KR20240108663A - Stable controlled-release pharmaceutical composition comprising bethanechol and a method for preparing thereof - Google Patents

Abstract

The present invention includes the steps of (1) mixing bethanechol or a pharmaceutically acceptable salt thereof as an active ingredient with water-soluble saccharides, water-insoluble cellulose, and swellable polymer to form granules; (2) mixing the granules with hydrophilic polymer and other additives such as suspension base; Provided is a controlled-release pharmaceutical composition for oral administration and a method for producing the same, including the step of (3) compressing the mixture to form a matrix preparation.
The controlled-release preparation for oral administration according to the present invention allows the tablet to immediately float in artificial gastric fluid and continuously release bethanechol through a swelling and erosion mechanism, and has a size suitable for taking, improving medication compliance. You can.

Description

Stable controlled-release pharmaceutical composition comprising bethanechol and a method for preparing the same}

The present invention relates to a stable controlled-release pharmaceutical composition containing bethanechol as an active ingredient and a method for preparing the same. More specifically, the form of a matrix tablet formed from granules containing (i) bethanechol or a pharmaceutically acceptable salt thereof as an active ingredient, and water-soluble saccharides and water-insoluble cellulose, and (ii) a swellable polymer and a hydrophilic polymer. It relates to a controlled-release pharmaceutical composition that immediately floats in artificial gastric fluid and a method for manufacturing the same.

Bethanechol is a cholinergic drug that acts selectively on muscarinic receptors in the postganglionic parasympathetic nervous system, and helps urination by increasing bladder detrusor muscle tension in the bladder smooth muscle. Contraction of the bladder muscle occurs when acetylcholine secreted from the nerve endings acts on the muscarinic receptors present in the bladder muscle. Acetylcholine is the most important neurotransmitter for bladder contraction in all vertebrates (see Overactive Bladder Guidelines). Since bethanechol is not broken down by cholinesterase, its duration of action is longer than that of acetylcholine, and although it has excellent muscarinic effects, it has almost no nicotinic effects.

In addition, bethanechol acts on the smooth muscles of the gastrointestinal tract, increasing gastrointestinal motility, increasing gastric tone, and restoring the rhythm of damaged peristalsis, so it is also used to treat dysphagia and paralytic ileus.

Bethanechol does not stimulate ganglia and voluntary muscles at doses that promote urination, defecation, and peristalsis, and has little effect on heart rate, blood pressure, and peripheral circulation at therapeutic doses.

Bethanechol or Bethanechol chloride is very soluble in water, and the usual dosage is up to 100 mg per day, with 25 mg tablets administered 3 to 4 times a day. When administered orally, bethanechol does not have a known absorption site in the digestive tract. Pharmacokinetically, the time to reach the highest blood concentration is a rapid onset of drug effect within 2 hours, and the duration of drug effect is 6 hours. It is assumed that the absorption site of bethanechol, which has an amine group, in the gastrointestinal tract is limited to the upper small intestine.

For highly soluble drugs such as bethanechol, the residence time must be extended through suspension, swelling, and erosion in order to extend the residence time in the gastrointestinal tract. A controlled-release formulation suitable for commercial scale production is desirable. do.

As a sustained-release preparation containing bethanechol, Republic of Korea Patent Registration No. 10-2062052 is a preparation containing 75 mg of bethanechol chloride. It is a sustained-release base containing 100,000 cps of hydroxypropylmethylcellulose, a swellable, high-viscosity water-soluble polymer, and an insoluble polymer. Polyvinyl acetate polyvinylpyrrolidone polymer (brand name: Kollidon SR) and insoluble ethylcellulose as a coating agent have been disclosed. However, since this system contains a large amount of bethanechol per tablet and excessive sustained release may occur, drugs with limited absorption sites in the gastrointestinal tract may have lower bioavailability due to excessive sustained release in vivo, unlike the drug dissolution rate in vitro. , it has the disadvantage of having to perform functional coating using multiple compartments at the production site. Korean Patent Registration No. 10-1317592 discloses a gastric retention type sustained-release preparation containing polyethylene oxide as a swelling agent and polyvinyl alcohol-polyethylene glycol graft copolymer as a release control mechanism, and purified sugar of polyethylene oxide as a swelling agent. There is a disadvantage in that the tablets are large because the proportion of parts by weight is excessively large. Therefore, in order to overcome these shortcomings and achieve effective bioavailability in vivo while lowering the content of bethanechol, the industry needs to develop a stable, controlled-release pharmaceutical manufacturing method in the form of a single matrix without a complicated manufacturing process. do.

