EP2029117A2 - Dissolution rapide de produits de combinaison - Google Patents

Dissolution rapide de produits de combinaison

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Publication number
EP2029117A2
EP2029117A2 EP08742580A EP08742580A EP2029117A2 EP 2029117 A2 EP2029117 A2 EP 2029117A2 EP 08742580 A EP08742580 A EP 08742580A EP 08742580 A EP08742580 A EP 08742580A EP 2029117 A2 EP2029117 A2 EP 2029117A2
Authority
EP
European Patent Office
Prior art keywords
dosage form
oral dosage
triptan
nsaid
bicarbonate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08742580A
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German (de)
English (en)
Inventor
Ilan Zalit
Uri Zadok
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Industries Ltd
Original Assignee
Teva Pharmaceutical Industries Ltd
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Filing date
Publication date
Application filed by Teva Pharmaceutical Industries Ltd filed Critical Teva Pharmaceutical Industries Ltd
Publication of EP2029117A2 publication Critical patent/EP2029117A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent

Definitions

  • the invention encompasses a method for the production of rapid dissolution tablets comprising at least two active pharmaceutical ingredients.
  • Migraine is the most common cause of vascular headache, and afflicts approximately 15% of women and 6% of men.
  • migraine is treated with a single drug or a combination of drugs known to be effective in treating migraine.
  • Most drugs effective in the treatment of migraines are members of one of three major pharmacologic classes: anti-inflammatory agents, 5-HTi antagonists, and dopamine antagonists. See HARRISON'S PRINCIPLES OF INTERNAL MEDICINE 73-76 (15th ed. 2001).
  • Sumatriptan succinate has the chemical name 3-[2-(dimethylamino)ethyl]-N- methyl-indole-5-methanesulfonamide succinate and the following chemical structure:
  • Naproxen sodium has the chemical name (S)-6-methoxy- ⁇ -methyl-2- naphthaleneacetic acid, sodium salt, and the following chemical structure:
  • Sumatriptan succinate is a selective 5-hydroxytriptaminei receptor subtype agonist currently marketed under the trade name IMITREX ® for the acute treatment of migraine attacks with or without aura in adults.
  • Naproxen sodium is a non-steroidal antiinflammatory drug (NSAID) with analgesic and antipyretic properties.
  • NSAID non-steroidal antiinflammatory drug
  • the mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. Both actives have been combined in a single tablet, which is expected to be marketed under the trade name TREXEVIA ® .
  • Current treatments for migraines include a range of over-the-counter analgesics and triptans.
  • the '089 publication suggests that in the stomach, the NSAID naproxen may form a gel-like matrix, which retards the dissolution of the triptan unless the two therapeutic agents are maintained in distinct side-by-side layers.
  • the '089 publication addresses this dissolution problem by separating the triptan and the NSAID into separate distinct layers, such that each layer contains at least 90% of either the triptan or the NSAID, as opposed to a single layer tablet matrix containing both agents or one layer forming a core surrounded by the other layer.
  • the '089 publication discloses that such an arrangement provides for the independent dissolution of each therapeutic agent, such that the dissolution rates approximate the rates if the drugs were given separately. Id.
  • 2007/0184109 also refers to pharmaceutical compositions comprising a 5HT i receptor agonist (such as sumatriptan succinate) or a pharmaceutically acceptable derivative thereof in combination with an NSAID (such as naproxen sodium) or pharmaceutically acceptable derivative thereof.
  • a 5HT i receptor agonist such as sumatriptan succinate
  • an NSAID such as naproxen sodium
  • the ' 109 publication compares the dissolution of sumatriptan succinate in two compositions of sumatriptan succinate and naproxen sodium, the first having the sumatriptan succinate and the naproxen sodium in the same zone and the second having the sumatriptan succinate and the naproxen sodium in separate layers of a bilayer tablet.
