JPS63215620A - Sustained release preparation - Google Patents

Abstract

PURPOSE:To obtain a sustained release preparation capable of controlling starting time of drug release and releasing a drug in a zero order, by coating nuclei comprising molded article of a mixture of a water-soluble high polymer substance and a drug with a water-soluble high polymer substance containing no drug. CONSTITUTION:Nucleic comprising molded article of a mixture of a water-soluble high polymer substance having >=100cp viscosity in 2% aqueous solution at 20 deg.C, such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose or PVA and a drug are coated with the same kind of water-soluble high polymer as the above-mentioned polymer, containing no drug. Starting time of drug release is controlled by selecting kind of the water-soluble high polymer substance and thickness of the coated layer.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to sustained release preparations, and more specifically, a core consisting of a drug-containing molded article based on a water-soluble polymeric substance;
The present invention relates to a core-containing sustained-release preparation in which this core is coated with an outer layer based on the same kind of water-soluble polymer substance that does not contain a drug.

The sustained release formulation of the present invention has a controlled drug release start time,
In addition, it is extremely useful in the medical field and pharmaceutical formulation field because of its zero-order release of drugs.

[Conventional technology]

As a method for controlling the release start time of a drug from a preparation after a certain period of time has elapsed after oral administration, a method of coating a drug-containing molded article with a digestive fluid-dependent film, for example,
In the case of enteric-coated preparations, a widely used method is to coat the preparation with a pH-dependent enteric coating.

These enteric coating agents include water-insoluble cellulose derivatives, starch, $a! Water-insoluble derivatives such as polyhydric alcohols, polyvinyl derivatives, maleic acid copolymers, acrylic acid copolymers 2, 7 rank, zein, etc. are known. (Inf1 Chem, Vol.

No. 5 "New Perspectives on Enteric Coatings", Nichiyaku Pharmacist Publishing (1981)).

On the other hand, in order to maintain a constant drug concentration in the blood and improve bioavailability, special polymer membranes and semi-finished products are used to maintain a constant drug release rate from the drug, that is, zero-order release preparations. A formulation using a permeable membrane has been proposed (see Practical Technology of Controlled Release, CMC (1985)).

[Problem that the invention seeks to solve]

Currently, in the medical field, target-release preparations such as enteric-coated preparations, which release drugs in specific organs after a certain period of time after oral administration, and drug concentration in the blood over a long period of time with a small number of administrations are being developed. There is a strong demand for sustained release agents of the so-called zero-order release type, which release a fixed amount of drug per unit time, in order to maintain a constant level of drug release, improve bioavailability, and relieve the burden on patients.

In the formulations coated with a pH-dependent enteric film cited as the prior art, the pH of the digestive juices varies depending on the physical condition,
Since it fluctuates significantly due to the influence of meals, etc., there is a risk that the drug will not necessarily be released as requested. Furthermore, since all of the coating materials exemplified in the above-cited literature are water-insoluble substances, organic solvents that are harmful to the human body must be used during the coating process. Next-release formulations are
Because it uses a special polymer membrane or semipermeable membrane, its application is limited to mucosal absorption or transdermal absorption, and its complicated dosage form makes it extremely difficult to manufacture.

An object of the present invention is to provide a sustained-release preparation in which the release of a drug from the preparation is independent of pH, the release start time can be controlled, and the drug is released zero-order.

[Means for solving problems]

As a result of intensive research to achieve the above-mentioned object, the present inventors have determined that a molded article containing a drug based on a water-soluble polymer substance that swells or gels when it contains water is used as a core, and this core is The present invention was completed based on the discovery that the drug release start time can be controlled by the coating thickness and the drug is released zero-order in a drug coated with a water-soluble polymeric substance.

In the present invention, the viscosity of a 2% aqueous solution at 20°C is 100c.
A sustained release preparation comprising a core made of a molded product of a mixture of a drug and a water-soluble polymeric substance with a concentration of p or more, and an outer layer of the same kind of water-soluble polymeric substance as above that covers this core. .

