KR20170070635A - Composite capsule formulation comprising dabigatran etexilate - Google Patents
Composite capsule formulation comprising dabigatran etexilate Download PDFInfo
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- KR20170070635A KR20170070635A KR1020150178411A KR20150178411A KR20170070635A KR 20170070635 A KR20170070635 A KR 20170070635A KR 1020150178411 A KR1020150178411 A KR 1020150178411A KR 20150178411 A KR20150178411 A KR 20150178411A KR 20170070635 A KR20170070635 A KR 20170070635A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4833—Encapsulating processes; Filling of capsules
Abstract
The present invention relates to a complex capsule preparation containing DABICARTIETEC SILATE. Since the complex capsule preparation according to the present invention efficiently packs a pharmacologically active ingredient into a limited space inside a capsule, It is possible to fill the capsules, which is advantageous in that productivity is improved and convenience for patients is improved. Furthermore, since the pharmacologically active ingredient is separately contained in the capsule and is charged separately from the organic acid, the pharmacologically active ingredient can be prevented from being contacted with the organic acid to be denatured, so that the product stability is excellent and the pharmacological activity can be maintained for a long period of time. In addition, the composite capsule can be manufactured by a simple process and can be applied to mass production.
Description
The present invention relates to a composite capsule comprising Darvagantietecyl silicate.
Dabigatran is an oral direct thrombin inhibitor approved by the US Food and Drug Administration and an oral direct thrombin inhibitor that is advantageous over warfarin and other vitamin K antagonists.
Dabigatran etexilate is a double prodrug of Darbigatran and is converted into a substantially effective compound in the body, namely Darbigatran. Dabigatranatech silicate was firstly disclosed in International Publication No. WO 98/37075, wherein 1-methyl-2- [N- [4- (N < RTI ID = 0.0 > Aminomethyl] benzimidazol-5-ylcarboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide is described.
Dabigatran etexilate is useful for the prevention of thromboembolism in patients who have experienced knee or hip arthroplasty and is also suitable for preventing stroke in patients with atrial fibrillation. The Darvitransitecylate is rapidly converted to Darvitran, a potent direct competing inhibitor of thrombin by the serum estetase, with a serum half-life of 12-17 hours, which does not require periodic monitoring.
As described above, darbagantransecticylate or a pharmaceutically acceptable salt thereof, which is useful as a thrombin inhibitor, is generally poorly absorbed in vivo and is usually formulated together with an organic acid. Organic acid is an acidic environment in vivo to help elute and absorb the dabigatranitechsilate.
However, there are the following difficulties in the development of a combination preparation of two or more active ingredients. First, the combination of different active ingredients to be used in the combination preparation should be easy and free, and unexpected difficulties may arise due to various problems arising from the pharmacokinetic and pharmacological properties of the drugs. Second, the size of the preparation containing the active ingredient and the pharmaceutically acceptable excipient should be a proper size without difficulty in administration, and if the drug content to be compounded is too much or too small, adjustment of the size to a suitable composition may be difficult. Third, the dissolution rate and stability of the drug may be lowered due to mutual reaction between different active ingredients in the preparation of the combined preparation. It is possible to prepare the composite preparation in the form of a two-layer tablet or a three-layer tablet, and separate separation of the drug into each layer can be attempted. However, in this case, special production facilities such as a two-layer tabletting machine or a three-layer tableting machine are required, A reaction may occur between the components in the reactor.
For example, Korean Patent Registration No. 10-1005716 discloses the use of ethyl 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] Benzimidazole-5-carbonyl) -pyridin-2-yl-amino] -propionic acid ethyl ester and a pharmaceutically acceptable salt thereof as active ingredients. Wherein the pellet-shaped tablet comprises an organic acid core forming step of extruding / sphering on a pelleting plate; Forming an isolation layer surrounding the core; And an active ingredient layer-forming step comprising the active ingredient. However, although the pellet-shaped tablets separate the organic acid and the active ingredient from each other by the quenching layer, since the respective layers are in close contact with each other, the interaction between the organic acid layer, the quencher and the active ingredient layer is likely to occur, . Further, since the organic acid layer is formed in the core portion, the organic acid can be eluted only after the active ingredient layer and the quencher have eluted in the in vivo elution, so that the active ingredient is not efficiently absorbed.
Accordingly, there is a need to develop a new combination preparation having improved stability of the active ingredient and convenience of medication by reducing the fluctuation of bioavailability by improving defective absorption of Darvitransitecylate or its pharmaceutically acceptable salt.