Accordingly, the present invention seeks to provide a controlled-release preparation for oral administration with a dose of 50 mg of bethanechol, a highly soluble drug, and can be easily and stably applied at the production site through a commonly used tablet manufacturing process. There must be. By allowing the tablet to float in the stomach within a short period of time and release the drug consistently, it is possible to continuously release bethanechol in the drug absorption area of the digestive tract in a controlled manner even by using a minimal amount of swellable, low-viscosity polymer and hydrophilic polymer. The aim is to provide a controlled-release pharmaceutical composition and manufacturing method for oral administration that improve medication compliance by having the following appropriate size.

In order to solve the above problem, the present inventors mixed bethanechol with water-soluble saccharides and water-insoluble cellulose in an appropriate ratio, formed granules with swellable polymers and hydrophilic polymers, and tableted them to form a matrix preparation. The controlled-release pharmaceutical preparation according to the present invention immediately floats in the dissolution liquid when the tablet is dissolved in artificial gastric fluid according to the dissolution test method 2 of the Korean Pharmacopoeia, and induces continuous release of bethanechol through the mechanism of swelling and erosion. . Therefore, the present invention can be said to be a gastric retention controlled-release preparation that can float in the human gastrointestinal tract, and the present invention was completed by discovering that it has a size suitable for administration.

The pharmaceutical composition according to the present invention is a commonly used tablet by using a combination of specific ingredients as a release control agent, that is, a combination of water-soluble saccharides and water-insoluble cellulose, and a combination of hypromellose, a swellable polymer, and polyethylene oxide, a hydrophilic polymer. It can be formulated into a stable single matrix form through the manufacturing process. That is, the pharmaceutical composition of the present invention has a single matrix form, so it can be simply manufactured through a tablet manufacturing process and can be easily applied at production sites. In addition, the pharmaceutical composition according to the present invention floats immediately in the stomach and induces continuous release of bethanechol through swelling and erosion, resulting in immediate-release and sustained-release dissolution patterns. The pharmaceutical preparation according to the present invention can continuously release bethanechol while using a minimum amount of polymer, and can be formulated to have a size suitable for administration (diameter of approximately 9.5 mm), thereby improving patient compliance with the drug. there is.

Figure 1 shows the dissolution results over time of the tablets of Formulation Example 2-1 to Formulation Example 2-6 of Example 2.
Figure 2 is a graph showing numerically the swelling effect (water uptake) for the tablets of Example 2 and the coated tablets of Comparative Example 2.
Figure 3 shows the dissolution results over time of the tablets of Formulation Example 2-6 of Example 2, the tablets of Comparative Example 1, and the coated tablets of Comparative Example 2.

The present invention is a controlled-release preparation containing bethanechol or a pharmaceutically acceptable salt thereof as an active ingredient, which contains granules containing water-soluble saccharides, water-insoluble cellulose, swellable low-viscosity polymer, hydrophilic polymer, and a suspending agent. Phosphorus, controlled release formulation is provided. The controlled release formulation may further include a disintegrant and a lubricant.

In addition, the present invention provides a matrix tablet formed from granules containing (i) bethanechol or a pharmaceutically acceptable salt thereof as an active ingredient, and water-soluble saccharides and water-insoluble cellulose, and (ii) a swellable polymer and a hydrophilic polymer. A method for manufacturing a controlled-release pharmaceutical composition that immediately floats in artificial gastric fluid is provided.

The controlled-release pharmaceutical composition of the present invention contains bethanechol as an active ingredient and can be used in an amount suitable for oral administration. For example, the controlled-release pharmaceutical composition of the present invention may contain 37.5 mg to 75 mg, preferably about 50 mg, of bethanechol as an active ingredient per unit tablet.

In the controlled-release pharmaceutical composition of the present invention, the water-soluble saccharide and the water-insoluble cellulose may be combined in a weight ratio of 1.5:1 to 4:1.

