JP2000178194A - Sustained release preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a sustained release preparation that alleviates and prevents the difficulty in rising caused by hypotension by using a specific compound. SOLUTION: This pharmaceutical preparation contains, as an active ingredient, a compound of the formula or its salts (as the salts, are preferably organic sulfate salt or substituted sulfate salt or the like, particularly methyl sulfate salt (methyl sulfate amezinium) in an amount of preferably 1-50 wt.%, more preferably 5-30 wt.%. In a preferred embodiment, a macromolecule for matrix (preferably slightly water-soluble or water-insoluble macromolecules, for example, ethylcellulose) is admixed as a drug-release controlling agent in an amount of 10-60%, more preferably in an amount of 10-60%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a pharmaceutical composition useful for treating or preventing hypotension.

[0002]

2. Description of the Related Art Hypotension is a disease caused by insufficient sympathetic nervous system operation, and its main symptoms include standing up dizziness and difficulty getting up when waking up. Most of these are difficult to get up.
In particular, as a treatment or prevention of hypotension, sympathomimetics are often used, but administration of such a drug can cope with orthostatic dizziness and the like. This is an action performed after the sleep, and it is difficult to administer the drug during sleep time. Theoretically, using a sustained-release agent, a drug should be designed so that the drug reaches an effective blood concentration at waking, but much is not known about metabolism during sleep, It has been extremely difficult to materialize such a formulation. That is, it has been desired to develop a means for improving and preventing hypotension, especially for difficulty waking up due to hypotension.

On the other hand, compounds such as amethinium methylsulfate and / or physiologically acceptable salts represented by the following formula (1) have a sympathomimetic action, and are therefore used as therapeutic agents for hypotension. However, it could not be inferred at all that it would be beneficial to treat and prevent the above-mentioned difficulty in getting up due to hypotension by formulating the product together with ethylcellulose and the like to obtain a sustained-release oral preparation.

[0004]

SUMMARY OF THE INVENTION The present invention has been made under such circumstances, and it is an object of the present invention to provide means for improving and preventing waking up caused by hypotension. .

[0005]

Under these circumstances, the present inventors have made intensive research efforts for a means of improving and preventing wake-up caused by hypotension, and as a result, formula (1)
It has been found that a sustained-release oral pharmaceutical composition containing a compound represented by the formula (1) and / or a physiologically acceptable salt thereof has such an effect, and has completed the invention. Hereinafter, the present invention will be described in detail focusing on embodiments.

[0006]

Embedded image Equation (1)

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION (1) Active ingredient of sustained release oral preparation of the present invention The active ingredient of sustained release oral preparation of the present invention is a compound represented by the above formula (1) and / or a physiologically acceptable compound. Is that salt. Here, examples of acceptable salts include mineral salts such as hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid; substituted sulfates such as methyl sulfate and paratoluene sulfonate; and organic acids such as citric acid, oxalic acid, and tartaric acid. Acid salts, carbonates and the like can be preferably exemplified. Of these, preferred are organic acid salts and substituted sulfates, with substituted sulfates being particularly preferred, and methyl sulfate being most preferred. This is because the dissolution properties are suitable for the present invention and the safety is high. That is, in the sustained release pharmaceutical oral composition of the present invention, the compound represented by the formula (1) and / or a physiologically acceptable salt thereof is most preferably amethinium methyl sulfate. The preferable content of the compound represented by the formula (1) and / or a physiologically acceptable salt thereof in the sustained-release orally administered pharmaceutical composition of the present invention is 1 to 50% by weight, More preferably, 5 to 30
% By weight.

(2) Release controlling agent used in sustained release oral preparation of the present invention The sustained release oral preparation of the present invention is characterized by containing a release controlling agent. As the release modifier, it is particularly preferable to use a polymer for matrix. As the polymer for matrix, a copolymer such as hydroxypropylmethylcellulose terephthalate, acrylate, methacrylate, acrylate organic amide, or methacrylate organic amide may be used. Preferred examples include enteric polymers such as Eudragit (registered trademark), which are polymers, and poorly water-soluble or insoluble polymers such as gelatin and ethyl cellulose. Of these, particularly preferred are poorly water-soluble or insoluble polymers, and among them, ethyl cellulose is most preferred. The preferred content of these release modifiers in the sustained release oral preparation of the present invention is 10 to 60% by weight, more preferably 15 to 40% by weight. These release modifiers can be contained in the pharmaceutical composition as a matrix or can be contained as a film-forming agent.

