WO2019182321A1

WO2019182321A1 - Sustained release bethanechol formulation and method for preparing the same

Info

Publication number: WO2019182321A1
Application number: PCT/KR2019/003167
Authority: WO
Inventors: Dong Yeon Kim; Jae Soo Shin; Hyeong Mo Jeong; Hyo Hyun Cho; Jae Song Cho; Soon Hyung Kwon; Myoung Hwa Lim; Hae Kyoung LIM
Original assignee: Il-Yang Pharm. Co., Ltd.
Priority date: 2018-03-20
Filing date: 2019-03-19
Publication date: 2019-09-26
Also published as: KR20190110196A; KR102062052B1

Abstract

The present invention relates to a sustained release formulation of bethanechol and a process for preparing the same. More specifically, the present invention relates to a sustained release formulation of bethanechol for once-a-day oral administration comprising (i) a matrix preparation formed from granules comprising bethanechol or a pharmaceutically acceptable salt thereof as an active ingredient, and a mixture of a swellable polymer and a water-insoluble polymer; and (ii) a coating layer comprising a mixture of an insoluble polymer and a hydrophilic polymer, coating the matrix preparation; and a process for preparing said formulation. The sustained release formulation for once-a-day oral administration according to the present invention can form a hydrogel while using a minimum amount of polymer, is thereby capable of continuously releasing bethanechol in a controlled manner for 24 hours, and has a suitable size for taking, which can improve the convenience of administration.

Description

SUSTAINED RELEASE BETHANECHOL FORMULATION AND METHOD FOR PREPARING THE SAME

The present invention relates to a sustained release formulation of bethanechol and a process for preparing the same. More specifically, the present invention relates to a sustained release formulation of bethanechol for once-a-day oral administration comprising (i) a matrix preparation formed from granules comprising bethanechol or a pharmaceutically acceptable salt thereof as an active ingredient, and a mixture of a swellable polymer and a water-insoluble polymer; and (ii) a coating layer comprising a mixture of an insoluble polymer and a hydrophilic polymer, coating the matrix preparation; and a process for preparing said formulation.

Bethanechol is a cholinergic drug that selectively acts on the muscarinic receptors at the postganglionic neuron of the parasympathetic nervous system. It enhances bladder detrusor tension in the bladder smooth muscle and helps urination. The contraction of the bladder muscle occurs when the acetylcholine secreted from the nerve endings acts on muscarinic receptors present in the bladder muscle, and the acetylcholine is the most important neurotransmitter of bladder contraction in all vertebrates (see Overactive Bladder Guidelines). Since bethanechol is not degraded by cholinesterase, it has longer duration of action than acetylcholine, and its muscarinic effect is excellent while having little nicotinic effect.

Bethanechol also acts on the smooth muscle of the gastrointestinal tract, enhancing gastrointestinal motility, increasing gastric tension and restoring the rhythm of damaged peristalsis, and thus is used for the treatment of dysphagia and paralytic ileus.

Bethanechol does not stimulate ganglion and voluntary muscles at doses that exert acceleration effect for urination, excretion or 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, its typical dosage is up to 100 mg per day, and it is directed that 25 mg tablets be administered three to four times daily. The time to reach the maximum blood concentration by oral administration is within 2 hours, indicating a fast expression of drug efficacy, and shows 6 hours of the duration of drug efficacy.

Designing a once-a-day dosage regimen through a sustained release formulation that slowly releases the drug can increase the patient's compliance with the medication by reducing the number of doses. For this purpose, it is necessary to maintain the drug concentration in blood continuously, thereby maintaining the drug efficacy for 24 hours.

The conventional sustained release formulations for a once-a-day dosage regimen achieved a controlled release, but problems have been found in that the amount of sustained release carriers used is too large or is difficult to apply to the actual production in the commercial aspect.

As a representative example, International Patent Publication No. WO 99/47125, which is directed to a sustained release formulation technology for metformin, discloses a sustained release technique of the osmotic principle using a semipermeable membrane, but it is difficult to produce a uniform semipermeable membrane, and the drug release can be affected by the changes in the gastric environment. International Patent Publication No. WO 1999/47128 discloses a biphasic sustained release formulation technique that uses an ionic polymer and a nonionic polymer to extend the retention time in the stomach, but a large amount of the sustained release agents is applied, which leads to an increase in the size of the formulation, making the convenience of taking inferior. International Patent Publication No. WO 2002/36100 discloses a sustained release formulation technique in which a sustained release film-coated formulation is perforated by a laser to control the drug release, but the value of industrial use is low because it requires expensive equipment. International Patent Publication No. WO 2003/28704 discloses a sustained release formulation technique of adjusting the water content by supplying a certain amount of water to the formulation, but it is difficult to establish a process condition for supplying the constant water content.

Drugs with high solubility, such as bethanechol, should be given a prolonged retention time in the stomach by swelling of the system, and controlled release formulations suitable for commercial scale production are preferred.

The gastric retention drug delivery system is a technique for retaining the formulation in the gastrointestinal tract, thereby maintaining the drug release continuously. It can be divided into various techniques depending on the mechanism of the gastric retention system. Representatively, it can be divided into Floating system which utilizes floating of the formulation; Mucoadhesive system which attaches the formulation to the mucosa of the stomach or small intestine; High density formulation system which causes sedimentation of the formulation; Swelling system which swells the formulation beyond the size of the pyloric canal of the stomach; and Magnetic system.