  • the '109 publication states that the dissolution of the first composition was "slower than expected," and that the slow dissolution "led to the conclusion that the naproxen sodium was disabling the dissolution of the sumatriptan granules when blended together.” See id. at p. 9, Tl 97.
  • the ' 109 publication states that "[c]ombining the two formulations as separate layers in a bilayer tablet allowed for the rapid release of sumatriptan succinate from the tablet, without as much interference from naproxen sodium.” See id. at p. 10, Tl 100.
  • the invention encompasses an oral dosage form comprising a therapeutically effective amount of a triptan and a therapeutically effective amount of an NSAID, wherein the dosage form includes at least one zone in which particles of the triptan and the NSAED are admixed, and not less than about 60% of the triptan dissolves in 30 minutes in 200 ml of 0.01N HCl solution in a USP Type II Dissolution Apparatus at a rotation speed of 40 rpm and a temperature of 37°C.
  • not less than about 70% of the triptan dissolves in 30 minutes, and more preferably not less than about 80% of the triptan dissolves in 30 minutes.
  • the oral dosage form further comprises at least one additive selected from the group consisting of (i) a carbonate, (ii) a bicarbonate, and (iii) a superdisintegrant, with the proviso that the superdisintegrant is not croscarmellose sodium.
  • the oral dosage form is in the form of a porous tablet.
  • the porosity of the tablet is at least about 10%.
  • the invention encompasses an oral dosage form comprising: (a) a therapeutically effective amount of a triptan, (b) a therapeutically effective amount of an NSAID, and (c) at least one additive selected from the group consisting of (i) a carbonate, (ii) a bicarbonate, and (iii) a superdisintegrant, wherein the dosage form includes at least one zone in which particles of the triptan and the NSAID are admixed, the additive is present in an amount of more than 10% by weight of the oral dosage form, and the superdisintegrant is not croscarmellose sodium.
  • the invention encompasses an oral dosage form comprising: (a) a therapeutically effective amount of a triptan, (b) a therapeutically effective amount of an NSAID, and (c) at least one additive selected from the group consisting of (i) a carbonate, (ii) a bicarbonate, and (iii) a superdisintegrant, wherein the dosage form includes at least one zone in which particles of the triptan and the NSAID are admixed, the ratio of the amount of NSAID to the total amount of additives is less than about 5, and the superdisintegrant is not croscarmellose sodium.
  • the invention encompasses a method for preparing the above-described oral dosage forms comprising separately granulating each of the triptan and the NSAID, combining the separate granulates with at least one extragranular pharmaceutically acceptable excipient to form a mixture, and compacting the mixture into the oral dosage form.
  • the invention encompasses a method for preparing the above-described oral dosage forms comprising granulating one of the triptan or the NSAID with at least one pharmaceutically acceptable excipient to form a granulate, adding to the granulate a dry blend comprising at least the other of the triptan or the NSAID and at least one pharmaceutically acceptable excipient to form a mixture, and compacting the mixture into the oral dosage form.
  • the invention encompasses a method for preparing the above-described oral dosage forms comprising coating an inert core with a layer comprising a triptan and an NSAID.
  • the invention encompasses a method of treating acute migraines comprising administering a therapeutically effective amount of at least one of the above-described dosage forms to a patient in need thereof.
  • the triptan is sumatriptan and the NSAID is naproxen.
  • Figure 1 illustrates exemplary tablet forms of triptan and NSAID.
  • Figure 1 illustrates exemplary tablet forms of triptan and NSAID.
  • FIG. 1 illustrates comparative dissolution of 2 separate tablets of sumatriptan and naproxen (Compositions 10 and 11), homogeneous compositions of sumatriptan and naproxen with sodium bicarbonate and the superdisintegrant crospovidone (Compositions 6 and 8), and a bi-layer tablet of sumatriptan and naproxen (Composition 13).
  • the invention addresses the above-described shortcomings of the prior art by providing rapidly dissolving tablets comprising a triptan and an NSAID, wherein the triptan and the NSAID are present in a single zone and each of the triptan and the NSAID maintains its individual dissolution characteristics irrespective of the presence of the other.
