KR20170069336A - Ezetimibe solid dispersion for tablets having improved solubility and preparing method of the same - Google Patents
Ezetimibe solid dispersion for tablets having improved solubility and preparing method of the same Download PDFInfo
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- KR20170069336A KR20170069336A KR1020150175901A KR20150175901A KR20170069336A KR 20170069336 A KR20170069336 A KR 20170069336A KR 1020150175901 A KR1020150175901 A KR 1020150175901A KR 20150175901 A KR20150175901 A KR 20150175901A KR 20170069336 A KR20170069336 A KR 20170069336A
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- ezetimibe
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- pvpk30
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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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
- A61K9/10—Dispersions; Emulsions
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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Abstract
The present invention relates to a solid preparation for tablets of tablets and a method of preparing the same, characterized in that they contain ezetimibe, PVPK30 and Poloxamer 188 in a weight ratio of 0.5 to 2: 1 to 3: 0.5 to 2, The solid content of the solid preparation of the ezetimibe prepared by the spray drying method after mixing the above ratios was remarkably improved, and in the case of tablets prepared by tabletting the solid dispersion of the solid preparation of ezetimibe, Can be greatly increased.
Description
The present invention relates to a solid dispersion for tablets having improved solubility of hardly soluble ezetimibe and a process for producing the solid dispersion.
Ezetimibe is a low-density lipoprotein (LDL) cholesterol-lowering drug that is used for dyslipidemia such as hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and LDL cholesterol To 18%. The efficacy of ezetimibe is lower than that of statins, which are most commonly used in the treatment of dyslipidemia, but it is considered to be safer than statins in that there are no muscle side effects. It is usually recommended as a secondary drug, not a primary drug, and is used in combination with statin alone when it is less effective.
Ezetimibe acts on the cholesterol transporter NPC1L1 (Niemann-Pick C1-like 1), which is involved in the absorption of cholesterol and cholesterol in the small intestine, and inhibits absorption of food or bile cholesterol through the small intestine I have a mechanism.
Unlike statin, an HMG-CoA reductase inhibitor that inhibits cholesterol biosynthesis in the liver, ezetimibe selectively inhibits the absorption of cholesterol in the small intestine, and its mechanism of action is different.
Thus, the use of ezetimibe in combination with statin can significantly reduce LDL-C levels through complementary effects.
In addition, as vistatis drugs have been shown to be effective for the prevention of cardiovascular disease for the first time, the availability of statins and vistatin combinations for cardiovascular disease is being reevaluated.
Therefore, ezetimibe is a very important drug in the treatment of dyslipidemia-related diseases, but dissolved drugs are absorbed by more than 90% in the intestinal tract. If the maximum dose needs to be dissolved, more than 250 mL of water is needed. biopharmaceutical classification system class II.
Therefore, in order to increase the therapeutic efficiency of ezetimibe, studies are required to improve the solubility of ezetimibe.
Accordingly, it is an object of the present invention to provide an ezetimibe solid dispersion for tablets having improved solubility.
It is another object of the present invention to provide a method for producing an ezetimibe solid dispersion for tablets having improved solubility.
In order to accomplish the above object, the present invention provides a pharmaceutical composition containing ezetimibe, polyvinylpyrrolidone K30, PVPK30, and Poloxamer 188 in a weight ratio of 0.5: 2: 1 to 3: 0.5: 2 And a solidifying agent for tablets.
In order to achieve the above-mentioned further object, the present invention provides a method for producing a polyvinylpyrrolidone K30 (polyvinylpyrrolidone K30, PVPK30) and Poloxamer 188 (0.5 to 2: 1 to 3: 0.5 to 2) To prepare a spray-drying liquid; And spray-drying the spray-drying liquid to prepare a solid dispersion; The present invention provides a method for preparing an edible solid preparation for tablets.
According to the present invention, the optimum ratio of ezetimibe, PVPK30, and Poloxamer 188 is 1: 2: 1. The solid dispersion prepared by the spray drying method after mixing at the above ratios has greatly improved fluidity, Tableted tablets exhibit excellent dissolution profiles, thus greatly increasing the therapeutic efficacy of ezetimibe.
