WO2017119629A1 - 용출률이 개선된 네비보롤을 포함하는 약학적 조성물 - Google Patents
용출률이 개선된 네비보롤을 포함하는 약학적 조성물 Download PDFInfo
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- WO2017119629A1 WO2017119629A1 PCT/KR2016/014771 KR2016014771W WO2017119629A1 WO 2017119629 A1 WO2017119629 A1 WO 2017119629A1 KR 2016014771 W KR2016014771 W KR 2016014771W WO 2017119629 A1 WO2017119629 A1 WO 2017119629A1
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- nebivolol
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
Definitions
- the present invention relates to a pharmaceutical composition having improved dissolution rate of nebivorol and a method for preparing the same. More specifically, the present invention relates to a pharmaceutical composition with improved dissolution rate, including nebivolol or a pharmaceutically acceptable salt, alkalizer and pharmaceutically acceptable additives thereof as an active ingredient.
- Beta-blockers are used to treat high blood pressure, angina pectoris, myocardial infarction, heart disease, migraine or essential tremor.
- nebivorol is a 2,2'-iminobisethanol derivative of the formula 1 below, and has a centrally symmetric structure with four chiral centers.
- Nebivorol is a ⁇ -receptor blocking drug, a mixture of D- and L-enantiomers, and is a different classical ⁇ -blocker in that it is highly selective for ⁇ 1-adrenergic receptors and has vasodilating effects related to its effect on endothelial nitric oxide. Is different from Nebivorol is thought to increase the concentration of nitric oxide through the L-arginine-nitric oxide pathway in the vascular endothelium and has been found to improve endothelial dysfunction and vascular elasticity.
- nebivorol is known to have desirable antioxidant properties for normal functioning of the vascular endothelium, and thus is used as an effective antihypertensive agent having desirable effects on the vascular endothelium and the cardiovascular system.
- nebivorol has been shown to be beneficial for the treatment of cardiovascular diseases such as hypertension, congestive heart failure, atherosclerosis and endothelial dysfunction.
- the pharmaceutical composition is provided in the form of a solid preparation suitable for oral administration, that is, a tablet, etc. in consideration of the convenience of taking, in which case bioavailability is very important.
- An important factor affecting bioavailability is the dissolution process of the drug in vivo, which can be identified by the dissolution rate through dissolution testing in the laboratory.
- Nebiborol shows a very low dissolution rate at a relatively high pH.
- the micronized Naviborol may contain a humectant together (European Patent Registration No. 0145067), or to have an equal dissolution rate in the form of nebiborol hydrochloride without using a humectant (Korean Patent Registration No. 896266), the prior art that discloses the use of crystalline nebiborol in combination with starch to obtain an equivalent level of dissolution (Korean Patent Publication No. 2011-0130872) is known.
- the present inventors have made diligent efforts to prepare nebiborol formulations which exhibit stable and improved dissolution rate without variation in pH in vivo, and therefore, when formulated with the addition of an alkalizing agent to the pharmaceutical composition, The present invention was completed by confirming that the solution had an excellent dissolution rate improvement effect even in a water solution or pH 5-7.
- an object of the present invention is to provide a pharmaceutical composition of nebiborol with improved dissolution rate and a method for producing the same.
- the present invention provides a pharmaceutical composition for preventing or treating cardiovascular disease, including nebiborol or pharmaceutically acceptable salts, alkalizers and pharmaceutically acceptable additives thereof. do.
- the pharmaceutically acceptable salt of nebivorol is preferably a nebiborol hydrochloride, and may be included in an amount of 0.2 to 10 parts by weight based on 100 parts by weight of the total composition.
- the alkalizing agent preferably exhibits a pH of 8 to 12 upon suspension or dissolution in water and may be selected from the group consisting of magnesium oxide, magnesium carbonate and magnesium aluminum silicate.
- the alkalizing agent may be included in an amount of 0.02 to 10 parts by weight based on 100 parts by weight of the total composition.
- the pharmaceutical composition according to another embodiment of the present invention may further include a component having a prophylactic or therapeutic activity for a cardiovascular disease, and these additional components are hydrochlorothiazide, ramipril, enalapril, lecaridipine , Nisoldipine, amlodipine, losartan, eprosartan, candesartan, telmisartan, valsartan, olmesartan, rosuvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin, simvastatin and their pharmaceutically acceptable At least one selected from the group consisting of possible salts, in particular rosuvastatin calcium.