In addition, the present invention includes the steps of (1) mixing bethanechol or a pharmaceutically acceptable salt thereof as an active ingredient with water-soluble saccharides, water-insoluble cellulose, and swellable polymers to form granules; (2) mixing the granules with hydrophilic polymer and other additives such as suspension base; Provided is a controlled-release pharmaceutical composition for oral administration and a method for producing the same, including the step of (3) compressing the mixture to form a matrix preparation.

Bethanechol is a compound having the following formula 1, and the compound name is 2-[(aminocarbonyl)oxy]-N,N,N-trimethyl-1-propanaminium carbamyl-β-methylcholine (2- [(aminocarbonyl)oxy]-N,N,N-trimethyl-1-propanaminium Cabamyl-β-methylcholine):

[Formula 1]

Bethanechol is a cholinergic drug that selectively acts on muscarinic receptors in the postganglionic parasympathetic nervous system. It increases bladder detrusor muscle tension in bladder smooth muscles and helps urination. Since bethanechol is not broken down by cholinesterase, its duration of action is longer than that of acetylcholine, and although it has excellent muscarinic effects, it has almost no nicotinic effects. In addition, bethanechol acts on the smooth muscles of the gastrointestinal tract, increasing gastrointestinal motility, increasing gastric tone, and restoring the rhythm of damaged peristalsis, so it is also used to treat dysphagia and paralytic ileus. Bethanechol does not stimulate ganglia and voluntary muscles at doses that promote urination, defecation, and peristalsis, and has little effect on heart rate, blood pressure, and peripheral circulation at therapeutic doses.

In one embodiment, the pharmaceutical composition of the present invention is characterized by being immediately suspended in artificial gastric fluid. Specifically, when a tablet is administered into artificial gastric fluid, the tablet floats within 1 minute and continues to float for 24 hours, allowing the drug to be released through swelling and erosion.

In one embodiment of the present invention, the content of bethanechol or a pharmaceutically acceptable salt thereof may range from 8 to 30% by weight based on the total weight of the controlled-release preparation.

Pharmaceutically acceptable salts of bethanechol include halides and acid addition salts, and halides include fluorine, chloride, bromide, and iodide. The acid addition salt includes an inorganic acid salt or an organic acid salt.

The inorganic acid salt includes, but is not limited to, hydrochloride, phosphate, sulfate, or disulfate. The organic acid salts include fatty organic acid salts such as acetate, dichloroacetate, adipate, alginate, ascorbate, camphorate, caprate, caproate, caprylate, cyclamate, galactarate, gluceptate, and glucuronate. , glutamate, oxoglutarate, lactobionate, thiocyanate, malonate, ursonate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propyol. Latex, malonate, succinate, suberate, sebacate, maleate, orotate, myristate, butyne-1,4-dioate, hexyne-1,6-dioate, citrate, lactate, beta hydroxy butyrate, glycolate, malate, tartrate; aliphatic sulfone organic acid salts such as methanesulfonate, propanesulfonate, camphorsulfonate, camsylate, edisylate, esylate, and isethionate; Aromatic organic acid salts such as benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, phenylacetate, phenylpropionate, phenylbutyrate, mandelate, salicylate, para -aminosalicylate, tannate, cinnamate; Salts such as aromatic sulfone organic acid salts such as benzenesulfonate, toluenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, or naphthalene-2-sulfonate are included, but are not limited thereto. Specifically, bethanechol chloride can be preferably used in the present invention.

The term “swellable polymer” used in the present invention refers to a pharmaceutically acceptable polymer that swells in an aqueous solution to control the release of a drug.

Swellable polymers usable in the present invention include hypromellose (hydroxypropylmethylcellulose), hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose sodium, cellulose acetate, It may be one or more derivatives selected from the group consisting of cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, and hydroxyethylmethylcellulose. Specifically, hypromellose (hydroxypropylmethylcellulose) may be preferably used in the present invention, but is not limited thereto as long as it is a pharmaceutically acceptable swellable polymer that can control release according to the purpose of the present invention. Also preferably, the swellable polymer has a viscosity of 4,000 to 100,000 cps.

