WO2016024844A1 - 오메가-3 지방산 에스테르 및 스타틴계 약물을 포함하는 경구용 복합제제 - Google Patents
오메가-3 지방산 에스테르 및 스타틴계 약물을 포함하는 경구용 복합제제 Download PDFInfo
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- WO2016024844A1 WO2016024844A1 PCT/KR2015/008523 KR2015008523W WO2016024844A1 WO 2016024844 A1 WO2016024844 A1 WO 2016024844A1 KR 2015008523 W KR2015008523 W KR 2015008523W WO 2016024844 A1 WO2016024844 A1 WO 2016024844A1
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- statin
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- gum
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- omega
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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
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
Definitions
- the present invention relates to a co-formulation comprising an omega-3 fatty acid ester and a statin drug.
- Omega-3 fatty acid esters play a role in lowering serum triglycerides (TG), lowering systolic and diastolic blood pressure and pulse rate without causing any side effects, and lowering the activity of blood coagulation factor ⁇ phospholipid complexes.
- TG serum triglycerides
- systolic and diastolic blood pressure and pulse rate without causing any side effects
- lowering the activity of blood coagulation factor ⁇ phospholipid complexes lowering the activity of blood coagulation factor ⁇ phospholipid complexes.
- Statin-based drugs are known to reduce the risk of coronary heart disease (CHD) to about one third, but have limited effects on TG and serum high density lipoprotein (HDL).
- CHD coronary heart disease
- HDL serum high density lipoprotein
- a combination drug of HMG-CoA reductase inhibitor and omega-3 fatty acid ester in hypercholesterolemia patients requiring blood triglyceride level control has the advantage of effectively lowering blood cholesterol level and triglyceride level simultaneously. Accordingly, various attempts have been made to prepare combination formulations of two drugs.
- Korean Patent Publication No. 10-2012-109950 discloses an oral complex composition comprising an omega-3 fatty acid ester and an HMG-CoA reductase inhibitor and a preparation method thereof
- Korean Patent Publication 10-2013-104059 discloses an omega-3 fatty acid inner layer; Water-soluble polymer interlayers; And an outer layer of an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof.
- US Patent Publication No. 2013/0115281 discloses multiple soft gelatin formulations in which a soft gelatin formulation comprising a solid formulation comprising a pretreated statin drug and a soft gelatin formulation comprising an omega-3 fatty acid ester are attached. Is disclosed.
- the invention disclosed in the documents of 1 and 2 is uniformly applied to the outer layer containing the omega-3, the statin-based drug is very large surface area compared to the general tablets, and thus, due to the external environment such as moisture, low pH Due to the interaction of the formulation, which can cause a decrease in stability, a decrease in content and an increase in the softening material, it is very difficult to adjust the dissolution pattern of statin-based drugs, and there is a high possibility of problems in content uniformity.
- statin-based drug may have an interaction with external moisture and air, which may cause a decrease in stability, a decrease in content, and an increase in softening material.
- An object of the present invention is a combination preparation containing an omega-3 fatty acid ester and a statin-based drug, a combination formulation that is highly stable, can suppress the increase of the flexible material, and can prevent the decrease in the content of the statin-based drug To provide.
- Another object of the present invention is to provide a co-formulation comprising an omega-3 fatty acid ester and a statin-based drug having excellent disintegration rate and dissolution rate.
- the present invention provides an omega-3 fatty acid ester-containing capsule; And it provides an oral combination formulation having a statin-based drug-containing tablets contained in the capsule.
- statin-based drug-containing tablet may further include a disintegrant, and the statin-based drug-containing tablet may be a tablet coated with a film coating base.
- the shell of the capsule is arivaba gum, tracacanta gum, karaya gum, katty gum, guar gum, loggers Kong gum, tara gum, konjac gum, algin, agar, carrageenan, flulan, pectin, gellan, It may be composed of at least one component selected from the group consisting of mannan, glycerin, gelatin and xanthan gum.
- statin-based drug contained in the co-formulation is 70 to 85% by weight based on the total weight of the co-formulation in 30 minutes to 1 hour under the conditions according to the general paddle method, or the rotational sample method According to the conditions may be an oral combination preparation that elutes 70 to 85% by weight based on the total weight of the combination preparation in 30 minutes to 1 hour.
