WO2010144066A1 - Method for the preparation of ezetimib nanocrystals - Google Patents
Method for the preparation of ezetimib nanocrystals Download PDFInfo
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- WO2010144066A1 WO2010144066A1 PCT/TR2010/000106 TR2010000106W WO2010144066A1 WO 2010144066 A1 WO2010144066 A1 WO 2010144066A1 TR 2010000106 W TR2010000106 W TR 2010000106W WO 2010144066 A1 WO2010144066 A1 WO 2010144066A1
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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
- 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
- A61K9/145—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 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
Definitions
- the present invention relates to a method for the preparation of nanocrystals of ezetimibe or ' its pharmaceutically acceptable salts and pharmaceutical formulations of ezetimibe comprising the nanocrystals prepared with this method.
- ezetimibe is (3R,4S)-l-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one and its chemical formula is shown below.
- Ezetimibe is used as a hypocholesterolemic agent for the treatment and prevention of atherosclerosis [US2006/70234996 A 1,2006].
- Ezetimibe is the first lipid-lowering drug that inhibits absorption of biliary and dietary-dependent cholesterol from the small intestine [B. Salisbury et al. Atherosclerosis, 115(1), 45-63, 1995].
- ezetimibe alone or combined with the statins was approved for use in the treatment of primary hypercholesterolemia in
- Tablet formulations which contain 10 mg ezetimibe are available on the market (Zetia , Merck/Schering-Plough Pharmaceuticals, USA; Ezetrol ® Merck/Schering-Plough Pharmaceuticals, Turkiye). Also, a combination of ezetimibe and simvastatin (10 mg ezetimibe, 10 mg simvastatin containing tablet) is on the market (Vytorin ® , Merck/Schering- Plough Pharmaceuticals, USA).
- Ezetimibe' s mechanism of action is different from other cholesterol lowering drugs; it does not inhibit cholesterol synthesis in the liver or does not increase bile acid excretion. Instead of this, it reduces blood cholesterol level by inhibiting the absorption of cholesterol in the small intestine. This distinct mechanism is complementary to that of the HMG-CoA reductase inhibitors which inhibits cholesterol synthesis [US2006/70234996 A 1,2006].
- Ezetimib is a new class lipid lowering compound that selectively inhibits intestinal uptake of cholesterol and related phytosterols. It inhibits absorption of biliary and dietary cholesterol from the small intestine effectively, without affecting the absorption of fat soluble vitamins (A, D, E, K vitamins), triglycerides and bile acids.
- Ezetimibe is a class II drug as defined by the Biopharmaceutical Classification System (BCS), which has low solubility and high permeability. The absolute bioavailability of ezetimibe could not be determined because of its very low solubility in water.
- BCS Biopharmaceutical Classification System
- Nanocrystal Technology Bioavailability of the pharmaceutical active ingredient is associated with its solubility.
- poorly water soluble or insoluble drugs are expected to have low oral bioavailability [H. Lieberman et al. Pharmaceutical Dosage Forms, 1980].
- Solubility of poorly water soluble drugs in gastrointestinal fluids will take a long time, its dissolution will be low, consecutively, because the drug is not completely soluble, it will not be able to show the pharmacological effect.
- drug bioavailability may be increased.
- Adverse effect is usually proportional to the concentration of the active drug substance; thus, reducing the concentration of the active drug substance can increase the safety for patients [D. Coppola, Pharm. Tech., 27 (11) 20, 2003].
- Dissolution and bioavailability of poorly water soluble drugs can be improved by reducing particle size.
- Nanocrystal technology does not increase dissolution rate like solid dispersions due to amorphous structure. It leads to an increase in dissolution rate depending on the increase in surface area obtained by reduction of the particle size of the crystal structured active drug substance down to the nano size range [H. Waard et al. J. Control. Release, 128, 179-183, 2008].
- Nanocrystal dispersions contain water, active drug substances and a stabilizer. If necessary, other substances such as buffers, salts and sugars can be added. They are stable systems because of the use of a stabilizer that prevents reagregragation of active drug substances during the preparation step [http://www.elan.corn/Images/Elan_Technology 07yl tcm3- 17145.pdf], Drug nanocrystals are usually produced in liquid dispersion media (as in the precipitation [M. Trottaa, J. Control. Release, 76, 119-128, 2001] and disintegration methods). Suspension of drug nanocrystals in liquid can be stabilized by adding surface active substances or polymers.