In one embodiment of the present invention, hypromellose as the swellable low-viscosity polymer refers to a viscosity of 4,000 cps in a 2% aqueous solution, and hypromellose as a swellable high-viscosity polymer refers to a viscosity of 100,000 cps in a 2% aqueous solution. do. Hypromellose is included in the controlled-release preparation in an amount ranging from 8 to 30% by weight based on the total weight of the controlled-release preparation. If the content of the swellable polymer is less than 8% by weight, it is difficult to effectively control the release of the drug, and if it exceeds 30% by weight, the drug release control effect is excessive and the size of the preparation becomes large, making it unsuitable for administration.

As used in the present invention, the term "water-soluble saccharide" may be one or more selected from the group consisting of lactose, mannitol, sorbitol, and dextrin, and is preferably lactose (lactose hydrate, anhydrous lactose), and the term "insoluble cellulose" refers to microcrystalline cellulose. , one or more types may be selected from the group consisting of powdered cellulose, crystalline cellulose, and calcium carboxymethyl cellulose, and preferably microcrystalline cellulose. It has been found in the present invention that the water-soluble saccharides and the water-insoluble cellulose not only serve as excipients in matrix tablets, but also serve as an initial release control agent for bethanechol when the above components are combined.

In one embodiment of the present invention, the “hydrophilic polymer” as the release-controlled base may be one or more selected from the group consisting of polyethylene oxide, polyoxyethylene lauryl ether, polyoxyethylene glycol, and macrogol analogs, and is preferably polyethylene. It is an oxide, and its brand name is POLYOX 303. The approximate molecular weight is about 7,000,000, and the release of bethanechol can be effectively controlled depending on the weight percent per tablet.

In one embodiment of the present invention, the flotation agent may be sodium carbonate, potassium carbonate, precipitated calcium carbonate, sodium bicarbonate, citric acid, fumaric acid, and mixtures thereof, but is not limited thereto.

In one embodiment of the invention, suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, talc, wax, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, and sodium oleate. , sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, sodium stearyl fumarate, sodium lauryl sulfate, and mixtures thereof can be used, but are not limited to these. Preferably, the lubricant is magnesium stearate or sodium lauryl sulfate.

In one embodiment of the present invention, suitable lubricants include silica, colloidal silicon dioxide, talc, magnesium stearate, etc., but are not limited thereto.

In one embodiment of the present invention, the controlled-release formulation of the present invention preferably exhibits an immediate-release form in which the cumulative release rate of the active ingredient is dissolved within 40% within 1 hour, and the cumulative release rate of the active ingredient is eluted by more than 90% after 8 hours. emission characteristics can be expressed.

In one embodiment of the invention, the controlled release formulation of the invention is preferably in tablet form.

In one embodiment of the present invention, the controlled-release formulation of the present invention can be preferably used for the known medicinal uses of bethanechol. Therefore, the preparation of the present invention can be used for the treatment of functional urinary retention after surgery or delivery, stimulation of urination, stimulation of defecation, stimulation of peristalsis, treatment of dysphagia, treatment of paralytic ileus, or treatment of neurogenic muscular dystrophy of the bladder, but is limited thereto. no.

The dosage of the controlled-release preparation of bethanechol for oral administration of the present invention will vary depending on the severity of the disease, body weight and metabolic status of the treatment subject. “Therapeutically effective amount” for an individual patient means an amount sufficient to achieve a therapeutic effect. Specifically, the therapeutically effective amount of bethanechol is up to 100 mg per day when administered to humans. The dosage and interval of administration of the controlled-release formulation containing bethanechol for oral administration of the present invention may be adjusted depending on the case.

In order to predict the in vivo pharmacological activity of the preparation by comparing the dissolution pattern and pharmacokinetics (PK) of the release-controlled preparation according to the present invention, the preparation of the example was administered to a Beagle dog to determine the pharmacokinetics ( PK) was analyzed. As a result, it was confirmed that the pharmacokinetics of bethanechol change depending on the in vitro dissolution pattern, and it was confirmed that the spindle-controlled preparation of the present invention, which shows an appropriate dissolution pattern of bethanechol in vitro, also exhibits desirable pharmacological activity in vivo. .