- the alkalizing agent is added in step a) or b).
- Nebiborol of the following formula (1) as an active ingredient of the pharmaceutical composition according to the present invention is a ⁇ -1 blocker having high selectivity, and is known to be useful for managing hypertension.
- Nebivorol in the composition according to the present invention can be used in various forms such as a free base of the nebiborol or a pharmaceutically acceptable salt thereof as long as the equivalent pharmacological activity is maintained.
- nebivorol is basic and can be converted to its pharmaceutically acceptable acid addition salt form by treatment with an appropriate acid.
- Suitable acids include hydrochloric acid (eg hydrochloric acid, hydrobromic acid), inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, and the like; Or acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, propanedioic acid, butanedioic acid, (Z) -2-butenedioic acid, (E) -2 -Butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid And organic acids such as tolu
- nebiborol is included 1.5 to 3.6 parts by weight in the form of hydrochloride relative to 100 parts by weight of the pharmaceutical composition.
- the pharmaceutical composition according to the present invention is an alkalizing agent in order to solve the problem that nebiborol or a pharmaceutically acceptable salt thereof, the dissolution rate is lowered at pH 5.0 to 7.0 such as water solution, thereby lowering the absorbency and bioavailability, Characterized in that it comprises a.
- Nebivorol is a weakly basic substance, and the solubility and dissolution rate decrease when the pH rises. Nevertheless, it has been found that the addition of the alkalizer according to the present invention significantly increases the dissolution rate of nebivorol, which was first revealed by the present invention in a completely unpredictable manner.
- the alkalizing agent may be selected to exhibit a pH of 8 to 12 upon suspension or dissolution in water, for example magnesium oxide, magnesium carbonate or magnesium aluminum silicate.
- an excellent dissolution rate is obtained not only at a low pH such as pH 1.2, but also at pH 5 to 7 such as a water solution. Despite the change, high dissolution rates of the drug were maintained. As a result, as a problem with the conventional nebivorol, it is possible to solve the low dissolution rate at a relatively high pH and thereby the abrupt dissolution rate change in the body.
- the content of the alkalizing agent is preferably included from 0.02 to 10 parts by weight, more preferably from 0.04 to 4 parts by weight based on 100 parts by weight of the total composition.
- the content of the alkalizing agent is less than 0.02 parts by weight based on 100 parts by weight of the total composition, the dissolution rate improvement effect is weak, and when larger than 10 parts by weight, the dissolution rate may be lowered, which is not preferable.
- a composition comprising magnesium carbonate, magnesium oxide, and magnesium aluminum silicate as an alkalizing agent together with nebivorol (Examples 1 to 5), and an alkalizing agent in a composite composition of nebibolol and rosuvastatin
- nebivorol Examples 1 to 5
- an alkalizing agent in a composite composition of nebibolol and rosuvastatin When included (Examples 6 to 9), it showed a significantly higher dissolution rate in the water solution compared to the formulation of the formulation (Comparative Example 1) or the formulations of Comparative Examples 2 and 3, which are similar to the commercial formulations containing no alkalizing agent. Confirmed.
- the pharmaceutical composition according to the present invention may further include a pharmaceutically acceptable additive within a range that does not affect the effects of the present invention, in addition to the pharmacologically active ingredient and the alkalizing agent.
- these pharmaceutically acceptable additives may be one or more selected from the group consisting of fillers, binders, disintegrants, glidants, and lubricants.
- Excipients that can be used in the composition according to the present invention include cellulose derivatives such as microcrystalline cellulose, low-substituted hydroxypropyl cellulose, methyl cellulose, starch such as potato starch, corn starch, lactose, fructose and the like.
- binder polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, poloxamer, polyethylene oxide, polymethyl acrylate, Natural gum, synthetic gum, copovidone, gelatin, etc. are mentioned.
- disintegrant examples include sodium starch glycolate, sodium carboxymethyl cellulose, croscarmellose sodium, low substituted hydroxypropyl cellulose, pregelatinized starch, crospovidone and the like.
- Examples of the fluidizing agent include colloidal silicon dioxide and magnesium metasilicate aluminate.
- glidants include magnesium stearate, stearic acid, sodium stearyl fumarate, glycerol palmitostearic acid, and the like.
