JP2817063B2 - Sustained-release vasodilator - Google Patents

Description

The present invention relates to a sustained-release vasodilator. More specifically, the present invention relates to a novel sustained-release vasodilator in which the vasodilator has been sustained-released.

(Prior art) The number of deaths due to cerebrovascular disease is the third leading cause of death in Japan.
In 1987, the annual death toll was about 120,000. Of these, intracerebral hemorrhage accounts for about 26%, and subarachnoid hemorrhage accounts for about 9%. Above all, subarachnoid hemorrhage occurs frequently in the middle-aged people aged 40 to 50 and has the misery of robbing the family. Cerebral aneurysms account for 70% of subarachnoid hemorrhages, and their treatment is exclusively referred to surgery. However, this surgery causes late spasms with a frequency of 30-50%. The prognosis associated with this vasospasm is poor, leaving some sequelae in about half the patients. Even if a cerebral aneurysm is found, several days after the attack and if the consciousness is poor, there are many cases where surgery after a certain waiting period is planned for fear of concurrent cerebral vasospasm due to surgical operation. Patients often lose their rupture during the period.

As for the treatment of such late cerebral vasospasm associated with subarachnoid hemorrhage, there is a symptomatic treatment as described later, but there is no safe therapeutic agent with a reliable therapeutic effect, a long duration of effect and a safe therapeutic agent.

(Problems to be Solved by the Invention) Regarding the cause of delayed cerebral vasospasm associated with this subarachnoid hemorrhage, although it is said that a decomposed product of erythrocytes is supposed to trigger it, details of the decomposed product are described below. For the mechanism,
It is not yet fully understood. Therefore, as a treatment, the clot in the subarachnoid space is removed to the opposite side,
Attempts have been made to use a large amount of steroid, phenoxybenzamine, or to use symptomatic hypertension with concomitant use of dopamine, but none of them has achieved remarkable effects. On the other hand, papaverine hydrochloride is a powerful cerebral vasodilator and is known to increase cerebral blood flow when taken orally, but it is easily degraded in the liver and has a short half-life. Has the disadvantage that it is fast. Intravenous administration is considered to be ineffective for improving cerebral blood flow, possibly due to dilation of peripheral blood vessels in the whole body, resulting in hypotension. High-dose systemic administration may cause AV block, nausea and appetite Side effects such as poor performance, constipation, dizziness, headache and sweating are also feared. The risk of embolization is high with arterial injection.

Under such circumstances, treatment of delayed cerebral vasospasm by administration of papaverine hydrochloride has not been sufficiently effective. On the other hand, by applying papaverine hydrochloride to the exposed blood vessels during the operation, transient but clear remission of spasm has been recognized. As described above, regarding the treatment of late cerebral vasospasm associated with subarachnoid hemorrhage, a safe therapeutic agent has been hitherto known as a safe therapeutic agent with a long duration of effect.

The present inventors have conducted various studies on effective therapeutic agents for late-onset cerebral vasospasm, and have found that long-term sustained release of a vasodilator is effective in solving this problem.

An object of the present invention is to provide a sustained-release vasodilator, particularly a therapeutic agent for late-onset cerebral vasospasm, which has a reliable therapeutic effect, has a long duration of effect, and is safe. Aim.

(Means for Solving the Problems) The present invention relates to a sustained-release vasodilator comprising a non-toxic drug solution having a vasodilator action in a cross-linked hyaluronic acid gel, and the drug being sustained-released. is there.

That is, the present invention relates to a method of containing a non-toxic drug having a vasodilator effect such as papaverine hydrochloride in a cross-linked hyaluronic acid gel obtained by cross-linking hyaluronic acid or a salt thereof (hereinafter abbreviated as hyaluronic acid (salt)). By causing the drug to sustained release, an effective sustained release vasodilator,
In particular, a delayed cerebral vasodilator is provided.

Generally, methods for sustained release of drugs are roughly classified into two types: physical sustained release and chemical sustained release. However, the latter has many difficult problems in elucidating the mechanism of action or confirming safety. On the other hand, sustained release by a physical method is considered to be a desirable method in the present invention because such problems are less likely to occur.