Hereinafter, the present invention will be described in more detail through examples. These examples are for illustrating the present invention in more detail, and the scope of the present invention is not limited by these examples.

Example 1: Preparation and evaluation of matrix tablets using swellable high-viscosity polymers and low-viscosity polymers

According to the ingredient contents listed in Table 1 below, a single matrix tablet containing bethanechol chloride was prepared. Specifically, 100,000 cps and 4,000 cps of bethanechol and hypromellose, which are swellable high-viscosity polymers and low-viscosity polymers, were wet-granulated and dried using microcrystalline cellulose and lactose hydrate as additives and purified water as a binding solvent, and added to the dried mixture. Polyethylene oxide (product name POLYOX 303), a hydrophilic polymer, crospovidone as a disintegrant, light anhydrous silicic acid (product name Silicia 350) as a lubricant, and magnesium stearate were mixed and compressed to prepare a single matrix tablet.

1) Experimental Example 1: Dissolution test of formulation

The formulations prepared in Formulation Examples 1 to 7 were subjected to an in-vitro dissolution test in 900 mL of artificial gastric fluid at pH 1.2 at 37°C at 50 rpm according to Method 2 of the General Test Method of the Korean Pharmacopoeia. The eluate was taken for each time period and the dissolution rate was analyzed by HPLC. The HPLC analysis conditions used were as follows.

- Column: Waters IC-Pak C M/D (150 Ⅹ 3.9 mm)

- Detector: Conductivity detector

- Mobile phase: Buffer solution: ACN (95:5)

- Flow rate: 0.9 mL/min

- Buffer solution: Dissolve 58 mg of edetic acid in 500 mL of water, add 0.3 mL of nitric acid, and then adjust to the 1000 mL mark with water.

The dissolution results of the formulations of Formulation Examples 1-1 to 1-7 are shown in [Table 2].

As shown in Table 2, when comparing Formulation Examples 1-1 and 1-4, Polyox 303 as a hydrophilic polymer was used in the tablet weight ratio range of 10%, and high-viscosity HPMC and low-viscosity HPMC were used in the tablet weight ratio range of 37.5%. When used, the cumulative release rate of the drug was low, below 80%. In addition, when comparing Formulation Examples 1-2 and 1-5, when polyox 303 was not used as the hydrophilic polymer, the cumulative release rate was more than 80% in 8 hours even when high-viscosity and low-viscosity HPMC were used at a tablet weight ratio of 37.5%. It can be said that the release rate of highly soluble bethanechol is effectively controlled when Polyox 303 is used. Meanwhile, when comparing the dissolution results of Formulation Examples 1-3 and 1-6, when Polyox 303 as a hydrophilic polymer was fixed at a tablet weight ratio of 10% and high-viscosity HPMC and low-viscosity HPMC were used at a tablet weight ratio of 7.5%, the It can be seen that the initial dissolution rate was not controlled. When comparing the dissolution results of Formulation Example 1-4 and Formulation Example 1-7, it can be seen that the initial dissolution rate of bethanechol is suppressed when only lactose is used as an additive. In order to adjust the dissolution rate for 1 hour to 40%, water-soluble saccharides and It was found that water-insoluble microcrystalline cellulose must be used in an appropriate combination.

From the results of Example 1, 4,000 cps of hypromellose, a swellable low-viscosity polymer, was used in the range of 7.5 to 37.5% per tablet weight%, more preferably in the range of about 16%, and the ratio of water-soluble lactose to water-insoluble cellulose At this ratio of 2.4:1, polyox 303, a hydrophilic polymer, is used in the range of about 10 to 13% per tablet weight%, and crospovidone, a critical disintegrant, is used in 5 to 7% to achieve the cumulative release rate of the latter half of bethanechol. It can be seen that Formulation Examples 1-7 set in the range are suitable.

Example 2 and Comparative Example 1: Preparation and evaluation of gastric retentive controlled-release single matrix tablet

Meanwhile, bethanechol is very water-soluble, the site of absorption in the digestive tract is not exactly known, and the molecular structure of bethanechol is known to have low bioavailability due to its structure having a tertiary amine group. Therefore, tablets are required to achieve constant and continuous drug release. A gastric retention controlled release preparation that allows the tablet to float in the stomach when administered orally may be desirable.