- the pharmaceutical composition of the present invention contains 40 to 95 parts by weight of excipient, 1 to 10 parts by weight of binder, 1 to 10 parts by weight of disintegrant, fluidization as pharmaceutically acceptable additives based on 100 parts by weight of the total composition 0.1 to 2 parts by weight and 0.1 to 2 parts by weight of the lubricant may be included.
- the dosage form of the pharmaceutical composition with improved dissolution rate according to the present invention is not particularly limited, and may be a dosage form suitable for various routes of administration orally, parenterally (muscle, subcutaneous, intravenous, etc.), in particular, oral dosage form is preferred.
- oral dosage forms include tablets, capsules, granules, troches, dispersants, suspensions, and the like, and may be provided in solid oral dosage forms such as tablets or capsules in consideration of convenience of taking. .
- the composition according to the present invention does not have a decrease in dissolution rate, and there is little variation due to pH change in the body, and thus can be used very effectively.
- the pharmaceutical composition according to the present invention is prepared by using an alkalizing agent such as magnesium carbonate, magnesium oxide and magnesium aluminum silicate, without undergoing a complicated and expensive process such as miniaturizing nebiborol or including a humectant.
- an alkalizing agent such as magnesium carbonate, magnesium oxide and magnesium aluminum silicate
- miniaturizing nebiborol or including a humectant As can be seen from the elution rate in the water solution does not occur, it shows an excellent dissolution rate of 80% or more within 15 minutes after dissolution. Accordingly, since the composition of the present invention does not require micronization or the addition of a humectant, the manufacturing cost can be reduced, and there is almost no variation in dissolution rate due to pH change, and thus the occurrence of variation in bioavailability according to pre- or post-prandial administration can be minimized. Constant pharmacological action and improved therapeutic effect can be expected.
- compositions of the present invention may be subjected to conventional methods of preparation in the form of solid oral formulations, for example, by direct compression molding, direct granulation, wet granulation or dry granulation. Can be prepared accordingly.
- a preferred method of preparing a pharmaceutical composition according to the present invention comprises the steps of: a) mixing nebiborol or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive to prepare a mixture; And b) molding the mixture, wherein the alkalizing agent is added in step a) or b).
- the mixing step may include the step of preparing granules by mixing and compressing an active ingredient including an effective amount of nebiborol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. More preferably, the granules can be produced by wet granulation.
- the forming step may include mixing and tableting the remaining amount of the pharmaceutically acceptable additive into granules prepared from the mixture.
- the alkalizing agent can be granulated with the active ingredient and additives in the mixing step or postmixed with the remaining pharmaceutically acceptable additives and granules produced in the mixing step in the forming step.
- the method may further comprise coating the molded pharmaceutical composition by a known method.
- composition of the present invention in addition to nebivorol or a pharmaceutically acceptable salt thereof, can be used for the prevention or treatment of cardiovascular diseases such as hypertension, congestive heart failure, atherosclerosis, metabolic abnormalities and endothelial dysfunction, and the like.
- cardiovascular diseases such as hypertension, congestive heart failure, atherosclerosis, metabolic abnormalities and endothelial dysfunction, and the like.
- the ingredients may be included together.
- ingredients having prophylactic or therapeutic activity for these cardiovascular diseases include hydrochlorothiazide, ramipril, enalapril, recarnidipine, nisoldipine, amlodipine, losartan, eprosartan, candesartan, telmisartan, Valsartan, olmesartan, rosuvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin, simvastatin, or pharmaceutically acceptable salts thereof, but is not limited thereto.
- the additional active ingredient is rosuvastatin or a pharmaceutically acceptable salt thereof, more preferably rosuvastatin calcium.
- the dissolution rate of the nebivorol does not occur at low pH as well as at a relatively high pH of 5 to 7, but rather, the dissolution rate can be greatly improved, and thus an improved therapeutic effect can be expected. Since no micronization of borol or the addition of a humectant is required, manufacturing costs can be reduced, and there is almost no variation in dissolution rate due to pH change, which can minimize variation in bioavailability according to pre- or post-prandial administration. As such, it is very useful for the preparation of complex formulations comprising other active ingredients, such as nebivorol formulations or rosuvastatin calcium.
- Table 1 below shows the composition of the drug substance per tablet.
