WO2008005039A1 - Solid compositions comprising tadalafil and at least one carrier - Google Patents
Solid compositions comprising tadalafil and at least one carrier Download PDFInfo
- Publication number
- WO2008005039A1 WO2008005039A1 PCT/US2006/043664 US2006043664W WO2008005039A1 WO 2008005039 A1 WO2008005039 A1 WO 2008005039A1 US 2006043664 W US2006043664 W US 2006043664W WO 2008005039 A1 WO2008005039 A1 WO 2008005039A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tadalafil
- carrier
- solid composite
- solid
- solution
- Prior art date
Links
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
- A61K9/08—Solutions
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
Definitions
- This invention relates to oral pharmaceutical compositions suitable for making pharmaceutical formulations for oral administration that provide for the rapid dissolution of the phosphodiesterase 5 inhibitor tadalafil.
- the pharmaceutical compositions comprise solid composites of tadalafil exhibiting high solubility and rate of dissolution.
- the invention further relates to methods of preparing these pharmaceutical formulations and the use of such pharmaceutical formulations for treating diseases associated with PDE5 inhibitors.
- cyclic nucleotide dependent protein kinases PGK
- PDEs cyclic nucleotide- gated channels
- PDEs class I phosphodiesterases
- PDEs are a large family of proteins, which were understood to be reported by Sutherland and co-workers (Rail & Sutherland 1958, Butcher & Sutherland 1962).
- the family of cyclic nucleotide phosphodiesterases appears to catalyze the hydrolysis of 3', 5'-cyclic nucleotides to the corresponding 5' monophosphates.
- Tadalafil the active ingredient in Cialis ® , has been used for the treatment of male erectile dysfunction.
- the prescribing information for Cialis ® describes this product as film- coated, almond-shaped tablets for oral administration, containing tadalafil and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin. See http://pi.lilly.com/us/cialis-pi.pdf.
- Tadalafil has the chemical name (6R-trans)-6-(l,3-benzodioxol-5-yl)-2,3,6,7,12,12a- hexahydro-2-methyl-pyrazino[r,2':l,6]pyrido[3,4-b]indole-l,4-dione.
- the structure assigned to tadalafil is shown below. (CAS# 171596-29-5):
- Tadalafil is a solid that is understood to be practically insoluble in water and only very slightly soluble in some organic solvents, such as methanol, ethanol, and acetone.
- Compounds having a low water solubility can have a low rate of dissolution and low bioavailability. See, e.g., Ansel et al., Pharmaceutical Dosage Forms and Delivery Methods (6 th ed., 1995), p. 105, 108.
- Another technique applied to improve solubility involves preparing formulations using "co-precipitates" of tadalafil, wherein an "intimate mixture” of tadalafil and a carrier in a non-aqueous water miscible solvent and, optionally, water are co-precipitated from the "intimate mixture” using an aqueous "co-precipitation medium” in which the carrier is substantially insoluble.
- an aqueous "co-precipitation medium" in which the carrier is substantially insoluble.
- Soft gel capsules containing tadalafil suspended in a pharmaceutically acceptable solvent have also apparently been developed in an attempt to prepare formulations of tadalafil with supposedly improved bioavailability.
- U.S. Patent No. 6,821,975 is listed in the FDA's "Orange Book” for the Cialis ® product, and is assigned on its face to the company that markets Cialis ® .
- This patent appears to be directed to a "free drug particulate form" of tadalafil "comprising particles of the compound wherein at least 90% of the particles have a particle size of less than about 40 microns.” Usually, preferably at least 90% of the particles have a particle size of less than 10 microns.
- the instant invention provides pharmaceutical formulations or compositions of tadalafil with significantly improved solubility and rates of dissolution as compared with both Cialis ® and very fine particle sized free drug tadalafil.