Accordingly, it is an object of the present invention to provide a combination preparation which improves the absorption failure of darbagantransecticylate or an acceptable salt thereof, thereby decreasing the fluctuation range of bioavailability, and the stability of the active ingredient and convenience of medication.
In order to accomplish the above object, the present invention provides a pharmaceutical composition comprising: i) a darbagtransectosylate independent portion comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof; And ii) an organic acid-independent portion comprising an organic acid or a pharmaceutically acceptable salt thereof, as separated components.
In order to accomplish this another object, the present invention provides a pharmaceutical composition comprising a) mixing darbitaltransecylate or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable additive in powder form, or tableting the mixed powder step; b) mixing the organic acid, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable additive in powder form, or tableting the mixed powder; And c) filling the hard capsule with the darbagtranatechylate powder or tablet prepared in step a) and the organic acid powder or tablet prepared in step b) in a separated state into the hard capsule. And a manufacturing method thereof.
The composite capsule containing Darvaglantietecylate of the present invention efficiently charges the pharmacologically active ingredient into the limited space inside the capsule, so that a high-dose pharmacologically active ingredient can be packed into a capsule of small size, And the convenience of the patient's medication is improved. Furthermore, since the pharmacologically active ingredient is separately contained in the capsule and is charged separately from the organic acid, the pharmacologically active ingredient can be prevented from being contacted with the organic acid to be denatured, so that the product stability is excellent and the pharmacological activity can be maintained for a long period of time. In addition, the composite capsule can be manufactured by a simple process and can be applied to mass production.
1 is a schematic diagram of a composite capsule according to an embodiment of the present invention.
Hereinafter, the present invention will be described in more detail.
As used herein, the term " combination preparation "refers to a preparation containing two or more drugs or a combination of active ingredients in a single administration unit such as a tablet or capsule.
The composite capsules of the present invention comprise i) a dabigatran etexrate independent portion comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof; And ii) an organic acid-containing portion containing an organic acid in a separated state.
The composite capsule of the present invention inhibits the clotting of blood, thereby preventing thrombogenesis and treating thrombotic diseases.
Specifically, the composite capsule is a dabigatranatech silicate independent part containing darbaganthenate silylate, which is effective for prevention of blood clotting and thrombolysis; And an organic acid-independent unit for reducing the bioavailability fluctuation by preventing the absorption failure of the Darvitransitecylate.
FIG. 1 is a schematic view of a composite capsule according to one embodiment of the present invention, wherein the composite capsule can be filled with a separate layer in the hard capsule, the Darbagantrasypsate independent part and the organic acid-independent part. Specifically, according to one example of the composite capsule, i) a dabigatranatech silicate independent layer comprising dabigatranatechsilate or a pharmacologically acceptable salt thereof; And ii) an organic acid-free layer comprising an organic acid or a pharmaceutically acceptable salt thereof.
In the composite capsule of the present invention, the Darvitransitic silicate-independent part and the organic acid-independent part may each independently be in the form of a powder (powder), a granule, a tablet, a pellet, a capsule or a combination thereof.
Specifically, the composite capsules of the present invention comprise i) dabigatranatechsilate powder or tablet comprising dabigatranatechsilate or a pharmaceutically acceptable salt thereof; And ii) an organic acid powder or a tablet containing an organic acid or a pharmaceutically acceptable salt thereof in a separated state.
More specifically, at least one of the Darvigantietecylate independent and organic acid independent moieties may be in the form of a tablet. For example, the composite capsule may be prepared by mixing a) a darbagtransethexylate tablet and an organic acid powder, b) a darbagtransethecylate powder and an organic acid tablet, or c) a darbigantrantecylate tablet and an organic acid tablet, It may be packed in a capsule. A schematic diagram of a light composite capsule comprising a darbagantrhetic shirrate tablet and an organic acid powder, which is an embodiment of the present invention, is shown in FIG.
The above-mentioned darbagantransectilate or a pharmaceutically acceptable salt thereof may be contained in an amount of 75 mg to 150 mg as darbagantransectosilate per capsule of the composite capsule, specifically, 75 mg as Darbagantethecylate, 0.0 > mg, < / RTI > or 150 mg. The daily dose of the Darvigantethec silicate or a pharmaceutically acceptable salt thereof may be about 150 mg to 300 mg on an adult basis.