Such physical methods include a method of encapsulating a drug with a film-like coating material, and a method of including the drug in a crosslinked polymer material having a three-dimensional network structure. As a therapeutic agent for delayed cerebral vasospasm etc. according to the present invention, since the required sustained release period may be about 2 to 4 weeks, the drug is contained in a cross-linked polymer material having a three-dimensional network structure. Is desirable.

The non-toxic drug having a vasodilatory action of the present invention (hereinafter sometimes referred to as a vasodilator) is non-toxic, in other words, basically safe for humans and other higher animals. Any drug can be used as long as it is confirmed to have Specifically, currently used papaverine hydrochloride, nicardipine hydrochloride, diltiazem,
Cinnarizine, cyclanderate, benzicran fumarate, bentoxifylline, hydergine, meclofenoxate hydrochloride, pyrithioxine hydrochloride and the like.

The amount of such agent in the sustained release vasodilator of the present invention depends on the specific purpose of use, in other words, the required local effective amount in the pharmacy, which is the vasodilator solution containing the cross-linked hyaluronic acid gel. In general, a 0.1% to 50% by weight solution can be used, depending on the concentration of the compound. With respect to the above-mentioned local effective amount, the concentration of a drug having a strong vasodilatory effect may be lower.

The hyaluronic acid used in the present invention is present as a constituent component in connective tissues such as joints, vitreous body, umbilical cord, cartilage, skin, and bird crest, and is important for tissue flexibility, structure maintenance, cell metabolism regulation, and the like. It is a substance that fulfills various functions. Hyaluronic acid is a naturally occurring polymer,
Does not cause an allergic reaction when injected into a living body, and has excellent biocompatibility. In addition, the solution of sodium hyaluronate has strong viscoelasticity and has a water retention effect, so that it is widely used as a raw material for cosmetics, and has uses as an ophthalmic remedy, eye drops, and arthropathy.

Conventionally, sodium hyaluronate has been industrially extracted from chickens, from the vitreous of bovine eyes, or from the umbilical cord,
Alternatively, a method (fermentation method) of culturing a microorganism having the ability to produce hyaluronic acid in a medium and producing the same has been performed. The hyaluronic acid (salt) used in the present invention may be one produced by an extraction method or a fermentation method.

At present, the molecular weight of industrially produced hyaluronic acid (salt) ranges from about 50,000 to about 3,000,000, and the molecular weight of hyaluronic acid (salt) used in the present invention may be any value within this range. Can also be used.

Hyaluronic acid (salt) becomes a cross-linked hyaluronic acid gel by using a cross-linking agent such as formaldehyde, an epoxy compound, and divinyl sulfone. A preferable crosslinking agent is divinyl sulfone in view of the physical properties of the crosslinked hyaluronic acid gel. This material readily reacts with hyaluronic acid (salt) in an aqueous alkaline solution at room temperature (20 ° C.) to give a cross-linked hyaluronic acid gel. The alkali concentration pH required for the crosslinking reaction is preferably 9 or more. The concentration of hyaluronic acid (salt) at the time of the crosslinking reaction is preferably 1 to 8% by weight. If the concentration is 1% by weight or less, a desirable crosslinked hyaluronic acid gel cannot be obtained even if the concentration of the crosslinking agent is increased. On the other hand, if the concentration is too high, the viscosity of the solution becomes too high, making the operation of the crosslinking reaction very difficult.

This gel swells in water and water-containing media. The swelling ratio depends on the degree of crosslinking of the gel. The degree of crosslinking can be adjusted by changing the molecular weight of hyaluronic acid (salt), the concentration of hyaluronic acid (salt) in the reaction mixture, the alkali concentration, the molar ratio of hyaluronic acid (salt) to divinyl sulfone, and the like. The reaction is fast and in most cases a strong gel can be obtained within minutes.