- Example 2 Example 3 Mg / Tab % Mg / Tab % Mg / Tab % Nebivolol HCl Wet granules 5.45 2.3 5.45 2.3 5.45 1.6 Latose monohydrate 168.99 70.6 170.49 71.3 185.35 53.0 Microcrystalline cellulose 46.00 19.2 46.00 19.2 80.00 22.9 Hypromellose 2910 4.60 1.9 4.60 1.9 12.00 3.4 Tween 80 0.46 0.2 0.46 0.2 - - Butylated hydroxyanisole - - - - - - Microcrystalline cellulose Post-mix - - - - - - - - sodium starch glycolate 10.00 4.2 10.00 4.2 10.00 4.2 10.00 4.2 Croscarmeliose Na - - - - - - MgO 20 ..
- granules were prepared according to the wet granulation method by adding a solution of BHA and Tween 80 dissolved in a mixture of purified water and ethanol. Thereafter, after mixing magnesium aluminum silicate and the remaining amount of additives as rosuvastatin calcium and alkalizing agent, the colloidal silicon dioxide and magnesium stearate are mixed as a lubricant, and a tableting machine (STP Machinery Co., Ltd., ZP198 Model) Using a circular punch of 10 mm and 7.5 mm in diameter, tablets were tableted to 350.0 mg (Example 6) and 147.0 mg (Example 7), respectively.
- a tableting machine STP Machinery Co., Ltd., ZP198 Model
- Opadry 03B28796 manufactured by Colorcon was dissolved in 80% ethanol and water, and the resulting tablet was spray coated to prepare a film-coated tablet.
- Table 2 below shows the composition of the drug substance per tablet.
- Example 4 Example 5
- Example 6 Example 7 Mg / Tab % Mg / Tab % Mg / Tab % Mg / Tab % Mg / Tab % Nebivolol HCl Wet granules 5.45 1.6 5.45 1.6 5.45 1.5 5.45 3.6
- Opadry 03F680010 manufactured by Colorcon
- 80% ethanol 80% ethanol
- the resulting tablet was spray coated to prepare a film coated tablet.
- Example 9 Mg / Tab % Mg / Tab % Nebivolol HCl Wet granules 5.45 1.5 5.45 1.5 Latose monohydrate 162.35 44.8 162.35 44.8 Microcrystalline cellulose 80.00 22.1 80.00 22.1 Hypromellose 2910 12.00 3.3 12.00 3.3 Tween 80 0.20 0.06 0.20 0.06 Microcrystalline cellulose Post-mix 48.00 13.3 63.60 17.6 sodium starch glycolate 15.00 4.1 15.00 4.1
- the dissolution test was carried out in a water solution at paddle method and 50 rpm.
- the 5 mL sample solution collected at 5, 10, 15, 30, 45, 90 and 120 minutes was filtered through a membrane filter and analyzed by HPLC method under the following conditions.
- the dissolution rate relative to the standard solution was calculated. The results are shown in Table 5 and FIG. 1.
- Example 1 0.0 68.4 85.9 87.1 90.7 91.1 91.5 91.7 92.4
- Example 2 0.0 64.7 78.7 86.0 87.2 88.7 90.0 91.5 93.3
- Example 3 0.0 68.1 75.8 84.2 84.8 85.4 86.0 86.6 87.1
- Example 4 0.0 71.8 83.7 85.8 92.3 92.6 93.0 93.3 93.7
- Example 5 0.0 74.2 81.9 84.4 87.8 88.4 90.0 91.8 93.0
- Example 6 0.0 80.6 91.3 93.0 95.6 96.9 97.6 98.0 98.3
- Example 8 0.0 68.3 88.8 91.9 93.8 - - - - -
- Example 9 0.0 68.0 78.8 83.5 87.8 - - - - Comparative Example 1 0.0 0.0 1.9 2.4 4.9 7.4 10.2 13.7 15.7 Comparative Example 2 0.0 56.6 57.0 55.4 55.5 55.9 54.7 54.6 54.
- the nebiborol single formulation and the combination formulation of neviborol and rosuvastatin according to the present invention all exhibited excellent dissolution rates of more than 83% and up to 93% within 15 minutes of initiation of dissolution.
- the tablets of Comparative Examples 1 to 3 prepared without adding an alkalizing agent showed a very low dissolution rate even after 2 hours from the start of dissolution.
