WO2011098536A1 - Prasugrel in micronized, crystalline form and pharmaceutical composition thereof - Google Patents
Prasugrel in micronized, crystalline form and pharmaceutical composition thereof Download PDFInfo
- Publication number
- WO2011098536A1 WO2011098536A1 PCT/EP2011/051988 EP2011051988W WO2011098536A1 WO 2011098536 A1 WO2011098536 A1 WO 2011098536A1 EP 2011051988 W EP2011051988 W EP 2011051988W WO 2011098536 A1 WO2011098536 A1 WO 2011098536A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- prasugrel
- pharmaceutically acceptable
- milling
- acceptable salt
- active ingredient
- Prior art date
Links
- 239000005465 B01AC22 - Prasugrel Substances 0.000 title claims abstract description 64
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 title claims abstract description 64
- 229960004197 prasugrel Drugs 0.000 title claims abstract description 64
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 54
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 238000003801 milling Methods 0.000 claims description 33
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 26
- 238000009837 dry grinding Methods 0.000 claims description 15
- 239000002245 particle Substances 0.000 claims description 12
- 229920000642 polymer Polymers 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 238000001238 wet grinding Methods 0.000 claims description 10
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 6
- -1 polyoxyethylene Polymers 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 229920001577 copolymer Polymers 0.000 claims description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical class C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- 206010050661 Platelet aggregation inhibition Diseases 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical class CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 2
- 150000005215 alkyl ethers Chemical class 0.000 claims description 2
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- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
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- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
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- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
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- 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
- A61K9/2004—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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
Definitions
- the present invention relates to Prasugrel or a pharmaceutically acceptable salt thereof, compositions containing said active ingredient as well as pharmaceutical compositions containing said active ingredient or a composition containing said active ingredient.
- the present invention further relates to methods for the preparation of the novel compositions.
- Prasugrel has the chemical name 2-acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridine.
- Prasugrel has the following structural formula:
- Prasugrel is administered orally as platelet aggregation inhibitor.
- the problem here is that Prasugrel is a sparingly soluble active ingredient.
- the free base of the active ingredient has a solubility of 57 pg/ml in water, but also the salts exhibit only a limited solubility.
- the solubility of an active ingredient can often be increased by micronization of the active ingredient particles.
- due to the high sensitivity to oxidation of Prasugrel direct dry milling in the ⁇ range is not possible, since conditional on both the mechanical and thermal influence in combination with the surface enlargement here the chemical degradation is to high.
- Prasugrel also has a strongly pH-dependent degradation. With pH values of ⁇ 3 a degradation of more than 1 % is observed already after 2 hours. This limits the potential excipients in the preparation of pharmaceutical formulations.
- WO 2008/072535 suggests processing Prasugrel together with a low-substituted hydroxypropylcellulose into pharmaceutical compositions.
- the active ingredient is intensely mixed with low-substituted hydroxypropylcellulose, hydroxypropylcellulose, and lactose for 3 minutes.
- magnesium stearate is added and the mixture is mixed again.
- the obtained powder is compressed to tablets.
- Prasugrel and hydroxypropylcellulose are mixed in the ratio of about 1 :1. The micronization of the active ingredient during the mixing process is not reported.
- WO 2008/072533 discloses Prasugrel-containing pharmaceutical compositions containing in addition to the active ingredient hydroxypropylcellulose in a weight ratio of about 1 :1.5. On that occasion, the mixtures are mixed for 3 minutes under high energy input in a Henschel mixer. In the given comparison example an appropriate mixture is mixed for 30 minutes in a diffusion mixer. Also here, no micronization of the active ingredient takes place.
- WO 2008/073759 suggests packaging them in an air and moisture tight container under a positive liquid gas pressure.
- Prasugrel can be transferred to a micronized, crystalline form under particular processing conditions, wherein said micronized, crystalline form or compositions containing said form, respectively, solve one or more of the above- mentioned problems.
- the present invention relates to Prasugrel or a pharmaceutically acceptable salt thereof in a micronized, crystalline form.
- crystalline form herein is meant any form of the active ingredient or its pharmaceutically acceptable salt that is essentially free and preferably entirely free of amorphous portions of the active ingredient or its pharmaceutically acceptable salt.
- essentially free of crystalline portions here is meant that the form contains less than 10% by weight, preferably less than 5% by weight, and most preferably less than 1% by weight active ingredient in an amorphous form, wherein the weight percentages relate to the total amount of Prasugrel or a pharmaceutically acceptable salt thereof.
