JP2573969B2 - Drug Intermittent Release Oral Formulation - Google Patents

Description

The present invention relates to an intermittent drug release oral preparation, and more particularly, to a dosage form applicable to the oral cavity, the release of a drug can be controlled intermittently, The present invention also relates to a drug release control formulation for the purpose of reducing the release time and the number of administrations.

2. Related Art and Problems to be Solved by the Invention Conventionally, coated tablets, dry coated tablets, multilayer tablets and the like have been known for the purpose of sustained release and sustainability of a drug by oral administration or the like. However, when actually administered to a living body, the drug cannot be retained at the absorption site for a long time due to the problem of migration speed in the gastrointestinal tract due to individual differences, so it is excreted from the body undigested without reaching the effective blood concentration. May be done. In addition, sustained-release or sustained-release may cause a decrease in bioavailability. In addition, by maintaining sustainability, the active ingredient may be present in the blood in the long term, causing problems such as drug resistance and chronic toxicity. Is also happening.

Also, in these drug sustained-release or sustained-release preparations,
Although the bioactive substance is gradually and continuously released from the matrix at a controlled constant rate, it is structurally impossible to interrupt the release, that is, to have an interval. However, some types of physiologically active substances are produced periodically at intervals in the living body, and when administered to tissues,
Depending on the situation, it may be desirable to release the physiologically active substance periodically with intervals.

The present inventors, in order to meet such a demand, after diligent studies to provide an oral application formulation that can release the drug intermittently at intervals,
It has been found that the release of a drug is intermittently controlled by combining a release control layer and a drug-containing layer and enclosing the drug-containing layer in the release control layer, thereby completing the present invention.

In other words, the present invention is a laminate of a release control layer and a drug-containing layer, wherein one or more drug-containing layers are sealed in the release control layer. It is intended to provide an intermittent drug release oral preparation.

The release control layer in the present invention contains a water-soluble or water-swellable polymer substance as a main component, and can be used as usual binders, lubricants, and plastics for improving the physical properties, shape, taste, and the like of the target preparation, if necessary. Agents, coloring agents, preservatives, flavoring agents,
It is formed from a system in which an excipient or the like is added and, if necessary, these are diluted and dissolved in an appropriate solvent (for example, water, ethanol, acetone, ethyl acetate, or a mixture thereof).

Examples of the water-soluble or water-swellable polymer include cellulose derivatives (eg, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, etc.). , Polyacrylic acid or a salt thereof, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, alginic acid or a salt thereof, an acrylic polymer, a natural rubber, a carboxyvinyl polymer and the like, and at least one of these is used.

The drug-containing layer in the present invention may be a single drug layer, but is usually composed of a system in which a drug is compounded in a release control layer containing the above-mentioned water-soluble or water-swellable polymer as a main component.

The drug is not particularly limited as long as it can be orally administered. For example, anti-inflammatory analgesics (indomethacin, diclofenac, ibuprofen, phenylbutazone,
Oxyfebutazone, mepyrizole, aspirin, ethenzamide, aminopyrine, phenacetin, etc., antiasthmatics (salbutamol sulfate, etc.), antidiarrheals (dl-salt isoproterenol, diphenyldol hydrochloride, betahistine mesilate, etc.), coronary vasodilation Agents (isosorbide dinitrate, nitroglycerin, nifedipine, etc.), arrhythmic agents (acebutolol hydrochloride, albrenolol hydrochloride, indeolol hydrochloride, oxbrenolol hydrochloride, carteolol hydrochloride, propranol hydrochloride, pindolol, disopyramide, etc.), anti-ulcer agents, Antibacterial agents (chlortetracycline,
Oxytetracycline, streptomycin, gentamicin, dihydrospreptomycin, bacitracin, erthromycin, ampicillin, penicillin, cephalosporin, etc.), antibiotics and the like, and at least one of them is used for use.

The intermittent drug release oral preparation according to the present invention is a combination of the release control layer and the drug-containing layer in a specific structure, and will be specifically described below with reference to the accompanying drawings.

In the preparation of the present invention, as shown in FIGS. 1 / (1) to (3), a drug-containing layer 2 is laminated on a release control layer 1 and one drug-containing layer 3 is separately provided in the release control layer 1. [See (1) and (3)] or two drug-containing layers
3, 4 [see (2)] are enclosed. When one drug-containing layer is encapsulated, the drug release interval is once,
In the case of two, two intervals can be provided. The number of intervals is determined according to the number of drug-containing layers encapsulated in this way. Furthermore, a normal adhesive layer 5 [see (2) and (3)] under the release control layer 1]
May be provided, whereby the preparation of the present invention can be adhered to a site in the oral cavity. The formation of each layer may be performed by a conventional method, for example, by tableting or spread lamination.

The dosage form of the preparation of the present invention is not particularly limited as long as it can be applied and held in the oral cavity, and may be selected, for example, from buccal type, troche type, sublingual tablet type, and other mucosal or gingival adhesive types. Can be.

