HK1138517B - Revaprazan-containing solid dispersion and process for the preparation thereof - Google Patents
Revaprazan-containing solid dispersion and process for the preparation thereof Download PDFInfo
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- HK1138517B HK1138517B HK10105215.6A HK10105215A HK1138517B HK 1138517 B HK1138517 B HK 1138517B HK 10105215 A HK10105215 A HK 10105215A HK 1138517 B HK1138517 B HK 1138517B
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Description
Technical Field
The present invention relates to a solid dispersion in which revaprazan (revaprazan) particles are surface-modified with a water-soluble polymer, a water-soluble saccharide, a surfactant, or a mixture thereof, and a method for preparing the same. The invention also relates to a pharmaceutical composition containing the solid dispersion and a method for preparing the pharmaceutical composition.
Background
The chemical name of revaprazan is 5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) pyrimidine, which is shown as the following formula 1. Revaprazan may be used in the form of acid addition salts, including, for example, the HCl salt (see international application publication No. WO 1996/05177).
Formula 1
Revaprazan or its salt reversibly binds to H of proton pump present in parietal cell+/K+Exchange site (H)+/K+Atpase) to competitively inhibit H+Secreted into the gastric lumen. Revaprazan or its salt with H+/K+Specific site binding of ATPase to inhibit H+And suppresses acid secretion into the stomach lumen, resulting in an increase in the pH in the stomach. Unlike irreversible proton pump inhibitors such as omeprazole, revaprazan or its salt is not dependent on acid activation of the drug in the stomach or the secretory state of the proton pump. Therefore, revaprazan or its salt is classified as an Acid Pump Antagonist (APA) based on a mechanism different from that of an irreversible proton pump inhibitor such as omeprazole.
Meanwhile, revaprazan has a very low aqueous solubility, i.e., less than 0.2mg/mL, and its dissolution in the gastrointestinal tract is very low due to the low solubility. Therefore, when revaprazan is orally administered, its absorption rate is relatively low. Revaprazan also has strong adhesion and agglomeration properties, and thus when revaprazan is formulated into a capsule or tablet, it may stick to a punch or die, thereby exhibiting low formulation moldability.
Disclosure of Invention
Technical problem
The present inventors have conducted studies to improve physicochemical properties of revaprazan, i.e., a low dissolution rate and low formulation moldability. As a result, it was found that when revaprazan particles are surface-modified with a water-soluble polymer, a water-soluble saccharide, and/or a surfactant to be prepared in the form of a solid dispersion, solubility and dissolution of revaprazan are significantly improved, thereby exhibiting significantly improved bioavailability. In addition, it was found that the adhesion and coalescence of revaprazan can be improved to increase its formulation moldability.
Therefore, it is an object of the present invention to provide solid dispersions containing revaprazan.
Another object of the present invention is to provide a pharmaceutical composition comprising the revaprazan-containing solid dispersion and a pharmaceutically acceptable carrier.
Another object of the present invention is to provide a method for preparing the revaprazan-containing solid dispersion.
It is another object of the present invention to provide a process for preparing said pharmaceutical composition.
Technical scheme
According to an aspect of the present invention, there is provided a solid dispersion in which revaprazan particles are surface-modified with a water-soluble polymer, a water-soluble saccharide, a surfactant, or a mixture thereof.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the solid dispersion and a pharmaceutically acceptable carrier.
According to another aspect of the present invention, there is provided a method for preparing the solid dispersion, the method comprising suspending revaprazan and one of a water-soluble polymer, a water-soluble saccharide, a surfactant, and a mixture thereof in water to obtain a suspension; and drying the suspension.
According to another aspect of the present invention, there is provided a method for preparing particles, the method comprising suspending revaprazan and one of a water-soluble polymer, a water-soluble saccharide, a surfactant, and a mixture thereof in water to obtain a suspension; and spray drying the suspension on a pharmaceutically acceptable carrier.
According to another aspect of the present invention, there is provided a method for preparing granules, the method comprising granulating by adding a binder solution to a mixture of the solid dispersion and a pharmaceutically acceptable carrier.
According to another aspect of the present invention, there is provided a process for preparing a tablet, the process comprising compressing a mixture of the solid dispersion and a pharmaceutically acceptable carrier, or compressing a mixture of particles obtained from the solid dispersion and a pharmaceutically acceptable carrier.
According to another aspect of the present invention, there is provided a method for preparing a capsule, the method comprising filling a mixture of the solid dispersion and a pharmaceutically acceptable carrier into a capsule, or filling a mixture of particles obtained from the solid dispersion and a pharmaceutically acceptable carrier into a capsule.
Advantageous effects
According to the present invention, revaprazan particles are surface-modified with a water-soluble polymer, a water-soluble saccharide, and/or a surfactant to be prepared in the form of a solid dispersion, thereby increasing permeation and dissolution properties of a drug (i.e., revaprazan), resulting in a significant increase in solubility and/or dissolution rate of revaprazan, thereby improving bioavailability thereof. And also reduces adhesion and coalescence and thus improves formulation formability. In addition, the solid dispersion can be prepared using water as a medium, and thus potential problems caused by the use of organic solvents, such as safety problems caused by residual solvents, can be avoided.