Abstract
Description
성분명 | 규격 | 실시예 1 | 실시예 2 | 실시예 3 | |||
Mg/Tab | % | Mg/Tab | % | Mg/Tab | % | ||
Nebivolol HCl | 습식과립 | 5.45 | 2.3 | 5.45 | 2.3 | 5.45 | 1.6 |
Latose monohydrate | 168.99 | 70.6 | 170.49 | 71.3 | 185.35 | 53.0 | |
Microcrystalline cellulose | 46.00 | 19.2 | 46.00 | 19.2 | 80.00 | 22.9 | |
Hypromellose 2910 | 4.60 | 1.9 | 4.60 | 1.9 | 12.00 | 3.4 | |
Tween 80 | 0.46 | 0.2 | 0.46 | 0.2 | - | - | |
Butylated hydroxyanisole | - | - | - | - | - | - | |
Microcrystalline cellulose | 후혼합 | - | - | - | - | - | - |
sodium starch glycolate | 10.00 | 4.2 | 10.00 | 4.2 | 10.00 | 4.2 | |
Croscarmeliose Na | - | - | - | - | - | - | |
MgO | 20.. | 0.8 | 0.50 | 0.2 | 0.10 | 0.04 | |
Magnesium aluminium sillicate | - | - | - | - | - | - | |
MgCO3 | - | - | - | - | - | - | |
Rosuvastatin Ca | - | - | - | - | - | - | |
Colloidal sillicon dioxide | 활택혼합 | 0.50 | 0.20 | 0.50 | 0.2 | 0.50 | 0.2 |
Mg Stearate | 1.20 | 0.5 | 1020 | 0.5 | 1.20 | 0.5 | |
에탄올 | - | - | - | - | - | - | |
물 | 35.00 | - | 35.00 | - | 35.00 | - | |
Opadry 03B28796 | - | - | - | - | - | - | |
습식과립물 소계 | 225.50 | - | 227.00 | - | 227.40 | - | |
합계 | 239.200 | 100.0 | 239.200 | 100.0 | 239.200 | 100.0 |
성분명 | 규격 | 실시예 4 | 실시예 5 | 실시예 6 | 실시예 7 | ||||
Mg/Tab | % | Mg/Tab | % | Mg/Tab | % | Mg/Tab | % | ||
Nebivolol HCl | 습식과립 | 5.45 | 1.6 | 5.45 | 1.6 | 5.45 | 1.5 | 5.45 | 3.6 |
Latose monohydrate | 185.35 | 53.0 | 189.35 | 54.1 | 162.32 | 44.8 | 68.33 | 45.0 | |
Microcrystalline cellulose | 80.00 | 22.9 | 80.00 | 22.9 | 80.00 | 22.1 | 33.70 | 22.2 | |
Hypromellose 2910 | 12.00 | 3.4 | 12.00 | 3.4 | 12.00 | 3.3 | 5.00 | 3.3 | |
Tween 80 | - | - | - | - | 0.20 | 0.06 | 0.10 | 0.07 | |
Butylated hydroxyanisole | - | - | - | - | 0.03 | 0.0 | 0.02 | 0.0 | |
Microcrystalline cellulose | 후혼합 | 40.00 | 11.4 | 40.00 | 11.4 | 42.00 | 11.6 | 17.70 | 11.6 |
sodium starch glycolate | 15.00 | 4.3 | - | - | 15.00 | 4.1 | 6.30 | 4.1 | |
Croscarmeliose Na | - | - | 15.00 | 4.3 | - | - | - | - | |
MgO | - | - | - | - | - | - | |||
Magnesium aluminium sillicate | 7.00 | 2.0 | - | - | 7.00 | 1.9 | 3.00 | 2.0 | |
MgCO3 | - | - | 3.00 | 0.9 | - | - | - | ||
Rosuvastatin Ca | - | - | - | 20.80 | 5.7 | 5.20 | 3.4 | ||
Colloidal sillicon dioxide | 활택혼합 | 1.70 | 0.5 | 1.70 | 0.5 | 1.70 | 0.5 | 0.70 | 0.5 |
Mg Stearate | 3.50 | 10. | 3.50 | 1.0 | 3.50 | 10. | 1.50 | 1.0 | |
에탄올 | - | - | - | - | 3.00 | - | 2.00 | - | |
물 | 45.00 | - | 45.00 | - | 41.00 | - | 18.00 | - | |
Opadry 03B28796 | - | - | - | - | 12.0 | 3.3 | 5.0 | 3.3 | |
습식과립물 소계 | 282.80 | - | 286.80 | - | 260.00 | - | 112.60 | ||
합계 | 350.000 | 100.0 | 350.000 | 100.0 | 350.000 | 100.0 | 350.000 | 100.0 |
성분명 | 공정 | 실시예8 | 실시예 9 | ||
Mg/Tab | % | Mg/Tab | % | ||