In addition, the organic acid or a pharmaceutically acceptable salt thereof may be contained in an amount of 20 to 200 parts by weight per 100 parts by weight of dabigatranatechsilate or a pharmaceutically acceptable salt thereof.
Wherein said organic acid or pharmaceutically acceptable salt thereof is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid and mixtures thereof; Its hydrate; Or an acid salt thereof.
In the composite capsules of the present invention, each of the Darvitransuites silicate-independent and the organic acid-independent moieties may each independently include pharmaceutically acceptable additives such as a diluent, a disintegrant, a binder, a stabilizer, a lubricant , Coloring agents, and mixtures thereof.
Specific examples of the diluent include microcrystalline cellulose, lactose, ruddy press, mannitol, calcium dihydrogen phosphate, starch, hydroxypropylcellulose, and mixtures thereof. The diluent may be used in an amount ranging from about 1 to 95% by weight, specifically from about 5 to 95% by weight, based on the total weight of each independent portion.
Further, specific examples of the disintegrant include crospovidone, sodium starch glycolate, croscarmellose sodium, hydroxypropylcellulose, starch, alginic acid or its sodium salt, and mixtures thereof. The disintegrant can be used in an amount ranging from 0.1 to 30% by weight, specifically from 2 to 15% by weight, based on the total weight of each independent part.
Specific examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), polyvinylacetic acid, polyvinylpyrrolidone, copovidone, macrogol, sodium lauryl sulfate, light silicic anhydride, Silicate derivatives such as synthetic aluminum silicate, calcium silicate or magnesium metasilicate aluminate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, galactose such as pregelatinized starch and acacia gum, cellulose derivatives such as gelatin and ethyl cellulose, And the like. The binder may be used in an amount ranging from 0.1 to 30% by weight, specifically from 2 to 20% by weight, based on the total weight of each independent part.
Further, specific examples of the stabilizing agent include ascorbic acid, sodium nitrite, sodium sulfite, sodium hydrogen sulfite, sodium edetate, erythorbic acid, tocopheryl acetate, tocopherol, butylhydroxyanisole, dibutylhydroxytoluene, Ethylenediamine tetraacetic acid, and the like. The stabilizer may be used in an amount of from 0.1% to 15% by weight based on the total weight of each independent portion.
Specific examples of the lubricant include stearic acid such as stearic acid, calcium stearate or magnesium stearate, polyethylene glycols, metal salts, talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, Wax, glyceryl fatty acid esters, glycerol dibehenate, and mixtures thereof. The lubricant may be used in an amount ranging from 0.3 to 5% by weight, specifically 0.5 to 3% by weight, based on the total weight of each independent part.
Further, specific examples of the coloring agent include yellow ferric oxide, red ferric oxide, edible yellow No. 4, edible yellow No. 5, edible red No. 3, edible red No. 102, edible blue No. 3 and the like. The colorant may be used in an amount of 0.01 wt% to 1 wt% based on the total weight of each independent part.
In the present invention, the Darvitransitic silicate independent part can be coated with a pharmaceutically acceptable coating agent. The coating agent may be a polymer commonly used in the art. For example, the dabigatranatech silicate independent part may be hydroxypropylmethylcellulose (hypromellose), hydroxypropylethylcellulose, hydroxypropylmethylcellulose Water-soluble cellulose ethers or esters such as cellulose, methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, and the like; Acrylic polymers such as methacrylate-methyl methacrylate copolymer; Polyvinyl polymers such as polyvinyl alcohol and polyvinyl acetate phthalate; And a mixture thereof may be coated using a coating agent.
It is preferred that the amount of the coating agent used is kept at a minimum to provide an optimal formulation size and to make effective production. For example, in an amount of from 1 to 7% by weight, specifically from 2 to 5% by weight, based on the total weight of the dabigatranite silicate-independent part.
The capsule used in the composite capsule of the present invention is not limited as long as it is a general hard capsule used in medicine. For example, hard capsules containing hypromellose, gelatin, pullulan, polyvinyl alcohol, and mixtures thereof may be used.
The size of the hard capsule that can be used in the composite capsule of the present invention is not limited as long as it is a general capsule size used in medicine. The size of the capsule has various internal capacities according to the size of the capsule. For example, the capsule No. 0 is about 0.68 mL, the capsule No. 1 is about 0.47 mL, the capsule No. 2 is about 0.37 mL, the capsule No. 3 is about 0.27 mL, No. 4 capsule is known to have an internal capacity of about 0.20 mL (Source: Seo Heung Capsule Homepage, Korea). No. 0, No. 1, No. 2, No. 3 or No. 4 capsules can be used in the present invention. Specifically, No. 0 capsules can be used.