  • the NSAID which is usually present in a high dose compared with the triptan, tends to form a gel-like matrix in the presence of an aqueous medium. The gel-like matrix erodes slowly and is likely to entrap the triptan, thereby delaying its release.
  • triptan means a triptan or a pharmaceutically acceptable salt or solvate thereof.
  • NSAID means an
  • sumatriptan means sumatriptan free base or a pharmaceutically acceptable salt or solvate thereof.
  • a preferred form of sumatriptan is sumatriptan succinate.
  • naproxen means naproxen free acid or a pharmaceutically acceptable salt or solvate thereof.
  • a preferred form of naproxen is naproxen sodium.
  • a therapeutically effective dosage means a dosage sufficient to treat migraines.
  • the person of ordinary skill in the art would be able to determine a therapeutically effective dosage based upon the description herein coupled with the general knowledge in the art. For a particular patient, a therapeutically effective dosage may depend on variables such as age, gender, weight, and extent of condition.
  • the term "zone" means a region in a dosage form that has a distinct composition.
  • the region has a substantially homogeneous composition, i.e., the region contains a substantially homogeneous mixture of particles of triptan and particles of NSAID.
  • the region contains a substantially homogeneous mixture of granulates of triptan, granulates of NSAID, and extragranular excipients.
  • a zone may be a core, a coating layer, or other type of layer in the oral dosage form, examples of which are depicted in Figure 1.
  • the invention encompasses oral dosage forms and compositions comprising a triptan and an NSAID.
  • Suitable triptans include, but are not limited to, sumatriptan, eletriptan, rizatriptan, frovatriptan, almotriptan, zolmitriptan, and naratriptan.
  • the triptan is sumatriptan.
  • Suitable NSAIDs include, but are not limited to, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, nabumetone, mefanamic acid, piroxicam, lornoxicam, meloxicam, rofecoxib, celecoxib, etoricoxib, and valdecoxib.
  • the NSAID is naproxen or rofecoxib. More preferably, the NSAK) is naproxen.
  • the oral dosage forms of the invention are in the form of rapidly dissolving tablets in which the triptan and the NSAED are combined in a single zone, while each of the triptan and the NSAID maintains its individual dissolution characteristics irrespective of the presence of the other.
  • a rapid dissolution will be understood to mean that not less than about 60% of the triptan in the oral dosage form dissolves in acidic media in 30 minutes. Preferably not less than about 70% of the triptan dissolves in acidic media in 30 minutes, and more preferably not less than about 80% of the triptan dissolves in acidic media in 30 minutes.
  • the term "acidic media” means 200 ml of 0.0 IN HCl solution in a USP Type II Dissolution Apparatus at a rotation speed of 40 rpm.
  • the rapid dissolution of the oral dosage form is achieved through the use of an effervescent couple.
  • the effervescent couple comprises a basic ingredient and an acidic ingredient, the basic ingredient liberating carbon dioxide when it and the acidic ingredient are contacted with water.
  • the effervescent couple can be formed, for example, by including both the base component and the acid component as extra-granular excipients in the oral dosage form, hi another example, the effervescent couple can be formed by including only the base component as an extra-granular excipient in the oral dosage form, and using stomach acid as the acid component, i.e., the base component reacts with stomach acid to form the effervescent couple once the oral dosage form is administered to a patient.
  • the base component is a carbonate or a bicarbonate.
  • Suitable bicarbonates include, but are not limited to, ammonium bicarbonate, and alkali metal bicarbonates such as potassium bicarbonate and sodium bicarbonate.
  • the bicarbonate is sodium bicarbonate.
  • the bicarbonate is present in an amount of more than 10% to about 20% by weight of the zone in which both particles of triptan and particles of NS AID are present.
  • the bicarbonate is present in an amount of about 1 1% to about 17% by weight of the zone in which both particles of triptan and particles of NSAID are present.