- the present invention relates to a solid composite including tadalafil and at least one carrier, wherein at least about 85% by weight (wt%) of the tadalafil is in intimate association with the at least one carrier and wherein at least 80 wt% of the tadalafil dissolves within about 10 minutes when a sample of solid composite containing about 20 mg of tadalafil is tested in 1000 mL of an aqueous medium at least as stringent as an 1000 mL aqueous medium including 0.15 wt% sodium lauryl sulfate and 6g NaH 2 PO 4 , having a pH of about 4.5 at 37 0 C, with paddles rotating at a speed of 50 rpm.
- wt% of the tadalafil is not in crystalline form.
- the solid composite is in the form of a solid solution.
- at least 60 wt%, more preferably at least 70 wt%, of the tadalafil dissolves within about 5 minutes under these conditions.
- the solid composites can be included in pharmaceutical compositions that also include tadalafil in free drug form and having a particle size distribution such that the d(0.9) is greater than about 40 ⁇ m.
- 50 wt% of the tadalafil of the pharmaceutical composition dissolves within about 5 minutes and 70 wt% of the tadalafil of the pharmaceutical composition dissolves within about 10 minutes when a sample of the pharmaceutical composition containing about 20 mg tadalafil is tested in 1000 mL of an aqueous medium at least as stringent as an 1000 mL aqueous medium including 0.15 wt% sodium lauryl sulfate and 6g NaH 2 PO 4 , having a pH of about 4.5 at 37 0 C, with paddles rotating at a speed of 50 rpm.
- the at least one carrier is a hydrophilic polymer.
- the ratio of the tadalafil to the at least one carrier is from about 1:0.5 to about 1:20, more preferably the ratio is from about 1 : 1 to about 1:10, even more preferably the ratio is from about 1 :3 to about 1 :6, and yet more preferably the ratio is about 1 :5 by weight.
- the carrier is povidone, hydroxypropyl methylcellulose, or polyethylene glycol. More preferably, the carrier is povidone (also known as polyvinylpyrrolidone).
- the invention in another aspect, relates to a solid composite including tadalafil and at least one carrier wherein at least about 85 wt% of the tadalafil is in solid solution in the at least one carrier.
- at least 80 wt% of the tadalafil dissolves within about 10 minutes when a sample of the solid composite containing about 20 mg of tadalafil is tested in 1000 mL of an aqueous medium at least as stringent as an 1000 mL aqueous medium including 0.15 wt% sodium lauryl sulfate and 6g NaH 2 PO 4 , having a pH of about 4.5 at 37°C, with paddles rotating at a speed of 50 rpm.
- the solid composites can be included in pharmaceutical compositions that also include tadalafil in free drug form and having a particle size distribution such that the d(0.9) value is greater than about 40 ⁇ m.
- 50 wt% of the tadalafil of the pharmaceutical composition dissolves within about 5 minutes and 70 wt% of the tadalafil of the pharmaceutical composition dissolves within about 10 minutes when a sample of the pharmaceutical composition containing about 20 mg of tadalafil is tested in 1000 mL of an aqueous medium at least as stringent as an 1000 mL aqueous medium including 0.15 wt% sodium lauryl sulfate and 6g NaH 2 PO 4 , having a pH of about 4.5 at 37°C, with paddles rotating at a speed of 50 rpm.
- the at least one carrier is a hydrophilic polymer.
- the at least one carrier is present in an amount such that the ratio of the tadalafil to the at least one carrier is from about 1 :3 to about 1 :6 by weight.
- the at least one carrier is povidone, hydroxypropyl methylcellulose, or polyethylene glycol. Povidone is especially preferred.
- the invention relates to a method of making a solid composite including tadalafil and at least one carrier.
- the method includes the steps of: a) combining the tadalafil, the at least one carrier and at least one solvent to form a solution; and b) removing the solvent from the combination to obtain the solid composite.
- the solid composite is a solid solution.
- the carrier is povidone, hydroxypropyl methylcellulose, or polyethylene glycol.