- Nanocrystals can be administered via several routes. Oral administration is possible in the form of tablets, capsules, sachets or powder; preferably in the form of a tablet. Nanosuspensions can also be administered via the intravenous route due to very small particle size, and in this way, bioavailability can reach 100 %.
- the scope of this invention is primarily; preparation of a pharmaceutical formulation by .using at least one hypocholesterolemic agent (ezetimibe) and one surface active (solubilizing) agent or stabilizer and with application of various pharmaceutical methods, while protecting the crystal structure of the active drug substance.
- the scope of this invention includes the protection of ezetimibe crystal structure and preparation of formulations whose average particle size of ezetimibe nanocrystals is lower than 2000 nm.
- one of the most important facts of the present invention is the preparation of pharmaceutical formulations which comprise ezetimibe nanocrystals without having any solubilizing agents.
- This invention also discloses the use of different methods for preparing ezetimibe nanocrystals. From these methods, high-speed homogenization methods, such as ultrasonic and mechanical high speed homogenization methods were used for the preparation of ezetimibe nanocrystals for the first time in this study.
- this invention includes the use of pharmaceutical formulations which comprise ezetimibe nanocrystals for treating inhibition of cholesterol absorption.
- pharmaceutical formulations which comprise ezetimibe nanocrystals for treating inhibition of cholesterol absorption.
- the objective of the present invention was the improvement of the solubility, dissolution rate, and hence, bioavailability of ezetimibe by decreasing particle size and preparing nanocrystal formulations.
- the tablets prepared with nanocrystal formulations were different from the market products in that they did not contain any solubilizing agent like SDS.
- Pluronic F 127 which was used in the formulations, is Poloxamer 407.
- a suspension of ezetimibe and poloxamer F 127 1:1 (w/w) was prepared in distilled water to a final concentration of 3 % (w/v). To obtain a homogeneous suspension, the suspension was mixed by a magnetic stirrer for half an hour. The suspension was mixed by a High Speed Homogenizer (Ultraturrax® T25 Basic, IKA Labortechnik, Germany) at 11000 rpm for 3 minutes. The dispersion medium was then removed by lyophilization for 72 hours at -55 0 C at 0.01 mmHg pressure. Ultrasonic High Speed Homogenization Method (UP)
- a suspension of ezetimibe and poloxamer F 127 1 :1 (w/w) was prepared in distilled water to a final concentration of 3 % (w/v). To obtain a homogeneous suspension, the suspension was mixed by a magnetic stirrer for half an hour. The suspension was mixed by an Ultrasonic Probe at 20% power for 1 minute. The dispersion medium was then removed by lyophilization for 72 hours at -55 0 C at 0.01 mmHg pressure.
- a suspension of ezetimibe and poloxamer F 127 1 :1 (w/w) was prepared in distilled water, with a final concentration of 3 % (w/v). To obtain a homogeneous suspension, the suspension was mixed by a magnetic stirrer for half an hour. The suspension was mixed by 16 agate balls, 20 mm in diameter, for 4 minutes. The dispersion medium was then removed by lyophilization for 72 hours at -55 0 C at 0.01 mmHg pressure.
- tablet formulations were prepared using the nanocrystals that were obtained by ball milling and Ultrasonic high speed homogenization methods.
- a tablet formulation of the physical mixture was also prepared.
- the formulations, which were prepared by means of wet granulation, have been pressed into tablets using eccentric tablet machines.
- Table 1 The composition of the tablet formulation comprising nanocrystals prepared by the Ultrasonic High Speed Homogenization method
- composition of the tablet formulation comprising nanocrystals prepared by the Ball Milling method
- composition of the tablet formulation comprising nanocrystals prepared from the physical mixture Table 4.
- composition of the tablet formulation comprising nanocrystals prepared by physical mixture
- Ezetimibe nanocrystals were analyzed using a Fourier Transform Infrared Spectrometer (Perkin Emler, USA). The infrared spectra were detected over the wavenumber range of 4000 - 650 cm "1 .