- the oral combination preparation according to the present invention includes an omega-3 fatty acid ester-containing capsule and a statin-based drug-containing tablet embedded in the capsule, so that the statin-based drug-containing tablet is essentially water, low pH. Since the contact with the external environment is completely blocked, there is an advantage of showing high stability.
- the oral combination preparation of the present invention exhibits a high disintegration rate and dissolution rate even though a tablet containing a statin-based drug is contained in the capsule, and furthermore, it disintegrates and dissolves within an appropriate time range, The drug may not be exposed to stomach acid.
- statin-based drug-containing tablets are encapsulated inside the capsule from the outside with the transparency of the capsule shell, thereby making the consumer more reliable, such as psychological and advertising effects.
- 1 is a view showing the excellent dissolution rate of the oral combination preparation of the present invention.
- Figure 2 is a view showing a photograph of the oral combination preparation prepared according to Example 1.
- the present invention is an omega-3 fatty acid ester-containing capsule; And it relates to oral combinations having a statin-based drug-containing tablets contained in the capsule, in one embodiment the combination may be a pharmaceutical combination.
- capsule means that the drug or drug is packed into capsules or manufactured by capsules
- tablette means that the drug or drug is compressed to a certain shape by adding an appropriate additive to the drug or drug.
- Omega-3 fatty acid esters may play a role in lowering serum triglycerides (TGs), lowering systolic and diastolic blood pressure and pulse rate, and lowering the activity of the blood coagulation factor phospholipid complex with little side effects in the human body.
- TGs serum triglycerides
- systolic and diastolic blood pressure and pulse rate lowering the activity of the blood coagulation factor phospholipid complex with little side effects in the human body.
- omega-3 fatty acids are omega-3 unsaturated fatty acids ( ⁇ -3 unsaturated fatty acids), omega-3 highly unsaturated fatty acids, polyunsaturated fatty acids (PUFA) Docosahexaenoic acid (DHA), eicosapentaenoic aicd (EPA), arachidonic acid (ARA), docosapentaenoic acid (Docosapentaenoic aicd) , ⁇ -linolenic acid, mixtures thereof, and the like.
- the omega-3 fatty acid ester may be an omega-3 fatty acid alkyl ester.
- Statin drugs can reduce cholesterol by slowing the production of cholesterol by inhibiting HMG-CoA reductase, which regulates the body's cholesterol production rate, or by increasing the liver's ability to remove LDL cholesterol already present in the blood. In other words, the main effect of statin drugs is to lower LDL cholesterol.
- Statin-based drugs are known to reduce the risk of coronary heart disease (CHD) to about one third, but have limited effects on TG and serum high density lipoprotein (HDL).
- CHD coronary heart disease
- HDL serum high density lipoprotein
- omega-3 fatty acid esters and statins may be effective when combined with high LDL and triglyceride levels. It is obvious.
- oral combination formulations combining omega-3 fatty acid esters and statin drugs may not only provide excellent effects as described above, but may also relieve the discomfort of patients having to take two drugs, thereby increasing medication compliance. There is also an advantage.
- co-formulations containing two or more active ingredients have the potential for two drugs to interact with each other, and the dissolution or disintegration of some of the components may be caused by other ingredients. It is not easy for a person skilled in the art.
- a formulation containing an omega-3 fatty acid ester is present in the core portion of the co-formulation and a statin-based drug is placed on the surface of the core portion. Since the surface of the core portion must be applied, the surface area becomes much larger than that of ordinary tablets.
- statin drugs Instability due to the external environment (such as moisture, low pH due to air containing CO 2 ) of statin drugs is well known in the art. As the surface of the statin-based drug contacts the air due to the external environmental factors, problems such as stability and content of the statin-based drug in the pharmaceutical formulation and increase in the softening material may appear. In the case of medicines, there is a problem that cannot be used industrially because they cannot be marketed without permission of the permitting authority due to these problems.
- statin-based drug is disposed on the surface of the core portion, it is very difficult to adjust the dissolution pattern, and there is a high possibility of problems in content uniformity. Therefore, there is a problem that the development cost is increased because a large number of trial and error of a person skilled in the art for the completion of such a formulation.
- a case of a soft gelatin formulation including a solid formulation including a statin-based drug and a multiple soft gelatin formulation attached to a soft gelatin formulation including an omega-3 fatty acid ester may be assumed.