Drawings
Fig. 1 shows the results of comparative dissolution tests of the formulation prepared according to the invention and the conventional formulation [ capsules containing the solid dispersion prepared according to example 3 (. DELTA.), tablets prepared according to example 3 (oral), and capsules containing revaprazan powder (. largecircle) ].
Fig. 2 shows the results of pharmacokinetic studies with beagle dogs on formulations prepared according to the present invention and a conventional formulation [ tablet (●) prepared according to example 36 and capsule a with revaprazan powder (solidup) ].
Fig. 3 is a scanning electron microscope micrograph of a solid dispersion (example 6) prepared according to the present invention.
FIG. 4 is a scanning electron microscope micrograph of a solid dispersion (example 11) prepared according to the present invention.
Fig. 5 is a polarization microscope image of revaprazan particles.
Detailed Description
The term "surface-modified" throughout the present specification means that a water-soluble polymer, a water-soluble saccharide, a surfactant, etc. are coated or attached on revaprazan particles.
The term "revaprazan" refers to 5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) pyrimidine, including pharmaceutically acceptable salts thereof such as revaprazan hydrochloride, revaprazan sulfate, revaprazan nitrate, revaprazan camphorsulfonate (i.e., revaprazan dexecamsylate), revaprazan thiocyanate, revaprazan phosphate, revaprazan carbonate, and the like. Preferably, the term "revaprazan" includes revaprazan hydrochloride.
According to the present invention, revaprazan particles are surface-modified with a water-soluble polymer, a water-soluble saccharide, and/or a surfactant to be prepared in the form of a solid dispersion, thereby increasing permeation and dissolution properties of a drug (i.e., revaprazan), resulting in a significant increase in solubility and/or dissolution rate of revaprazan, thereby improving bioavailability thereof. And also reduces adhesion and coalescence and thus improves formulation formability. In addition, the solid dispersion can be prepared using water as a medium, and thus potential problems caused by the use of organic solvents, such as safety problems caused by residual solvents, can be avoided.
The present invention provides a solid dispersion in which revaprazan particles are surface-modified with a water-soluble polymer, a water-soluble saccharide, a surfactant, or a mixture thereof.
The water-soluble polymer may be selected from polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol, water-soluble polyacrylic acid copolymer (e.g., Eudragit E or carbomer), polyvinyl alcohol, and mixtures thereof, and is preferably selected from polyvinylpyrrolidone, hydroxypropylmethylcellulose, polyethylene glycol, and mixtures thereof. More preferably, the water-soluble polymer may be polyvinylpyrrolidone.
The water-soluble saccharide may be selected from lactose, white sugar, sucrose, mannitol, sorbitol, xylitol, trehalose, maltitol, dulcitol, inositol, dextrin, cyclodextrin (e.g. alpha-, beta-, gamma-or hydroxypropyl-beta-cyclodextrin, and especially hydroxypropyl-beta-cyclodextrin), and mixtures thereof. Preferably, the water-soluble saccharide may be selected from lactose, mannitol, cyclodextrin and mixtures thereof.
The surfactant may be selected from sorbitan esters or polyoxyethylene sorbitan fatty acid esters (e.g. polysorbate 80)TM) Sucrose fatty acid ester (Ryoto ester L1695)TM) Polyethylene glycol-15-hydroxystearate (e.g. Solutol HS 15)TM) Polyoxyethylene glycolated natural or hydrogenated castor oils (e.g. Cremophor RH 40)TM、Cremophor RH 60TM) Polyoxyethylene-polyoxypropylene copolymer (e.g. poloxamer 407)TMPoloxamer 118TM) Synthetic vitamin E derivatives (e.g., vitamin E TPGS)TM) Polyoxyethylene alkyl esters (e.g. Brij 52)TM) Fatty acid polyglycolyglycerides (e.g. Gelucire 44/14)TM) Polyglycerin fatty acid esters (e.g., Pluroloeique)TM) Bile acids (e.g., taurocholic acid), sodium lauryl sulfate, lecithin, glycerol fatty acid esters (e.g., glycerol monostearate), polyoxyethylene stearate, and mixtures thereof. Preferably, the surfactant may be selected from sorbitan esters or polyoxyethylene sorbitan fatty acid esters, sucrose fatty acid esters, polyethylene glycol-15-hydroxystearate, polyoxyethylene glycolated natural or hydrogenatedHydrogenated castor oil, polyoxyethylene-polyoxypropylene copolymers, synthetic vitamin E derivatives, fatty acid polyglycolyglycerides, and mixtures thereof. More preferably, the surfactant may be sucrose fatty acid ester, polyoxyethylene glycolated natural or hydrogenated castor oil, polyethylene glycol-15-hydroxystearate, polyoxyethylene-polyoxypropylene copolymer, or a mixture thereof.