- X-ray diffractograms of each formulation were recorded using an Ultima X-Ray Diffractometer. Standart runs using a 40 kV voltage and a scanning rate of 0.02° min 1 over a 2 ⁇ range of 0 - 40° were used.
- Thermal properties of the powder samples were investigated using a DSC Q 100 (TA Instruments, USA). Approximately, a sample of 5 - 20 mg was weighed in an aluminum pan, and a heating rate of 10 0 C / min was employed in the range of 10 - 250 0 C. Analyses were performed under a nitrogen purge (50 ml.min "1 ). Empty aluminum pans were used as a reference. The change of heat of the samples was monitored with respect to change in temperature.
- a Malvern Zeta Sizer (Nano Series Nano ZS) was utilized. A preweighed (10 - 30 mg) amount of the nanocrystal formulations prepared with different methods (both mechanical and ultrasonic High Speed Homogenization, ball milling) was dispersed in water up to a volume of 5 ml in a volumetric flask. These aqueous dispersions were then vortexed for 3 minutes and particle size analysis was carried out by 3 consecutive measurements for each sample.
- the dissolution studies were carried out utilizing the USP apparatus II (pedal) method, all stirred at 50 rpm at 37 ⁇ 0.5 °C.
- the % dissolved ezetimibe amount was calculated using the amount of ezetimibe in 20 mg nanocrystal formulations.
- Characteristic C O tension bands of the carbonyl group at 1760 - 1690 cm "1 ,
- a Malvern Zeta Sizer (Nano Series Nano ZS) was utilized in order to determine the particle size distribution of the formulations.
- the average particle size values regarding these formulations are given in Table 5. According to these data, the average particle size of the nanocrystal formulations decreased to a significant extent as compared to ezetimibe and physical mixture, and the difference in particle size could be considered as statistically significant.
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Abstract
The present invention relates to a method for the preparation of nanocrystals of ezetimibe or its pharmaceutically acceptable salt and pharmaceutical formulations of ezetimibe comprising the nanocrystals prepared with this method. The methods involve ultrasonic high speed homogenization or mechanical high speed homogenization.
Description
METHOD FOR THE PREPARATION OF EZETIMIB NANOCRYSTALS
FIELD OF THE INVENTION
The present invention relates to a method for the preparation of nanocrystals of ezetimibe or ' its pharmaceutically acceptable salts and pharmaceutical formulations of ezetimibe comprising the nanocrystals prepared with this method.
BACKGROUND OF THE INVENTION
Chemical name of ezetimibe is (3R,4S)-l-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one and its chemical formula is shown below.
Ezetimibe is used as a hypocholesterolemic agent for the treatment and prevention of atherosclerosis [US2006/70234996 A 1,2006]. Ezetimibe is the first lipid-lowering drug that inhibits absorption of biliary and dietary-dependent cholesterol from the small intestine [B. Salisbury et al. Atherosclerosis, 115(1), 45-63, 1995]. In 2002, ezetimibe alone or combined with the statins was approved for use in the treatment of primary hypercholesterolemia in
USA. Tablet formulations which contain 10 mg ezetimibe are available on the market (Zetia , Merck/Schering-Plough Pharmaceuticals, USA; Ezetrol® Merck/Schering-Plough Pharmaceuticals, Turkiye). Also, a combination of ezetimibe and simvastatin (10 mg ezetimibe, 10 mg simvastatin containing tablet) is on the market (Vytorin ®, Merck/Schering- Plough Pharmaceuticals, USA).
Ezetimibe' s mechanism of action is different from other cholesterol lowering drugs; it does not inhibit cholesterol synthesis in the liver or does not increase bile acid excretion. Instead of
this, it reduces blood cholesterol level by inhibiting the absorption of cholesterol in the small intestine. This distinct mechanism is complementary to that of the HMG-CoA reductase inhibitors which inhibits cholesterol synthesis [US2006/70234996 A 1,2006]. Ezetimib is a new class lipid lowering compound that selectively inhibits intestinal uptake of cholesterol and related phytosterols. It inhibits absorption of biliary and dietary cholesterol from the small intestine effectively, without affecting the absorption of fat soluble vitamins (A, D, E, K vitamins), triglycerides and bile acids.