- statin-based drug may interact with external moisture and air, and thus, it may not solve the problems of deterioration in stability, content decrease, and increase in softening material of the statin-based drug.
- the capsule containing the omega-3 fatty acid ester has a structure in which a tablet containing a statin-based drug is infiltrated into the capsule. Since the tablet is encapsulated inside the capsule and the external water and air cannot pass through the capsule layer containing the lipophilic omega-3 fatty acid ester, the statin-based drugs included in the tablet are water, air, etc. Contact with the external environment is fundamentally blocked, which makes statin drugs stable for a long time.
- the present invention provides an omega-3 fatty acid ester-containing capsule; And a tablet containing a statin-based drug (eg, atorvastatin or rosuvastatin) embedded in the capsule, for a long period of storage at various temperature and humidity conditions. It was confirmed that the combination formulation showed excellent stability through no change in the statin-based drug content.
- a statin-based drug eg, atorvastatin or rosuvastatin
- omega-3 fatty acid ester-containing capsules In another embodiment, omega-3 fatty acid ester-containing capsules; And a tablet containing a statin-based drug (eg, atorvastatin or rosuvastatin) contained within the capsule, the capsule may be completely disintegrated within 30 minutes when the release experiment is performed.
- a statin-based drug eg, atorvastatin or rosuvastatin
- the statin-based drug of about 70-85 wt% or more of the total weight of the co-formulation could be eluted within 30 minutes to 1 hour.
- the dissolution experiment eluted about 70-85% by weight of the statin-based drug of the total weight of the co-formulation within 30 minutes to 1 hour at 50-150 rpm.
- the co-formulation disintegrates and / or elutes within an appropriate time range, the co-formulation disintegrates and / or elutes too quickly, thereby preventing the problem of statin-based drugs from being exposed to the acid located above.
- the formulation structure of the oral combination preparation of the present invention does not have any negative effect on the effective and effective effects of the omega-3 fatty acid esters and statin-based drugs in the body.
- the omega-3 fatty acid ester contained in the oral co-formulation of the present invention is preferably 30 to 80% by weight based on the total weight of the oral co-formulation.
- omega-3 fatty acid ester is less than 30% by weight based on the total weight of the oral co-formulation, there is a disadvantage in that sufficient therapeutic effect is not obtained, and in the case of more than 80% by weight, the convenience of taking due to the increased size of the manufactured soft capsule There is a downside to falling.
- statin-based drug included in the oral co-formulation of the present invention is preferably 0.5 to 10% by weight based on the total weight of the oral co-formulation.
- statin-based drug is less than 0.5% by weight based on the total weight of the oral combination formulation, there is a disadvantage in that sufficient therapeutic effect is not obtained. If the statin-based drug is more than 10% by weight, side effects may occur due to the overdose of the drug.
- Statin-based drugs included in the oral combination formulation of the present invention include atorvastatin, rosuvastatin, lovastatin, lovastatin, simvastatin, pravastatin, fluvastatin, and fluvastatin. At least one member selected from the group consisting of pharmaceutically acceptable salts thereof.
- salts refers to salts prepared according to conventional methods in the art, and methods for preparing such salts are known to those skilled in the art.
- the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable inorganic and organic acids and bases.
- acids examples include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like.
- Salts derived from suitable bases may include alkali metals such as sodium, or potassium, alkaline earth metals such as magnesium.
- Statin-based drug-containing tablet of the present invention may be in the form of a film coated tablet coated with a film coating base
- the film coating base is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose and polyvinylacetate It may include more than one species.
- the film coating base may use Opadry® including Opadry White, Opadry Pink, Opadry Green, Opadry Orange, Opadry Blue, Opadry Yellow, Opadry Brown, and the like. have.
- the interaction between the two drugs may be a problem when preparing an oral combination preparation including a statin-based drug and an omega-3 fatty acid ester. Therefore, the oral combination preparation of the present invention has a structure in which a tablet containing a statin-based drug is embedded in a capsule containing an omega-3 fatty acid ester, thereby preventing interaction between the two drugs. .
- Tablets containing a statin-based drug of the oral combination preparation of the present invention include a pharmaceutically acceptable excipient, a binder, a disintegrant, a disintegration accelerator, a lubricant, a coating agent, a film coating base, an enteric film coating base, a soft capsule base and Suspending agents of soft capsules; and the like.
- the disintegrant may be used in excess.
