KR100320771B1 - Compositions and Manufacturing Methods of Clebopride Sustained Release Preparations - Google Patents

Abstract

The present invention relates to sustained-release preparations of gastrointestinal function modulators, and more particularly, release control of clevoprid or salts thereof, which are widely used in gastrointestinal motility patients such as gastrointestinal neurosis, gastritis and indigestion, irritable colon syndrome and nausea and vomiting. The present invention relates to a sustained-release preparation which reduces the frequency of doses and reduces side effects by preparing a double matrix using a polymer having swelling or mucoadhesiveness.

Description

Compositions and Manufacturing Methods of Clebopride Sustained Release Preparations

As the initial burst effect during oral administration of the gastrointestinal function regulating agent clevoprid, the drug concentration in the blood rapidly rises at the beginning of the administration, which causes various side effects. Therefore, in order to reduce such side effects, it is an object of the present invention to control the blood concentration by releasing the drug through the formulation development.

The present invention relates to sustained-release preparations of gastrointestinal function modulators, more specifically, swelling of clevoprid or salts thereof widely used in gastrointestinal motility patients, such as gastrointestinal neuropathy, gastritis and indigestion, irritable colon syndrome and nausea and vomiting. It is manufactured in the form of matrix using a polymer, etc., to control the temporary release of the drug using the swelling and solubility of the polymer to obtain a sustained release pattern of a constant rate, and also to prevent toxicity and side effects due to the over-release of the drug The present invention relates to a sustained release preparation of a gastrointestinal function modulator that can avoid low patient compliance due to multiple doses.

Currently, gastrointestinal function modulators include metoclopramide, a paraaminobenzoic acid derivative, domperidone, a benzimidazole derivative, cisapride, and clevoprid, which are benzamides, and are generally prescribed in three to four times a day. It is becoming. These drugs are mainly used for blocking dopamine receptors and are used for nausea, vomiting, gastric and duodenal ulcers, gastrointestinal neurosis, gastritis, dyspepsia, and irritable colon syndrome. It is also a drug used for nausea and vomiting during surgery, after anesthesia, or after chemotherapy or anticancer drugs. In particular, clevoprid is a derivative of a new benzamide-based drug that enhances the anti-dopaminergic effect of metoclopramide, and selectively acts on dopamine receptors present in gastrointestinal smooth muscle, chez (chemoreceptor trigger zone), and cerebral limbic system. In other words, it blocks the dopamine receptors in the gastrointestinal myenteric plexus, which is effective in promoting peristalsis and intestinal movement of gastric foods. In addition, by suppressing the activity of C-AMP to reduce gastrin secretion in gastric mucosa to treat gastroduodenal ulcers. The average half-life of clevoprid is 1.5 hours, the distribution volume is 3.9 L / hr, and the average clearance of desbenzyl clevoprid, the major metabolite, is 79.32 L / hr. [Drug Invest., 4 (1), 47. 59 (1992)] Side effects of clevoprid include endocrine problems such as hyperprolactinemia, amenorrhea, gynecomastia, and erectile dysfunction, drowsiness, nervousness, insomnia, agitation, and tongue caused by combination with other benzamide drugs. Psychiatric nervous system symptoms such as paralysis, cleft lip, oral stiffness, suppleness and constipation, nausea, vomiting, and loss of appetite such as nausea, abnormal physiologic system such as muscular stiffness and occasional elevation of S-GOT and S-GPT. Hepatic dysfunction may occur. This is due to the initial high blood levels of the drug and studies to lower the peak blood levels are needed to alleviate the side effects. [Physicians' Desk Reference Prescription Information for Pharmaceauticals and Biologicals 6 Ed., P. 1474, p. 2443 (1991)].

Many modern people have chronic dyspepsia due to busy daily life, irregular eating habits, and excessive drinking and smoking. In particular, candidates and office workers have a higher chance of developing gastro-duodenal ulcer, dyspepsia, irritable colon syndrome due to excessive stress. Therefore, the use of gastrointestinal function modulators has been increasing for the purpose of normalizing aberrant gastrointestinal motility and reducing symptoms. Most of these gastrointestinal function modulators are anti-dopamine drugs that require excessive doses at once, or may cause extraordinary symptoms such as drowsiness or irritability in certain individuals. Do. These side effects are due to the initial high blood concentration, and in order to alleviate the side effects, it is necessary to study to lower the peak blood concentration and maintain the proper blood concentration. In addition, in the case of the existing general tablets, there is a difficulty to take as needed even during a short maintenance time and at night.