- the solvent is a lower aliphatic alcohol or C 3 - C 8 ketone.
- the at least one solvent is one in which the tadalafil has a solubility of at least about 1.2 mg tadalafil per 1 mL solvent at 25°C.
- the solvent is removed by evaporation.
- the solvent removal is effected with a fluidized bed dryer, preferably by spraying the solution into an initially empty fluidized bed dryer.
- the solvent is a mixture of acetone and water in a ratio of acetone to water of from about 30:1 to about 1:1, more preferably from about 11 :2 to about 3:1.
- the solution is sprayed onto at least one pharmaceutically acceptable excipient in the fluidized bed dryer.
- the solvent is removed by spray drying.
- the invention relates to a solid composite including tadalafil that, when tested in an aqueous solution having a pH between about 4.5 and 7.0, at least 80 wt% of the tadalafil dissolves within about 10 minutes. Preferably, at least 60 wt% of the tadalafil dissolves within about 5 minutes.
- the solid composite includes at least one carrier.
- the invention in another aspect, relates to a solid composite including about 20 mg of tadalafil wherein at least 80 wt% of the tadalafil dissolves within about 10 minutes when tested in 1000 mL of an aqueous medium at least as stringent as an 1000 mL aqueous medium including 0.15 wt% sodium lauryl sulfate and 6g NaH 2 PO 4 , having a pH of about 4.5 at 37°C, with paddles rotating at a speed of 50 rpm.
- the solid composite includes at least one carrier.
- the invention relates to a tadalafil solid composite having a higher solubility (or at least a higher solubility in water-based media) as compared with micronized free drug forms of tadalafil.
- the invention relates to a tadalafil solid solution having a higher solubility (or at least a higher solubility in water-based media) as compared with a free drug form of tadalafil having a particle size distribution such that the d(0.9) value is about 4 ⁇ m.
- the invention relates to a solid oral pharmaceutical composition including tadalafil wherein at least about 85 wt% of the tadalafil is in non-crystalline form.
- the tadalafil is in an amorphous form.
- the invention in another aspect, relates to a solid composite including tadalafil and at least one carrier wherein the tadalafil and the at least one carrier are in intimate association that is formed by evaporating the solvent from a solution of tadalafil and the at least one carrier.
- the at least one carrier is povidone and the tadalafil and the povidone are present in a ratio of about 1 :5 by weight.
- the invention in another aspect, relates to a pharmaceutical composition of tadalafil including a) tadalafil in amorphous form in intimate association with at least one carrier, and b) tadalafil in free drug form having a particle size distribution such the d(0.9) value is greater than about 40 ⁇ m.
- parts a) and b) are present in such proportion that 50 wt% of the tadalafil of the pharmaceutical composition dissolves within about 5 minutes and 70 wt% of the tadalafil of the pharmaceutical composition dissolves within about 10 minutes when a sample of the pharmaceutical composition containing about 20 mg of tadalafil is tested in 1000 mL of an aqueous medium at least as stringent as an 1000 mL aqueous medium including 0.15 wt% sodium lauryl sulfate and 6g NaH 2 PO 4 , having a pH of about 4.5 at 37°C, with paddles rotating at a speed of 50 rpm.
- the present invention provides solid composites including tadalafil and at least one carrier, wherein at least about 85 wt% of the tadalafil is in intimate association with the at least one carrier, as opposed to being in the free drug form.
- at least 85 wt% of the tadalafil is not in crystalline form.
- tadalafil means the free base tadalafil and pharmaceutically acceptable salts and solvates thereof, although there is no intention to limit the scope of tadalafil compounds.
- the tadalafil in the solid composites and in the methods described herein for making the solid composites is the free base.
- “Intimate association” or “intimately associated” means the at least one carrier and tadalafil interact on the. molecular level, there being no easily detectable separate tadalafil phase. That is, the at least one carrier and tadalafil are included in the same, single, phase.