- the excess means more than 20% by weight based on the total weight of the tablet including the statin drug.
- the oral combination formulation of the present invention may include a statin-based drug, although it may have an effect on the stability of the tablet by drawing moisture in the air. Since the purified tablet is incorporated into the capsule containing the omega-3 fatty acid ester, even when an excessive disintegrant is used, the tablet is completely blocked from moisture and thus does not affect the stability of the tablet.
- the envelope or envelope of the capsule containing the omega-3 fatty acid ester is arivaba gum, tracacanta gum, karaya gum, gati gum, guar gum, loggerhead bean gum, tara gum, konjac It may be composed of one or more components selected from the group consisting of gum, algin, agar, carrageenan, pullulan, pectin, gellan, mannan, glycerin, gelatin and xanthan gum.
- the envelope may be concentrated glycerin or gelatin (eg, OMACOR ® ).
- the envelope of the capsules may be determined at the state of the art in terms of the type and content of ingredients so that the preparations such as omega-3 fatty acid esters contained therein can have an appropriate disintegration rate and dissolution rate.
- atorvastatin calcium, microcrystalline cellulose, lactose monohydrate and calcium carbonate were mixed in a mixer, mixed with a binder solution (polysorbate 80, hydroxypropyl cellulose), and then a speed mixer granulator. After granulation at 8 ° C., dried at 50 ° C. for 8 hours, and then granulated using a power mill, and then mixed with croscarmellose sodium and magnesium stearate, and then compressed into tablet presses. Thereafter, a polyvinylacetate (PVA) and water were mixed to prepare a coating solution, and the tableted tablet was coated with the coating solution and then dried to prepare an atorvastatin film-coated tablet.
- PVA polyvinylacetate
- the atorvastatin film-coated tablet is embedded therein, and after injecting omega-3 fatty acid ester, the soft capsule molding machine Sealed using.
- Example 1 Contains statins Purification Department (mg) Atorvastatin calcium 21.7 Microcrystalline cellulose 40.0 Lactose Carb 54.5 Calcium carbonate 66.0 Croscarmellose Sodium 12.0 DST - Polysorbate 80 0.8 Hydroxypropyl cellulose 4.0 Magnesium stearate 1.0 refine Coating part (mg) HPMC - PVA 6 Capsule Content solution (mg) Omega-3 1,000 Capsule Outer shell (mg) Carrageenan 200 Concentrated glycerin 50
- HPMC hydroxypropyl methyl cellulose
- atorvastatin calcium, microcrystalline cellulose, lactose hydrate, calcium carbonate and croscarmellose sodium were mixed in a mixer, and mixed with a binder solution (polysorbate 80, hydroxypropyl cellulose). After granulating in a speed mixer granulator, the mixture was dried at 50 ° C. for 8 hours in a dryer, and then granulated using a power mill granulator, followed by post-mixing with 7.5 mg of croscarmellose sodium and magnesium stearate. It was compressed with the following rotary tableting machine.
- hydroxypropylmethylcellulose (HPMC) and water were mixed to prepare a coating solution, and the tableted tablets were coated with the coating solution and then dried to prepare an atorvastatin film-coated tablet. Then, the atorvastatin film-coated tablet incorporation and soft capsule molding process was prepared in the same manner as in Example 1.
- Example 3 Contains statins Purification Department (mg) Atorvastatin calcium 21.7 Microcrystalline cellulose 40 Lactose Carb 51.5 Calcium carbonate 66 Croscarmellose Sodium 15 DST - Polysorbate 80 0.8 Hydroxypropyl cellulose 4 Magnesium stearate One refine Coating part (mg) HPMC 6 PVA - Capsule Content solution (mg) Omega-3 1,000 Capsule Outer shell (mg) Carrageenan 200 Concentrated glycerin 50
- Example 3 It was prepared in the same manner as in Example 3 except that the amount of lactose monohydrate was reduced to 36.5 mg and the amount of croscarmellose sodium was increased to 30 mg in the statin purification unit of Table 2. The croscarmellose sodium was added in half and half to premix and postmix, respectively.