Various pharmaceutical formulations using the gastric retention drug delivery system are known. For example, US Patent No. 6,340,475 and Korean Patent No. 0545480 disclose gastric retentive formulation patents for highly soluble drugs. However, since the gastric retentive formulations are designed using only hydrophilic polymers such as polyethyleneoxide or hydroxypropyl methylcellulose (HPMC), there is a problem that the possibility of disintegration of the formulation due to dissolution of the drug is high and there is a lack of floating power, which leads to the difficulty in achieving stomach retention, and thus it is very difficult to control the release of the drug in vivo.

In Korean Patent Nos. 0791844, 0858848 and 1043816, a swellable base and a water-insoluble base were used together to effectively control drug release in a small amount. However, when the two bases were used together, the release rate of the drug can be controlled, but the hydrogel forming rate of the swellable base is lowered due to the hydrophobic water-insoluble base, and thus the initial swelling rate might be lowered, which is a drawback.

Korean Patent Laid-Open Publication No. 10-2009-0088997 discloses a technique for producing sustained release tablets using wax. Recently, various wax-type pharmaceutical excipients have been developed, and thus techniques for producing sustained release formulations using wax have also been diversified. A common feature of these techniques is the utilization of the point that the wax can be easily melted. Various techniques are known including a melt extrusion method; a melt granulation method; a method of melting the wax or dissolving the wax in a suitable solvent to coat the surface of the particles; and a method of dispersing a drug in the molten wax and molding it into tablets. There is also a method wherein the wax is not melted but is used in wet granulation or direct tableting like conventional excipients to produce tablets.

However, when a composition such as granules containing wax is compression-molded into tablets, if the content of the wax is high, the disadvantages of physical properties of the wax appear such as insufficient compressibility and surface adhesion. The fluidity of the particles in the hopper is lowered at the time of tabletting, and there is a severe adherence to punches, which is a serious problem in actual production. Such adhesion can be mitigated to some extent by the addition of a lubricant, but the amount of the lubricant used is generally up to 5% by weight of the granule. Excessive use of a lubricant causes capping and laminating during tablet production. In fact, when a wax-type excipient is used in wet granulation or direct tableting, the amount of wax in the composition is generally less than 30% due to such problems. In actual production, it is difficult to fundamentally solve the adhesion problem of the composition such as granules containing wax only by adding the lubricant, and a method of improving the physical properties of the granules is needed.

In the case of bethanechol which is a highly soluble drug, a matrix itself can be easily disintegrated after administration into the body, and thus a controlled release effect cannot be exerted, which may lead to side effects such as drug burst effect (dose dumping). There is still a need to develop a sustained release formulation of bethanechol using the gastric retention drug delivery system to overcome the aforementioned disadvantages, wherein said sustained release formulation is suitable for production on a commercial scale.

The present invention is intended to provide a sustained release formulation for once daily oral administration of bethanechol, which is a highly soluble drug. The present invention is intended to provide a sustained release formulation of bethanechol for once-a-day oral administration that can continuously release bethanechol in a controlled manner for 24 hours while using a minimum amount of polymer and has a suitable size for taking, which can improve the convenience of administration; and a process for preparing the formulation.

In order to solve the above problems, the present inventors discovered that when bethanechol is mixed with a swellable polymer and a water-insoluble polymer to form granules, the granules are tableted to obtain a matrix preparation, and then the matrix preparation is coated with a coating layer that comprises an insoluble polymer and a hydrophilic polymer, the thus-obtained formulation can continuously release bethanechol in a controlled manner for 24 hours and has a suitable size for taking. They thereby completed the present invention.

The present invention is characterized by co-using a swellable polymer and a water-insoluble polymer when forming a matrix preparation, which leads to the use of a minimum amount of polymer.

In addition, the present invention is characterized by coating the matrix preparation with a coating solution that comprises an insoluble polymer and a hydrophilic polymer, which leads to the formation of hydrogel, thereby controlling the rate of gelation.

The sustained release formulation for once-a-day oral administration according to the present invention can form a hydrogel while using a minimum amount of polymer, is thereby capable of continuously releasing bethanechol in a controlled manner for 24 hours, and has a suitable size for taking, which can improve the convenience of administration.

Specifically, the sustained release formulation according to the present invention is characterized in that a matrix preparation comprising a swellable polymer and a water-insoluble polymer is coated by an insoluble polymer and a hydrophilic polymer, which leads to the effective controlled release of the drug while using a minimum amount of polymer.

In addition, the sustained release formulation according to the present invention is characterized in that the insoluble polymer and the hydrophilic polymer is mixed in a specific ratio to form a coating layer, thereby adjusting the time of hydration of the polymer to compensate for the occurrence of drug burst effect (dose dumping).

Therefore, the sustained release formulation according to the present invention can reduce the amount of the sustained release agents necessary for controlled release of bethanechol while decreasing the number of times of administration compared with the conventional formulations, thereby having a suitable size for taking, which can improve the convenience of administration. The formulation is very useful because it can ultimately improve the patient's compliance with the medication.

Figure 1 shows the dissolution rates in the pH 6.8 dissolution medium of the formulations prepared in Comparative Examples 1 to 6.