- Free drug or free drug form mean solid particles of tadalafil, not in intimate association with a carrier, suitable for pharmaceutical use.
- Non-crystalline and “not in crystalline form” mean materials that do not produce X- ray powder diffraction patterns having peaks characteristic of crystalline tadalafil and that do not exhibit a discernable endotherm in differential scanning calorimetry under ordinary conditions - e.g. using heating rates of 2 to 20 degrees per minute.
- Amorphous tadalafil is an example of non-crystalline tadalafil.
- the term "about” refers to the normal variation in that measured quantity that would be expected by the skilled artisan making the measurement and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring equipment used.
- no crystalline tadalafil is detectable in the solid composites.
- the tadalafil in the solid composites of the invention are preferably in an amorphous state.
- the solid composites are solid solutions of tadalafil in the carrier.
- the individual physical properties related to the crystalline structure of the component(s) present in lesser amounts, commonly referred to as the solute(s) are lost. Presence of the solute(s) can be detected spectroscopically or by measure of the colligative properties of the solid solution.
- the tadalafil may come out of solution or remain undissolved in the carrier without departing from the scope of the invention.
- at least 85 wt% of the tadalafil is in solution in the solid solution.
- at least about 90 wt%, yet more preferably at least about 95 wt%, and even more preferably at least about 99 wt% of the tadalafil is in solution in the solid solution. That is, in a most-preferred embodiment, all or substantially all of the tadalafil is in solution in the solid solution.
- the at least one carrier is a hydrophilic polymer such as povidone, hydroxypropyl methylcellulose, and polyethylene glycol.
- the carrier is povidone. Hydroxypropyl methyl cellulose phthalate, polymethyacrylate, and hydroxypropyl cellulose can also be suitable as carriers in the present invention bu ⁇ are not preferred carriers for use in the practice of the present invention.
- the drug to carrier weight ratio in the solid composites of the present invention is in a range of about 1 :0.5 to about 1 :20, more preferably about 1 : 1 to about 1:10, even more preferably about 1:3 to about 1:6 and most preferably about 1:5.
- the solid composites of the present invention can be prepared by a) combining tadalafil, at least one carrier, and at least one solvent to form a solution; and b) removing the solvent to obtain the solid composite.
- the solid composite prepared by such a method is in the form of a solid solution, wherein substantially all, most preferably all, of the tadalafil is in solid solution in the at least one carrier.
- solvents suitable for preparing the solid composites include a) organic solvents and b) combinations of organic solvents and water, that are capable of dissolving at least 85 wt% of the tadalafil and substantially all of the carrier.
- the solvent is capable of dissolving at least 85 wt% of the tadalafil and 85 wt% of the carrier.
- the solvent is capable of dissolving substantially all of the tadalafil and carrier.
- the solvent is capable of dissolving all of the tadalafil and carrier.
- Suitable solvents include lower aliphatic alcohols and C3-C8 ketones.
- “Lower aliphatic alcohols” herein means organic compounds having the general structure R-OH, wherein R is a linear or branched Ci_C ⁇ alkyl group.
- Lower aliphatic alcohols that are preferred for use in the process of the invention include methanol, ethanol, isopropyl alcohol (PA), and butanol.
- C3-Cg ketones useful as solvents in the invention include acetone, methylisobutyl ketone (MIBK) and methylethyl ketone (MEK).
- Especially preferred solvents are ethanol, acetone, and isopropyl alcohol. Most preferably, the solvent is ethanol.
- Preferred combinations of organic solvent and water include acetone and water, preferably in a ratio of acetone: water of from about 30:1 to about 1:1, more preferably in a ratio of from about 11 :2 to about 3:1.
- the at least one solvent is one in which tadalafil has a solubility of at least about 1.2 mg tadalafil per 1 mL solvent at 25°C.