Therefore, the present invention intends to develop a dosage of 3 to 4 times a day as a dosage of 1 to 2 times a day, and aimed at a formulation that realizes continuous release of the drug and is easy to mass-produce in manufacture. Sustained release preparations have advantages in many therapeutic effects. By reducing the number of doses, it is thought that not only improve patient compliance and increase treatment effect, but also effective medicines can be used. Also, by keeping the blood concentration of drugs constant, the prevention of side effects due to the rapidly rising blood concentration, It maintains the therapeutic effect at prolonged dose intervals without large amplitude of blood concentration. And as the bad substance is slowly released from the formulation, even blood concentration is maintained, thereby reducing the amplitude of the blood concentration due to multiple administrations of the existing formulation. In addition, there is an advantage that the bioavailability of the drug can be increased by a small amount of administration.

In the present invention, the drug that promotes gastrointestinal motility rapidly transports the preparation to the large intestine, so that the water-soluble polymer having swelling and adhesion to the gastrointestinal mucosa is considered in consideration of the possibility of excretion before the drug is sufficiently eluted. As a method of delaying and sustaining the release rate of the drug, the matrix in which the drug is dispersed in the release control mechanism is prepared, and the digestive fluid in the gastrointestinal tract is formed in a double tablet form in order to rapidly approach the initial blood concentration to the effective blood concentration. The purpose of this study is to design a sustained release formulation approaching the rapid dissolution of the initial phase and the zero order dissolution phase after a certain time by using a method of controlling the release of the drug through the swelling of the polymer and the dual formulation design.

Figure 1 shows the release state of the gastrointestinal function regulator malic clevoprid over time in vitro, Figure 2 shows the blood concentration of clevoprid after oral administration to beagle dogs.

In the present invention, 0.01 to 5.0% (wt%) of gastrointestinal function regulators are distributed in 10.0 to 79.99% (wt%) of swellable or mucoadhesive polymer, and 20.0 to 89.99% (wt%) of release modulator are dispersed. It is characterized by providing a sustained-release preparation of gastrointestinal function modulators that can be easily produced in a double matrix form and can be taken once or twice a day for adults. Referring to the present invention in more detail as follows.

Since the clevoprid or salt thereof is evenly distributed in the swellable polymer, the drug can be released in the patient's body for a longer time period and faster than before without the burst effect which is the initial drug over-release phenomenon. It is characterized by sustained-release preparations containing gastrointestinal function modulators in the form of dual matrix, which is easy to mass-produce, and economical and convenient in terms of dosage.

First, looking at each of the components used in the present invention in more detail as follows.

As the type of gastrointestinal function modifier that can be applied in the present invention, the sustained-release agent of the present invention can be applied to at least one selected from clevoprid and salts thereof.

In addition, the present invention is to select the swellable or mucoadhesive polymers as a dispersion of clevoprid or salts thereof, to form a pore-resistant channel between the specific molecular weight and the polymer matrix can control the release of the drug And the use of a dual release matrix in consideration of the optimization of the release in relation to blood concentration, and the swellable or mucoadhesive polymer selected in the present invention is completely harmless to the human body. However, the one which has swelling property or mucoadhesion property for a predetermined time is used. In the past, swellable or mucoadhesive polymers have been used for sustained release application to various drugs, but no preparations containing clevoprid or salts thereof have been used. Tablets, injections or solutions.

The swellable or mucoadhesive polymer of clevoprid according to the present invention is used as carbomer, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polyethylene oxide (PEO), polyvinylpi Lollidon / vinylacetate copolymer, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polymethacrylate, povidone, alginic acid, sodium alginate, xanthan gum, gum arabic, chitosan, starch, dextrin and the like can be used. It can overcome the shortcomings due to the rapid release rate and initial burst effect of the effective drug, which is a problem in the conventional general formulation, and thus, compared to the conventional technology, it is possible to reduce the side effects as well as to improve the effects such as ease of taking and extending the effective time. have. In particular, these swellable or mucoadhesive polymers vary depending on the type, but preferably have a molecular weight of 4,000 to 900,000 Daltons, because if the molecular weight is less than 4,000, the swelling or mucoadhesion is too easy to control the release and 900,000 If it is exceeded, the swelling period is too long, so that the desired drug release form cannot be obtained. In addition, one type selected from the group consisting of sodium lauryl sulfate, sodium dodecyl sulfate, sodium chloride, cyclodextrin, sodium bicarbonate, starch, lactose, mannitol, sorbitol, white sugar and refined white sugar, calcium phosphate, calcium sulfate, citric acid and salts thereof These can be used, and they are distributed between the swellable or mucoadhesive polymers to act as a pore-channel to control the release of the drug to build an optimal release mode.