The composite capsule of the present invention may be administered orally, buccally, or sublingually.
Since the composite capsule according to the present invention efficiently charges the pharmaceutical composition into the space inside the limited capsule, a high-dose pharmacologically active ingredient can be charged into the capsule of small size. Therefore, there is an advantage that productivity is improved and convenience of medication is improved. In addition, the two active ingredients can be completely separated by including Darvitransitecylate and organic acid in separate form within the hard capsule. Accordingly, the mutual influence on the dissolution rate between the pharmacologically active components is small, and the dissolution rate is excellent.
In addition, since the reactivity between the active ingredients is minimized, the product stability due to changes over time can be maximized and the therapeutic effect can be maximized. In addition, there is no need to separately develop an analysis method for evaluating the stability of the product over time, Can be used.
The composite capsule of the present invention comprises the steps of: a) mixing dabigatranatechsilate or a pharmaceutically acceptable salt thereof in a powder form together with a pharmaceutically acceptable additive, or tableting the mixed powder; b) mixing the organic acid, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable additive in powder form, or tableting the mixed powder; And c) filling the hard capsule with the darbagtranatechylate powder or tablet prepared in step a) and the organic acid powder or tablet prepared in step b) in a separated state into a hard capsule. do.
In the above steps a) and b), the tableting may be performed by tableting the mixed powder, and may be performed by granulating the mixed powder and then tableting. The tablets produced may have an appropriate hardness, for example, an average hardness after tableting ranging from about 1 to 30 kp.
In particular, at least one of the steps a) and b) may comprise a purification step, whereby at least one of the dabigatranatech silicate and the organic acid may be packed into the capsule in tablet form. As an example, in step a), purification of darbagtransecticylate is performed, and in step b), the organic acid is mixed in powder form, and in step c), the darbagtransethexylate tablet and the organic acid powder are separated And then filling the capsule into the hard capsule.
Also in said steps a) and b), it may comprise coating said tablet with a pharmaceutically acceptable coating agent. As an example, in step a), the coating is carried out after the purification of Darvagranti silylate, and in step b) the organic acids are mixed in powder form, and in step c) By filling the powder into a hard capsule in a separated state, a composite capsule can be produced. Specific examples of the coating agent suitable for the darbagantrotectilate component and the organic acid component are as described above.
Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.
Example 1: Compound Capsule I
1-1. Darbigatlantek silicate Independent part: Coating tablet
(1) Purification
Darbigatlantec silicate 150.0 mg
Microcrystalline cellulose 68.4 mg
Croscarmellose sodium 10.0 mg
5.0 mg of hydroxypropylcellulose
Magnesium stearate 2.5 mg
Purified water 15.0 mg
(2) Coating
4.0 mg of hydroxypropylcellulose
Hippromelose 4.0 mg
Purified water 80.0 mg
1-2. Organic acid independent part: Powder
Citric acid 170.0 mg
Magnesium stearate 1.7 mg
The mixture obtained by mixing the ingredients described in the purification part of the Darvigantietecyl silicate independent part in the form of powder was wet granulated with hydroxypropyl cellulose as a binding solution, and the mixture was dried with 20 mesh and dried. Magnesium stearate was mixed therein and the mixture was compressed by using a circular punch having a diameter of 5.5 mm. Thereafter, the components described in the coating part were dissolved in purified water to prepare a coating liquid, and the tablet was coated with Darvagantratech silicate tablet.
Separately, the components described in Organic Acid Independence were mixed in powder form.
The coated Darvagranatech silicate tablets and the organic acid powder were packed in Hard Capsule No. 0 containing capsules of Hypromellose to prepare a composite capsule comprising 150.0 mg of Darbigantr Ietecylate and 170.0 mg of citric acid .
Example 2: Compound Capsule II
2-1. Darbigatlantek silicate Independent part: Coating tablet
2-2. Organic acid independent part: Powder
The procedure of Example 1 was repeated except that 166.5 mg of tartaric acid was used instead of 170.0 mg of citric acid in the organic acid independent portion to prepare a composite capsule containing 150.0 mg of darbagantransecticylate and 166.5 mg of tartaric acid Respectively.