- Crystalline portions of a present active ingredient may be characterized for example by DSC measurement and IR spectroscopy.
- the crystalline form can be distinguished from the non-crystalline form of the active ingredient for example also by IR spectroscopy.
- Figure 1 shows the IR spectrum of crystalline Prasugrel.
- Figure 2 shows the IR spectrum of amorphous Prasugrel.
- an additional peak at about 1778 cm "1 and for the crystalline Prasugrel additionally peaks at about 1254 cm "1 , and about 830 cm “1 .
- the bands of the IR spectra are summarized in the following table 1 (for Figure 1) and 2 (for Figure 2). Table 1
- the crystalline base in the DSC shows a sharp peak at 123°C.
- An example for this is represented in figure 6.
- active ingredient is meant Prasugrel or a pharmaceutically acceptable salt thereof.
- suitable as pharmaceutically acceptable salts are for example the hydrochloride, hydrobromide, sulphate, phosphate, alkylsulphonic acid salts, such as methane sulphonate, trifluoromethane sulphonate, and ethane sulphonate, arylsulphonic acid salts, such as benzene sulphonate, p-toluene sulphonate, 1 -naphthalene sulphonate, 2-naph- thalene sulphonate, and 1 ,5-naphthalene disulphonate, as well as salts of organic acids, such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, and maleate.
- the active ingredient according to the present invention is the Prasugrel base.
- Prasugrel or a pharmaceutically acceptable salt thereof can be recovered in a micronized, crystalline form by certain manufacturing methods.
- the active ingredient together with a hydrophilic polymer can be processed in a milling process and thus micronized. It is assumed, that the presence of the hydrophilic polymer reduces the degradation of the active ingredient during milling.
- the active ingredient together with the hydrophilic polymer can be micronized for example by means of a dry milling method or by wet milling. In both methods it has proven to be important that only few amounts of polymer are present to stabilize the crystalline state of the active ingredient and prevent amorphization.
- active ingredient and polymer must be intimately mixed so that the active ingredient in the micronized form does not agglomerate again to bigger active ingredient particles. Suitable manufacturing methods are described in more detail below.
- the weight ratio of Prasugrel based on the free base to hydrophilic polymer should be > 1 :4, preferably >1 :1 , preferably ⁇ 2:1 , more preferably ⁇ 5:1.
- Preferable weight ratios of Prasugrel to hydrophilic polymer are for example about 4:1 or about 5:1.
- Suitable hydrophilic polymers are water soluble polymers, for example polymers having a water solubility at room temperature of > 0.01 mg/ml.
- One or more hydrophilic polymers together with the active ingredient can be processed to the compositions according to the invention.
- the compositions can contain further pharmaceutically acceptable excipients.
- hydrophilic polymer comprises polymers having polar groups.
- polar groups are hydroxy, amino, carboxy, carbonyl, ethers, esters, sulphonates. Particularly preferred are hydroxy groups.
- the hydrophilic polymer has a molecular weight in the range between 1000 and 250,000 g/mol, preferably 2000 to 100,000 g/mol, and particularly preferably between 4000 and 50,000 g/mol.
- a 2% by weigh solution of the hydrophilic polymer in pure water preferably has a viscosity between 2 and 8 mPas at 25°C. The viscosity is determined according to the European Pharmacopoeia (Ph. Eur.), 6 th edition, section 2.2.10.
- the hydrophilic polymer preferably has a glass transition temperature (Tg) between 20°C and 150°C, preferably 25°C to 100°C.
- the glass transition temperature (Tg) is the temperature at which the hydrophilic polymer becomes brittle at cooling and soft at heating. That means that the hydrophilic polymer becomes soft above the glass transition temperature and can be plastically deformed without breaking.
- the glass transition temperature is determined by means of a Mettler-Toledo ® DSC 1 , wherein a heating rate of 10°C/min and a cooling rate of 15°C/min are used.
- the hydrophilic polymer can be selected from the group consisting of cellulosederivatives, such as hydroxypropylmethylcellulose, hydroxypropylcellulose, carb- oxymethylcellulose, preferably as sodium or calcium salt, hydroxyethylcellulose, polyvinylpyrrolidone, preferably having a molecular weight of from 10,000 to 60,000 g/ml, copolymers of polyvinylpyrrolidone, preferably copolymers comprising vinylpyrrolidone and vinylacetate units (e.g.