A formulation study was conducted to contain bethanechol according to the ingredients and contents shown in Table 3 below and allow it to float immediately upon administration in artificial gastric fluid, and a single matrix tablet was manufactured using the ingredients shown in Table 3.

Specifically, 4,000 cps of bethanechol and hypromellose, a swellable low-viscosity polymer, microcrystalline cellulose, and lactose hydrate were mixed, wet granulated using purified water as a binding solvent, dried, and polyethylene oxide (product name), a hydrophilic polymer, was added to the dried mixture. POLYOX 303), sodium carbonate, citric acid, sodium bicarbonate as a suspending agent, crospovidone as a disintegrant, light anhydrous silicic acid (product name: Silicia 350), and magnesium stearate as a lubricant, mixed, and compressed into tablets with a diameter of approximately 9.5 mm. Single matrix tablets were prepared.

2) Experimental Example 2: Measurement of tablet hardness, floating time and dissolution rate

The tablets of Formulation Examples 2-1 to 2-6 according to Example 2 and Comparative Example 1) were evaluated for hardness of the tablets and the suspension time and dissolution rate of the tablets using the dissolution test method of Experimental Example 1, and the results were respectively [ It is shown in [Table 4] and [Table 5].

From the results in [Table 5], it can be seen that formulation examples 2-4 to 2-6 containing sodium bicarbonate alone float much faster than formulation examples 2-1 to 2-3 containing both sodium carbonate and citric acid. When comparing Formulation Example 2-1 and Formulation Example 2-3, it is shown that the hardness of the tablet has a greater effect on the floating of the tablet than the content of sodium carbonate and citric acid. In contrast, in the case of Formulation Examples 2-4 to 2-6 containing only sodium bicarbonate, it can be seen that the tablets float quickly regardless of the hardness of the tablets. In Comparative Example 1, even though sodium bicarbonate was used at a weight ratio of 11.9% per tablet, the floating time of the tablet was about 5 minutes. It is assumed that immediate tablet floating did not occur because Polyox 303 was used at a rather high weight ratio of 29.9% per tablet. From the dissolution results in [Table 5], it can be seen that the initial release rate of bethanechol can be appropriately controlled when the weight ratio of microcrystalline cellulose and lactose used in Preparation Example 2-6 is about 2.4:1, and the release rate of polyox 303 can be appropriately controlled. A similar dissolution rate was shown compared to Formulation Example 1-7 with a high content. In addition, Comparative Example 1, which contained a high weight ratio of Polyox 303, showed a lower dissolution rate than Formulation Example 2-6. Therefore, it can be seen that Polyox 303 is preferably in the range of 3 to 13% by weight of the tablet. From the results of [Table 4] and [Table 5], when the controlled-release preparation containing bethanechol is administered orally with water on an empty stomach in the stomach, which is the digestive organ, the tablet immediately floats and then has a constant swelling-erosion mechanism. It is believed that drug release occurred.

Comparative Example 2: Preparation and evaluation of 100,000cps of hydroxypropylmethylcellulose as a swellable polymer, polyvinyl acetate polyvinylpyrrolidone polymer (product name: Kolidon SR) as an insoluble polymer, and insoluble ethylcellulose as a coating agent.

Referring to the examples of Republic of Korea Patent Registration No. 10-2062052, coated tablets were prepared and evaluated using the composition of Example 5 and the insoluble coating composition of Example 16. A preparation containing 50 mg of bethanechol chloride, 50 mg of bethanechol chloride, 170 mg of microcrystalline cellulose, 150 mg of Kollidon SR, 80 mg of high viscosity HPMC2208, 100,000 cps, sieved through a 35 mesh sieve, added with purified water, wet granulated, dried at 60 degrees, and dried. 5 mg of Aerosil 200 and 8 mg of magnesium stearate were added to the mixture, mixed, and compressed to obtain a hardness of 18 kp. Separately, a coating solution containing 21.96 mg of Opadry EC (ethyl cellulose) and 2.44 mg of HPMC 2910 6cps was prepared in 90% ethanol, and then the tablets were coated using a coating machine. The coated tablets were subjected to the dissolution test of the preparation in Experimental Example 1, and the dissolution results are shown in [Table 6].