In addition, the fast disintegrating moiety may be one or more selected from sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, starch, lactose, calcium phosphate, carboxymethylcellulose calcium, white sugar and mannitol.

The sustained release preparation of clevoprid or a salt thereof according to the present invention is prepared in a matrix form by a conventional manufacturing method using the above-mentioned swellable or mucoadhesive polymer and a release controlling substance. As a method of preparing a formulation, a wet solid dispersion manufacturing method, a wet simple mixing method, or a dry simple mixing method may be used. Among these, the dry simple mixing method is the most easily mass-produced and controlled for sustained release. It is a manufacturing method by.

As an example of preparing a sustained-release preparation of clevoprid according to the present invention, a manufacturing method using a dry simple mixing method and a wet solid dispersion manufacturing method will be described in detail.

In the dry simple mixing method, the swellable or mucoadhesive polymer 10.0 to 79.99 is prepared by simply mixing 20.0 to 89.99% (wt%) of the above-described release controlling substance and 0.01 to 5.0% (wt%) of clevoprid or salt thereof. Mix again with% (% by weight) and mix with an appropriate amount of lubricant (mixture 1). Clevoprid or its salt is then used to prevent drug bias in the dispersion. Apart from the usual prescription excipients lactose, microcrystalline cellulose, calcium phosphate, colloidal silica, povidone, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, starch, croscarmellose sodium, sodium starch glycolate and glidants One or more selected ones and 0.01 to 2.5% (wt%) of clevoprid or salts thereof are homogeneously mixed in a conventional manner. (Mixed mixture 2) The mixtures 1 and 2 thus prepared are each prepared by a special tableting machine (multiple tableting machine). It is injected into a powder injector to prepare a conventional multi-purification method.

In the wet solid dispersion production method, 10.0 to 79.99% (wt%) of the swellable or mucoadhesive polymer is dissolved in a solution in which 0.01 to 5.0% (wt%) of clevoprid or its salt is completely dissolved in a suitable solvent. Swell. The end point at this time is the point at which the whole becomes a complete homogenate, and depends on the type and amount of the solvent and the type and amount of the polymer. Solvents that can be used include at least one selected from water, ethanol, methanol, acetone, methylene chloride and chloroform. The wet homogenate thus prepared is mixed homogeneously with the release control material again and then completely dried under warm air at 40 to 80 ° C. Below 40 ° C., the drying rate is too slow, and above 80 ° C., there may be an abnormality in the stability of the polymer and drug, so as not to exceed the above temperature range. A fully dried dispersion of clevoprid or its salt is formulated into Nos. 14 to 30 and mixed with a suitable ratio of lubricant (mixture 1). Separately, excipients of general prescription lactose, microcrystalline cellulose, calcium phosphate and colloidal silica At least one selected from povidone, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, starch, croscarmellose sodium, sodium starch glycolate and glidants and the like and homogenous clevoprid or salts thereof in a conventional manner. (Mix 2) The mixtures 1 and 2 thus prepared are injected into a powder injector of a special tableting machine (multi tableting machine), respectively, to prepare a conventional multi-tablet manufacturing method.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by Examples.

Example 1

Lactose 26.2% (wt%), sodium lauryl sulfate 3.6% (wt%), malic acid clevoprid 50 times acid 12.4% (wt%), starch 7.3% (wt%) and then polyvinylpyrrolidone / 7.3% (wt%) of vinyl acetate copolymer, 14.5% (wt%) of hydroxypropylmethylcellulose (MW 15,000), 0.7% (wt%) of colloidal silica, and 0.7% (wt%) of magnesium stearate are mixed again. (Mixture 1) At this time, clevoprid or its salt is used to prevent drug bias in the dispersion by using acid dispersion. Separately lactose 14.6% (wt%), microcrystalline cellulose 4.4% (wt%), sodium starch glycolate 1.3% (wt%), polyvinylpyrrolidone 0.3% (wt%) magnesium stearate and colloidal silica 0.3% (Wt%) and 6.2% (wt%) of cleaved malic acid with 50 times acidity are mixed homogeneously in a conventional manner. (Mixture 2) The powder injector of each of the mixtures 1 and 2 thus prepared is a special tableting machine (multiple tableting machine). It is prepared by the conventional multi-purification manufacturing method by injecting in.