Ezetimibe is a class II drug as defined by the Biopharmaceutical Classification System (BCS), which has low solubility and high permeability. The absolute bioavailability of ezetimibe could not be determined because of its very low solubility in water.
When the methods and products that are described in the WO 2007/103453 Al, WO 2008/101723 A2 and WO 2008/089984 A2 patent applications are examined regarding morphology and / or particle size, it is seen that they differ from the present invention.
When we search patents about ezetimibe, the tablet formulation which has been indicated within the scope of the patent with the number EP 1353696 Bl has been taken as a standard example in our study.
The basic methods patent about nanocrystals is US 05145684 (8 Sept. 1992). Later on; US 6.375.986 (23 April 2002), WO 02/24163 Al (28 March 2002), US 6.592.903 (15 July 2003), WO 03/080024 A2 (2 Oct 2003), WO 03/103640 Al (18 December 2003), US 2400725/ Al (8 April 2004), US 24115134A1 (17 June 2004), WO 2004/060351 A2 (22 July 2004), US 24156792A1 (12 Aug 2004), US 25019412A1 (27 Jan 2005), US 6.946.485 (20 Sept. 2005), US 7.101.576 (5 Sept. 2006), WO 2006/002140A2 (5 Jan 2006), WO 2007/092088A1 (16 Aug 2007) were also published.
Nanocrystal Technology Bioavailability of the pharmaceutical active ingredient is associated with its solubility. In other words, poorly water soluble or insoluble drugs are expected to have low oral bioavailability [H. Lieberman et al. Pharmaceutical Dosage Forms, 1980]. Solubility of poorly water soluble drugs in gastrointestinal fluids will take a long time, its dissolution will
be low, consecutively, because the drug is not completely soluble, it will not be able to show the pharmacological effect. By nanocrystal technology, due to increased amount of the soluble drug, drug bioavailability may be increased. Adverse effect is usually proportional to the concentration of the active drug substance; thus, reducing the concentration of the active drug substance can increase the safety for patients [D. Coppola, Pharm. Tech., 27 (11) 20, 2003]. Dissolution and bioavailability of poorly water soluble drugs can be improved by reducing particle size.
Most of the new chemical compounds developed have a poor solubility in water and thus low oral bioavailability. The water solubility of 40% of the active drug substances that are in use and 60% of the active drug substances that are at the investigation stage is very low. The water solubility of active drug substances that are currently in use are less than 40% and that are at the investigation stage is less than 60%. [C. Keck et al. Eur. J. Pharm. and Biopharm., 62, 3-16, 2006; C. Lipinski et al. Advanced Drug Delivery Reviews, 23, 3-25, 1997; R. H. Mϋller et al. Int. J. Pharm., 317, 82-89, 2006]. Because more than 40% of active drug substances have low solubility in water, some problems can occur in their formulation and use. Bioavailability of poorly water soluble drugs will be affected positively when their dissolution rate is increased. Poorly water soluble drugs show serious adverse clinical effects like non-steady absorption due to variability among patients and individual patient dosing. Prior to absorption of a drug, the active drug substance should be released from the dosage form and it must be dissolved in the gastrointestinal tract. Drugs which have high permeability, low solubility and thus are Class II according to BCS, are not easily dissolved [G. Amidon et al.Pharm. Res., 12(3), 413-420, 1995] and so they may not be absorbed from the GI tract sufficiently. When particles with a size smaller than a micron are formulated, their suface area can be increased, and thus, the dissolution rate and bioavailability can be increased [M. Crisp et al. J. Control. Release, 117, 351-359, 2007; J. Jinno et al. J. Control. Release, 111, 56-64, 2006].