In the present invention, the water-soluble polymeric substance used for the core base and the outer layer is a water-soluble polymeric substance that swells or gels when it contains water and is used as a pharmacopoeia-specified pharmaceutical base. . For example, hydroxypropyl cellulose (RPC), hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), sodium carboxymethylcellulose (C
Various grades of cellulose derivatives such as MC-Na),
Sodium polyacrylate, polyvinyl alcohol (P
Examples include synthetic polymers such as VA), natural polymers such as sodium alginate, gum arabic, and carrageenan. In particular, the hydroxypropoxyl group is 53.4 to 77
．． RPC containing 5% by weight and 4 to 32% by weight of hydroxypropoxyl groups and 16.5 to 30% of methoxyl groups.
HPMC containing % by weight is preferably used.

The drug can be appropriately selected depending on the purpose and is not particularly limited.

For example, drugs used to treat diseases or disorders in the small intestine and beyond where the release onset time is preferably controlled include steroids such as prednisolone and hydrocortisin, antibiotics such as erythromycin, tetracycline, chlorogin, and neomycin, antiparasitic drugs, indomethacin,
Examples include drugs that irritate the gastric mucosa, are unstable in acidic environments, and are poorly soluble, such as spironolactone, etensamide, ibuprofen, furosemide, progesterone, acetamiphenone, estradiol, quinidine, digoxi, and theophylline.

In addition, as drugs with preferable zero-order release, antihistamines such as loropheniramine maleate and diphenylbilarin, anti-inflammatory analgesics such as diclofenafuc sodium,
Examples include antacids and vitamins.

The sustained release preparation of the present invention has a core formed by mixing and molding the drug using the water-soluble polymeric substance as a base, and an outer layer formed by coating the core with the water-soluble polymeric substance. In this case, the water-soluble polymeric substance used for the core base and the water-soluble polymeric substance used for the outer layer may be of different types.

The sustained release preparation of the present invention can be manufactured by the following method, but is not limited to these methods.

A mixture of a predetermined amount of the drug and the water-soluble polymer substance is made into granules for tabletting by a general granulation method such as direct tableting, spray granulation, extrusion granulation, compacting, or stirring granulation. The core is manufactured by using a method such as manufacturing and tableting these,
Next, an outer layer is formed by a method of spray coating the core with a solution of the water-soluble polymeric substance, a compression coating method of directly tableting a powdered water-soluble polymeric substance around the core, or the like.

In addition to the water-soluble polymer substance and drug, the sustained-release preparation of the present invention may optionally contain surfactants, pigments, lactose, crystalline cellulose, starch, talc, etc. in each of the core and outer layers.
Additives such as calcium hydrogen phosphate, calcium carbonate, and titanium oxide can be added.

[For production]

As described above, the sustained-release preparation of the present invention has a core made of a molded article based on a water-soluble polymeric substance containing a drug, and an outer layer made of a water-soluble polymeric substance that does not contain a drug. It is characterized by being a dry-coated preparation consisting of.

When the preparation of the present invention is orally administered, the water-soluble polymeric substance used for the core and outer layer of the preparation absorbs digestive juices, causing the entire preparation to swell or gel. The drug in the core then diffuses into the swollen or gelled water-soluble polymeric material and is released from the formulation.

Therefore, from administration of the formulation to release of the drug, a certain amount of time is required for swelling or gelling of the formulation and diffusion of the drug therein. By selecting the type of water-soluble polymeric substance used for the core and outer layer and the thickness of the outer layer, the drug release initiation time is controlled.

On the other hand, the rate of release of the drug is determined by the concentration diffusion of the drug in the swollen or gelled water-soluble polymer, so it becomes constant after the swelling or gel of the water-soluble polymer stabilizes, and the drug reaches zero. It is estimated that it will be released next.

If the viscosity of the water-soluble polymer material used for the core and outer layer at 20°C is too low, the rate of dissolution into the digestive fluid will be faster than the rate at which it absorbs the digestive fluid and swells or gels, resulting in a stable swollen body or gelling. This makes it difficult to control the drug release start time and the zero-order release of the drug. therefore,
The viscosity at 20° C. of the water-soluble polymeric substance used for the core and outer layer is preferably 100 cp or more.

〔Example〕

The present invention will be explained in more detail with reference to Examples and Comparative Examples.

However, the scope of the present invention is not limited to the same extent by the following examples.

In addition, in the following examples, "%" and "part" are based on weight, and "viscosity" is a value of a 2% aqueous solution at 20°C.