- atorvastatin calcium, calcium carbonate, pregelatinized starch and microcrystalline cellulose were mixed in a mixer, mixed with a binder solution (polysorbate 80, hydroxypropyl cellulose), and then a speed mixer was prepared. After granulating in granulator, it was dried for 8 hours at 50 ° C. in a dryer, and then granulated using a power mill granulator, and then mixed with sodium croscarmellose, sodium starch glycolate, magnesium stearate, and colloidal silicon oxide. The tablet was then compressed using a rotary tablet press. Thereafter, Opadry white (OY-C-7000A) and water were mixed to prepare a coating solution, the tablets were coated with the tableted liquid and then dried to prepare an atorvastatin tablet.
- a binder solution polysorbate 80, hydroxypropyl cellulose
- the atorvastatin tablet was incorporated therein, and the omega-3-acid ethyl ester 90 was injected, followed by the soft capsule. Sealing was carried out using a molding machine.
- Example 6 Contains statins Purification Department (mg) Atorvastatin calcium 10.85 Calcium carbonate 33.0 Croscarmellose sodium 8.0 Starch sodium glycolate 5.0 Pregelatinized starch 20.0 Microcrystalline cellulose 19.60 Polysorbate 80 0.4 Hydroxypropyl cellulose 2.0 Colloidal silicon dioxide 0.65 Magnesium stearate 0.50 refine Coating part (mg) HPMC - Opadray white (OY-C-7000A) 3.0 Capsule Content solution (mg) Omega-3-Acid Ethyl Ester 90 1,000 Capsule Outer shell (mg) gelatin 293.0 Concentrated glycerin 135.0
- rosuvastatin calcium and anhydrous calcium hydrogen phosphate were mixed in a mixer, mixed with microcrystalline cellulose, lactose monohydrate and crospovidone, and then magnesium stearate (extracted from Palm oil) was added and then mixed. After the process, I compressed it with a rotary tablet press. Thereafter, Opadry 03F640026 pink, ethanol and water were mixed to prepare a coating solution, and the tableted tablets were coated with the coating solution and then dried to prepare rosuvastatin tablets.
- the rosuvastatin-coated tablet was incorporated into the inside, and the omega-3-acid ethyl ester 90 was injected. It was sealed using a capsule molding machine.
- Example 7 Contains statins Purification Department (mg) Rosuvastatin Calcium 10.4 Lactose Carb 58.0 Microcrystalline cellulose 15.0 Anhydrous calcium hydrogen phosphate 10.9 Crospovidone 5.0 Magnesium stearate 1.5 refine Coating part (mg) Opadray 03F640026 pink 3.0 Capsule Content solution (mg) Omega-3-Acid Ethyl Ester 90 1,000 Capsule Outer shell (mg) gelatin 293.0 Concentrated glycerin 135.0
- the atorvastatin film-coated tablet Prepared (without atorvastatin coated tablets and capsule formulation).
- a statin-based drug is contained within a pharmaceutical formulation containing an omega-3 fatty acid ester.
- rosuvastatin coated tablets were prepared. (Rosvastatin coated tablet incorporation and capsule molding process omitted).
- Example 2 0 100.72 101.02 100.98 100.82 One 100.81 99.42 101.12 100.62 2 99.98 97.96 100.61 101.21 3 99.25 95.42 100.12 100.42 6 97.03 90.23 99.25 99.72
- Example 1 Example 2 0 100.52 100.92 100.23 100.45 2 100.14 97.56 100.42 100.74 4 100.34 95.21 100.27 100.42 6 99.46 91.12 100.16 100.34 8 99.14 88.13 99.98 100.26 12 97.25 80.42 99.46 99.56 18 96.75 72.48 99.14 99.37
- Example 3 After storing the samples prepared in Example 3 and Comparative Example 3 at room temperature (20 ⁇ 2 °C) and 60 ⁇ 5% relative humidity, the content of atorvastatin calcium for each sample after 0, 1 and 3 months It is shown in Table 7 after the calculation.
- the atorvastatin tablet contained in the soft capsule of Example 3 showed a similar degree of stability as compared to the atorvastatin single tablet of Comparative Example 3.
- Example 3 After storing the samples prepared in Example 3 and Comparative Example 3 at 45 ⁇ 2 °C and 75 ⁇ 5% RH, after calculating the content of atorvastatin calcium for each sample after 0, 1 and 3 months Table 8 shows.
- the atorvastatin tablet contained in the soft capsule of Example 3 showed a similar degree of stability as compared to the atorvastatin single tablet of Comparative Example 3.