To increase oral bioavailability, going down to the micron level may sometimes not be sufficient, so, the next step which is the nano level, may be necessary. Techniques, such as adding a cosolvent, cyclodextrins, preparing oil-in-water emulsions for intravenous applications are developed for poorly water soluble drugs, but these techniques have limited application since the active drug substance must have spesific physicochemical properties (for example, cyclodextrins must have suitable molecular weight for optimal conjugation of the
conical structure with the drug) [C. Keck et al. Eur. J. Pharm. and Biopharm., 62, 3-16, 2006]. One of the methods for increasing the dissolution rate is preparing amorphous solid dispersions [D. Law et al. J. Pharm. Sci. 92(3), 505-515, 2003]. These systems are theoretically one of the appropriate methods for increasing dissolution rate, but molecules in the amorphous state are not thermodynamilly stable; they can convert to the crystal form during storage [A. Serajuddin et al. J. Pharm. Sci. 88,(10), 1058-1066, 1999; V. B. Pokharkar et al. Powder Technology, 167, 20-25, 2006]. This transformation is an unwanted situation because the dissolution rate can change completely with crystal structure transition from the amorphous structure. On the other hand, if the drug nanocrystals can be prepared, an advantage can be obtained due to stable crystal phase. Nanocrystal technology does not increase dissolution rate like solid dispersions due to amorphous structure. It leads to an increase in dissolution rate depending on the increase in surface area obtained by reduction of the particle size of the crystal structured active drug substance down to the nano size range [H. Waard et al. J. Control. Release, 128, 179-183, 2008].
Nanocrystal dispersions contain water, active drug substances and a stabilizer. If necessary, other substances such as buffers, salts and sugars can be added. They are stable systems because of the use of a stabilizer that prevents reagregragation of active drug substances during the preparation step [http://www.elan.corn/Images/Elan_Technology 07yl tcm3- 17145.pdf], Drug nanocrystals are usually produced in liquid dispersion media (as in the precipitation [M. Trottaa, J. Control. Release, 76, 119-128, 2001] and disintegration methods). Suspension of drug nanocrystals in liquid can be stabilized by adding surface active substances or polymers. Contrary to micronized drugs, nanocrystals can be administered via several routes. Oral administration is possible in the form of tablets, capsules, sachets or powder; preferably in the form of a tablet. Nanosuspensions can also be administered via the intravenous route due to very small particle size, and in this way, bioavailability can reach 100 %.
DETAILED DESCRIPTION OF THE INVENTION
The scope of this invention is primarily; preparation of a pharmaceutical formulation by .using at least one hypocholesterolemic agent (ezetimibe) and one surface active (solubilizing) agent or stabilizer and with application of various pharmaceutical methods, while protecting the crystal structure of the active drug substance.
At the same time, the scope of this invention includes the protection of ezetimibe crystal structure and preparation of formulations whose average particle size of ezetimibe nanocrystals is lower than 2000 nm. In this aspect, one of the most important facts of the present invention is the preparation of pharmaceutical formulations which comprise ezetimibe nanocrystals without having any solubilizing agents.
Hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, sodiumcarboxymethylcellulose, sodium alginate, povidone 30, povidone 90, polyvinyl alcohol, polysorbate 80, D-α-tocopherol polyethyleneglycol 1000 succinate, polyethyleneglycol, gelatine, Eudragit® polyoxyethyleneglycol esters, polyoxyethyleneglycol ethers, polyvinyl pyrolidone, and poloxamers, can be given as examples of polymeric stabilizers and surface active (solubilizing) agents for the preparation of ezetimibe nanocrystals.
This invention also discloses the use of different methods for preparing ezetimibe nanocrystals. From these methods, high-speed homogenization methods, such as ultrasonic and mechanical high speed homogenization methods were used for the preparation of ezetimibe nanocrystals for the first time in this study.
The increase of dissolution rate of the nearly developed ezetimibe formulations was shown in comparison with tablets of physical mixtures. These results showed that it was not the hydrophilic copolymer used to prepare the nanocrystal, but in fact the preparation method of nanocrystals that led to the increase in the dissolution rate.
Surprisingly, by this invention it was shown that it was possible to prepare tablets containing ezetimibe nanocrystals without any solubilizing agents such as sodium dodesyl sulfate (SDS) and pharmaceutical formulations, whose in vitro dissolution rates similar to and even better than the reference product. Moreover, it was shown that these pharmaceutical formulations that contained ezetimibe nanocrystals are stable during their shelf-life.
At the same time this invention includes the use of pharmaceutical formulations which comprise ezetimibe nanocrystals for treating inhibition of cholesterol absorption.