The solid dispersion according to the present invention may be prepared using one or a combination of a water-soluble polymer, a water-soluble saccharide, and a surfactant. For example, revaprazan particles may be surface modified by natural or hydrogenated castor oil that has been glycolated with polyvinylpyrrolidone, sucrose fatty acid esters, and polyoxyethylene.
The amount of revaprazan added to the solid dispersion as active ingredient according to the invention depends on the unit dosage form administered to achieve the therapeutic goal, e.g. to treat ulcers. For example, the unit dosage form may comprise revaprazan in the range of 10 to 600mg, in particular 50 to 400 mg. Although the average particle size of revaprazan is not limited, the average particle size thereof may be about 50 μm or less.
The amount of the water-soluble polymer, the water-soluble saccharide, or the surfactant contained in the solid dispersion according to the present invention may be adjusted in consideration of the properties of the solid dispersion to be prepared. Preferably, the revaprazan particles may be surface-modified with one of 5 to 900 parts by weight, preferably 20 to 200 parts by weight, of a water-soluble polymer, a water-soluble saccharide, a surfactant, and a mixture thereof, based on 100 parts by weight of revaprazan. More preferably, revaprazan particles may be surface-modified with 5 to 30 parts by weight of polyvinylpyrrolidone, 20 to 100 parts by weight of sucrose fatty acid ester, and 10 to 100 parts by weight of polyoxyethylene glycolated natural or hydrogenated castor oil, based on 100 parts by weight of revaprazan.
The scope of the present invention includes pharmaceutical compositions comprising the solid dispersion and a pharmaceutically acceptable carrier.
According to the inventionPharmaceutically acceptable carriers for the compositions include any conventional diluents, disintegrants, lubricants and the like. Examples of the diluent include lactose, xylitol, maltitol, cellulose, microcrystalline cellulose, white sugar, silicon dioxide, dextrin, dextrate, calcium dihydrogen phosphate (calcium dihydrogen phosphate), xanthan gum, polyvinylpyrrolidone, carboxymethyl cellulose, glucose, polydextrose (polydextrose), starch, pregelatinized starch, corn starch, ProsolvTM、MicroceLacTMHydroxypropyl cellulose, hydroxypropyl methyl cellulose, mixtures thereof and the like. Examples of the disintegrant include croscarmellose sodium, crospovidone, low-substituted hydroxypropylmethylcellulose, and the like. Examples of the lubricant include sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, magnesium trisilicate, talc, and the like. The composition according to the present invention further comprises additives such as sodium bicarbonate, sodium starch glycolate, sucrose fatty acid ester, and the like. The kind of the pharmaceutically acceptable carrier may be appropriately selected by those skilled in the art according to the preparation to be obtained.
The pharmaceutical composition may be formulated in various forms such as granules, tablets, capsules, dry syrup or powder, preferably granules, tablets or capsules. Those formulations can be prepared using conventional methods known in the art of pharmacy. For example, the pharmaceutical composition may be formulated into a tablet by mixing the surface-modified solid dispersion with a diluent, a disintegrant, a lubricant, or the like and compressing the mixture. Alternatively, the pharmaceutical composition may be formulated into a tablet by granulating the surface-modified solid dispersion with a diluent or the like, mixing the obtained granules with a diluent, a disintegrant, a lubricant or the like, and compressing the obtained mixture. The pharmaceutical composition may also be formulated into capsules by filling the mixture into capsules. And may be further film coated or enteric coated to improve stability, drug compliance, and appearance.
The scope of the invention includes methods for preparing the solid dispersions. The method comprises the following steps: suspending revaprazan and one of a water-soluble polymer, a water-soluble saccharide, a surfactant, and a mixture thereof in water to obtain a suspension; and drying the suspension.
As described above, using water as a medium makes it possible to avoid potential problems caused by the use of organic solvents, such as safety problems caused by residual solvents.
In the method for preparing the solid dispersion, the suspension may be obtained by adding revaprazan to an aqueous solution containing a water-soluble polymer, a water-soluble saccharide, a surfactant, or a mixture thereof while strongly stirring the aqueous solution. Alternatively, the suspension may also be obtained by adding revaprazan and one of a water-soluble polymer, a water-soluble saccharide, a surfactant, and a mixture thereof to water, and then vigorously stirring the resulting mixture. The stirring (i.e., dispersion) may be carried out using any conventional method known in the art of pharmacy. For example, the stirring may be performed using a stirrer equipped with a stirring blade, an ultrasonic oscillator, a microfluidizer (microfluidizer), a high-pressure homogenizer, a mixer containing a stirring blade, or a homogenizer. A stirrer equipped with stirring fins may be used to obtain a homogeneous suspension, and a homogenizer or microfluidizer may also be used to obtain a more homogeneous suspension.