Example 2

Lactose 29.8% (% by weight), malic acid clevoprid 50-fold 12.4% (% by weight), starch 7.3% (% by weight), and then polyvinylpyrrolidone / vinylacetate copolymer 7.3% (% by weight), 14.5% (wt%) of hydroxypropylmethylcellulose (MW 15,000), 0.7% (wt%) of colloidal silica, and 0.7% (wt%) of magnesium stearate are mixed again (mixture 1). ), 4.4% (wt%) of microcrystalline cellulose, 1.3% (wt%) sodium starch glycolate, 0.3% (wt%) polyvinylpyrrolidone magnesium stearate and 0.3% (wt%) colloidal silica and cleric malic acid 6.2% (weight%) of bofried 50-fold dispersion is mixed homogeneously in a conventional manner.

Example 3

Component (Mix 1) Weight ratio (%) Component (Mix 2) Weight ratio (%) Malsan Crevo Fried 50 times 23.3 Malsan Crevo Fried 50 times 5.2 Hydroxypropyl Methyl Cellulose4,000 10.3 Lactose 13.7 Polyethylene Oxide 900,000 20.5 Polyvinylpyrrolidone 0.3 Colloidal silica 0.7 Colloidal silica 0.3 Magnesium stearate 0.7 Magnesium stearate 0.3 Lactose 13.7 Microcrystalline cellulose 1.2 Starch 5.1 Sodium starch glycolate 3.6

It is prepared in the same manner as in Example 1 using the above constituents.

Example 4

Component (Mix 1) Weight ratio (%) Component (Mix 2) Weight ratio (%) Malsan Crevo Fried 50 times 20.7 Malsan Crevo Fried 50 times 5.2 Hydroxypropyl Methyl Cellulose 18.8 Lactose 12.2 Carbomer 18.2 Polyvinylpyrrolidone 0.2 Colloidal silica 0.6 Colloidal silica 0.2 Magnesium stearate 0.6 Magnesium stearate 0.2 Lactose 12.2 Microcrystalline cellulose 1.1 Starch 6.1 Sodium starch glycolate 3.7

It is prepared in the same manner as in Example 1 using the above components.

Example 5

Component (Mix 1) Weight ratio (%) Component (Mix 2) Weight ratio (%) Malsan Crevo Fried 50 times 0.41 Malsan Crevo Fried 50 times 5.2 Hydroxypropyl Methyl Cellulose4,000 5.5 Lactose 12.2 Hydroxypropyl Methyl Cellulose15,000 10.0 Polyvinylpyrrolidone 0.2 Colloidal silica 0.6 Colloidal silica 0.2 Magnesium stearate 0.6 Magnesium stearate 0.2 Lactose 44.7 Microcrystalline cellulose 1.1 Starch 15.2 Sodium starch glycolate 3.7

Hydroxypropylmethylcellulose is added to a homogeneous solution of malic clevoprid completely dissolved in 25-fold 80% ethanol. Lactose and starch are added to the wet homogenate thus prepared, mixed homogeneously, and completely dried under warm air at 70 ° C. (at least 12 hours). (Mixture 1) Separately, the mixture 2 is prepared in the same manner as in Example 1 above. Prepared by the multi-purification method of.

Comparative Example 1

ingredient Weight ratio (%) Malsan Crevo Fried 50 times 22.7 Lactose 53.5 Polyvinylpyrrolidone 1.1 Colloidal silica 1.0 Magnesium stearate 1.0 Sodium starch glycolate 4.7 Microcrystalline cellulose 16.0

As said component, it mixes and tablets in a conventional method.

Comparative Example 2

ingredient Weight ratio (%) Malsan Crevo Fried 50 times 26.9 Hydroxypropyl Methyl Cellulose 20.2 Colloidal silica 0.8 Magnesium stearate 0.8 Lactose 31.6 Starch 19.8

As said component, it mixes and tablets in a conventional method.

Experimental Example 1:

The tablets obtained in Examples 1 and 2 and Comparative Examples 1 and 2 were subjected to a release test under conditions of water of 37 ± 0.5 ° C. and a paddle rotational speed of 100 rpm, respectively, and then 5, 10, 30, 60, 120, The eluate was collected and analyzed at 240, 360 and 480 minutes, and the results are shown in FIG. 1 and compared.