Nebivolol HCl | 습식과립 | 5.45 | 1.5 | 5.45 | 1.5 |
Latose monohydrate | 162.35 | 44.8 | 162.35 | 44.8 | |
Microcrystalline cellulose | 80.00 | 22.1 | 80.00 | 22.1 | |
Hypromellose 2910 | 12.00 | 3.3 | 12.00 | 3.3 | |
Tween 80 | 0.20 | 0.06 | 0.20 | 0.06 | |
Microcrystalline cellulose | 후혼합 | 48.00 | 13.3 | 63.60 | 17.6 |
sodium starch glycolate | 15.00 | 4.1 | 15.00 | 4.1 | |
Magnesium carbonate | 1.00 | 0.3 | 1.00 | 0.3 | |
Rosuvastatin Ca | 20.80 | 5.7 | 5.20 | 1.4 | |
Colloidal sillicon dioxide | 활택 혼합 | 1.70 | 0.5 | 1.70 | 0.5 |
Mg Stearate | 3.50 | 1.0 | 3.50 | 1.0 | |
Opadry 03B28796 | 12.0 | 3.3 | 12.0 | 3.3 | |
합계 | 362.0 | 100.0 | 362.0 | 100.0 |
성분명 | 규격 | 비교예1 | 비교예2 | 비교예3 | |||
Mg/Tab | % | Mg/Tab | % | Mg/Tab | % | ||
Nebivolol HCl | 습식과립 | 5.45 | 2.3 | 5.45 | 1.6 | 5.45 | 1.6 |
Latose monohydrate | 141.75 | 59.3 | 191.89 | 54.8 | 192.35 | 55.0 | |
Microcrystalline cellulose | 46.00 | 19.2 | 80.00 | 22.9 | 120.00 | 34.03 | |
Hypromellose 2910 | 4.60 | 1.9 | 12.00 | 3.4 | 12.00 | 3.4 | |
Tween 80 | 0.46 | 0.2 | 0.46 | 0.1 | - | - | |
Butylated hydroxyanisole | - | - | - | - | - | - | |
Microcrystalline cellulose | 후혼합 | 23.00 | 9.6 | 40.00 | 11.4 | - | - |
sodium starch glycolate | - | - | 15.00 | 4.3 | - | - | |
Croscarmeliose Na | 16.10 | 6.7 | - | - | 15.00 | 4.3 | |
MgO | - | - | - | - | - | ||
Magnesium aluminium sillicate | - | - | - | - | - | - | |
MgCO3 | - | - | - | - | - | - | |
Rosuvastatin Ca | - | - | - | - | - | - | |
Colloidal sillicon dioxide | 활택 혼합 | 0.69 | 0.3 | 1.70 | 0.5 | 1.70 | 0.5 |
Mg Stearate | 1.15 | 0.5 | 3.50 | 1.0 | 3.50 | 1.0 | |
에탄올 | - | - | - | - | - | - | |
물 | 35.00 | - | 35.00 | - | 35.00 | - | |
Opadry 03B28796 | - | - | - | - | - | - | |
습식과립물 소계 | 198.26 | - | 289.80 | - | 329.80 | - | |
합계 | 239.200 | 100.0 | 350.000 | 100.0 | 350.000 | 100.0 |
검체명 | 0 | 5 | 10 | 15 | 30 | 45 | 60 | 90 | 120 |
실시예1 | 0.0 | 68.4 | 85.9 | 87.1 | 90.7 | 91.1 | 91.5 | 91.7 | 92.4 |
실시예2 | 0.0 | 64.7 | 78.7 | 86.0 | 87.2 | 88.7 | 90.0 | 91.5 | 93.3 |
실시예3 | 0.0 | 68.1 | 75.8 | 84.2 | 84.8 | 85.4 | 86.0 | 86.6 | 87.1 |
실시예4 | 0.0 | 71.8 | 83.7 | 85.8 | 92.3 | 92.6 | 93.0 | 93.3 | 93.7 |
실시예5 | 0.0 | 74.2 | 81.9 | 84.4 | 87.8 | 88.4 | 90.0 | 91.8 | 93.0 |
실시예6 | 0.0 | 80.6 | 91.3 | 93.0 | 95.6 | 96.9 | 97.6 | 98.0 | 98.3 |
실시예8 | 0.0 | 68.3 | 88.8 | 91.9 | 93.8 | - | - | - | - |
실시예9 | 0.0 | 68.0 | 78.8 | 83.5 | 87.8 | - | - | - | - |
비교예1 | 0.0 | 0.0 | 1.9 | 2.4 | 4.9 | 7.4 | 10.2 | 13.7 | 15.7 |
비교예2 | 0.0 | 56.6 | 57.0 | 55.4 | 55.5 | 55.9 | 54.7 | 54.6 | 54.54 |
비교예3 | 0.0 | 53.1 | 50.7 | 44.1 | 34.1 | 26.8 | 21.5 | 13.2 | 11.5 |
Claims (10)
- 네비보롤 또는 이의 약학적으로 허용 가능한 염, 알칼리화제 및 약학적으로 허용 가능한 첨가제를 포함하는, 심혈관 질환 예방 또는 치료용 약학적 조성물.