Figure 2 shows the dissolution rates in the pH 6.8 dissolution medium of the formulations prepared in Comparative Examples 7 to 9 and Examples 1 to 4.

Figure 3 shows the dissolution rates in the pH 6.8 dissolution medium of the formulations prepared in Examples 5 to 11 and Comparative Example 10.

Figure 4 shows the dissolution rates in the pH 6.8 dissolution medium of the formulations prepared in Example 5 and the formulations prepared in Comparative Examples 12 to 15.

Figure 5 shows the dissolution rates in the pH 6.8 dissolution medium of the formulations prepared in Examples 16 to 18 and the formulation prepared in Comparative Example 11.

Figure 6 shows the dissolution rates in the pH 1.2 dissolution medium, pH 4.0 dissolution medium, pH 6.8 dissolution medium and water of the formulation prepared in Example 16.

Figure 7 shows the results of a pre-clinical test conducted on the formulation prepared in Example 16.

The present invention provides a sustained release formulation of bethanechol for once-a-day oral administration, comprising: (i) a matrix preparation formed from granules comprising bethanechol or a pharmaceutically acceptable salt thereof as an active ingredient, and a mixture of a swellable polymer and a water-insoluble polymer; and (ii) a coating layer comprising a mixture of an insoluble polymer and a hydrophilic polymer, coating the matrix preparation.

In addition, the present invention provides a process for preparing the aforementioned sustained release formulation of bethanechol for once-a-day oral administration, comprising: (a) mixing bethanechol or a pharmaceutically acceptable salt thereof as an active ingredient with a swellable polymer and a water-insoluble polymer to form granules; (b) tableting the granules to obtain a matrix preparation; and (c) coating the matrix preparation with a coating solution that comprises an insoluble polymer and a hydrophilic polymer to form a coating layer

Bethanechol is a compound of the following Formula 1, and its chemical name is 2-[(aminocarbonyl)oxy]-N,N,N-trimethyl-1-propanaminium cabamyl-β-methylcholine:

[Formula 1]

Bethanechol is a cholinergic drug that selectively acts on the muscarinic receptors at the nerve endings of the parasympathetic nervous system. It enhances bladder detrusor tension in the bladder smooth muscle and helps urination. Since bethanechol is not degraded by cholinesterase, it has longer duration of action than acetylcholine, and its muscarinic effect is excellent while having little nicotinic effect. Bethanechol also acts on the smooth muscle of the gastrointestinal tract, enhancing gastrointestinal motility, increasing gastric tension and restoring the rhythm of damaged peristalsis, and thus is used for the treatment of dysphagia and paralytic ileus. Bethanechol does not stimulate ganglion and voluntary muscles at doses that exert acceleration effect for urination, excretion or peristalsis, and has little effect on heart rate, blood pressure and peripheral circulation at therapeutic doses.

In one embodiment of the present invention, the content of bethanechol is in the range of 10 to 50% by weight based on the total weight of the sustained release formulation.

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

The inorganic acid salts include, but are not limited to, hydrochloride, phosphate, sulfate or disulfate. The organic acid salts include, but are not limited to, aliphatic organic acid salts including acetate, dichloroacetete, adipate, alginate, ascorbate, camphorate, caprate, caproate, caprylate, cyclamate, galactarate, gluceptate, glucuronate, glutamate, oxoglutarate, lactobionate, thiocyanate, malonate, ursonate, propionate, decanoate, acrylate, fomate, isobutyrate, heptanoate, propiolate, succinate, suberate, sebacate, maleate, orotate, myristate, butyne-1,4-dioate, hexyne-1,6-dioate, citrate, lactate, betahydroxybutyrate, glycorate, malate and tartrate; aliphatic sulfonic organic acid salts including methane sulfonate, propane sulfonate, camphosulfonate, camsylate, edisylate, esylate and isethionate; aromatic organic acid salts including benzoate, chloro benzoate, dinitro benzoate, hydroxy benzoate, methoxy benzoate, phthalate, terephthalate, phenyl acetate, phenyl propionate, phenyl butyrate, mandalate, salicylate, para-amino salicylate, tannate and cinnamate; and aromatic sulfonic organic acid salts including benzene sulfonate, toluene sulfonate, xylene sulfonate, naphthalene-1-sulfonate and naphthalene-2-sulfonate. In one specific embodiment, bethanechol chloride can be preferably used for the present invention.

As used herein, the term "swellable polymer" refers to a pharmaceutically acceptable polymer that swells on an aqueous solution to control the release of the drug.

The swellable polymers that can be used for the present invention are cellulose derivatives, wherein said cellulose derivatives are one or more selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose sodium, cellulose acetate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate and hydroxyethyl methyl cellulose. In one specific embodiment, hydroxypropyl methylcellulose can be preferably used for the present invention. However, any pharmaceutically acceptable swellable polymers can be used for the present invention as long as they are capable of controlling the release according to the purpose of the present invention. Preferably, the swellable polymer has a viscosity of 15000 to 100000 cps.

In one embodiment of the present invention, the swellable polymer can be contained in the sustained release formulation in the range of 8 to 60% by weight based on the total weight of the sustained release formulation. When the content of the swellable polymer is less than 8% by weight, it is difficult to effectively control the release of the drug, and when the content of the swellable polymer is more than 60% by weight, the effect of controlling the release of the drug is insignificant and the size of the formulation becomes too large that is not suitable for administration.