  • the acid component when included in the oral dosage form, may be any pharmaceutically acceptable acid.
  • Suitable acids include, but are not limited to, ascorbic acid, citric acid, tartaric acid, succinic acid, fumaric acid, malic acid, lactic acid, propionic acid, sorbic acid, and benzoic acid.
  • the acid is ascorbic acid, citric acid or tartaric acid.
  • the acid component is present in an amount so as to produce an approximately a 1 : 1 molar ratio between the basic groups on the base component and the acidic groups on the acid component.
  • the rapid dissolution of the oral dosage form may be achieved by using a large amount of superdisintegrant as an extragranular excipient, with the proviso that the superdisintegrant is not croscarmellose sodium.
  • Suitable superdisintegrants include, but are not limited to, crospovidone and sodium starch glycolate.
  • the superdisintegrant is crospovidone.
  • the crospovidone is present in an amount of about 7% to about 20% by weight of the zone in which both particles of triptan and particles of NSAID are present, and preferably more than 10% to about 17% by weight of the zone in which both particles of triptan and particles of NSAID are present.
  • the rapid dissolution of the oral dosage form may be achieved by using a mixture of additives as extra-granular excipients, i.e., a mixture of carbonate, bicarbonate, and/or superdisintegrant.
  • the additives are present in a total amount of more than 10% by weight of the zone in which both particles of triptan and particles of NSAID are present.
  • the additives are present in a total amount of more than 10% to about 60% by weight, more preferably more than 10% to about 50% by weight, and most preferably more than 10% to about 40% by weight of the zone in which both particles of triptan and particles of NSAID are present.
  • the ratio of the amount of NSAID to the total amount of additives is less than about 5.
  • the ratio of the amount of NSAID to the total amount of additives is about 1 to about 4.5, more preferably about 2 to about 4.5, and most preferably about 2.5 to about 4.5.
  • the rapid dissolution of the oral dosage form may be achieved by producing a highly porous tablet.
  • An increased dissolution rate can be obtained by increasing the porosity (void spaces) of the tablet. Void spaces in the tablet matrix facilitate the permeation of water to rapidly erode the entire tablet. This may be achieved by adding a volatilizable adjuvant to the composition, which is subsequently removed by sublimation or thermal decomposition. See, e.g., U.S. Patent Nos.
  • the degree of porosity may be expressed as the percent of weight lost from the dosage form following removal of the volatilizable adjuvant.
  • the porosity of the tablet is at least about 10%, i.e., upon removal of the volatilizable adjuvant, 10% of the tablet weight is lost.
  • the weight loss (and thus the porosity of the tablet) can be measured, for example, by techniques disclosed in the articles mentioned in the immediately preceding paragraph.
  • the desired weight loss may be achieved by incorporating into the extra granular excipients a solid adjuvant which is volatilizable at either elevated temperatures, or reduced pressures, or a combination of both.
  • Suitable volatilizable adjuvants include materials that undergo sublimation and materials that thermally decompose to gases.
  • Materials that undergo sublimation include, but are not limited to, camphor, menthol, benzoic acid, urethane, urea, vanillin, tetramethylene tetramine, and naphthalene.
  • the material that undergoes sublimation is camphor or menthol.
  • Materials that thermally decompose to gases include, for example, ammonium bicarbonate.
  • the rate of rapid dissolution may be adjusted by controlling the hardness of the tablet.
  • the hardness of the tablet is about 10 to about 30 SCU, and more preferably about 12 to about 25 SCU. Hardeness is typically measured by the method disclosed in REMINGTON - THE SCIENCE AND PRACTICE OF PHARMACY, 882-883 (20th ed. 2000), hereby incorporated by reference.
  • the compositions described herein may be prepared in accordance with methods that are standard in the art.
  • the triptan and NSAID are granulated separately using any acceptable granulation method, using, for example, a high-shear granulator. Any acceptable granulation solvent may be employed, such as, but not limited to, water, ethanol, isopropanol, or any combination thereof. More preferably, the granulation solvent is water.