Example 3: Compound Capsule III
3-1. Darbigatlantek silicate Independent part: Coating tablet
3-2. Organic Acid Independence: Refining
Citric acid 170.0 mg
Magnesium stearate 1.7 mg
Microcrystalline cellulose 10.5 mg
Lactose monohydrate 20.0 mg
Croscarmellose sodium 12.5 mg
Polyethylene glycol 4.5 mg
The components described in the above organic acid independent part were mixed in the form of powder and then the mixture was compressed by using a circular punch having a diameter of 5.5 mm to prepare organic acid tablets. A composite capsule containing 150.0 mg of Etecilate and 170.0 mg of citric acid was prepared.
Example 4: Compound Capsule IV
4-1. Darbigatlantec silicate Independent part: Powder
Darbigatlantec silicate 150.0 mg
Magnesium stearate 1.6 mg
4-2. Organic Acid Independence: Refining
The procedure of Example 3 was repeated except that the components described in the independent part of the Darvigantietecylate were used in a powder form to obtain 150.0 mg of darbagantransecticylate and 170.0 mg of citric acid Was prepared.
Example 5: Compound Capsule V
5-1. Darbigatlantek silicate Independent part: Coating tablet
5-2. Organic acid independent part: Powder
A composite capsule was prepared in the same manner as in Example 1, except that a hard capsule containing gelatin as a capsule base was used, to thereby yield 150.0 mg of darbagantransecylate and 170.0 mg of citric acid.
Comparative Example One: Simple mixing tablets Compound preparation
(1) Purification
Darbigatlantec silicate 150.0 mg
Citric acid 170.0 mg
Microcrystalline cellulose 78.9 mg
Lactose monohydrate 20.0 mg
Croscarmellose sodium 20.5 mg
Polyethylene glycol 4.5 mg
5.0 mg of hydroxypropylcellulose
Magnesium stearate 5.0 mg
Purified water 15.0 mg
(2) Coating
5.0 mg of hydroxypropylcellulose
Hippromelose 5.0 mg
Purified water 100.0 mg
The mixture obtained by mixing the components described above was wet granulated with a solution prepared by dissolving hydroxypropylcellulose in water, and the mixture was dried with 20 mesh and dried. Magnesium stearate was mixed and tableted using a tablet machine.
Hydroxypropylcellulose was dissolved in purified water in the tablets which had been tableted, and the resulting solution was used as a coating solution to prepare a complex preparation containing 150.0 mg of Darbagantransecylate and 170.0 mg of citric acid.
Comparative Example 2: Simple mixing tablets complex Capsule I
The composite preparation prepared in Comparative Example 1 was packed in a hard capsule mainly made of hypromellose to prepare a complex capsule containing 150.0 mg of Darbigatran tecyl silicate and 170.0 mg of citric acid.
Comparative Example 3: Simple mixing tablets complex Capsule II
A composite capsule preparation was prepared in the same manner as in Comparative Example 2 except that hard capsules based on gelatin were used as a capsule base, to thereby obtain 150.0 mg of darbagantransecylate and 170.0 mg of citric acid.
Comparative Example 4: Double layer Compound preparation
4-1. Dabigatranitech silicate-containing layer
Darbigatlantec silicate 150.0 mg
Microcrystalline cellulose 68.4 mg
Croscarmellose sodium 10.0 mg
5.0 mg of hydroxypropylcellulose
Magnesium stearate 2.5 mg
Purified water 15.0 mg
4-2. Organic acid-containing layer
Citric acid 170.0 mg
Microcrystalline cellulose 10.5 mg
Lactose monohydrate 20.0 mg
Croscarmellose sodium 12.5 mg
Polyethylene glycol 4.5 mg
Magnesium stearate 2.5 mg
4-3. coating
5.0 mg of hydroxypropylcellulose
Hippromelose 5.0 mg
Purified water 100.0 mg
The mixture obtained by mixing the components described in the Darvigantrishse silicate-containing layer was wet granulated using a solution prepared by dissolving hydroxypropylcellulose in water as a binding solution, followed by sizing to 20 mesh and drying. Magnesium stearate was mixed and tableted using a tablet machine.
On the other hand, the ingredients described in the organic acid-containing layer were mixed and then tableted together with the previously prepared Darvigantieteksilate tablets to prepare a two-layer tablet.
A double-layer tablet was prepared by dissolving hypromellose and hydroxypropylcellulose in purified water in a tablet of the tablet in the form of a coating solution to prepare a complex preparation containing 150.0 mg of darbagantransecylate and 170.0 mg of citric acid.