Examples:
Formulation Studies:
The objective of the present invention was the improvement of the solubility, dissolution rate, and hence, bioavailability of ezetimibe by decreasing particle size and preparing nanocrystal formulations. The tablets prepared with nanocrystal formulations were different from the market products in that they did not contain any solubilizing agent like SDS.
Pluronic F 127, which was used in the formulations, is Poloxamer 407.
Mechanical High Speed Homogenization Method (UT)
A suspension of ezetimibe and poloxamer F 127 1:1 (w/w) was prepared in distilled water to a final concentration of 3 % (w/v). To obtain a homogeneous suspension, the suspension was mixed by a magnetic stirrer for half an hour. The suspension was mixed by a High Speed Homogenizer (Ultraturrax® T25 Basic, IKA Labortechnik, Germany) at 11000 rpm for 3 minutes. The dispersion medium was then removed by lyophilization for 72 hours at -55 0C at 0.01 mmHg pressure. Ultrasonic High Speed Homogenization Method (UP)
A suspension of ezetimibe and poloxamer F 127 1 :1 (w/w) was prepared in distilled water to a final concentration of 3 % (w/v). To obtain a homogeneous suspension, the suspension was mixed by a magnetic stirrer for half an hour. The suspension was mixed by an Ultrasonic Probe at 20% power for 1 minute. The dispersion medium was then removed by lyophilization for 72 hours at -55 0C at 0.01 mmHg pressure.
Ball Milling Method (BM)
A suspension of ezetimibe and poloxamer F 127 1 :1 (w/w) was prepared in distilled water, with a final concentration of 3 % (w/v). To obtain a homogeneous suspension, the suspension was mixed by a magnetic stirrer for half an hour. The suspension was mixed by 16 agate balls, 20 mm in diameter, for 4 minutes. The dispersion medium was then removed by lyophilization for 72 hours at -55 0C at 0.01 mmHg pressure.
Preparation of Tablet Formulations
When the results of particle size and dissolution rate measurements of powder nanocrystal formulation were considered, tablet formulations were prepared using the nanocrystals that were obtained by ball milling and Ultrasonic high speed homogenization methods. As a control group, a tablet formulation of the physical mixture was also prepared. As it is explained below, the formulations, which were prepared by means of wet granulation, have been pressed into tablets using eccentric tablet machines.
Table 1. The composition of the tablet formulation comprising nanocrystals prepared by the Ultrasonic High Speed Homogenization method
Table 2. The composition of the tablet formulation comprising nanocrystals prepared by the Ball Milling method
Table 3. The composition of the tablet formulation comprising nanocrystals prepared from the physical mixture
Table 4. The composition of the tablet formulation comprising nanocrystals prepared by physical mixture
In the formulations shown in Tables 1 - 4, instead of ezetimibe, the above mentioned formulations corresponding to 10 mg ezetimibe (Ultrasonic High Speed Homogenization Method, ball milling, physical mixture containing SDS, and physical mixture with no SDS) were used. The same excipients were chosen as in the original market product (Zetia®). The tablet containing the physical mixture was prepared both with and without SDS in order to make comparisons.
In order to prepare the tablet formulations, ezetimibe, lactose and 1/3 of croscarmellose sodium was placed in a mortar. A 1% of aqueous solution of Povidone 30 was instilled on the granulated mixture until it became a paste, while homogeneously mixing by a pestle. The paste was passed through a granulator, dried in a 50 °C oven and lastly sieved by a number 8 sieve. Then, microcrystalline cellulose (avicel PH 102) and the remaining part (2/3) of the croscarmellose sodium were added onto this granule. After putting magnesium stearate into an empty jar, the granulated mixture was added and they were mixed up together. Finally, tablets of 100 mg weight were compressed utilizing an eccentric model tablet machine.
Characterization of Formulations
FT-IR Analysis of Formulations
Ezetimibe nanocrystals were analyzed using a Fourier Transform Infrared Spectrometer (Perkin Emler, USA). The infrared spectra were detected over the wavenumber range of 4000 - 650 cm"1.
