotating paddle method (eluent: 0.1N hydrochloric acid, pH 1.
2, 900 ml; 50 revolutions/min) was used. According to FIG. 1, it is clear that ipsapirone hydrochloride is eluted at a constant elution rate over a period of 10 hours or more.

*Hydroxypropyl cellulose manufactured by Nippon Soda Co., Ltd.; viscosity 6.0-10.0CP (2% aqueous solution,
20℃), hydroxypropyl group 53.4-77.5%
, true specific gravity 1.2224 ** Hydroxypropyl cellulose manufactured by Nippon Soda Co., Ltd.; viscosity 150-400CP (2% aqueous solution, 20°C), hydroxypropyl group 53.4-77.5%, true specific gravity 1.
2224.

Example 2 Propranolol hydrochloride 200g HPC-M in the same manner as Example 1
(Nisso) A composition for a drug storage intermediate layer consisting of 2594 g and magnesium stearate and a composition for a controlled release layer consisting of 1 g of HPC-M (Nisso) 499 g magnesium stearate were prepared and compressed into one tablet. A disc-shaped three-layer tablet containing 10 mg of propranolol hydrochloride was obtained.

Example 3 Verapamil hydrochloride 800g HP in the same manner as in Example 1
Composition for drug storage intermediate layer consisting of MC 2194g and magnesium stearate and HPMC 499
g A composition for a controlled release layer consisting of 1 g of magnesium stearate was prepared and tableted to obtain a disc-shaped three-layer tablet containing 40 mg of verapamil hydrochloride per tablet.

[Brief explanation of drawings]

FIG. 1 is a dissolution curve of the three-layer tablet obtained in Example 1.

Claims (1)

[Claims] Claim 1: A drug storage intermediate layer containing at least one water-soluble polymeric substance and at least one pharmacologically active substance, and at least one drug storage intermediate layer laminated on both sides of the drug intermediate layer.
A three-layer tablet formulation comprising a release control layer mainly composed of a water-soluble polymeric substance.