Test Example 1: Accelerated storage stability evaluation
The accelerated storage tests were carried out on the combined preparations containing the dabigatranetecylate and organic acid obtained in Examples 1 to 5 and Comparative Examples 1 to 4 under the following conditions to determine the content of dabigatran tecyl silicate The results are shown in Table 1 below, and the degree of occurrence of the dabigatranitech silicate flexible substance was measured. The results are shown in Table 2 below.
<Acceleration condition>
Storage conditions: High Density Polyethylene (HDPE) bottles at 40 ° C and 75% relative humidity Packaging
Test time: Initial, 1 month, 2 months, 4 months and 6 months
≪ Evaluation of a flexible material that is a dabigatranitech silicate and a dabigatlantite silicate &
According to the 'Liquid Chromatography Method' of the Korean Pharmacopoeia 10th Edition, 'General Test Methods', the content of the corresponding time point was obtained by comparing with the standard solution prepared in advance.
From the results of Tables 1 and 2, it can be seen that Examples 1 to 5 all exhibited little decrease in the amount of accelerated materials for 6 months, 4, the content of about 5% or more decreased during 6 months of accelerating, and it was confirmed that the generation amount of the flexible substance was also remarkably high. Thus, it can be seen that the dabigatranatech silicate-containing layer is separated from the organic acid, excipient and the like and exists as an independent part, so that the pharmacological activity can be maintained for a long period of time due to the maintenance of the high content and the reduction of the generation of the flexible substance.
Claims (11)
Wherein said Darvitransuites silicate independent and organic acid independent moieties are each independently in the form of a powder, granules, tablets, pellets, capsules or combinations thereof.
Characterized in that at least one of the Darvitransitic silicate-independent and organic acid-independent moieties is in the form of a tablet.
Characterized in that it further comprises a pharmaceutically acceptable additive selected from the group consisting of the Darvigantietecylate independent and organic acid independent additive selected from the group consisting of diluents, disintegrants, binders, stabilizers, lubricants, colorants and mixtures thereof By weight.
The above Darvigantietecyl silicate independent parts include hydroxypropylmethyl cellulose (heptromelose), hydroxypropylethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose acetate succinate and hydroxypropylmethylcellulose phthalate A water-soluble cellulose ether or ester; An acrylic polymer comprising a methacrylate-methyl methacrylate copolymer; Polyvinyl polymers including polyvinyl alcohol and polyvinyl acetate phthalate; Hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, and mixtures thereof.
Characterized in that the coating agent is used in an amount of 1 to 7% by weight, based on the total weight of the Darvigantrant cy cleate independent part.
Wherein the organic acid or a pharmaceutically acceptable salt thereof is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid, and mixtures thereof; Its hydrate; ≪ / RTI > and an acid salt thereof.
Characterized in that the complex is encapsulated in an amount of 75 mg to 150 mg as darbatlantethecylate or a pharmaceutically acceptable salt thereof as darbagantransecticylate per capsule of the first capsule.
Characterized in that the organic acid or its pharmaceutically acceptable salt is contained in an amount of 20 to 200 parts by weight based on 100 parts by weight of the dabigatranatechylate or a pharmaceutically acceptable salt thereof.
b) mixing the organic acid, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable additive in powder form, or tableting the mixed powder; And
c) filling the hard capsule with the darbagtranatechylate powder or tablet prepared in step a) and the organic acid powder or tablet prepared in step b) in a separated state, .
Characterized in that at least one of said steps a) and b) comprises a purification step.
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020150178411A KR20170070635A (en) | 2015-12-14 | 2015-12-14 | Composite capsule formulation comprising dabigatran etexilate |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR20170070635A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019132840A1 (en) * | 2017-12-27 | 2019-07-04 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A pharmaceutical formulation for oral administration comprising dabigatran etexilate |
| WO2019132839A1 (en) * | 2017-12-27 | 2019-07-04 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Oral pharmaceutical compositions of dabigatran |
| WO2020209813A1 (en) * | 2019-04-09 | 2020-10-15 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A capsule formulation of dabigatran etexilate |
-
2015
- 2015-12-14 KR KR1020150178411A patent/KR20170070635A/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019132840A1 (en) * | 2017-12-27 | 2019-07-04 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A pharmaceutical formulation for oral administration comprising dabigatran etexilate |
| WO2019132839A1 (en) * | 2017-12-27 | 2019-07-04 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Oral pharmaceutical compositions of dabigatran |
| WO2020209813A1 (en) * | 2019-04-09 | 2020-10-15 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A capsule formulation of dabigatran etexilate |
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