As used herein, the term "water-insoluble polymer" refers to a pharmaceutically acceptable polymer that controls release of a drug and is not dissolved or hardly soluble in water. In addition to the purpose of inhibiting the release of bethanechol, the water-insoluble polymer in the present invention has another purpose of preventing the decrease of the viscosity of the swellable polymer having a large molecular weight from being degraded by decomposition.

The water-insoluble polymers that can be used for the present invention are polyvinyl derivatives, wherein said polyvinyl derivatives are one or more selected from the group consisting of polyvinyl acetate polyvinyl pyrrolidone polymer (e.g., trade name: Kollidon^® SR), polyvinyl alcohol and polyvinyl acetal diethylaminoacetate. In one specific embodiment, polyvinyl acetate polyvinyl pyrrolidone polymer (e.g., trade name: Kollidon^® SR) can be preferably used for the present invention. However, any pharmaceutically acceptable water-insoluble polymers can be used for the present invention as long as they are capable of controlling the release according to the purpose of the present invention.

In one embodiment of the present invention, the water-insoluble polymer can be contained in the sustained release formulation in the range of 20 to 60% by weight based on the total weight of the sustained release formulation. According to the following working examples of the present invention, the sustained release formulation which contains 30% by weight of the water-insoluble polymer (Example 5) exhibited a low dissolution rate compared with the sustained release formulation which contains 22% by weight of the water-insoluble polymer (Example 13) or the sustained release formulation which contains 14% by weight of the water-insoluble polymer (Example 15), which can effectively control the release of the drug (see Table 8). This is because in Examples 13 and 15, the penetration of water into the tablets rapidly occurs, and thus the effect of the water-insoluble polymer is reduced.

In one embodiment of the present invention, the sustained release formulation of the present invention may further comprise a filler, a lubricant, a glidant, a sweetener and the like.

In one embodiment of the present invention, suitable fillers include, but are not limited to, microcrystalline cellulose, mannitol, lactose, starch, ruddy presses, calcium dihydrogen phosphate, sugar, sorbitol or combinations thereof. In one specific embodiment, microcrystalline cellulose can be preferably used for the present invention.

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

In one embodiment of the present invention, suitable glidants include, but are not limited to, silica, colloidal silicon dioxide, talc, magnesium stearate and the like.

The sustained release formulation of the present invention comprises a coating layer that coats the aforementioned matrix preparation formed from granules comprising bethanechol or a pharmaceutically acceptable salt thereof as an active ingredient, and a mixture of a swellable polymer and a water-insoluble polymer. The coating layer comprises a mixture of an insoluble polymer and a hydrophilic polymer.

In one embodiment of the present invention, the content of the coating layer is in the range of 3 to 10% by weight based on the total weight of the sustained release formulation.

In one embodiment of the present invention, the insoluble polymer can be Opadry ethylcellulose (Opadry EC).

In one embodiment of the present invention, the hydrophilic polymer can be low-viscosity hydroxypropyl methylcellulose.

In one embodiment of the present invention, the insoluble polymer and the hydrophilic polymer in the coating layer can be contained in the weight ratio of 10:1 to 5:1. In one specific embodiment, the weight ratio of the insoluble polymer (Opadry EC) : the hydrophilic polymer (low-viscosity hydroxypropyl methylcellulose) can be 10 to 5 : 1, preferably 9 : 1.

In the following working examples, the sustained release preparation (Example 16) which was obtained by coating the tablet prepared in Example 5 with a mixture of Opadry EC (trade name of Colorcon) and low-viscosity hydroxypropyl methylcellulose (HPMC 2910) at a weight ratio of 9:1 was compared with the other sustained release preparations (Examples 17 and 18) which were obtained by coating the same tablet with a different weight ratio of Opadry EC (trade name of Colorcon) and low-viscosity hydroxypropylmethyl cellulose (HPMC 2910). The formulations of Examples 17 and 18 exhibited a faster dissolution rate than the formulation of Example 16 during the initial dissolution at 30 minutes to 4 hours. On the other hand, in the case of the sustained release formulation (Comparative Example 11) which was obtained by coating the tablet prepared in Example 5 only with the insoluble polymer (Opadry EC), the effect of the insoluble coating film increased and the penetration of water slowed, thereby delaying the release of the drug for 8 hours.

Thus, the sustained release formulation of the present invention can effectively control the release rate of the drug by controlling the rate of water penetration into the tablet by controlling the ratio of the insoluble polymer (Opadry EC) to the hydrophilic polymer (low-viscosity hydroxypropyl methylcellulose). Furthermore, it can compensate for the occurrence of drug burst effect (dose dumping) that may occur within 2 hours of dissolution.

In one embodiment of the present invention, the sustained release formulation according to the present invention may preferably have the following release characteristics: 15 to 35% of the active ingredient released after 1.5 hours and more than 80% of the active ingredient released after 8 hours. In another embodiment, the sustained release formulation of the present invention may have the following release characteristics: 20 to 40% of the active ingredient released after 2 hours and more than 80% of the active ingredient released after 8 hours.

In one embodiment of the present invention, the sustained release formulation according to the present invention is preferably in the form of a tablet.