Figure 1 is a graph showing the results of a comparison of the concentrations of the antimicrobial agents such as ezetimibe, polyvinylpyrrolidone K30, PVPK30, and Pollock, prepared in optimized ratios according to the present invention in pH 4.5 buffer containing 0.45% sodium lauryl sulfate (SLS) The results of confirming the dissolution profiles of tablets tableted with the solid dispersion containing SOROM 188 (poloxamer 188)
Figure 2 shows the results of a tablet formulation of a solid dispersion comprising ezetimibe, PVPK30 and Polosamer 188 prepared in optimized proportions according to the invention in pure water containing 0.45% sodium laurylsulphate (SLS) The result of confirming the dissolution profile,
Figure 3 shows the elution profile of tablets tableted with a solid dispersion comprising ezetimibe, PVPK30 and Polosamer 188 prepared in optimized proportions according to the present invention in a pH 6.8 buffer containing 0.45% sodium laurylsulphate (SLS) .
Figure 4 shows the dissolution profiles of tablets tableted with solid dispersions containing ezetimibe, PVPK30 and Polosamer 188 prepared in optimized ratios according to the invention in a pH 1.2 buffer containing 0.45% sodium laurylsulphate (SLS) .
Hereinafter, the present invention will be described in detail.
The inventors of the present invention conducted studies to improve the solubility of the poorly soluble drug ezetimibe. The inventors of the present invention found that the solubility of the solid dispersion prepared by mixing the ezetimibe, PVPK30 and Poloxamer 188 in an optimum ratio, It was confirmed that the tablets prepared by tableting the above solid dispersion were improved in the dissolution rate, thus completing the present invention.
Generally poorly soluble drugs are prepared with solid dispersion to improve solubility. The solid dispersion means a solid form composed of two or more components, and is mainly composed of a water-soluble polymer and a poorly soluble drug. The drug is dispersed in the molecular state in the molten water-soluble polymer, and solidifies in an amorphous (mostly) or crystalline form. It is powdered and used to make tablets or capsules. When the solid dispersion is added to water, the water-soluble carrier is rapidly melted, and the insoluble molecules are surrounded by water, thereby improving the solubility.
The spray drying method is one of the methods of preparing a solid dispersion, in which a solution or a suspension is quickly dried with a high-temperature gas and then evaporated to obtain the remaining powder.
It is one of the preferred methods for heat-sensitive components because of its very short contact with high temperatures, which is less affected by heat.
The above polyvinylpyrrolidone K30 (polyvinylpyrrolidone K30, PVPK30) is white or pale yellow, hygroscopic and fast-dissolving in water. It is usually used as a binder and is the preferred excipient for the direct method. When used in direct method, it forms a hard, transparent, glazed film. It also has the property of stabilizing emulsions, suspensions and dispersions. In other words, it has the effect of controlling the viscosity to protect the material.
The poloxamer is usually used as a wetting agent and is used as an emulsifier or solubilizer. It has an effect of improving solubility and absorption effect and enhancing bioavailability in tablets having low solubility and is therefore suitable for use in the production of solid dispersion. In case of low content, it is well soluble in water and each molecule is dispersed in micelle form. In the case of a high content, it forms a gel and has the effect of aggregating a large number of molecules. It also acts as a surfactant and causes formation of dispersion, stabilization, foaming, and emulsion formation.
Accordingly, the present invention is characterized in that it comprises ezetimibe, polyvinylpyrrolidone K30, PVPK30 and Poloxamer 188 in a weight ratio of 0.5 to 2: 1 to 3: 0.5 to 2 Thereby providing an edetemib solid dispersion for purification.
More preferably, ezetimibe, PVPK30 and Poloxamer 188 in a weight ratio of 1: 2: 1.
If the PVPK30 or the poloxamer is contained in an excess or less than the above range, the produced solid dispersion may exhibit electrostatic phenomenon and low flowability, and may cause problems of agglomeration with the drug or high viscosity.
The ezetimibe solid dispersion according to the present invention is sprayed under the conditions of an injection temperature of 100 to 120 DEG C, an ejection temperature of 70 to 90 DEG C, two fluid nozzles, a pump of 1.0 to 5.0 mL / min and an aspiration rate of 100% And may be produced by a spray drying method using a spray dryer.
The ezetimibe solid dispersion according to the present invention may be a microparticle having an average diameter of 10 μm to 100 μm. When the average diameter is smaller than the above range, the electrostatic phenomenon and low flowability may be exhibited, The problem may be caused to be difficult, and in the case where it is larger, there may arise a problem that it can not be uniformly mixed with the excipient in mixing with the excipient.