- Example 7 After storing the samples prepared in Example 7 and Comparative Example 5 at room temperature (20 ⁇ 2 °C) and 60 ⁇ 5% relative humidity, and after 0, 1 and 3 months, the content of rosuvastatin calcium for each sample After calculation, it is shown in Table 9 below.
- the rosuvastatin tablet contained in the soft capsule of Example 7 showed a similar degree of stability as compared to the rosuvastatin single tablet of Comparative Example 5.
- Example 7 After storing the samples prepared in Example 7 and Comparative Example 5 at 45 ⁇ 2 °C and 75 ⁇ 5% RH, after calculating the content of rosuvastatin calcium for each sample after 0, 1 and 3 months Table 10 shows.
- the rosuvastatin tablet contained in the soft capsule of Example 7 showed a similar degree of stability as compared to the rosuvastatin single tablet of Comparative Example 5.
- Atovastatin calcium according to the time of the samples prepared in Examples 3, 4 and 5 and Comparative Examples 3 and 4 under the following test conditions in accordance with the second method (Korean paddle method, KP) The dissolution rate of was measured. The results are shown in FIG.
- both the combination preparations of Examples 1 and 7 and the tablets of Comparative Examples 1 and 5 completely disintegrated in about 30 minutes.
- the capsules of the examples completely disintegrate in 30 minutes, and the omega-3 fatty acid esters flowed to the outside, and the disintegration degree was excellent. have.
- Example 1 (atorvastatin calcium) and Example 7 (rosuvastatin calcium) according to the first method (rotational sample method) and the second method (general paddle method) of the Korean Pharmacopoeia Dissolution Test method The dissolution rate over time of the sample prepared in) was measured.
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Abstract
Description
실시예1 | |
스타틴계 약물 함유 정제부 (mg) | |
아토바스타틴 칼슘 | 21.7 |
미결정셀룰로오스 | 40.0 |
유당수화물 | 54.5 |
탄산칼슘 | 66.0 |
크로스카멜로오스나트륨 | 12.0 |
DST | - |
폴리소르베이트80 | 0.8 |
히드록시프로필셀룰로오스 | 4.0 |
스테아르산마그네슘 | 1.0 |
정제 코팅부 (mg) | |
HPMC | - |
PVA | 6 |
캡슐제 내용액 (mg) | |
오메가-3 | 1,000 |
캡슐제 외피 (mg) | |
카라기난 | 200 |
농글리세린 | 50 |
실시예3 | |
스타틴계 약물 함유 정제부 (mg) | |
아토바스타틴칼슘 | 21.7 |
미결정셀룰로오스 | 40 |
유당수화물 | 51.5 |
탄산칼슘 | 66 |
크로스카멜로오스나트륨 | 15 |
DST | - |
폴리소르베이트80 | 0.8 |
히드록시프로필셀룰로오스 | 4 |
스테아르산마그네슘 | 1 |
정제 코팅부 (mg) | |
HPMC | 6 |
PVA | - |
캡슐제 내용액 (mg) | |
오메가-3 | 1,000 |
캡슐제 외피 (mg) | |
카라기난 | 200 |
농글리세린 | 50 |
실시예 6 | ||
스타틴계 약물 함유 정제부 (mg) | ||
아토바스타틴 칼슘 | 10.85 | |
탄산칼슘 | 33.0 | |