  • the NSAID granulate may be mixed with colloidal silicon dioxide before adding the triptan granulate and the remaining inactive ingredients.
  • any acceptable pharmaceutical excipient may be used.
  • the composition may comprise binders (such as polyvinylpyrrolidone), disintegrants (such as crospovidone, microcrystalline cellulose, and sodium starch glycolate), lubricants (such as magnesium stearate and hydrogenated vegetable oil), and fillers (such as lactose and mannitol).
  • the tablets may optionally be coated.
  • the invention further encompasses a method of treatment comprising administering the pharmaceutical formulation to a mammal.
  • the mammal is a human.
  • the pharmaceutical formulation comprises sumatriptan succinate and naproxen sodium in the form of a rapidly dissolving tablet in which the sumatriptan succinate and the naproxen sodium are combined in a single zone and is administered to treat acute migraines, which is expected to be the approved use for TREXIMA ® .
  • the amount of active compounds administered and the dosing regimen used will depend on the particular drug selected, the age and general condition of the subject being treated, the severity of the subject's condition, and the judgment of the prescribing physician.
  • the pharmaceutical formulation comprises sumatriptan succinate and naproxen sodium in the form of a rapidly dissolving tablet in which the sumatriptan succinate and the naproxen sodium are combined in a single zone and is administered to treat acute migraines, which is expected to be the approved use for TREXIMA ® .
  • the amount of active compounds administered and the dosing regimen used will depend on the particular drug selected, the age and general condition of the subject being treated, the severity of the subject's condition, and the judgment of
  • composition for sumatriptan succinate granulation is provided in Table 1.
  • Table 1 Composition of sumatriptan succinate granulation.
  • composition for naproxen sodium granulation is provided in Table 2.
  • Naproxen sodium, microcrystalline cellulose and povidone were mixed for 2 minutes in a high shear granulator at a mixer speed of 460 rpm. Water was added until a suitable granulation was achieved at a mixer speed of 920 rpm and a chopper speed of 2220 rpm. The resulting wet granulate was transferred to a fluid bed drier (Glatt-2), with an inlet temperature of 60 0 C and an outlet temperature of 35°C, and dried. Loss on drying (LOD) was determined using a Mettler-Toledo HR73 Halogen Moisture Analyzer, and was found to be 2.84%. The dried granulate was then milled using an 18 mesh screen.
  • Glatt-2 fluid bed drier
  • LOD Loss on drying
  • Example 3 Preparation of compositions containing granulates of naproxen and sumatriptan [0053] The granulates from Examples 1-2 were combined in pharmaceutical compositions according to Tables 3a, 3b, 3c, and 3d. About 15-20 tablets were prepared from each batch.
  • Table 3a Comparative formulations of naproxen and sumatriptan without sodium bicarbonate or the superdisintegrant crospovidone.
  • the porosity of composition 5 was measured to be about 4.4%.
  • Table 3d Formulations of naproxen and sumatriptan with both sodium bicarbonate and the superdisintegrant crospovidone.
  • colloidal silicon dioxide used was AEROSIL R 972. All other compositions in Tables 3a to 3d contained AEROSIL ® 200.
  • compositions were tabletted using a Kilian SP300 tabletting machine, with a mean hardness of about 20-24 SCU (high hardness, HH). Compositions 8 and 9 were tabletted to a mean hardness of about 13-15 SCU (low hardness, LH).
  • composition 5 Tablets from composition 5 were then placed in a vacuum oven heated to about 35°C for about 5 hours.
  • Example 4 Preparation of a comparative composition containing sumatriptan
  • Example 1 The granulation of Example 1 was used in a composition according to Table 4.
  • Example 5 Preparation of a comparative composition containing naproxen
  • Example 2 The granulation of Example 2 was used in a composition according to Table 5.