- Povidon, VA64, BASF preferably having a molecular weight between 40,000 and 70,000 g/ml, polyoxyethylene alkylether, polyethylene glycol, co-block polymers of ethylene oxide and propylene oxide (Poloxamer, Pluronic), polymethacrylate derivatives, polyvinyl alcohol, polyvinyl alcohol derivatives and polyethylene glycol derivatives, such as macrogol glycerol stearate.
- Preferred hydrophilic polymers are macrogol glycerol stearate, block copolymers of ethylene oxide and propylene oxide, polyethylene glycol, and hydroxypropylmethylcellulose.
- the active ingredient Prasugrel or a pharmaceutically acceptable salt thereof are present in a micronized form in the pharmaceutical composition. That means, that the volume- weighted average particle diameter D50 is between 0.1 and 10 ⁇ , preferably between 0.1 and 5 ⁇ , and the D90 is between 0.2 and 20 ⁇ , preferably between 0.2 and 16 ⁇ .
- the determination of the particle size is carried out in accordance to the European Pharmacopoeia (Ph. Eur.), 6 th edition, section 2.9.31 , preferably with a Mastersizer 2000 by Malvern Instruments.
- the evaluation is carried out by the Fraunhofer model.
- the micronized, crystalline form of the active ingredient can be obtained by means of a milling process in the presence of the hydrophilic polymer.
- the milling can be dry or wet milling.
- the milling step can be followed by further processing steps, such as for example lyophilization, spray drying, or granulation onto a carrier.
- milling of the active ingredient polymer mixture is required to micronize the active ingredient without transferring it into the amorphous form.
- a suitable period can be determined by the skilled person in that whether the employed crystalline active ingredient is present in the desired particle size distribution after the milling step. If necessary, the period of the milling step may be extended. As a rule, milling of at least 30 min, preferably at least 1 h results in the desired micronization of the active ingredient.
- Wet milling may be carried out e.g. in an Ultraturrax at revolutions between 11 ,000 and 24,000 rounds per minute, preferably about 11 ,000 rounds per minute.
- wet milling may be carried out in a Netsch mill (e.g., Netsch Micro Cer).
- a Netsch mill e.g., Netsch Micro Cer
- a particular fine and narrow particle size distribution can be achieved.
- the milling step is dry milling then this takes place for example in a ball mill, optionally under cooling, for example by means of liquid nitrogen.
- an air jet mill such as e.g., a 50 AS by Hosokava Alpine, wherein the pressure of the injector gas is between 2 and 8 bar, preferably at about 5 bar, and the milling gas has a pressure between 0.5 and 5 bar, preferably about 2 bar.
- Spray drying subsequent to wet milling can be carried out e.g. in a Buchi B290.
- composition according to the invention can in its preparation by milling contain further pharmaceutically acceptable excipients.
- pharmaceutically acceptable excipients are for example emulsifying agents, in particular having an HLB value >12.
- SDS sodium lauryl sulphate.
- Amount and type of the employed hydrophilic polymers and other excipients influence the release and stabilization of the micronized, crystalline form of the active ingredient.
- the present invention also relates to a method for the preparation of a composition described above comprising dry or wet milling of Prasugrel or a pharmaceutically acceptable salt thereof in the presence of the hydrophilic polymer.
- dry milling then this can be carried out under cooling, for example by means of liquid nitrogen.
- milling is carried out by means of an air jet mill.
- the present invention relates to a composition obtained by the method described above.
- compositions can subsequently be processed by using further pharmaceutically acceptable excipients to pharmaceutical compositions, in particular for the platelet aggregation inhibition.
- the finished administration forms can be e.g. tablets, capsules, sachets, or powders.
- the pharmaceutical composition can contain one or more further pharmaceutical acceptable excipients, such as e.g., fillers, lubricants, flow control agents, release agents, disintegrants ("Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende füre", edited by H. P. Fiedler, 4 th edition, and "Handbook of Pharmaceutical Excipients", 3 rd edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London).
- the pharmaceutical composition can contain one or more fillers.
- a filler is a substance increasing the bulk volume of the mixture and thus the size of the resulting dosage form.
- Preferred examples for fillers are lactose, microcrystalline cellulose (e.g., Avicel) and calcium hydrogenphosphate.
- the filler may be present in an amount of 0 to 90% by weight, preferably between 25 and 85 % by weight of the total weight of the composition.
- Lubricants The function of the lubricant is to ensure that the pelletizing and the ejection take place without much friction between the solids and the walls.