According to the preparation of the present invention having the above constitution, the following advantages can be obtained.

i) The problem of chronic toxicity and drug resistance due to the conventional sustainability is eliminated, and the number of administrations, which is an advantage of the sustained-release preparation, can be reduced.

ii) By applying to the oral cavity, the influence of pH in the digestive tract and the like can be avoided, and stable release of the active ingredient can be achieved.

iii) A single dose can release several doses of the drug, so that only one drug needs to be administered several times a day.
It can be administered once or twice daily. Therefore, it is possible to prevent frequent forgetfulness of drinking and mistake of taking time.

iv) In particular, the time taken is less strictly adhered to than the patient, but the intermittent release control of the preparation of the present invention allows the drug to be released at the time taken, thereby further improving the therapeutic effect of the drug. be able to.

v) Conventional long-acting preparations tend to be less effective at night, etc., even though they are long-lasting.
The use of the preparation of the present invention allows the active ingredient to be released independently even at night, so that it can be used to prevent attacks at dawn such as angina.

 Next, the present invention will be described more specifically with reference to examples.

Example 1 A preparation shown in FIG. 1 / (1) is prepared.

Release control layer 1 75 g of karaya gum, 12 g of polyvinyl alcohol, 0.5 g of magnesium stearate and 7 g of crystalline cellulose are uniformly mixed.

Drug-containing layer (outer layer 2 and inner core 3) 30 g of polyacrylic acid, 10 g of lactose and 10 g of nifedipine
Mix uniformly.

Formulation 25 mg each as a drug-containing layer in the inner core and outer layer,
250 mg is taken as a release control layer and tableted according to a conventional method.

Example 2 A preparation shown in FIG. 1 / (2) is prepared.

Release control layer 1 85 g of hydroxypropylmethylcellulose acetate succinate, 10 g of methylcellulose and 5 g of polyvinylpyrrolidone are uniformly mixed.

Drug-containing layer (outer layer 2 and inner core 3,4) 88 g of sodium carboxymethylcellulose, talc 2
g, ethyl cellulose 5 g and salbutamol sulfate 5 g are uniformly mixed.

Adhesive layer 5 25 g of sodium alginate, 25 g of polyacrylic acid and 50 g of gelatin are uniformly mixed.

Formulation 20 mg each as a drug-containing layer in the inner core and outer layer,
Take 300 mg as the release control layer and 100 mg as the adhesive layer, and perform tableting according to a conventional method.

Example 3 A preparation shown in FIG. 1 / (3) is prepared.

Release control layer 1 2 g of hydroxypropylcellulose and 5 g of methacrylic acid copolymer (Eudragit S, manufactured by Rohm Pharma Co.) were added to 100 mg of ethanol and propylene glycol 1
Dissolve in 00 ml.

Drug-containing layer (outer layer 2 and inner core 3) 10 g of polyvinylpyrrolidone and 3 g of isosorbide dinitrate
Is dissolved in 50 ml of ethanol, 50 ml of purified water and 3 ml of 1,3-butanediol.

Adhesive layer 5 5 g of carboxyvinyl polymer is dissolved in 100 ml of ethanol and 5 ml of propylene glycol.

Formulation First, the composition of the adhesive layer 5 was cast on a glass plate, dried to form a film, and then the composition corresponding to the lower half of the release control layer 1 was cast and dried. Film. Next, the drug-containing layer 3 (inner core) separately formed in the same manner as described above was punched into a diameter of 6 mm, and this was pressed on the release control layer, and then the upper half of the release control layer 1 was re-equipped. Then, the composition of the drug-containing layer 2 (outer layer) is sequentially cast, dried and formed into a film, and then punched into a diameter of 10 mm to obtain a film-like preparation having a total thickness of 0.9 mm.

A drug dissolution test was performed on the preparations of Examples 1 to 3 by the rotating basket method in accordance with JP XI. The results are shown in FIGS.

[Brief description of the drawings]

FIGS. 1 / (1) to (3) are cross-sectional views each showing an example of the preparation of the present invention, and FIGS.
It is a graph which shows the result of the drug elution test of the preparation obtained in -3. 1: release control layer, 2, 3, 4: drug-containing layer

Claims (5)

(57) [Claims] 1. An intermittent drug release oral cavity comprising a laminate of a release control layer and a drug-containing layer, wherein one or more drug-containing layers are encapsulated in the release control layer. Applicable formulation. 2. The preparation according to claim 1, wherein the drug-containing layer is a drug-containing release control layer. 3. The preparation according to claim 1, wherein the release control layer comprises a water-soluble or water-swellable polymer. 4. The water-soluble or water-swellable polymer substance is a cellulose derivative, polyacrylic acid or a salt thereof, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, alginic acid or a salt thereof, an acrylic polymer,
2. The preparation according to the above 1, wherein the preparation is at least one selected from the group consisting of a natural gum and a carboxyvinyl polymer. 5. The method according to claim 1, wherein the cellulose derivative is at least one selected from the group consisting of methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate and hydroxypropylmethylcellulose acetate succinate. The preparation according to claim 4.