X-ray Analysis of Formulations
X-ray diffractograms of each formulation were recorded using an Ultima X-Ray Diffractometer. Standart runs using a 40 kV voltage and a scanning rate of 0.02° min 1 over a 2 θ range of 0 - 40° were used.
DSC (Differential Scanning Calorimetry) Analysis of Formulations
Thermal properties of the powder samples were investigated using a DSC Q 100 (TA Instruments, USA). Approximately, a sample of 5 - 20 mg was weighed in an aluminum pan, and a heating rate of 10 0C / min was employed in the range of 10 - 250 0C. Analyses were performed under a nitrogen purge (50 ml.min"1). Empty aluminum pans were used as a reference. The change of heat of the samples was monitored with respect to change in temperature.
Analysis of Particle Size Distribution of Formulations
In order to determine the particle size distribution of the prepared formulations, a Malvern Zeta Sizer (Nano Series Nano ZS) was utilized. A preweighed (10 - 30 mg) amount of the nanocrystal formulations prepared with different methods (both mechanical and ultrasonic High Speed Homogenization, ball milling) was dispersed in water up to a volume of 5 ml in a volumetric flask. These aqueous dispersions were then vortexed for 3 minutes and particle size analysis was carried out by 3 consecutive measurements for each sample.
Dissolution Studies
In vitro dissolution studies were performed using a SOTAX dissolution apparatus. From the dissolution medium, a 5 ml sample was withdrawn at 10, 20, 30 and 45 minutes, and then the same amount of fresh medium was added to the dissolution medium. The % amount of dissolved ezetimibe was determined from these samples. For each formulation and control
group, the experiment was repeated for 6 times. For each formulation and control group, % dissolved ezetimibe values were plotted with respect to time. The dissolution medium used in this work was 500 ml 0.45 % SDS in 50 mM pH 4.5 acetate buffer which has been reported in the "Dissolution Methods for Drug Products" guide of FDA. The dissolution studies were carried out utilizing the USP apparatus II (pedal) method, all stirred at 50 rpm at 37 ± 0.5 °C. The % dissolved ezetimibe amount was calculated using the amount of ezetimibe in 20 mg nanocrystal formulations.
Characterization of Formulations
FT-IR Analysis of Formulations
As it is shown in Figure 1, there are some characteristic peaks, as mentioned below, that belong to ezetimibe, also seen in the FT-IR spectra of the formulations. As it is seen in Figure 1, there is no difference between the FT-IR spectra of ezetimibe in the formulations and the FT-IR spectrum of ezetimibe itself. This result indicates that ezetimibe structure is preserved in the nanocrystal formulations. The characteristic peaks related to ezetimibe structure are as follows:
Characteristic C=O tension bands of the carbonyl group at 1760 - 1690 cm"1,
C=C resonance double bond tension bands that belong to the aromatic chain at 1600 - 1500 cm"1,
Strong C-O tension bands of the ester group at 1300 - 1000 cm"1,
Strong aliphatic tension bands at 3000 - 2850 cm"1 ,
Expanded O-H tension bands of the carboxylic acid group at 3650 — 2700 cm" ,
C-F tension bands at 1000 - 1200 cm"1,
P-disubstituted benzene tension bands at 800 - 1000 cm"1.
X-ray Analysis of Formulations
The X-ray diffractograms of the nanocrystal formulations, Poloxamer F 127, ezetimibe and physical mixture are given in Figure 2 for comparison. X-ray diffraction patterns showed that
there were no differences among formulations regarding crystal structure, and in all formulations, ezetimibe crystal structure was preserved.
DSC (Differential Scanning Calorimetry) Analysis of Formulations
DSC thermograms of the nanocrystal formulations, Poloxamer F 127, ezetimibe and physical mixture are given in Figure 3. The DSC analysis results indicate that the ezetimibe melting peak disappeared completely in all nanocrystal formulations. These results imply that ezetimibe was covered completely with Poloxamer F 127 in all nanocrystal formulations.