크로스카멜로오스 나트륨 | 8.0 | |
전분 글리콜산 나트륨 | 5.0 | |
전호화 전분 | 20.0 | |
미결정셀룰로오스 | 19.60 | |
폴리소르베이트 80 | 0.4 | |
히드록시프로필셀룰로오스 | 2.0 | |
콜로이드성 이산화규소 | 0.65 | |
스테아르산 마그네슘 | 0.50 | |
정제 코팅부 (mg) | ||
HPMC | - | |
오파드라이흰색(OY-C-7000A) | 3.0 | |
캡슐제 내용액 (mg) | ||
오메가-3-산에틸 에스테르 90 | 1,000 | |
캡슐제 외피 (mg) | ||
젤라틴 | 293.0 | |
농글리세린 | 135.0 |
실시예 7 | ||
스타틴계 약물 함유 정제부 (mg) | ||
로수바스타틴 칼슘 | 10.4 | |
유당수화물 | 58.0 | |
미결정셀룰로오스 | 15.0 | |
무수인산수소칼슘 | 10.9 | |
크로스포비돈 | 5.0 | |
스테아르산 마그네슘 | 1.5 | |
정제 코팅부 (mg) | ||
오파드라이 03F640026 핑크 | 3.0 | |
캡슐제 내용액 (mg) | ||
오메가-3-산에틸 에스테르 90 | 1,000 | |
캡슐제 외피 (mg) | ||
젤라틴 | 293.0 | |
농글리세린 | 135.0 |
아토바스타틴칼슘의 함량( % ) | ||||
시간(month) | 비교예1 | 비교예2 | 실시예1 | 실시예2 |
0 | 100.72 | 101.02 | 100.98 | 100.82 |
1 | 100.81 | 99.42 | 101.12 | 100.62 |
2 | 99.98 | 97.96 | 100.61 | 101.21 |
3 | 99.25 | 95.42 | 100.12 | 100.42 |
6 | 97.03 | 90.23 | 99.25 | 99.72 |
아토바스타틴칼슘의 함량( % ) | ||||
시간(month) | 비교예1 | 비교예2 | 실시예1 | 실시예2 |
0 | 100.52 | 100.92 | 100.23 | 100.45 |
2 | 100.14 | 97.56 | 100.42 | 100.74 |
4 | 100.34 | 95.21 | 100.27 | 100.42 |
6 | 99.46 | 91.12 | 100.16 | 100.34 |
8 | 99.14 | 88.13 | 99.98 | 100.26 |
12 | 97.25 | 80.42 | 99.46 | 99.56 |
18 | 96.75 | 72.48 | 99.14 | 99.37 |
아토바스타틴칼슘의 함량( % ) | ||
시간(month) | 비교예 3 | 실시예 3 |
0 | 103.7 ± 1.3 | 102.0 ± 0.9 |
1 | 100.6 ± 3.4 | 104.2 ± 0.9 |
3 | 102.4 ± 0.7 | 103.3 ± 0.4 |
아토바스타틴칼슘의 함량( % ) | ||
시간(month) | 비교예 3 | 실시예 3 |
0 | 103.7 ± 1.3 | 102.0 ± 0.9 |
1 | 104.0 ± 1.4 | 102.6 ± 0.9 |
3 | 99.8 ± 1.0 | 99.7 ± 0.3 |
로수바스타틴칼슘의 함량( % ) | ||
시간(month) | 비교예 5 | 실시예 7 |
0 | 100.2 ± 1.1 | 101.7 ± 1.4 |
1 | 99.8 ± 1.3 | 101.5 ± 1.3 |
3 | 99.5 ± 1.4 | 102.3 ± 1.2 |
로수바스타틴칼슘의 함량( % ) | ||
시간(month) | 비교예 5 | 실시예 7 |
0 | 99.8 ± 0.9 | 102.1 ± 1.1 |
1 | 101.4 ± 1.2 | 100.8 ± 0.7 |
3 | 100.5 ± 1.1 | 101.2 ± 1.3 |
Claims (12)
- 오메가-3 지방산 에스테르 함유 캡슐제; 및 상기 캡슐제 내부에 함입되어 있는 스타틴 계열의 약물 함유 정제를 구비한 경구용 복합제제.
- 제1항에 있어서,상기 스타틴 계열의 약물은 아토바스타틴(Atorvastatin), 로수바스타틴(Rosuvastatin), 로바스타틴(Lovastatin), 심바스타틴(Simvastatin), 프라바스타틴(Pravastatin), 플루바스타틴(Fluvastatin) 및 이의 약제학적으로 허용 가능한 염으로 이루어진 군으로부터 선택된 1종 이상인 것인, 경구용 복합제제.
- 제1항에 있어서,상기 스타틴 계열의 약물 함유 정제는 붕해제를 더 포함하는 것인, 경구용 복합제제.
- 제3항에 있어서,상기 붕해제는 히드록시프로필메칠셀룰로오스, 옥수수전분, 한천가루 메칠셀룰로오스, 벤토나이트 히드록시프로필스타치, 카르복시메칠셀룰로오스나트륨, 알긴산나트륨, 카르복시메칠셀룰로오스칼슘 구연산칼슘, 라우릴황산나트륨 무수규산, 덱스트란, 이온교환수지, 초산폴리비닐, 포름알데히드처리 카제인, 아밀로오스 구아르고무(Guar gum), 젓조 폴리비닐피롤리돈, 인산칼슘 겔화전분, 아라비아고무, 아밀로펙틴, 펙틴 폴리인산나트륨, 에칠셀룰로오스, 백당, 규산마그네슘알루미늄, 디-소르비톨액, 크로스포비돈, DST, 크로스 카멜로오스 나트륨 및 전분글리콜산 나트륨으로 이루어진 그룹으로부터 선택되는 1종 이상인 것인, 경구용 복합제제.