Since cross-linked hyaluronic acid gel has a three-dimensional network structure,
Various substances having pharmacological activity can be contained in this lattice. The pharmacologically active substances entrapped in this lattice are released into the environment by diffusion. Control of the pharmacologically active substance to the environment can be performed by changing the degree of hyaluronic acid gel crosslinking and the concentration of the pharmacologically active substance in the gel.

Methods for incorporating a substance having pharmacological activity into the crosslinked hyaluronic acid gel include a method in which the crosslinked hyaluronic acid gel is placed in a drug solution and the drug is diffused in the gel. There is a method of re-swelling in water, and a method of dissolving the drug in an aqueous solution of hyaluronic acid (salt) and adding a cross-linking agent to the solution to gel. Although these three methods give essentially the same product, each method has its own characteristics in obtaining a specific product as compared to the other methods, so the nature of the drug and the desired concentration of the drug in the system -It is desirable to select a method in consideration of the release rate and the like.

The sustained-release vasodilator of the present invention thus obtained has various shapes, for example, a columnar shape, a disk shape, a prism shape, a square plate shape,
It is an oval gel whose size or volume is 1-5 mm in diameter, 2-4
0mm, it is about volume 20~800mm ^3.

(Effect of the Invention) The drug of the present invention thus obtained can be used by embedding it directly in the affected part, that is, locally, and is used as a sustained-release vasodilator, especially as a therapeutic agent for delayed cerebral vasospasm. The effect is reliable, the duration of the effect is long, and it is safe, and the vasodilator of the target drug is gradually released, so that the desired drug effect can be exhibited.

Hereinafter, the present invention will be described with reference to examples. However, they do not limit the invention.

(Example) Example 1 0.5 g of sodium hyaluronate (molecular weight 1.2 × 10 ⁶ ) was added to 0.5 g.
It was mixed with 20 ml of 2M sodium hydroxide to form a homogeneous solution.
Then, while stirring this solution, divinyl sulfone 0.25
ml was added. After about 15 minutes, a strong gel had formed. While stirring the gel vigorously, add 30% citric acid to remove the gel.
Adjusted to pH5. One gram of this gel was left overnight in 20 ml of a 15% aqueous solution of papaverine hydrochloride to swell to obtain 2.4 g of a swelled gel.

After 1 g of the swollen gel was sufficiently washed with physiological saline, it was placed in an Erlenmeyer flask, 50 ml of physiological saline was added, and a papaverine hydrochloride elution test was performed at 37 ° C. 50 ml of saline was changed daily. The elution amount per day was as shown in the following table.

Example 2 An animal experiment was performed on the swollen gel prepared in Example 1. Animal experiments used two monkeys (male weight 7.4 kg and 8.1 kg).

First, a monkey weighing 7.4 kg was cranulated under anesthesia, the papaverine swelling gel of Example 1 was placed in the subarachnoid space, and a silicon tube was placed so that blood could be injected into the subarachnoid space. For a monkey weighing 8.1 kg, the head was opened under anesthesia, and only a silicon tube was installed so that blood could be injected into the subarachnoid space. After collecting fresh blood from the artery of each monkey of these two monkeys, 9 ml of the autologous blood was gradually injected into the subarachnoid space over 10 minutes through a pre-installed silicon tube, and after the subarachnoid hemorrhage, Cerebral vasospasm was formed.

The general symptoms of monkeys without this drug were incapacitated and crouched, with no appetite and occasional headache. A photograph of the basilar artery with the transbrachial artery under anesthesia showed about 30% vasospasm. In contrast, in monkeys to which papaverine hydrochloride swollen gel had been administered in advance, cerebral vasospasm was not observed, but rather tended to expand, and the neurological symptoms were mild.