(3) Sustained-release oral preparation of the present invention The sustained-release oral preparation of the present invention comprises a compound represented by the above formula (1) and / or a physiologically acceptable salt thereof and a release modifier. It contains. In the pharmaceutical composition of the present invention, in addition to these components, optional components usually contained in the pharmaceutical composition,
It can be contained within a range that does not impair the effects of the present invention. Such optional ingredients include, for example, excipients, binders, coating agents, lubricants, sugar coatings, disintegrants, bulking agents, flavoring agents, emulsifying / solubilizing / dispersing agents, stabilizers, pH adjusters, Preferred examples include isotonic agents. The sustained-release oral preparation of the present invention can be produced by treating these components according to a conventional method. For example, these components are kneaded by adding a volatile medium, kneaded, extruded and dried, and then formed by sieving or tableting, or tumbling phase granulation of these components and sieving or tableting. Or by coating the granules or tablets thus prepared with a coating agent dissolved in a solvent.

[0010]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but it goes without saying that the present invention is not limited to only these Examples.

Example 1 Matrix type granules The components of a) were mixed, and the mixture was kneaded with a kneader. This is extruded and granulated (screen; 0.8 to 1.0 m)
m), and the resulting mixture was sized with a marmellaizer to obtain Granule 1. I Amedinium methyl sulfate 7.0 parts by weight Lactose 58.0 parts by weight Crystalline cellulose 13.5 parts by weight Hydroxypropyl cellulose 1.5 parts by weight Ethyl cellulose 20.0 parts by weight b Purified water 30.0 parts by weight

<Example 2> Matrix type tablet The components of (a) were mixed, and fluidized bed granulation was performed while adding a solution prepared by dissolving (b) in an equal mixture of ethanol and methylene chloride in 180 parts by weight. This was sized with a 24 mesh (710 μm) sieve. Further, 0.8% of magnesium stearate based on the dry weight of the granules was added and the mixture was compressed into tablets to obtain tablets 2. I Amedinium methyl sulfate 7.0 parts by weight Lactose 62.0 parts by weight Microcrystalline cellulose 11.0 parts by weight b Ethyl cellulose 20.0 parts by weight

<Example 3> Components of film control type granules I were mixed, and the mixture was kneaded with a kneader. This is extruded and granulated (screen; 0.8 to 1.0 m)
m) and the resulting mixture was sized with a marmellaizer to obtain granules. The granules were coated with a solution prepared by dissolving the component (c) in 450 parts by weight of an equal mixture of ethanol and methylene chloride to obtain granules 3 of a film control type. I Amedinium methyl sulfate 7.0 parts by weight Lactose 58.0 parts by weight Crystalline cellulose 13.5 parts by weight Hydroxypropyl cellulose 1.5 parts by weight Ethyl cellulose 20.0 parts by weight B Purified water 30.0 parts by weight C Ethyl cellulose 45.0 parts by weight Parts triethyl citrate 5.0 parts by weight

Example 4 Film-Controlled Type Tablet The components of (a) were mixed, and fluidized bed granulation was performed while adding (b). This was sized with a 24 mesh (710 μm) sieve. Further, 0.8% magnesium stearate based on the dry weight of the granules was added and the mixture was compressed into tablets to obtain tablets. This tablet was coated with a solution prepared by dissolving the component (c) in 450 parts by weight of an equal mixture of ethanol and methylene chloride to obtain a tablet 4 of a film control type. I Amedinium methyl sulfate 7.0 parts by weight Lactose 72.0 parts by weight Crystalline cellulose 17.5 parts by weight b Hydroxypropyl cellulose 3.5 parts by weight Purified water 66.5 parts by weight C Ethyl cellulose 45.0 parts by weight Triethyl citrate 5. 0 parts by weight

Example 5 Pharmacokinetics Using a male beagle dog weighing 10.6 kg, a simulation of blood drug concentrations before and after sleep was performed. That is, 10 mg / Kg of each of the preparations of Examples 1 to 4 was orally administered in the amount of amethinium methylsulfate using a catheter, blood was collected one hour later, at the same time, anesthetized with ether for 6 hours, and one hour after awakening Blood was collected again. The serum was removed, deproteinized with the same amount of methanol, and the drug concentration in the serum was measured by high performance liquid chromatography. The blood concentration after awakening of anesthesia was divided by the blood concentration before anesthesia and multiplied by 100 to obtain the blood maintenance rate. Table 1 shows the results. This indicates that the sustained-release oral preparation of the present invention can cause an effective concentration of the drug in the blood even after sleep. That is, it is clear that administration and administration of the sustained-release oral preparation of the present invention can treat and prevent wake-up difficulties.

[0016]

[Table 1]

[0017]

According to the present invention, it is possible to provide means for improving and preventing wake-up difficulties caused by hypotension.

Claims (4)

[Claims] 1. A sustained release oral pharmaceutical composition comprising a compound represented by the formula (1) and / or a physiologically acceptable salt thereof. Embedded image Equation (1) 2. The sustained-release oral pharmaceutical composition according to claim 1, wherein the compound represented by the formula (1) and / or a physiologically acceptable salt thereof is amethinium methyl sulfate. 3. The sustained-release oral pharmaceutical composition according to claim 1, comprising a matrix polymer as a release modifier. 4. The sustained release oral pharmaceutical composition according to claim 3, wherein the matrix polymer is ethyl cellulose.