- the lubricant is an alkaline-earth metal stearate, such as magnesium stearate, or a fatty acid, such as stearic acid.
- the lubricant is present in an amount of 0 to 2% by weight, preferably between 0.5 and 1.5% by weight of the total weight of the pharmaceutical composition.
- Disintegrants Usually, by a disintegrant is meant a substance that is capable of breaking up the tablet into smaller pieces as soon as it is in contact with a liquid.
- Preferred disintegrant are croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (Crospovidon) or sodium carboxymethyl glycolate (e.g. Explotab) and sodium bicarbonate.
- the blasting agent is present in an amount of 0 to 20% by weight, preferably between 1 and 15% by weight of the total weight of the composition.
- Flow control agents As the flow control agent there can be used e.g. colloidal silica. Preferably the flow control agent is present in an amount of 0 to 8% by weight, more preferably in an amount between 0.1 and 3% by weight of the total weight of the composition.
- Stabilizers/Antioxidants As stabilizers and antioxidants there can be used ascorbic acid and ascorbate, EDTA and its salts, citric acid and citrates, butylated hydroxyanisole, butyl hydroxy toluene or vitamin E. Preferably vitamin E is used as stabilizer.
- Figure 1 shows the IR spectrum of crystalline Prasugrel
- Figure 2 shows the IR spectrum of amorphous Prasugrel
- Figure 3 shows the release profile of the formulation of example 1 (triangles) in comparison to the release profile of the commercial Prasugrel product Efient ® (squares),
- Figure 4 shows the release profile of the formulation of example 2 (triangles) in comparison to the release profile of the commercial Prasugrel product Efient ® (squares),
- Figure 5 shows the release profile of the formulation of example 3 (triangles) in comparison to the release profile of the commercial Prasugrel product Efient ® (squares),
- Figure 6 shows the DSC of the milled composition of example 3.
- Figure 7 shows the release profile of the formulation of example 4 (triangles) in comparison to the release profile of the commercial Prasugrel product Efient ® (squares),
- Figure 8 shows the release profile of the formulation of example 5 (triangles) in comparison to the release profile of the commercial Prasugrel product Efient ® (squares),
- Figure 9 shows the release profile of the formulation of example 6 (triangles) in comparison to the release profile of the commercial Prasugrel product Efient ® (squares),
- Figure 10 shows the release profile of the formulation of example 7 (triangles) in comparison to the release profile of the commercial Prasugrel product Efient ® (squares),
- Figure 11 shows the release profile of the formulation of example 8 (triangles) in comparison to the release profile of the commercial Prasugrel product Efient ® (squares).
- the present invention is explained in more detail with respect to the following examples without that they should be interpreted to be limiting.
- Pluronic block copolymers of ethylene oxide and propylene oxide
- HPMC hydroxypropylmethylcellulose
- Example 1 (Formulation 1):
- the DSC of the milled composition shown figure 3 exhibits a sharp peak at 123°C and thus confirms that the micronized active ingredient is present in the crystalline form.
- Example 7 (Formulation 7):
- the release profiles were measured in 900 ml of 50 mM acetate buffer (pH 4.5) at 37°C and 75 rpm according to the USP method (App. II).