Analysis of Particle Size Distribution of Formulations
A Malvern Zeta Sizer (Nano Series Nano ZS) was utilized in order to determine the particle size distribution of the formulations. The average particle size values regarding these formulations are given in Table 5. According to these data, the average particle size of the nanocrystal formulations decreased to a significant extent as compared to ezetimibe and physical mixture, and the difference in particle size could be considered as statistically significant. As it is depicted in Table 5, while the average particle size of ezetimibe was 6432 ± 1024 run and of the physical mixture was 6302 ± 670 nm in terms of intensity, it was found that there was an 80 % decrease achieved with the ball milling method, 73 % decrease with the ultrasonic high speed homogenization method, and 67 % decrease with the mechanical high speed homogenization method.
Table 5. Average particle size of ezetimibe and the nanocrystal formulations.
Average ± Standard Deviation
Dissolution Studies
The results of the dissolution studies are given in Figure 4 and Table 6.
Table 6. Dissolution data of different tablet formulations which contained nanocrystal formulations in 500 ml 0.45 % SDS in 50 mM pH 4.5 acetate buffer (n=6) (BD = Ball Milling, PM-SDS - SDS was not included in the physical mixture (PM) , PM+SDS - SDS was included in the physical mixture, UP = Ultrasonic High Speed Homogenization, Ezetrol = Commercial Product)
By calculating f2 (similarity factor) with model - free techniques, the difference between the commercial product and the tablets containing the nanocrystal formulations regarding the dissolution rate profiles was determined. These results are given in Table 7. The similarity test is made up for comparing the outcomes of the in vitro dissolution rate tests. If the value of the similarity factor is equal to or above 50, then it refers to the presence of similarity among the in vitro dissolution profiles of the formulations.
X: average, % VC: percent coefficient of variation
Table 7. Comparison of the commercial product and the tablets containing nanocrystal formulations by the f2 similarity factor (BM-T= Ball Milling Tablet - Commercial Product, UP-T= Ultrasonic High Speed Homogenization Tablet - Commercial Product)
It appears from the results that the tablets which were prepared by both ball milling and ultrasonic high-speed homogenization, are similar to the commercial product in the dissolution medium containing 500 ml pH 4.5 5OmM Acetate Buffer/0.45 % SDS.
Figure 1. FT-IR spectra of the nanocrystal formulations, ezetimibe, physical mixture and the excipient.
Figure 2. Diffractograms of X-Ray analysis of the nanocrystal formulations, ezetimibe, physical mixture and the excipient.
Figure 3. Differential Scanning Calorimeter Thermograms of the nanocrystal formulations, ezetimibe, physical mixture and the excipient.
Figure 4. The % amounts of dissolved ezetimibe in the dissolution medium containing 500 ml pH 4.5 5OmM Acetate Buffer/0.45 % SDS from the tablets containing the nanocrystal formulations (n=6).
Claims
1. An ultrasonic high speed homogenization method for preparing the nanocrystal particles of ezetimibe, or a pharmaceutically acceptable salt thereof, wherein the average particle size of ezetimibe nanocrystals is lower than 2000 nm, characterized in that the method comprises the following steps; a. Mixing of ezetimibe and a hydrophilic copolimer such as stabilizer b. Dispersion of the mixture in an aqueous medium, c. Mixing of the dispersion with an ultrasonic probe, d. Lyophilization of the dispersion.
2. A mechanical high speed homogenization method for preparing the nanocrystal particles of ezetimibe, or a pharmaceutically acceptable salt thereof, wherein the average particle size of ezetimibe nanocrystals is lower than 2000 nm, characterized in that the method comprises the following steps; a. Mixing of ezetimibe and a hydrophilic copolimer such as stabilizer b. Dispersion of the mixture in an aqueous medium, c. Mixing the dispersion by using mechanical high speed homogenization, d. Lyophilization of the dispersion.
3. Pharmaceutical formulations comprising ezetimibe nanocrystals obtainable by the method of claims 1 and 2, wherein the average particle size of nanocrystals is lower than 2000 nm.
4. The pharmaceutical formulation according to claim 3, wherein the formulation is in the form of tablets, capsules, sachets or powder; preferably in the form of a tablet.
5. The pharmaceutical formulation according to claim 3 or 4, wherein the formulation does not contain any solubilizing agents, such as sodium lauryl sulfate.
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CN103655481A (en) * | 2012-09-18 | 2014-03-26 | 江苏柯菲平医药有限公司 | Preparation method of ezetimibe orally-taken preparation |
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