In one embodiment of the present invention, the sustained release formulation according to the present invention may be preferably used for the known medicinal uses for bethanechol. Therefore, the sustained release formulation of the present invention can be used for treatment of functional urinary retention after surgery or postpartum; simulation of urination; stimulation of excretion, stimulation of peristalsis; treatment of dysphagia; treatment of paralytic ileus; or treatment of neuromuscular relaxation in the bladder, but is not limited thereto.

The dosage of the sustained release formulation of bethanechol for once-a-day oral administration according to the present invention will vary depending on the severity of the disease, and the weight and metabolic status of the subject being treated. A "therapeutically effective amount" for an individual patient refers to an amount sufficient to achieve the desired therapeutic effect. Specifically, the therapeutically effective amount of bethanechol is up to 100 mg per day when administered to a human, and typically 25 mg tablets may be administered three to four times a day. The sustained release formulation of bethanechol for once-a-day oral administration according to the present invention can be administered once a day, and the dose and the interval may be adjusted in some cases.

In order to predict the in vivo pharmacological activity of the sustained release formulation according to the present invention by comparing the dissolution profile and the pharmacokinetics (PK) of said formulation, the formulations of the working examples were administered to beagle dogs and pharmacokinetics (PK) were analyzed. As a result, it could be confirmed that the pharmacokinetics of bethanechol were changed according to the in vitro dissolution profile, and the sustained release formulation of the present invention which exhibited a proper dissolution profile of bethanechol in vitro, showed a preferable pharmacological activity in vivo, too.

Hereinafter, the present invention will be explained in more detail based on the following working examples. However, these working examples are provided only to specifically illustrate the present invention, and the scope of the present invention is not intended to be limited to these working examples in any way.

(1) Comparative Examples 1 to 6: Confirmation of drug release delaying effect by the use of wax-type excipients and water-insoluble polymers, and by a direct compression method

According to the contents of ingredients as shown in Table 1 below, bethanechol chloride sieved through a No. 30 mesh sieve, Kollidon^® SR (trade name of BASF), high-viscosity hydroxypropyl methylcellulose (HPMC 2208), a wax-type excipient kolliwax S-fine (trade name of BASF) and povidone K-90 were mixed for 10 minutes, and then Aerosil 200 sieved through a No. 35 mesh sieve was mixed thereto for 10 minutes. Finally, magnesium stearate was sieved through a No. 35 mesh sieve, mixed to the above mixture for 5 minutes, and then compressed by a conventional direct compression method to prepare bethanechol chloride tablets of Comparative Examples 1 to 6.

[Table 1]

Measurement of dissolution rate of formulations

In vitro dissolution tests were carried out on the formulations prepared in Comparative Examples 1 to 6 using 900mL of phosphate buffer (pH 6.8) as an dissolution medium at the paddle speed of 50 rpm at 37°C according to dissolution method of Korean pharmacopeia. The eluate was taken at each time point, and the dissolution rate was analyzed by HPLC. The HPLC analysis conditions used are as follows.

- Column: Waters IC-Pak C M/D (150 Х 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 add water to be 1000 mL.

The dissolution results of the formulations of Comparative Examples 1 to 6 are shown in Table 2 and depicted in Figure 1.

[Table 2]

As shown in Table 2 above, in comparing the dissolution rates of Comparative Example 1 which contained only the water-insoluble polymer, Kollidon^® SR, and Comparative Example 2 which contained a reduced amount of Kollidon^® SR, it could be confirmed that Comparative Example 2 exhibited 20% faster release of the drug than Comparative Example 1. From this, it was understood that the water-insoluble polymer, Kollidon^® SR, is effective in delaying the release of the drug.

From the dissolution result of Comparative Example 6 which contained a wax-type excipient Compritol 888 which is glyceryl behenate, it could be confirmed that the initial release was already 52.7%, which indicates no sustained release effect.

In addition, in comparing the dissolution rates of Comparative Example 1 and Comparative Example 3 which further contained a wax-type excipient, Kolliwax S-fine, it could be confirmed that Comparative Example 3 shows a more delayed release of the drug than Comparative Example 1. It is determined that the addition of the wax type excipient resulted in the formation of an oil film in the mixture and affected the dissolution profile of the tablet.

In comparing the dissolution rates of Comparative Example 3 which contained Kollidon^® SR, Comparative Example 5 which contained high-viscosity hydroxypropyl methylcellulose (HPMC 2208), and Comparative Example 4 which did not contain the above substances but contained povidone K-90, it could be confirmed that Comparative Example 3 and Comparative Example 5 showed a greater sustained release effect than Comparative Example 4.

However, all of the formulations of Comparative Examples 1 to 6 released about 40% or more of the drug after 30 minutes from the initiation of the dissolution, which may result in occurrence of side effects due to drug burst effect (dose dumping) upon administration by a patient. Therefore, it can be understood that production of the sustained release tablets by the compositions of these comparative examples and by a direct compression method was not an effective production method.

The dissolution results of Table 2 above are depicted in Figure 1.