- 제1항에 있어서, 네비보롤의 약학적으로 허용 가능한 염은 네비보롤 염산염인 조성물.
- 제1항에 있어서, 알칼리화제는 물에 현탁 또는 용해시 pH 8 내지 12를 나타내는 것인 조성물.
- 제3항에 있어서, 알칼리화제는 산화마그네슘, 탄산마그네슘 및 마그네슘 알루미늄 실리케이트로 이루어진 군으로부터 선택되는 적어도 하나인 조성물.
- 제1항에 있어서, 네비보롤 또는 이의 약학적으로 허용 가능한 염은 조성물 전체 100 중량부에 대해 0.2 내지 10 중량부로 포함되는 조성물.
- 제1항에 있어서, 알칼리화제는 조성물 전체 100 중량부에 대하여 0.02 내지 10 중량부로 포함되는 조성물.
- 제1항 내지 제6항 중 어느 한 항에 있어서, 심혈관 질환의 예방 또는 치료 활성을 갖는 성분을 추가로 포함하는 조성물.
- 제7항에 있어서, 심혈관 질환의 예방 또는 치료 활성을 갖는 성분은 히드로클로로티아지드, 라미프릴, 에날라프릴, 레카르니디핀, 니솔디핀, 암로디핀, 로사르탄, 에프로사르탄, 칸데사르탄, 텔미사르탄, 발사르탄, 올메사르탄, 로수바스타틴, 아토르바스타틴, 프라바스타틴, 플루바스타틴, 로바스타틴, 심바스타틴 및 이들의 약학적으로 허용 가능한 염으로 이루어진 군에서 선택된 적어도 하나인 조성물.
- 제8항에 있어서, 심혈관 질환의 예방 또는 치료 활성을 갖는 성분은 로수바스타틴 칼슘인 조성물.
- a) 네비보롤 또는 이의 약학적으로 허용 가능한 염과 약학적으로 허용 가능한 첨가제를 혼합하여 혼합물을 제조하는 단계; 및b) 상기 혼합물을 성형하는 단계를 포함하되,상기 단계 a) 또는 b)에서 알칼리화제를 첨가하는 것을 특징으로 하는,제1항의 약학적 조성물의 제조방법.
Priority Applications (5)
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MX2018008443A MX2018008443A (es) | 2016-01-08 | 2016-12-16 | Composición farmacéutica que comprende nebivolol con tasa de disolución mejorada. |
MYPI2018702352A MY201954A (en) | 2016-01-08 | 2016-12-16 | Pharmaceutical composition comprising nebivolol with improved dissolution rate |
AU2016385282A AU2016385282B2 (en) | 2016-01-08 | 2016-12-16 | Pharmaceutical composition comprising nebivolol with improved dissolution rate |
CA3010857A CA3010857C (en) | 2016-01-08 | 2016-12-16 | Pharmaceutical composition comprising nebivolol with improved dissolution rate |
CN201680078111.1A CN108463250B (zh) | 2016-01-08 | 2016-12-16 | 包含具有改善溶解率的奈比洛尔的药物组合物 |
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KR20160002626 | 2016-01-08 | ||
KR10-2016-0002626 | 2016-01-08 | ||
KR1020160171842A KR102203229B1 (ko) | 2016-01-08 | 2016-12-15 | 용출률이 개선된 네비보롤을 포함하는 약학적 조성물 |
KR10-2016-0171842 | 2016-12-15 |
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US20140057954A1 (en) * | 2012-08-22 | 2014-02-27 | Forest Laboratories Holdings Ltd. | Chemical composition |
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