1, in the case of clevoprid sustained release preparations according to the present invention of Examples 1 and 2, after rapidly dissolving to about 30 to 40% by the initial 0.5 hours, thereafter, the dissolution behavior was nearly zero. In vivo administration, it was found that the initial effective blood concentration can be rapidly approached and then absorbed steadily by a certain amount. On the other hand, in the case of Comparative Example 1 as a general tablet, it may cause a burst effect by showing an initial rapid dissolution pattern, and in Comparative Example 2 shows a steady release, but it is insufficient to reach the initial effective blood concentration for rapid drug efficacy. As a result, the release of clevoprid and its salts as swellable or mucoadhesive polymers can be controlled, and the dual matrix structure design with fast disintegrating portion can be used in the drug release design intended by the present invention. It can be seen that more excellent.

Experimental Example 2:

The tablets obtained in Examples 1 and 2 and Comparative Example 1 were orally administered to beagle dogs, and blood was collected at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours for analysis. The results are shown in FIG. 2 and compared.

According to Figure 2, in the case of clevoprid sustained release preparations according to the present invention of Examples 1 and 2, unlike the comparative example 1 in which the blood concentration is rapidly increased initially, there is a modest increase in blood concentration, the initial burst effect It can be seen that there is no and the drug lasts at least 12 hours. On the other hand, in the case of Comparative Example 1 is a general tablet, it may exhibit an initial rapid dissolution pattern may cause a burst effect. As a result, in vivo oral administration, it was confirmed that the release control of clevoprid and its salts as swellable or mucoadhesive polymers can be controlled in the same manner as in Experimental Example 1, which means that the dual matrix matrix design can simultaneously control drug efficacy and side effects. It can be seen that it is excellent in terms of design and at the same time meets the object of the present invention.

As described above, the sustained-release preparation of clevoprid according to the present invention, endocrine system abnormalities such as hyperprolactinemia, amenorrhea, gynecomastia, erectile dysfunction and drowsiness, nervousness, which are side effects due to sudden high blood drug concentration The program can avoid mental nervous system symptoms such as insomnia, sympathy, tongue palsy, and cleft lip, oral stiffness, suppleness and constipation, nausea, vomiting, and loss of appetite, such as muscular root stiffness. Safe oral administration can be achieved while maintaining blood levels in a controlled manner. In addition, since the drug is maintained only once or twice a day, it is convenient, economical, and consequently improves patient compliance, thereby increasing treatment efficiency.

Claims (6)

0.01 to 5.0% (wt%) of clevoprid or its salt and 20.0 to 89.99% (wt%) of releasing agent are swellable or mucoadhesive polymers having a molecular weight of 4,000 to 900,000 daltons. Sustained release formulation of clevoprid or salt thereof, dispersed in a weight percent) and in the form of a double matrix having a fast disintegrating moiety. The method according to claim 1, wherein the swellable or mucoadhesive polymer is carbomer, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polyethylene oxide (PEO), polyvinylpyrrolidone / vinyl Clevoprid characterized by one or more selected from acetate copolymers, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polymethacrylate, povidone, alginic acid, sodium alginate, xanthan gum, gum arabic, chitosan, starch, dextrin or Sustained release preparation of the salt. The method of claim 1, wherein the release regulator is sodium lauryl sulfate, sodium dodecyl sulfate, sodium chloride, cyclodextrin, sodium bicarbonate, lactose, mannitol, sorbitol, white sugar and refined white sugar, calcium phosphate, calcium sulfate, citric acid and salts thereof, starch A sustained-release preparation of clevoprid or a salt thereof, wherein the release modifier is one or more selected from among them, and these release modulators are distributed between swellable or mucoadhesive polymers to control the release of the drug by acting as a pore to channel. The fast disintegrating moiety is at least one selected from sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, starch, lactose, calcium phosphate, carboxymethylcellulose, white sugar and mannitol. Sustained release preparation of clevoprid or its salt. The sustained-release preparation of clevoprid or salt thereof according to claim 1, wherein the preparation is in the form of a matrix having a dual structure and is used once or twice daily. A method for producing a sustained release preparation of clevoprid or salts of claims 1 to 5 using one of a wet solid dispersion method, a wet simple mixing method or a dry simple mixing method.