(2) Comparative Examples 7 to 9, and Examples 1 to 4: Confirmation of drug release delaying effect by the use of wax-type excipients and water-insoluble polymers and by a wet granulation method

According to the contents of ingredients as shown in Table 3 below, bethanechol chloride sieved through a No. 30 mesh sieve, Kollidon^® SR, high-viscosity hydroxypropyl methylcellulose (HPMC 2208), microcrystalline cellulose 101, povidone K-90, a wax-type excipient Compritol 888 (trade name of Gattefosse) and ethylcellulose were mixed with an appropriate amount of distilled water as a binding solution at 100 to 3000 rpm for 5 minutes to produce granules. The resulting granules were sieved through a No. 16 mesh sieve and dried in a cabinet dryer at 60 to 65°C (LOD was 2.5% or less). After the granules were passed through to mesh, Aerosil 200, wax-type excipient Kolliwax S-fine and low-viscosity hydroxypropyl methylcellulose (HPMC 2208) were sieved through a No. 35 mesh sieve and mixed for 10 minutes. Finally, magnesium stearate was sieved through a No. 35 mesh sieve, mixed to the above mixture for 5 minutes, and then compressed by a conventional method to prepare bethanechol chloride tablets.

[Table 3]

The formulations prepared in Comparative Examples 7 to 9 and Examples 1 to 4 were tested and analyzed in the same manner as in the dissolution test conducted in the above Comparative Examples 1 to 6, and the dissolution results are shown in Table 4 and depicted in Figure 2.

[Table 4]

As shown in Table 4 above, it could be confirmed that when the tablets were prepared from the pre-formed granules, the sustained release was more effective than the dissolution results of Comparative Examples 1 to 6.

As a result of comparing the dissolution rates of Examples 1 to 4 and Comparative Examples 7 and 8, it could be confirmed that Examples 1 to 4 exhibited lower dissolution rates than Comparative Examples 7 and 8, but the sustained release effect was not significant compared to the increase of the amount of the sustained release agents (e.g., Example 1). For the purpose of the sustained release of the water-soluble drug bethanechol chloride, sustained release agents were used. However, even though the amount of the sustained release agents is increased over a certain level, there was no significant difference in the sustained release effect compared to the increased amount, which indicates that the above is not an effective strategy. In addition, the increase in the amount of the sustained release agents results in an increase in the weight and size of the tablets, which rather may cause a problem that the convenience of administration to a patient is decreased.

In comparing Example 2 and Example 4, it was confirmed that the wax-type excipient Kolliwax S-fine, which was effective in the direct compression method, had no significant effect in the granulation method. It was determined that this was because the wax-type excipient Kolliwax S-fine did not sufficiently cover the granules with the oil film, resulting in no effect.

Furthermore, the addition of ethylcellulose (Example 4), povidone K-90 (Example 2) which is widely used as a binding agent, or a wax-type excipient Compritol 888 (trade name of Gattefosse), which is glyceryl behenate (Example 3), to the granules did not result in a significant effect.

The dissolution results of Comparative Example 9 which did not contain the water-insoluble polymer and the swellable polymer but contained only a wax-type excipient Compritol 888 (trade name of Gattefosse), which is glyceryl behenate, showed no sustained release effect, and no final dissolution rate was determined.

The dissolution results shown in Table 4 above are depicted in Figure 2.

(3) Examples 5 to 11 and Comparative Example 10: Confirmation of drug release delaying effect depending on the types of swellable polymers

According to the contents of ingredients as shown in Table 5 below, bethanechol chloride sieved through a No. 30 mesh sieve, high-viscosity hydroxypropyl methylcellulose (HPMC 2208), microcrystalline cellulose 101 and Kollidon^® SR were mixed with an appropriate amount of distilled water as a binding solution at 100 to 3000 rpm for 5 minutes to produce granules. The resulting granules were sieved through a No. 16 mesh sieve and dried in a cabinet dryer at 60 to 65°C (LOD was 2.5% or less). After the granules were passed through to mesh, Aerosil 200 was sieved through a No. 35 mesh sieve and mixed for 10 minutes. Finally, magnesium stearate was sieved through a No. 35 mesh sieve, mixed to the above mixture for 5 minutes, and then compressed by a conventional method to prepare bethanechol chloride sustained release tablets.

[Table 5]

The formulations prepared in Examples 5 to 11 and Comparative Example 10 were tested and analyzed in the same manner as in the dissolution test conducted in the above Comparative Examples 1 to 6, and the dissolution results are shown in Table 6 and depicted in Figure 3.

[Table 6]

As shown in Table 6 above, even when a high-viscosity hydroxypropyl methylcellulose (HPMC 2208) was added to the granulation layer or the mixing portion by an increased amount (see Examples 7 to 9), no difference in dissolution rate was observed.

The formulation of Example 10 was prepared by adding to the mixing layer a low-viscosity hydroxypropyl methylcellulose (HPMC 2208), which is a swellable low molecular weight compound. However, the drug release of Example 10 was the same as that shown by Example 5, and thus the drug release delaying effect was not observed by the low-viscosity hydroxypropyl methylcellulose (HPMC 2208).

In addition, the dissolution results of Example 11 which was prepared by adding carboxymethylcellulose sodium did not show a significant drug release delaying effect.

Comparative Example 10 was prepared by adding an increased amount of the high-viscosity hydroxypropyl methylcellulose (HPMC 2208) and the low-viscosity hydroxypropyl methylcellulose (HPMC 2208) without adding a water-insoluble polymer (e.g., Kollidon^® SR). The dissolution results did not show a significant drug release delaying effect. From this, it could be determined that even when the high-viscosity hydroxypropyl methylcellulose (HPMC 2208) and the low-viscosity hydroxypropyl methylcellulose (HPMC 2208) are further added, it is still difficult to control the release profile of the water-soluble drug bethanechol chloride to a degree that 20 to 40% of the drug is released in 2 hours.