In the method for preparing the solid dispersion, the drying may be performed using any conventional drying method known in the pharmaceutical art, such as spray drying, freeze drying, or vacuum drying. Preferably, the drying may be performed by spray drying. The spray drying may be carried out using any conventional method with a fluid bed granulator or spray dryer.
The scope of the invention includes methods for preparing pharmaceutical compositions comprising the solid dispersions.
For example, according to an embodiment of the present invention, the particles may be prepared by a method including suspending revaprazan and one of a water-soluble polymer, a water-soluble saccharide, a surfactant, and a mixture thereof in water to obtain a suspension; and spray drying the suspension on a pharmaceutically acceptable carrier. The suspension can be obtained in the same manner as in the method of preparing the solid dispersion.
The spray drying may be carried out according to any conventional method using a fluid bed granulator, a rotary granulator (cylinder granulator), a high speed granulator, or the like. Pharmaceutically acceptable carriers for the spray drying step may include diluents such as microcrystalline cellulose, lactose, corn starch, mannitol, potato starch, pregelatinized starch, cellulose, MicroceLacTM、ProsolvTMDextrate, dextrin, monocalcium phosphate, citric acid, succinic acid, and the like; disintegrating agents such as crospovidone, sodium starch glycolate, croscarmellose sodium, sodium bicarbonate or low-substituted hydroxypropylcellulose; lubricants such as magnesium stearate, silicon dioxide, and the like; and solid surfactants such as sucrose fatty acid esters (Ryoto Ester)TMMitsubishi Co.), sodium lauryl sulfate, and the like.
Furthermore, according to another embodiment of the present invention, granules may be prepared by a method comprising granulating by adding a binder solution to a mixture of the solid dispersion and a pharmaceutically acceptable carrier.
The binder solution may be water; c1-4Alcohols (e.g., ethanol); water and C1-4Mixtures of alcohols (e.g., ethanol solutions); or by adding water or C1-4Alcohol (e.g. ethanol), and water and C1-4One of the alcohol mixtures (e.g. ethanol solution) is added to a solution prepared with any conventional binder used in the pharmaceutical field. The binder comprises at least one selected from the group consisting of polyvinyl alcohol, xanthan gum, acacia, alginic acid or a salt thereof, polyvinylpyrrolidone, gelatin, hydroxypropylmethylcellulose, carbomer, hydroxypropylcellulose, ethylcellulose and mixtures thereof. The amount of the binder is not limited and may be about 10 weight% based on the total weight of the granulated pharmaceutical composition% of the total weight of the composition. When the amount of the binder exceeds 10% by weight of the total weight of the granulated pharmaceutical composition, the granule may be hardened and thus its disintegration may be prolonged. If desired, the binder solution may further comprise a polyoxyethylene glycolated natural or hydrogenated castor oil (e.g. Cremophor RH 40)TM)。
Furthermore, according to another embodiment of the present invention, a tablet may be prepared by a method comprising compressing a mixture of the solid dispersion and a pharmaceutically acceptable carrier, or compressing a mixture of granules obtained from the solid dispersion and a pharmaceutically acceptable carrier (e.g., a lubricant such as magnesium stearate).
Further, according to another embodiment of the present invention, the capsule may be prepared by a method including filling a mixture of the solid dispersion and a pharmaceutically acceptable carrier into the capsule or filling a mixture of particles obtained from the solid dispersion and a pharmaceutically acceptable carrier into the capsule.
The present invention will be further described in detail with reference to the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Examples
Example 1: preparation of solid dispersions
20g of polyvinylpyrrolidone and 80g of sucrose fatty acid Ester (Ryoto Ester L1695)TMMitsubishi co., japan) was dissolved in 2,000ml of purified water. To the resulting solution was added 100g of revaprazan while stirring it with a mechanical stirrer to obtain a suspension. The resulting suspension was spray-dried with a mini spray dryer (Buchi 190) at an inlet temperature of 120 to 130 ℃ and an outlet temperature of 80 to 90 ℃ to obtain a solid dispersion.
Examples 2 to 19: preparation of solid dispersions
Solid dispersions were prepared in the same manner as in example 1, based on the components and amounts shown in table 1. The amount of purified water used was 10ml/1g of the total amount of ingredients used.