- the release profiles of the formulations of examples 1-8 are represented in the figures 3-5 and 7-11 each together with the release profile of the commercial Prasugrel product Efient ® . It can be seen that the compositions according to invention in comparison to the commercial Prasugrel product provide a faster release of the active ingredient. Moreover, it is shown from the examples 9 and 10 that the hygroscopicity of the pharmaceutical composition and also the degradation of the active ingredient in the pharmaceutical formulation are reduced in comparison to the commercial Prasugrel product.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11702655A EP2534157A1 (en) | 2010-02-11 | 2011-02-10 | Prasugrel in micronized, crystalline form and pharmaceutical composition thereof |
EA201201109A EA201201109A1 (en) | 2010-02-11 | 2011-02-10 | ELECTRIC WOOD IN THIN-CUT CRYSTALLINE FORM AND PHARMACEUTICAL COMPOSITION CONTAINING |
US13/578,443 US8940757B2 (en) | 2010-02-11 | 2011-02-10 | Prasugrel in micronized, crystalline form and pharmaceutical composition thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP10153348A EP2360159A1 (en) | 2010-02-11 | 2010-02-11 | Prasugrel in micronized, crystalline form and pharmaceutical compound of same |
EP10153348.7 | 2010-02-11 |
Publications (1)
Publication Number | Publication Date |
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WO2011098536A1 true WO2011098536A1 (en) | 2011-08-18 |
Family
ID=42932041
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/EP2011/051988 WO2011098536A1 (en) | 2010-02-11 | 2011-02-10 | Prasugrel in micronized, crystalline form and pharmaceutical composition thereof |
Country Status (4)
Country | Link |
---|---|
US (1) | US8940757B2 (en) |
EP (2) | EP2360159A1 (en) |
EA (1) | EA201201109A1 (en) |
WO (1) | WO2011098536A1 (en) |
Cited By (7)
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WO2011134369A1 (en) | 2010-04-27 | 2011-11-03 | 孙远 | Pharmaceutical composition for improving solubility of prasugrel and its preparation method |
WO2013150322A1 (en) | 2012-04-02 | 2013-10-10 | Egis Pharmaceuticals Public Limited Company | Prasugrel-containing immediate release stable oral pharmaceutical compositions |
CN103610674A (en) * | 2013-12-09 | 2014-03-05 | 海南灵康制药有限公司 | Solid preparation containing micronized prasugrel |
CN104173316A (en) * | 2013-05-22 | 2014-12-03 | 山东新时代药业有限公司 | Capsule of hydrobromic acid prasugrel |
EP3106151A1 (en) * | 2015-06-19 | 2016-12-21 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical compositions of prasugrel hydrobromide |
EP3156049A1 (en) * | 2015-10-15 | 2017-04-19 | Alembic Pharmaceuticals Limited | Pharmaceutical composition of prasugrel |
WO2018073437A1 (en) | 2016-10-21 | 2018-04-26 | Laboratorios Lesvi, Sl | Pharmaceutical formulations of prasugrel and processes for the preparation thereof |
Families Citing this family (2)
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EP2275087B8 (en) * | 2010-02-22 | 2012-11-21 | Jrs Pharma GmbH+Co.kG | Prasugrel controlled release formulations |
GR1009230B (en) * | 2016-10-12 | 2018-02-22 | Φαρματεν Αβεε | Pharmaceutical prasugrel besylate-containing formula |
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Cited By (12)
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WO2011134369A1 (en) | 2010-04-27 | 2011-11-03 | 孙远 | Pharmaceutical composition for improving solubility of prasugrel and its preparation method |
EP2564847A1 (en) * | 2010-04-27 | 2013-03-06 | Sun, Yuan | Pharmaceutical composition for improving solubility of prasugrel and its preparation method |
EP2564847A4 (en) * | 2010-04-27 | 2013-10-02 | Sun Yuan | Pharmaceutical composition for improving solubility of prasugrel and its preparation method |
WO2013150322A1 (en) | 2012-04-02 | 2013-10-10 | Egis Pharmaceuticals Public Limited Company | Prasugrel-containing immediate release stable oral pharmaceutical compositions |
US8603537B2 (en) | 2012-04-02 | 2013-12-10 | Egis Pharmaceuticals Plc | Prasugrel containing quickly released stable oral pharmaceutical compositions |
CN104173316A (en) * | 2013-05-22 | 2014-12-03 | 山东新时代药业有限公司 | Capsule of hydrobromic acid prasugrel |
CN103610674A (en) * | 2013-12-09 | 2014-03-05 | 海南灵康制药有限公司 | Solid preparation containing micronized prasugrel |
CN103610674B (en) * | 2013-12-09 | 2015-01-07 | 海南灵康制药有限公司 | Solid preparation containing micronized prasugrel |
EP3106151A1 (en) * | 2015-06-19 | 2016-12-21 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical compositions of prasugrel hydrobromide |
WO2016203018A1 (en) * | 2015-06-19 | 2016-12-22 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Pharmaceutical compositions of prasugrel hydrobromide |
EP3156049A1 (en) * | 2015-10-15 | 2017-04-19 | Alembic Pharmaceuticals Limited | Pharmaceutical composition of prasugrel |
WO2018073437A1 (en) | 2016-10-21 | 2018-04-26 | Laboratorios Lesvi, Sl | Pharmaceutical formulations of prasugrel and processes for the preparation thereof |
Also Published As
Publication number | Publication date |
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US20130035355A1 (en) | 2013-02-07 |
EP2360159A1 (en) | 2011-08-24 |
EA201201109A1 (en) | 2013-03-29 |
EP2534157A1 (en) | 2012-12-19 |
US8940757B2 (en) | 2015-01-27 |
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