The dissolution results of Table 6 above are depicted in Figure 3.

(4) Examples 12 to 15: Confirmation of drug release delaying effect depending on the content of swellable polymers and water-insoluble polymers

The granules were prepared according to the contents of ingredients shown in Table 7 below and tableted to obtain tablets.

Specifically, Example 12 was prepared in the same manner as Example 5, except that lactose hydrate was used instead of microcrystalline cellulose 101 when forming the granules.

Example 13 was prepared in the same manner as Example 5, except that the content of Kollidon^® SR was reduced when forming the granules.

Example 14 was prepared in the same manner as Example 5, except that the content of high-viscosity hydroxypropyl methylcellulose (HPMC 2208) was reduced when forming the granules.

Example 15 was prepared in the same manner as Example 5, except that the content of high-viscosity hydroxypropyl methylcellulose (HPMC 2208) which is the swellable polymer was reduced to 5.5% or less, and the content of Kollidon^® SR which is the water-insoluble polymer was reduced to 20% or less, when forming the granules.

[Table 7]

The formulations prepared in Examples 12 to 15 were tested and analyzed in the same manner as in the dissolution test conducted in the above Comparative Examples 1 to 6, and the dissolution results are shown in Table 8 and depicted in Figure 4.

[Table 8]

As shown in Table 8 above, in order to compare microcrystalline cellulose 101 and lactose hydrate, which are the fillers of the tablets' weight, the microcrystalline cellulose 101 used in the granule-forming portion in Example 5 was changed to lactose hydrate in Example 12, and dissolution tests were conducted. As a result, it could be confirmed that the dissolution proceeds faster in Example 12. It was understood from this example that microcrystalline cellulose 101 shows a better tendency as a filler because it controls the drug release better than lactose hydrate when forming the granules.

Example 13 which contained a reduced amount of the water-insoluble polymer Kollidon^® SR showed a faster drug release than Example 5.

Example 14 which contained a reduced amount of the swellable polymer high-viscosity hydroxypropyl methylcellulose (HPMC 2208) also showed a faster drug release than Example 5.

Example 15 which was prepared by reducing the content of the swellable polymer high-viscosity hydroxypropyl methylcellulose (HPMC 2208) to 5.5% or less and reducing the content of the water-insoluble polymer Kollidon^® SR to 20% or less when forming the granules, also showed a faster drug release than Example 5.

From the above results, it was concluded that the sustained release rate could be controlled depending on the amount of the swellable polymer and the amount of the water-insoluble polymer. Based on the above results, the composition of Example 5 was judged to be a prescription with the size, weight and dissolution rate of the most optimized formulation for effective control of drug release.

The dissolution results of Table 8 above are depicted in Figure 4.

(5) Examples 16 to 18 and Comparative Example 11: Confirmation of drug release delaying effect depending on the insoluble coating

The tablets prepared in Example 5 were respectively coated with the insoluble polymer Opadry EC (trade name of Colorcon) and the hydrophilic polymer low-viscosity hydroxypropyl methylcellulose (HPMC 2910) in the varying ratios as shown in Table 9 below. The mixture solution was made into an 8% mixed solution using 90% ethanol and stirred for 3 hours. After confirming the dissolution state of the coating solution, the coating solution was finally passed through a No. 100 mesh sieve to prepare a coating solution, and the coating solution was coated on the tablets to be 5% based on the weight of the naked tablets of Example 5.

[Table 9]

The formulations prepared in Examples 16 to 18 and Comparative Example 11 were tested and analyzed in the same manner as in the dissolution test conducted in the above Comparative Examples 1 to 6, and the dissolution results are shown in Table 10 and depicted in Figure 5.

[Table 10]

As shown in Table 10 above, Comparative Example 11 showed a dissolution rate of 6% over 4 hours of dissolution, which indicates that the insoluble coatings controlled the release of the drug. On the other hand, when the insoluble polymer and the hydrophilic polymer are mixed to form a film according to Examples 16 to 18, the penetration of water into the tablet can be controlled, so that Examples 16 to 18 showed a tendency to prevent the drug burst effect (dose dumping) that can occur within 2 hours of dissolution because the effect of the insoluble coating film is usually reduced, thereby controlling the drug release.

From the above results, it was determined that Example 16 is a suitable sustained release formulation that exhibited a desirable drug release profile such that 20 to 40% of the drug released after 2 hours, and 80% or more of the drug released after 8 hours from the start of the dissolution test.

The dissolution results of Table 10 above are depicted in Figure 5.

(6) Analysis of dissolution of Example 16 at various pH conditions

For the formulation of Example 16 which exhibited a preferable drug release profile, the dissolution tests were carried out in the same manner as in the dissolution test methods conducted in the above Comparative Examples 1 to 6 in the pH 1.2 dissolution medium, the pH 4.0 dissolution medium, the pH 6.8 dissolution medium and water.

The results are shown in Table 11 and depicted in Figure 6.

[Table 11]

As shown in Table 11 above, Example 16 showed a preferable drug release control pattern such that the drug release rate was 20 to 40% after 2 hours and 80% or more after 8 hours from the start of the dissolution test, and 100% of the drug was released at about 18 to 24 hours.