TABLE 1
| Examples of the embodiments | Revaprazan | Polyvinyl pyrrolidone | Sucrose fatty acid ester | Gelucire 44/14TM | Solutol HS 15TM | Polysorbitol ester 80TM | Cremophor RH 40TM | Poloxamer 407TM |
| 2 | 100g | 150g | ||||||
| 3 | 100g | 100g | ||||||
| 4 | 100g | 50g | ||||||
| 5 | 100g | 5g | ||||||
| 6 | 100g | 100g | ||||||
| 7 | 100g | 50g | ||||||
| 8 | 10g | 50g | ||||||
| 9 | 100g | 10g | 30g | |||||
| 10 | 10g | 90g | ||||||
| 11 | 100g | 10g | 70g | 15g | ||||
| 12 | 100g | 20g | 60g | 20g | ||||
| 13 | 100g | 20g | 15g | 40g | ||||
| 14 | 100g | 15g | 120g | 20g | ||||
| 15 | 100g | 15g | 11.25g | 26.25g | ||||
| 16 | 100g | 20g | 10g | 10g | 50g | |||
| 17 | 100g | 20g | 15g | 60g | ||||
| 18 | 100g | 10g | 60g | 20g | 20g | |||
| 19 | 10g | 50g | 10g | 10g |
Example 20: preparation of solid dispersions
20g of beta-cyclodextrin and 80g of lactose were dissolved in 2,000ml of purified water. To the resulting solution was added 100g of revaprazan while stirring it with a mechanical stirrer to obtain a suspension. The resulting suspension was homogenized by passing through a microfluidizer three times at 10,000-15,000psi pressure. The resulting suspension was spray-dried with a mini spray dryer (Buchi 190) at an inlet temperature of 120 to 130 ℃ and an outlet temperature of 80 to 90 ℃ to obtain a solid dispersion.
Examples 21 to 32: preparation of solid dispersions
Solid dispersions were prepared in the same manner as in example 20, based on the ingredients and amounts shown in table 2. The amount of purified water used was 10ml/1g of the total amount of ingredients used.
TABLE 2
| Examples of the embodiments | Revaprazan | Hydroxypropyl beta-cyclodextrin | Lactose | Mannitol | Hydroxypropyl methyl cellulose | Vitamin E TPGSTM | Polyvinylpyrrolidone | Polyethylene glycol 6000 | Poloxamer 407TM |
| 21 | 100g | 100g | 20g | ||||||
| 22 | 100g | 60g | |||||||
| 23 | 100g | 100g | |||||||
| 24 | 10g | 60g | 20g | 20g | |||||
| 25 | 100g | 20g | 60g | ||||||
| 26 | 100g | 50g | |||||||
| 27 | 100g | 100g | |||||||
| 28 | 100g | 50g | 50g | ||||||
| 29 | 100g | 150g | 50g | ||||||
| 30 | 100g | 10g | 10g | ||||||
| 31 | 100g | 60g | 50g | ||||||
| 32 | 100g | 60g | 50g | 50g |
Example 33: preparation of solid dispersions
10g of polyvinylpyrrolidone and 15g of Cremophor RH 40 were mixedTM(manufactured by BASF Co., Ltd.), and 70g of sucrose fatty acid Ester (Ryoto Ester)TMMitsubishi Co.) was added to 110ml of purified water. While the resulting solution was stirred with a mechanical stirrer, 100g of revaprazan was slowly added thereto to obtain a suspension. The obtained suspension was homogenized in a homogenizer at a speed of rotation from 10,000 to 15,000rpm for ten minutes. The resulting suspension was spray-dried using a fluid bed granulator (manufactured by Glatt co.) at an inlet temperature of 110 to 130 ℃ and an injection pressure of 1.0 to 2.0bar to obtain a surface-modified solid dispersion.
Example 34: preparation of particles containing solid dispersions
10g of polyvinylpyrrolidone and 15g of Cremophor RH 40 were mixedTM(manufactured by BASF Co., Ltd.), and 50g of sucrose fatty acid Ester (Ryoto Ester)TMMitsubishi Co.) was added to 110ml of purified water. While the resulting solution was stirred with a mechanical stirrer, 100g of revaprazan was slowly added thereto to obtain a suspension. The resulting suspension was homogenized by stirring at 300rpm or more for 2 hours to obtain a homogenized suspension.
67.5g of microcrystalline cellulose, 20g of crospovidone, 10g of sodium bicarbonate, 10g of sodium starch glycolate, 20g of sucrose fatty acid ester (Ryoto ester)TMMitsubishi Co.) were sieved through a 20 mesh sieve and then mixed together to prepare the carrier for particle formation.
While fluidizing the carrier for forming the granules using a fluidized bed granulator (manufactured by Glatt co.), the above homogenized suspension was spray-dried under conditions of an inlet temperature of 50 to 60 ℃, an outlet temperature of 35 to 45 ℃ and an injection pressure of 1.5bar to obtain a solid dispersion in the form of granules.
Examples 35 to 40: preparation of particles containing solid dispersions
A solid dispersion in the form of particles was prepared in the same manner as in example 34, based on the ingredients and amounts shown in table 3. The amount of purified water used was 1.5ml/1g of the total amount of ingredients used.
TABLE 3
Example 41: preparation of particles containing solid dispersions
481.5g of microcrystalline cellulose and 360g of sucrose fatty acid ester (Ryoto ester)TMMitsubishi co.), 90g of crospovidone, and 90g of sodium bicarbonate were sieved through a 20-mesh sieve, and then 1,260g of the solid dispersion prepared according to example 9 was added thereto. The resulting mixture was mixed in a high speed granulator for 1 minute. By mixing 135g of Cremophor RH 40TMThe binder solution was prepared in 90ml of a 50% (v/v) ethanol solution. While the mixture was rotated at a speed of 300rpm in a high-speed granulator, the binder solution was added thereto to obtain granules containing a solid dispersion.