Example 3 0.5 g of sodium hyaluronate (molecular weight 1.2 × 10 ⁶ ) in 1M
It was mixed with 25 ml of sodium hydroxide to form a homogeneous solution. 25 ml of ethanol was added to this solution with stirring to make a homogeneous solution, and then 3.5 ml of epichlorohydrin was added, followed by a reaction at 40 ° C. for 2 hours. After adding 25 ml of distilled water after the reaction, 30%
The pH was adjusted to 5 with citric acid to obtain a gel. 3000g of this gel
The mixture was centrifuged at pm for 15 minutes to obtain a uniform gel. afterwards
The precipitate was washed with 1M saline and dehydrated with ethanol to obtain a precipitate.
0.5 g of this precipitate was left in a 10% papaverine hydrochloride solution overnight,
11.5 g of a swollen gel was obtained. After 1 g of the swollen gel was sufficiently washed with a physiological saline solution, it was placed in an Erlenmeyer flask, 50 ml of a physiological saline solution was added, and a papaverine hydrochloride elution test was performed at 37 ° C. 50
ml of saline was changed daily. The elution amount per day is
The results are shown in the following table.

Example 4 0.52 g of sodium hyaluronate was dissolved in 19.4 ml of 0.2N sodium hydroxide, 0.52 g of nicardipine hydrochloride was added to the solution and stirred, and 1.0 ml of 4N sodium hydroxide was added to raise the pH of the mixture. Was. In the obtained homogeneous solution,
A solution containing 0.23 g of divinyl sulfone in 1.0 ml of 0.2N sodium hydroxide was added and the mixture was stirred for about 5 minutes. The liquid mixture was molded on a glass plate as a 2 mm-thick film and left for 1 hour. The resulting film is stirred for 30 minutes in an isopropanol-water (9: 1) mixture and then
Treated in pure isopropanol for 0 minutes, dried in air for 30 minutes and finally dried at room temperature under vacuum for 60 minutes. The obtained dry milky white film was placed in 50 ml of 0.15 M saline and immersed and washed at 4 ° C. for 24 hours. This saline washing solution was discarded, and 50 ml of 0.15M saline solution was newly added and immersed for 24 hours.
The obtained film was cut into a size of 4 mm × 20 mm to give a sustained-release nicardipine hydrochloride film.

2 anesthetized dogs (adult mongrel, body weight 8.7kg, and 11.0k
g), cisternal puncture was performed using a syringe needle to
5 ml of autologous fresh blood collected from the femoral artery
It was poured into the large tank over a period of minutes.

One day later, X-rays showed that the basilar artery had contracted, and the basilar artery had a diameter of about 28% contraction. The general symptom at this time is possible to stand up,
He showed narcotic walking and ataxic walking. One of these animals (with a body weight of 8.7 kg) was opened under anesthesia, and the sustained-release nicardipine hydrochloride film was placed in the area where spasm was observed. He had recovered to near the normal vessel diameter before.

In contrast, dogs that did not receive the sustained release nicardipine hydrochloride film required about 6 days for vasospasm to recover to near normal vascular diameter.

────────────────────────────────────────────────── ─── Continued on the front page (58) Fields surveyed (Int.Cl. ⁶ , DB name) A61K 45/00 A61K 47/36 A61K 31/455 A61K 31/485 A61K 31/55 CA (STN) REGISTRY (STN ) WPIDS (STN)

Claims (5)

(57) [Claims] 1. A sustained-release vasodilator comprising a non-toxic drug solution having a vasodilator action contained in a cross-linked hyaluronic acid gel to make the drug sustained-release. 2. The method according to claim 1, wherein the non-toxic drug having a vasodilatory action is at least one selected from the group consisting of papaverine hydrochloride, nicardipine hydrochloride, diltiazem, cinnarizine, cyclanderate, and bensicran fumarate. Release vasodilator. 3. The sustained-release vasodilator according to claim 1, wherein the crosslinked hyaluronic acid gel is obtained by a crosslinking reaction between hyaluronic acid or a salt thereof and divinyl sulfone. 4. The sustained-release vasodilator according to claim 1, wherein the crosslinked hyaluronic acid gel is obtained by a crosslinking reaction between hyaluronic acid or a salt thereof and a polyfunctional epoxy compound. 5. The sustained-release vasodilator according to claim 1, which is in the form of a product for topical administration.