3) Experimental Example 3: Evaluation of swelling effect

The swelling degree (%) was evaluated using the tablets of Formulation Example 2-6 of Example 2 and the coated tablets of Comparative Example 2.

The tablets were placed in a dissolution tester vessel containing 250 mL of pH 1.2 artificial gastric fluid maintained at 37°C, and the tablets were taken out at intervals of 1 hour, 1.5 hours, 4 hours, 6 hours, 8 hours, and 12 hours at 50 rpm, dissolution test method 2. Then, the weight was measured according to the formula below and the swelling degree (%) was measured, and the results are shown in [Table 7] and Figure 2.

Swelling (%) = (Ws - Wi)/Wi ⅹ 100

Ws: weight of swollen sample,

Wi: initial weight of tablet

It can be seen that the tablets of Formulation Example 2-6 float within a few seconds and have a faster swelling effect than the coated tablets of Comparative Example 2, and thus the erosion action takes place more quickly after 6 hours. Therefore, it can be seen that the tablet of Formulation Example 2-6 releases drug through a swelling-erosion mechanism.

4) Experimental Example 3: Pharmacokinetic evaluation of bethanechol in beagle dogs

Pharmacokinetic evaluation of bethanechol in beagle dogs was performed using the tablets of Formulation Examples 2-6 of Example 2, the coated tablets of Comparative Example 2, and Mytonin tablets*2.

The test method was a random cross-sectional study of 8 beagle dogs. Preparation Example 2-6 tablets of Example 2, Comparative Example 2 coated tablets, and 2 mytonin tablets were collected at 0 hours before administration and 1, 1.5, 2.0, 2.5, 3.0, 6.0, and 12 hours after administration to separate plasma. Afterwards, the blood concentration of bethanechol in the plasma was measured. Pharmacokinetic parameters include the area under the blood concentration-time curve (AUC) from the time of administration to the final blood concentration quantification time t, peak blood concentration (Cmax), time to reach peak blood concentration (Tmax), and blood elimination half-life (T 1/2). ) was calculated. The results are shown in [Table 8] below.

As shown in [Table 8], the Tmax of the coated tablets of Preparation Example 2-6 tablets and Comparative Example 2 was delayed by 2.38 hr and 2.44 hr, respectively, compared to the Tmax of Mytonin tablets due to sustained release. According to the blood concentration time curve, Red (AUC0~12), highest blood concentration (Cmax) shows much higher blood concentration in Formulation Example 2-6 than in Comparative Example 2 coated tablet. This is believed to be because the initial dissolution rate of the tablets of Formulation Example 2-6 was higher than that of the coated tablets of Comparative Example 2. The coated tablet of Comparative Example 2 was coated with ethylcellulose, an insoluble coating agent, which resulted in excessive sustained release, resulting in a lower initial dissolution rate. As a result, the highest blood concentration Cmax was lower than that of Formulation Example 2-6. The reason for this is that while the tablets of Preparation Example 2-6 released drug through a swelling and erosion mechanism, the coated tablets of Comparative Example 2 released drug through a swelling mechanism, showing a relatively low blood concentration. there is. As for half-life (T _1/2 ), the tablets of Preparation Example 2-6 showed a longer half-life than the coated tablets and mytonin tablets of Comparative Example 2.

Claims (21)