Examples 42 to 44: preparation of particles containing solid dispersions
Particles containing a solid dispersion were prepared in the same manner as in example 41, based on the components and amounts shown in table 4.
TABLE 4
| Example 42 | Example 43 | Example 44 | |
| Solid Dispersion of example 1 | 1,200g | ||
| Solid Dispersion of example 5 | 1,260g | ||
| Solid Dispersion of example 11 | 1,170g | ||
| Microcrystalline cellulose | 700g | 700g | |
| Lactose | 200g | ||
| Crospovidone | 100g | 100g | |
| Sodium bicarbonate | 100g | 100g | |
| Sucrose fatty acid ester | 300g | ||
| Cremophor RH 40TM | 300g | 300g | 100g |
Examples 45 to 48: preparation of granules containing surface-modified solid dispersions
According to the ingredients and amounts shown in Table 5, except that Cremophor RH 40 was not usedTMAnd particles containing a solid dispersion were prepared in the same manner as in example 41, except that 90ml of a 50% (v/v) ethanol solution was used as a binder solution.
TABLE 5
| Example 45 | Example 46 | Example 47 | Example 48 | |
| Solid Dispersion of example 3 | 1,200g | |||
| Solid Dispersion of example 6 | 1,200g | |||
| Solid Dispersion of example 14 | 1,530g | |||
| Example 17 solid Dispersion | 1,170g | |||
| Microcrystalline cellulose | 500g | 500g | 700g | 700g |
| Lactose | 300g | |||
| Corn starch | 300g | 200g | ||
| Crospovidone | 90g | 100g | 100g | 100g |
| Sodium bicarbonate | 90g | 100g | ||
| Corn ethanol sodium salt | 100g | 100g | ||
| Sucrose fatty acid ester | 200g |
[0086] Example 49: preparation of particles containing solid dispersions
500g of microcrystalline cellulose, 360g of sucrose fatty acid ester (Ryoto ester)TMMitsubishi co.), 90g of crospovidone, and 90g of sodium bicarbonate were sieved through a 20-mesh sieve, and then 1,300g of the solid dispersion prepared according to example 9 was added thereto. The resulting mixture was mixed in a high speed granulator for 1 minute. A binder solution was prepared by dissolving 20g of hydroxypropylmethylcellulose in 100ml of 80% (v/v) ethanol solution. While the mixture was rotated at a speed of 300rpm in a high-speed granulator, the binder solution was added thereto to obtain granules containing a solid dispersion.
Example 50: preparation of tablets
200g of the solid dispersion prepared according to example 1, 150g of microcrystalline cellulose, 20g of sodium starch glycolate, 20g of crospovidone, and 10g of magnesium stearate were mixed and then compressed using a single tablet press to obtain tablets (weight per tablet: 800mg and amount of revaprazan per tablet: 200 mg).
Test example 1: dissolution test
The solubility of solid dispersions containing revaprazan was measured in purified water. The solid dispersion containing 1g of revaprazan was added to a beaker containing 50ml of purified water, followed by vigorous stirring for 6 hours in a water bath at 25 ℃ using a magnetic stirrer. 1. After 2 and 6 hours, each sample was collected and filtered using a 0.45 μm filter. The filtrate was diluted with methanol in an amount such that the absorbance of the filtrate was in the range of 0.2 to 1.0. The absorbance of the diluted filtrate was then measured at 270nm using a UV spectrophotometer (Agilent 8453, Agilent technologies, USA). The concentration of revaprazan was obtained from the absorbance values obtained using a standard curve.
About 20mg of revaprazan standard was dissolved in methanol until the total volume of the solution reached 10 ml. 1ml of the resulting solution was added to a 100ml flask and then purified water was added thereto to obtain a standard stock solution. The standard stock solution was diluted with purified water to obtain standard solutions of 2. mu.g/ml, 5. mu.g/ml, 8. mu.g/ml, and 10. mu.g/ml. The absorbance of each of the standard solutions was measured at a maximum absorption wavelength of 270nm to obtain a standard curve. The standard curve has moderate linearity and almost passes through (0.0) (correlation coefficient r)2> 0.98). The results are shown in Table 6.
TABLE 6
| Solubility (ug/ml) | |
| Revaprazan powder | 173 |
| Example 2 | 905 |
| Example 3 | 505 |
| Example 4 | 237 |
| Example 6 | 303 |
| Example 7 | 240 |
| Example 18 | 803 |
It can be seen from table 6 that the solubility of the surface-modified solid dispersions of the invention is significantly improved.