(7) Pre-clinical test for Example 16

The dissolution profiles at various pH conditions in vitro were confirmed for the sustained release formulation of bethanechol chloride of Example 16. Here, pharmacokinetics (PK) for the formulation was confirmed by pre-clinical testing as follows.

The test method was as follows. To Beagle dogs (n=4), 75 mg of the sustained release formulation of bethanechol chloride of Example 16 was administered orally as a single tablet once a day, and 25 mg of the commercially available Mytonin tablet was administered orally three times a day, a total of 3 tablets. After the administration, a blood sample was obtained at a predetermined time, blood plasma was separated therefrom and the concentration of bethanechcol chloride in the blood plasma was measured. As the pharmacokinetic parameters, the area under the plasma concentration-time curve (AUC) from the administration time to the final blood concentration determination time t, the peak blood concentration (C_max), the peak blood concentration reaching time (T_max) and the half-life in blood (T_1/2) were calculated. The results are shown in Figure 7 and the following Table 12.

[Table 12]

As shown in Table 12 above, the AUC of the Mytonin tablet which was administered in 25 mg three times a day was 2548.28 ng/mL, and the AUC of the formulation of Example 16 which was administered in 75 mg once a day was 2365.09 ng/mL, which are similar levels. C_max was 260.64 ng/ml and 272.99 ng/ml, respectively, which are also similar results. The bethanechol chloride sustained release tablet of the working example showed an equivalent level of AUC of 0.93 and C_max of 1.05 relative to the control drug Mytonin tablet.

Therefore, it was confirmed that the sustained release tablet containing 75 mg of bethanechol chloride was effective as a once-daily preparation.

Claims

A sustained release formulation of bethanechol for once-a-day oral administration, comprising:

(i) a matrix preparation formed from granules comprising bethanechol or a pharmaceutically acceptable salt thereof as an active ingredient, and a mixture of a swellable polymer and a water-insoluble polymer; and

(ii) a coating layer comprising a mixture of an insoluble polymer and a hydrophilic polymer, coating the matrix preparation.
The sustained release formulation according to Claim 1, wherein the content of bethanechol is in the range of 10 to 50% by weight based on the total weight of the sustained release formulation.
The sustained release formulation according to Claim 1, wherein the pharmaceutically acceptable salt of bethanechol is bethanechol chloride.
The sustained release formulation according to Claim 1, wherein the swellable polymer in the matrix preparation is one or more cellulose derivatives selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose sodium, cellulose acetate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate and hydroxyethyl methyl cellulose.
The sustained release formulation according to Claim 4, wherein the swellable polymer is hydroxypropyl methylcellulose.
The sustained release formulation according to Claim 4, wherein the swellable polymer has a viscosity of 15000 to 100000 cps.
The sustained release formulation according to Claim 1, wherein the content of the swellable polymer in the matrix formulation is 8 to 60% by weight based on the total weight of the sustained release formulation.
The sustained release formulation according to Claim 1, wherein the water-insoluble polymer in the matrix preparation is one or more polyvinyl derivatives selected from the group consisting of polyvinyl acetate polyvinyl pyrrolidone polymer, polyvinyl alcohol and polyvinyl acetal diethylaminoacetate.
The sustained release formulation according to Claim 8, wherein the water-insoluble polymer is polyvinyl acetate polyvinyl pyrrolidone polymer (trade name: Kollidon^® SR)
The sustained release formulation according to Claim 1, wherein the content of the water-insoluble polymer in the matrix preparation is in the range of 20 to 60% by weight based on the total weight of the sustained release formulation.
The sustained release formulation according to Claim 1, wherein the matrix preparation further comprises a filler.
The sustained release formulation according to Claim 11, wherein the filler is microcrystalline cellulose.
The sustained release formulation according to Claim 1, wherein the insoluble polymer in the coating layer is Opadry ethylcellulose.
The sustained release formulation according to Claim 1, wherein the hydrophilic polymer in the coating layer is low-viscosity hydroxypropyl methylcellulose.
The sustained release formulation according to Claim 1, wherein the insoluble polymer and the hydrophilic polymer in the coating layer are contained in the weight ratio of 10:1 to 5:1.
The sustained release formulation according to Claim 1, wherein the content of the coating layer is in the range of 3 to 10% by weight based on the total weight of the sustained release formulation.
The sustained release formulation according to any one of Claims 1 to 16, which has the following release characteristics: 15 to 35% of the active ingredient released after 1.5 hours and more than 80% of the active ingredient released after 8 hours.
The sustained release formulation according to any one of Claims 1 to 16, which is in the form of a tablet.
The sustained release formulation according to any one of Claims 1 to 16, which is for use in treatment of functional urinary retention after surgery or postpartum; simulation of urination; stimulation of excretion, stimulation of peristalsis; treatment of dysphagia; treatment of paralytic ileus; or treatment of neuromuscular relaxation in the bladder.
A process for preparing a sustained release formulation of bethanechol for once-a-day oral administration as claimed in any one of Claims 1 to 16, comprising:

(a) mixing bethanechol or a pharmaceutically acceptable salt thereof as an active ingredient with a swellable polymer and a water-insoluble polymer to form granules;

(b) tableting the granules to obtain a matrix preparation; and

(c) coating the matrix preparation with a coating solution that comprises an insoluble polymer and a hydrophilic polymer to form a coating layer.