A controlled-release preparation containing bethanechol or a pharmaceutically acceptable salt thereof as an active ingredient,
A controlled-release preparation comprising granules containing water-soluble saccharides, water-insoluble cellulose, swellable low-viscosity polymer, hydrophilic polymer, and a suspending agent. The controlled-release preparation according to claim 1, wherein the content of bethanechol or a pharmaceutically acceptable salt thereof is in the range of 8 to 30% by weight based on the total weight of the controlled-release preparation. The controlled-release preparation according to claim 1, wherein the pharmaceutically acceptable salt of bethanechol is bethanechol chloride. According to paragraph 1,
The water-soluble sugar is selected from the group consisting of lactose hydrate and anhydrous lactose,
The controlled-release preparation, wherein the insoluble cellulose is selected from the group consisting of microcrystalline cellulose, powdered cellulose, crystalline cellulose, and calcium carboxymethylcellulose. According to paragraph 4,
The water-soluble sugar is lactose hydrate,
A controlled-release preparation, characterized in that the water-insoluble cellulose is microcrystalline cellulose. The controlled-release preparation according to claim 5, wherein the water-soluble saccharide and the water-insoluble cellulose are combined in a weight ratio of 1.5:1 to 4:1. According to paragraph 1,
The swellable low-viscosity polymer is selected from the group consisting of hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, and hydroxyethylcellulose,
A controlled-release preparation, characterized in that the hydrophilic polymer is selected from the group consisting of polyethylene oxide, polyoxyethylene lauryl ether, polyoxyethylene glycol, and macrogol analogs. The controlled-release preparation according to claim 7, wherein the swellable low-viscosity polymer is hypromellose. The controlled-release preparation according to claim 8, wherein the content of the swellable low-viscosity polymer is in the range of 7.5 to 37.5% by weight based on the total amount of the controlled-release preparation. The controlled-release preparation according to claim 9, wherein the swellable low-viscosity polymer has a viscosity of 3,500 to 5,600 cps. The controlled-release preparation according to claim 7, wherein the hydrophilic polymer is polyethylene oxide. The controlled-release preparation according to claim 8, wherein the content of the hydrophilic polymer is in the range of 3 to 13% by weight based on the total weight of the controlled-release preparation. The controlled-release preparation according to claim 1, wherein the suspending agent is selected from the group consisting of sodium carbonate, citric acid and sodium bicarbonate. The controlled-release preparation according to claim 13, wherein the suspending agent is sodium bicarbonate. The controlled-release preparation according to claim 13, wherein the suspending agent is in the range of 5 to 20% by weight based on the total weight of the controlled-release preparation. The controlled-release preparation according to any one of claims 1 to 15, further comprising a disintegrant, a lubricant, or a mixture thereof. The method according to any one of claims 1 to 15, wherein 35 to 55% by weight of the active ingredient is dissolved after 1.5 hours, and more than 90% by weight of the active ingredient is dissolved after 8 hours. Controlled release formulation. The controlled-release preparation according to any one of claims 1 to 15, which is formulated as a double-layer tablet or a single-layer tablet. The controlled-release preparation according to claim 1, wherein the preparation is a single matrix preparation available for oral administration that suspends within 1 minute during a dissolution test in artificial gastric fluid. The method according to any one of claims 1 to 15, for the treatment of functional urinary retention after surgery or delivery, stimulation of urination, stimulation of defecation, stimulation of peristalsis, treatment of dysphagia, treatment of paralytic ileus, or treatment of neurogenic muscle atony of the bladder. A controlled release formulation characterized in that it is used. A method for producing a controlled-release preparation that can be provided for oral administration, comprising bethanechol or a pharmaceutically acceptable salt thereof as an active ingredient,
The controlled release formulation is
It is a matrix preparation containing granules containing water-soluble saccharides, water-insoluble cellulose, swellable low-viscosity polymer, hydrophilic polymer, suspending agent, disintegrant, and lubricant,
The manufacturing method includes mixing bethanechol or a pharmaceutically acceptable salt thereof with water-soluble saccharides, water-insoluble cellulose, and swellable polymers to form granules; Adding and mixing the granules with a hydrophilic polymer, suspending agent, disintegrant, and lubricant; And comprising the step of compressing the mixture into tablets to form a matrix preparation,
Here, the water-soluble saccharide is selected from the group consisting of lactose hydrate and anhydrous lactose, and the insoluble cellulose is selected from the group consisting of microcrystalline cellulose, powdered cellulose, crystalline cellulose, and calcium carboxymethylcellulose,
The water-soluble saccharides and the water-insoluble cellulose are present in a weight ratio of 1.5 to 4:1,
The swellable low-viscosity polymer is selected from the group consisting of hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, and hydroxyethylcellulose,
The hydrophilic polymer is selected from the group consisting of polyethylene oxide, polyoxyethylene lauryl ether, polyoxyethylene glycol, and macrogol analogs,
Wherein the suspension mechanism is selected from the group consisting of sodium carbonate, citric acid and sodium bicarbonate,
Method for manufacturing a controlled-release preparation that can be provided for oral administration.