Test example 2: adhesion and coalescence tests
Bulk and tamped densities of revaprazan powder and the surface modified solid dispersions prepared according to examples 3 and 6 were measured and their karl indices were obtained to measure their flowability. About 3g of the solid dispersion was carefully added to a plastic measuring cylinder and its volume was measured to obtain the bulk density. Then, it was tapped 3,000 times using a tamp density tester to measure the volume to obtain a tamped density. From the obtained bulk density and tamped density, a karl index was calculated to evaluate fluidity. The results are shown in Table 7.
TABLE 7
| Karl index | |
| Revaprazan powder | 41.2 |
| Example 3 | 21.9 |
| Example 6 | 17.6 |
ρ o: bulk density
ρ t: tamped density
Carr index (ρ o- ρ t)/ρ t 100
Referring to table 7, revaprazan powder having high adhesion and agglomeration showed a carr index of 40% or more and its flowability was very low. On the other hand, the surface-modified solid dispersion has high fluidity and improved compression properties.
Test example 3: observation of particle surfaces using scanning electron microscopy
The surface of the particles containing the solid dispersion of revaprazan was measured using a Scanning Electron Microscope (SEM). The samples prepared according to examples 6 and 11 were fixed on a metal base (stub) to which a double-sided tape had been attached, and then platinum was coated under an argon atmosphere using an ion sputtering apparatus (JFC-1100E, Jeol co. Each coated sample was loaded into an SEM (JSM 5410 LV, JEOL co., Japan). The magnification was adjusted at a voltage of 15kV to observe the surface of the particles. For reference, the shape of revaprazan particles was also observed using a polarization microscope to compare with the surface-modified solid dispersion as described above. Revaprazan was placed on the slide, and a few drops of mineral oil were dropped therein for dispersion. The sample was covered with a cover glass, and then loaded on a movable plate (mobile plate) of a polarization microscope (Nikon eklipse E600 POL, nikonco., Japan) to observe the shape of the crystal while adjusting the polarization angle.
Referring to fig. 3 and 4, revaprazan does not show any crystalline image. However, the solid dispersion containing revaprazan shows a crystalline morphology covered by the surface-modifying material.
Test example 4: comparative dissolution test
Comparative dissolution tests were conducted to evaluate the dissolution characteristics of the surface-modified solid dispersions according to the invention. Capsules containing revaprazan were prepared as comparative samples. Specifically, 50mg of revaprazan powder was mixed with 10% (w/w) sodium starch glycolate as a disintegrant. The mixture was filled into hard gelatin capsules. The solid dispersion prepared according to example 3 was mixed with 10% (w/w) sodium starch glycolate and then the resulting mixture was filled into hard gelatin capsules. Dissolution tests were carried out with tablets prepared according to example 36 and the above samples in 900ml of 0.1N HCl solution at a temperature of 37. + -. 0.5 ℃ and a stirring speed of 50 rpm. Samples of 3ml were collected every 15 min, 30 min, 45 min, 60 min and 90 min and immediately supplemented with the same amount of medium. The dissolution rate was measured by measuring the concentration of revaprazan at 270nm from the collected dissolution sample using a UV spectrophotometer. The results are shown in FIG. 1.
Referring to fig. 1, the revaprazan powder formulation has a dissolution rate of 30% or less within 30 minutes, but the dissolution rate of the formulation according to the present invention is as high as 95% or more.
Test example 5: pharmacokinetic Studies
Male beagle dogs of about 10 kg were selected, their weights were measured, and it was confirmed visually whether they had any wounds. No food other than water was provided to the beagle dogs for 15 hours prior to administration of the test substance. Then, revaprazan tablets (comparative formulation) prepared from a mixture of revaprazan, lactose, sodium starch glycolate and magnesium stearate and tablets prepared according to example 36 were administered orally with 20 to 40ml of water. The dose administered was 200mg revaprazan per subject. Approximately 1.0ml of blood was collected using heparin-treated syringes before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hours after administration. The collected blood was centrifuged at 3,000rpm for 5 minutes, and the separated serum was carried to an effendorf tube and allowed to stand at-20 ℃. Then, the frozen collected blood was thawed, and then the amount of revaprazan in the serum was measured using HPLC.
Maximum amount of measured serum concentration (C) obtained from serum concentration-time curve was usedmax) And the time (T) required to reach maximum serum concentrationmax) And the area under the time curve of serum concentration from 0 hour to 8 hours (AUC) was measured using the trapezoidal rule0-8hr). Area AUC under the serum concentration-time curve from 0 hr to ∞ was measured using a trapezoidal rule extrapolation0-∞. The area under the serum concentration-time curve from the final data to ∞ was obtained by dividing the final serum concentration by the elimination constant. The blood concentration of the drug as well as the pharmacokinetic parameters are represented by mean ± s.e.m. values and the statistical significance of the in vivo experimental results is calibrated according to analysis of variance using the duncru multipass test method.