- 제3항에 있어서,상기 붕해제는 크로스포비돈, DST, 크로스 카멜로오스 나트륨 및 전분글리콜산 나트륨으로 이루어진 그룹으로부터 선택되는 1종 이상인 것인, 경구용 복합제제.
- 제1항에 있어서,상기 오메가-3 지방산 에스테르가 경구용 복합제제 전체 중량에 대하여 30 내지 80 중량%로 포함되는 것인, 경구용 복합제제.
- 제1항에 있어서,상기 스타틴 계열의 약물이 경구용 복합제제 전체 중량에 대하여 0.5 내지 10 중량%로 포함되는 것인, 경구용 복합제제.
- 제1항에 있어서,상기 스타틴 계열의 약물 함유 정제는 필름코팅기제로 코팅된 것인, 경구용 복합제제.
- 제8항에 있어서,상기 필름코팅기제는 히드록시프로필셀룰로오스, 히드록시프로필메칠셀룰로오스, 에틸셀룰로오스 및 폴리비닐아세테이트로 이루어진 군으로부터 선택된 1종 이상인 것인, 경구용 복합제제.
- 제1항에 있어서,상기 캡슐제의 외피는 아리바아검, 트라카칸타검, 카라야검, 가티검, 구아검, 로거스트콩검, 타라검, 곤약검, 알긴, 한천, 카라기난, 플루란, 펙틴, 젤란, 만난, 글리세린, 젤라틴 및 잔탄검으로 이루어진 군으로부터 선택된 1종 이상의 성분으로 이루어진 것인, 경구용 복합제제.
- 제1항에 있어서,상기 복합제제에 포함된 스타틴 계열의 약물이 일반패들법에 따른 조건에서 30분 내지 1시간에 복합제제 총 중량 기준으로 70~85 중량%가 용출되는 것인, 경구용 복합제제.
- 제1항에 있어서,상기 복합제제에 포함된 스타틴 계열의 약물이 회전검체통법에 따른 조건에서 30분 내지 1시간에 복합제제 총 중량 기준으로 70~85 중량%가 용출되는 것인, 경구용 복합제제.
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KR1020157022218A KR101752700B1 (ko) | 2014-08-13 | 2015-08-13 | 오메가-3 지방산 에스테르 및 스타틴계 약물을 포함하는 경구용 복합제제 |
CN201580055280.9A CN106794149A (zh) | 2014-08-13 | 2015-08-13 | 含ω‑3脂肪酸酯和他汀类的口服给药复合制剂 |
CN202210667299.0A CN115025060A (zh) | 2014-08-13 | 2015-08-13 | 含ω-3脂肪酸酯和他汀类的口服给药复合制剂 |
PH12017500269A PH12017500269B1 (en) | 2014-08-13 | 2017-02-13 | Composite formulation for oral administration comprising omega-3 fatty acid esters and statins |
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WO2017135739A1 (ko) * | 2016-02-05 | 2017-08-10 | 한국유나이티드제약 주식회사 | 지용성 약물 및 방유성 기제가 코팅된 고형제제를 포함하는 경구용 복합제제 |
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WO2017171484A1 (ko) * | 2016-03-31 | 2017-10-05 | 한미약품 주식회사 | 오메가-3 지방산 또는 이의 에스테르, 및 하이드록시메틸글루타릴 코엔자임에이 환원효소 억제제를 포함하는 경구용 복합 제제 |
KR102240935B1 (ko) | 2019-06-04 | 2021-04-15 | (주) 노바렉스 | 핑거루트 추출물을 유효성분으로 함유하는 정제의 붕해성 및 저장안정성 향상을 위한 기술 |
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PH12017500269A1 (en) | 2017-07-03 |
CN115025060A (zh) | 2022-09-09 |
KR101752700B1 (ko) | 2017-07-03 |
KR20160030383A (ko) | 2016-03-17 |
PH12017500269B1 (en) | 2017-07-03 |
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