In addition, the present invention relates to a process for preparing a spray-drying liquid by mixing ezetimibe, polyvinylpyrrolidone K30, PVPK30 and Poloxamer 188 in a weight ratio of 0.5: 2: 1 to 3: 0.5: 2 Producing; And spray-drying the spray-dried liquid to prepare a solid dispersion. The method for preparing the solid dispersion of tablets according to the present invention comprises the steps of:
BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
< Reference example 1> Solvent selection
In accordance with the Pharmaceuticals Residual Solvent Standard, all residual solvents should be removed to a level appropriate to the product standard, quality control and quality control standards or other quality standards. Ethanol with low toxicity and high solubility was selected as solubilizing solvent in the preparation of spray liquid of ezetimibe. The classification of residual solvents in accordance with the Guidelines for Drug Residue Solvent is divided into three categories, which are classified as Category 3: Low Toxic Solvents. In other words, ethanol is less toxic and less dangerous to the human body. If the amount is less than 50mg per day, it can be used without setting the exposure limit concentration.
When ethanol was used as a solvent in the spray drying method, it was expected that most of the ethanol would evaporate because of its rapid evaporation rate.
< Example 1> Ezetimibe , PVPK30 And the optimum ratio of poloxamer 188
1. As an excipient Polyvinylpyrrolidone K30 ( polyvinylpyrrolidone K30, PVPK30 ) use
PVPK30, an excipient in which the solubility of ezetimibe was increased in the preparation of a solid dispersion of ezetimibe, was selected by referring to a previously known paper (Int J Pharm Pharm Sci, Vol 5, Suppl 2, 331-335).
A spray-drying liquid was prepared by mixing 20 g of drug and excipient into 100 mL of ethanol at a weight ratio of ezetimibe: PVPK30 = 1: 3. 5 g of the drug, ezetimibe, was first added to ethanol and completely dissolved using a magnetic bar, followed by the addition of 15 g of PVPK30 and complete dissolution of the two substances for 10 minutes. And spray drying was carried out using a spray dryer (Buchi mini spray dryer B-191, 1994, Buchi Co., Flawil, Switzerland).
The spray drying conditions were set at an injection temperature of 105 ° C., a discharge temperature of 75 ° C., two fluid nozzles, a pump of 1.2 ml / min, and an aspiration rate of 100%.
As a result, a solid dispersion of ezetimibe was obtained, but the solid dispersion had a very small average diameter of less than 10 mu m, thereby exhibiting electrostatic phenomenon and low flowability. In addition, due to low flowability, it was difficult to obtain a solid dispersion and the yield was poor. That is, a material which is not suitable for preparing tablets.
2. Poloxamer 188 as an excipient ( poloxamer 188) use
In order to obtain a solid dispersion having an ideal physical property using another excipient, Poloxamer 188, which is another excipient used in the production of solid dispersion, was selected from the article described in 1. of Example 1 above. A spray-drying liquid was prepared in the same manner as in 1. of Example 1 above. 20 g of drug and excipient were mixed with 100 mL of ethanol at a weight ratio of ezetimibe: Poloxamer 188 = 1: 3 to prepare a spray-drying liquid, which was completely dissolved and spray-dried.
As a result, Poloxamer 188 and ezetimibe aggregated with each other to form a gel, which stuck to the cyclone of the spray dryer, and the viscosity was so high that it could not be obtained at all.
3. As an excipient PVPK30 and Poloxamer 188 mixed use
A solid dispersion was prepared by mixing 10 g of PVPK30 and 5 g of Poloxamer 188 in the same manner as in Example 1,
As a result, it was confirmed that a solid dispersion having improved physical properties was obtained when an excipient mixed with PVPK30 and Poloxamer 188 was used. Further, to determine the proper ratio between the two excipients, spray drying was carried out by varying the content of Poloxamer 188 in the spray dried liquid as shown in Table 1 below.
As a result, when the content of Poloxamer 188 was 2.5 g or 4 g, the viscosity of the resulting solid dispersion became excessively high, and when the content of Poloxamer 188 was 7 g, the particle size of the solid dispersion became small, there was. When the content of Poloxamer 188 was 5 g, a solid dispersion having desired physical properties was obtained.
Thus, based on the results, the optimal ratios of ezetimibe, PVPK30 and Poloxamer 188 were determined. The determined optimum ratio was ezetimibe: PVPK30: poloxamer 188 = 1: 2: 1.
< Example 2> solid Dispersion Property measurement
1. Fluidity flowability ) evaluation
If there is a problem in the flowability of the solid dispersion, there may be a deviation in the properties (mass, hardness, etc.) of the tablets prepared with the solid dispersion or a product quality problem related to separation, mixing and content uniformity. Therefore, the hausner ratio, which can be obtained by using the bulk density and the tap density, is used to evaluate the fluidity of the solid dispersion. It can be seen that the ezetimibe has very low flowability since the actual ezetimibe has a very high value of the value of the housing ratio of 1.56.