(1) Preparation of formulation (a) Sample (A-1) 22.4% methoxyl groups, 9 hydroxypropoxyl groups
．． 40 parts of HPMC of 1%, viscosity 4.1)0 cp and 10 parts of chlorpheniramine maleate were mixed uniformly and compressed into tablets with a diameter of 1) mm, a thickness of 1.5 mm, and a weight of 150 mg.
A disc-shaped molded body was obtained.

Next, this molded body is used as a core, and the HPM is applied to the outer periphery of the core.
C50 part was compressed and coated to a diameter of 13 mm and a thickness of 1
-9 rms A disk-shaped dry-coated preparation (A-1) with a weight of 300 mg was prepared.

Sample (A-2) In the preparation of sample (A-1), hydroxypropoxyl group 6 was used instead of HPMC used as the base material for the core and outer layer.
3.6%, viscosity 3. ．． Sample (A-1) was treated in the same manner as sample (A-1) except that 400 cp HPC was used.
Disk-shaped dry-coated preparation (A) with the same dimensions and weight as 1)
-2) was prepared.

(C) Sample (A-3) On the outer periphery of the nucleus prepared using the same recipe as sample (A-2),
HF with the same specifications as that used for preparing sample (A-2)
Compression coating of O72 part, diameter 13 mm, thickness 2
．． 3 mm, weight 360 mg disc-shaped dry-coated preparation (
A-3) was prepared.

(d) Sample (A-4) In the preparation of sample (A-1), hydroxypropoxyl group 6 was used instead of HPMC used as the base material for the core and outer layer.
Except that a homogeneous mixture of 40 parts of HFO of 3.4%, viscosity of 8.7 cp and 60 parts of HFO of 62.9% of hydroxypropoxyl groups, viscosity of 280 cp was used.
A disk-shaped dry-coated preparation (A-4) having the same dimensions and weight as sample (A-1) was prepared by processing in the same manner as sample (A-1).

<81 Sample (A-5) Sample (A-2) was prepared in the same manner as Sample (A-2) except that diclofenac sodium was used instead of the drug chlorpheniramine maleate. A disk-shaped dry-coated preparation (A-5) having the same dimensions and weight as the sample (A-2) was prepared.

(f) Comparative sample (CA-1) HFO with the same specifications as that used for preparing sample (A-2)
A disk-shaped preparation (C
A-1) was prepared.

(2) Dissolution test The dissolution rate of the drug from each sample prepared in the above (1) and the comparative sample was measured by a dissolution test method based on the paddle method of the Japanese Pharmacopoeia.

For the eluate, use the Japanese Pharmacopoeia 1st solution 1) at 37°C.
The test was conducted at a paddle speed of 1) 00 rpm.

The amount of drug eluted was determined by analyzing the eluate using an absorbance method. (Measurement wavelength: Chlorpheniramine maleate 265
nm, diclofenac sodium 276 nm) The results of the dissolution test are shown in Table 1 and FIG.

〔Effect of the invention〕

As is clear from FIG. 1 showing the results of the above example, the system ff) using a comparative sample in which the drug was uniformly dispersed in the formulation.
In contrast, in the formulations of the present invention ((a) to (e)), the drug elution starts immediately after the start of the test and draws a quadratic curve in which the elution rate gradually decreases. The elution rate of the drug is controlled and linear, resulting in a so-called zero-order release in which a constant amount of drug is released per unit time.

The present invention provides a preparation in which the elution start time of a drug is controlled and the drug is released zero-order, and its medical and industrial significance is extremely large.

[Brief explanation of the drawing]

FIG. 1 represents drug elution curves obtained in Examples and Comparative Examples. Vertical axis: Drug elution rate (%) Horizontal axis: Elapsed time (hr) (a) Sample (A-1>, (b) Sample (A-2)
), (C) Sample (A-3), (d) Sample (A
-4), (e) Sample (A-5),

Claims (1)

[Claims] (1) A core consisting of a molded product of a mixture of a water-soluble polymer substance and a drug whose viscosity in a 2% aqueous solution at 20°C is 100 cp or more, and a water-soluble polymer of the same type as above that does not contain a drug and coats this core. Sustained-release preparation characterized by comprising an outer layer based on a substance (2) A water-soluble polymeric substance is heated at 20°C.
Claim 1 ( Sustained-release preparations described in section 1)