  • Example 6 Preparation of a bi-layer tablet containing sumatriptan and naproxen
  • Dissolution of the sumatriptan in tablets prepared in Example 3 was studied using a USP Apparatus 2 (paddles), rotation speed of 40 rpm, at a temperature of 37°C. See U.S. PHARMACOPEIA, 2413-2414 (28th ed. 2005), hereby incorporated by reference.
  • the medium used was 0.01N HCl or a buffered solution at pH 6 with 0.15% sodium dodecyl sulfate. In some cases, 0.01N HCl was used for 30 minutes, neutralized with a sodium phosphate and sodium hydroxide solution, buffered to pH 6 and 0.15% sodium dodecyl sulfate added.
  • compositions having less than 10% of carbonate, bicarbonate, or superdisintegrant release about 25% or less of the sumatriptan following exposure to 0.01N HCl for 30 minutes.
  • Compositions having more than 10% of carbonate, bicarbonate, or superdisintegrant release about 50% to 100% of the sumatriptan following exposure to 0.01N HCl for 30 minutes.
  • the dissolution profile of sumatriptan in the compositions having more than 10% of carbonate, bicarbonate, or superdisintegrant is comparable to the dissolution profile of sumatriptan when it is administered separately from naproxen, either in a separate tablet or in a bi-layer tablet wherein the naproxen and the sumatriptan are in separate layers.
  • compositions 10 and 11 homogeneous compositions of sumatriptan and naproxen with sodium bicarbonate and the superdisintegrant crospovidone (Compositions 6 and 8), and a bi- layer tablet of sumatriptan and naproxen (Composition 13) was carried out using a USP Apparatus II (paddles), rotation speed 40 r.p.m, at a temperature of 37°C. Tablets were initially placed in 200 mL 0.0 IN HCl solution for 30 minutes. The solution was then neutralized using 10 mL of phosphate neutralizing buffer (60 g/L sodium dihydrogen phosphate, titrated to pH 6 with sodium hydroxide, and sodium hydroxide added until a pH of 10 is reached).
  • phosphate neutralizing buffer 60 g/L sodium dihydrogen phosphate, titrated to pH 6 with sodium hydroxide, and sodium hydroxide added until a pH of 10 is reached).

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Abstract

La présente invention concerne des formes de dosage orales pharmaceutiques à dissolution rapide de triptans et de AINS, des procédés de préparation de ceux-ci et des procédés de traitement au moyen de ceux-ci.
EP08742580A 2007-04-04 2008-04-03 Dissolution rapide de produits de combinaison Withdrawn EP2029117A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US92203107P 2007-04-04 2007-04-04
US93261307P 2007-05-31 2007-05-31
US7056308P 2008-03-21 2008-03-21
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CA3066426A1 (fr) 2008-01-09 2009-07-16 Charleston Laboratories, Inc. Compositions pharmaceutiques renfermant un antiemetique et un analgesique opioide
CA2765866C (fr) 2008-06-20 2016-06-21 Alphapharm Pty Ltd Composition pharmaceutique monophasee d'un inhibiteur 5-ht1 et d'un ains
US8906949B2 (en) 2010-05-21 2014-12-09 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Orally disintegrating tablets of zolmitriptan and process for preparing the same
CN102552423B (zh) * 2012-02-20 2013-07-24 崔新明 一种治疗偏头痛的药物组合物
EP3191093A4 (fr) * 2014-09-09 2018-04-25 Charleston Laboratories, Inc. Compositions pharmaceutiques
CA3055170A1 (fr) 2016-03-04 2017-09-08 Charleston Laboratories, Inc. Compositions pharmaceutiques
TR201720429A2 (tr) 2017-12-15 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Flurbi̇profen ve 5-ht1&#8211#&reseptör agoni̇stleri̇ni̇n farmasöti̇k kompozi̇syonlari
TR201921902A1 (tr) * 2019-12-27 2021-07-26 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Flurbiprofen ve eletriptan içeren ağızda dağılan tabletler

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