AUC of tablets prepared according to example 360-8hr(ng.hr/Ml) is 1401. + -. 332, AUC over conventional revaprazan tablet0-8hr(ng.hr/Ml)261 + -52 is five times higher (p < 0.05). C of the formulation of example 36 obtained from the blood concentration time Curvemax652ng/Ml, whereas that of conventional revaprazan tablets is 165 ng/Ml.
Claims (13)
1. A revaprazan solid dispersion, wherein revaprazan particles are surface-modified with one of 5 to 900 parts by weight of a water-soluble polymer, a water-soluble saccharide, a surfactant, and a mixture thereof, based on 100 parts by weight of revaprazan, wherein
The water-soluble polymer is selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, water-soluble polyacrylic acid copolymer, polyvinyl alcohol and mixture thereof;
the water soluble saccharide is selected from lactose, sucrose, mannitol, sorbitol, xylitol, trehalose, maltitol, dulcitol, inositol, dextrin, cyclodextrin and mixture thereof; and
the surfactant is selected from sorbitan ester or polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester, polyethylene glycol-15-hydroxystearate, polyoxyethylene glycolated natural or hydrogenated castor oil, polyoxyethylene-polyoxypropylene copolymer, D-alpha-tocopheryl polyethylene glycol 1000 succinate, polyoxyethylene 2-hexadecyl ether, fatty acid polyglycolester, polyglyceryl fatty acid ester, bile acid, sodium lauryl sulfate, lecithin, glycerin fatty acid ester, polyoxyethylene stearate and mixture thereof.
2. The revaprazan solid dispersion of claim 1, wherein revaprazan particles are surface modified with polyvinylpyrrolidone, sucrose fatty acid ester, and polyoxyethylene glycolated natural or hydrogenated castor oil.
3. The revaprazan solid dispersion of claim 1, wherein the revaprazan particles are surface-modified with one of 20 to 200 parts by weight of a water-soluble polymer, a water-soluble saccharide, a surfactant, and a mixture thereof, based on 100 parts by weight of revaprazan.
4. The revaprazan solid dispersion of claim 1, wherein revaprazan particles are surface-modified with 5 to 30 parts by weight of polyvinylpyrrolidone, 20 to 100 parts by weight of sucrose fatty acid ester, and 10 to 100 parts by weight of polyoxyethylene glycolated natural or hydrogenated castor oil, based on 100 parts by weight of revaprazan.
5. Pharmaceutical composition comprising a solid dispersion of revaprazan according to one of claims 1 to 4 and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is in the form of granules, tablets, or capsules.
6. A process for preparing a revaprazan solid dispersion according to one of claims 1-4, comprising suspending revaprazan and one of a water-soluble polymer, a water-soluble saccharide, a surfactant, and a mixture thereof in water to obtain a suspension; and drying the suspension.
7. The method of claim 6, wherein said drying is by spray drying.
8. A process for preparing granules containing revaprazan solid dispersion according to one of claims 1-4, comprising suspending revaprazan and one of a water-soluble polymer, a water-soluble saccharide, a surfactant, and a mixture thereof in water to obtain a suspension; and spray drying the suspension on a pharmaceutically acceptable carrier.
9. A process for preparing granules, which comprises granulating by adding a binder solution to a mixture of the revaprazan solid dispersion according to one of claims 1 to 4 and a pharmaceutically acceptable carrier.
10. The method of claim 9, wherein the binder solution is water; c1-4An alcohol; water and C1-4A mixture of alcohols; or by adding at least one binder selected from polyvinyl alcohol, xanthan gum, acacia, alginic acid or its salt, polyvinylpyrrolidone, gelatin, hydroxypropylmethylcellulose, carbomer, hydroxypropylcellulose, ethylcellulose and mixtures thereof to water, C1-4Alcohol, or water with C1-4Alcohol mixtures.
11. The method of claim 10, wherein the binder solution further comprises a polyoxyethylene glycolated natural or hydrogenated castor oil.
12. Process for the preparation of tablets, comprising compressing a mixture of a solid dispersion of revaprazan according to one of claims 1 to 4 and a pharmaceutically acceptable carrier, or compressing a mixture of granules obtained from a process according to one of claims 8 to 11 and a pharmaceutically acceptable carrier.
13. A process for preparing a capsule, the process comprising filling a mixture of the revaprazan solid dispersion according to one of claims 1 to 4 and a pharmaceutically acceptable carrier into the capsule, or filling a mixture of the granules obtained from the process according to one of claims 8 to 11 and a pharmaceutically acceptable carrier into the capsule.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2006-0132722 | 2006-12-22 | ||
| KR20060132722 | 2006-12-22 | ||
| PCT/KR2007/006738 WO2008078922A1 (en) | 2006-12-22 | 2007-12-21 | Revaprazan-containing solid dispersion and process for the preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1138517A1 HK1138517A1 (en) | 2010-08-27 |
| HK1138517B true HK1138517B (en) | 2013-01-25 |
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