The evaluation criteria of the flowability according to the value of the ratio of the housing ratio are shown in Table 2 below.
In the case of the solid dispersion comprising the ezetimibe prepared in Example 1 and PVPK30, the Hauser ratio value was 1.458. In other words, the improvement of flowability was not achieved. However, in the case of the solid dispersion prepared from ezetimibe, PVPK30 and Poloxamer 188 prepared in Example 3, the fluidity of the solid dispersion was improved to 1.289.
< Example 3> Preparation of tablets and measurement of physical properties
Based on the results obtained in Example 2, tablets were prepared by tabletting the solid dispersion prepared from ezetimibe, PVPK30, and Poloxamer 188 prepared in Example 3, above.
The tablets were compressed into a single punch tablet machine (Erweka AR 401, Erweka, Germany), and the solid dispersions and the excipients used for tabletting were mixed directly to give an appropriate ratio, punch) and then compressed at a constant pressure.
PVPK30 (ratio = 1: 3) was mixed with the solid dispersion (T1) containing the prepared ezetimibe, PVPK30 and poloxamer 188 (ratio = 1: 2: 1) (T2) containing the same amount of the excipient and the same amount of the pure ezetimibe (10 mg), and the same ratio of excipients was administered to the tablets without spray drying T3) was used as a sample to determine the physical properties of the tablets.
(
Ezetimibe
+
PVPK30
+ Pollock Sommer 188)
(
Ezetimibe
+
PVPK30
)
(pure
Ezetimibe
)
(Avicel PH-101)
(Aerosil R972)
(sodium lauryl sulfate, SLS)
* API: active pharmaceutical ingredients
The dissolution conditions were determined by the FDA (Food and Drug Administration) dissolution test method, and the paddle method was used. The rate was 50 rpm, the elution volume was 500 mL, the temperature was 37.5 ° C., the sampling time was 10, 20, 30, Respectively. The composition of the eluate is distilled water and buffer solution containing 0.45% SLS. The buffer solution is the standard solution described in the KPEK General Tests: 75. Standard product, reagent solution, standard solution for volume analysis, standard solution, color comparison solution, optical filter for wavelength and transmittance correction, PH 1.2 hydrochloric acid hydrochloric acid buffer, pH 4.5 acetic acid / sodium acetate buffer or pH 6.8 phosphate buffer described in the meter / container, sterilization method and aseptic procedure were used.
As a result, as shown in FIGS. 1 to 4, it was confirmed that the solid dispersions T1 and T2 exhibited a higher dissolution rate than T3 at the respective pHs, and thus the dissolution rate was improved by spray drying. In addition, when the dissolution profiles of T1 and T2 in the buffer solution (FIGS. 1, 3 and 4) were compared, it was found that the T1 dissolution profile of the solid dispersion of the present invention was faster, The dissolution rate was improved.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. It is to be understood that various modifications and changes may be made without departing from the scope of the appended claims.
Claims (4)
The ezetimibe solid dispersion is prepared by spray drying at an injection temperature of 100 to 120 캜, an outlet temperature of 70 to 90 캜, two fluid nozzles, a pump of 1.0 to 5.0 mL / min, and an aspiration rate of 100% ≪ tb >< / TABLE >
Wherein the solid dispersion of ezetimibe is a microparticle having an average diameter of 10 mu m to 100 mu m.
And spray-drying the spray-dried liquid to prepare a solid dispersion.
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| KR1020150175901A KR20170069336A (en) | 2015-12-10 | 2015-12-10 | Ezetimibe solid dispersion for tablets having improved solubility and preparing method of the same |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110917156A (en) * | 2019-12-18 | 2020-03-27 | 乐普制药科技有限公司 | Ezetimibe buccal tablet and preparation method thereof |
| CN111803458A (en) * | 2020-08-10 | 2020-10-23 | 北京福元医药股份有限公司 | Ezetimibe pharmaceutical preparation |
-
2015
- 2015-12-10 KR KR1020150175901A patent/KR20170069336A/en not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110917156A (en) * | 2019-12-18 | 2020-03-27 | 乐普制药科技有限公司 | Ezetimibe buccal tablet and preparation method thereof |
| CN111803458A (en) * | 2020-08-10 | 2020-10-23 | 北京福元医药股份有限公司 | Ezetimibe pharmaceutical preparation |
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