- at least 85 wt% of the tadalafil and a majority of the carrier are in solution in the at least one solvent. More preferably, at least 85 wt% of the tadalafil and 85 wt% of the carrier are in solution in the at least one solvent. Even more preferably, substantially all of the tadalafil and carrier are in solution in the at least one solvent. In particularly preferred embodiments, all of the tadalafil and carrier are in solution in the at least one solvent.
- the combining of tadalafil, at least one carrier and at least one solvent includes the step of mixing a solvent with tadalafil and at least one carrier in any order.
- the tadalafil, carrier, and solvent are mixed using any suitable mixing method, such as by using magnetic stirrers, mixer stirrers, shakers, or sonification, to mention just a few.
- Tadalafil in any form can be used as a starting material to prepare the solid composites.
- the tadalafil can be synthesized by any suitable means.
- Solvent removal can be by any suitable method.
- the preferred method is evaporation.
- Particularly preferred methods of removing the at least one solvent include fluidized bed drying and spray-drying the solution of tadalafil.
- Spray-drying broadly refers to processes involving breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture.
- spray-drying processes and equipment are described in Perry's Chemical Engineer's Handbook, pgs. 20-54 to 20-57 (Sixth Edition 1984).
- the obtained solid composites of tadalafil in intimate association with the at least one carrier can be recovered and dried.
- the solid composites can be formulated into pharmaceutical compositions.
- Pharmaceutically acceptable excipients e.g. surfactants (e.g. sodium lauryl sulfate), binders, fillers, glidants, lubricants, disintegrants and the like can be used in such compositions.
- the solid composites can be formulated into solid oral pharmaceutical compositions useful for making, e.g., solid oral dosage forms such as capsules, tablets, or gelcaps.
- the solid composites are collected and used as is within a capsule or optionally combined with one or more pharmaceutically acceptable excipients, e.g.
- surfactants e.g. sodium lauryl sulfate
- binders binders
- fillers glidants, lubricants, disintegrants and the like
- glidants e.g. sodium lauryl sulfate
- Solid composites that are formulated into pharmaceutical compositions and then to a dosage form like a tablet include pharmaceutically acceptable excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
- Lubricants can be added, for example, during tablet formulation to reduce adhesion and ease release from the tablet punch and dye.
- the solid composites are formulated into pharmaceutical compositions to be administered parenterally, rectally, transdermally, bucally, or nasally.
- suitable forms of parenteral administration include an aqueous or non-aqueous solution or emulsion, while for rectal administration suitable forms for administration include suppositories with hydrophilic or hydrophobic vehicle.
- suitable transdermal delivery systems known in the art
- suitable aerosol delivery systems known in the art.
- Pharmaceutical compositions to be administered orally are preferred.
- these two steps may be combined in a single step by, for example, spraying the solution containing the tadalafil, carrier and solvent onto to a fluidized bed of the excipient while drying. As a result, the solid composite will be formed on the excipient.
- compositions may contain additional tadalafil, meaning tadalafil in addition to the tadalafil in the solid composite. Consequently, one can control the rate of dissolution from a composition of tadalafil to match a profile within a large range. For example, where a slower rate of dissolution is preferred, the composition would preferably comprise a large percentage of "additional" (free drug) tadalafil as compared to a composition where a higher rate of dissolution is desired.
- the tadalafil in free drug form used to adjust the dissolution is preferably that with a particle size distribution such that the d(0.9) value would be greater than about 40 ⁇ m, for example, about 50 ⁇ m.
- the amount of the solid composite used in a pharmaceutical formulation is preferably an amount that provides a therapeutically effective amount of tadalafil. It will be appreciated that the amount of solid composite used will differ according to the drug:carrier ratio in the particles. "Effective” or “therapeutically effective” amount of a drug or pharmacologically active agent means an amount of the drug or agent that is nontoxic and sufficient to provide the desired effect, e.g., treatment of erectile dysfunction.
- the amount of PDE5 inhibitor 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. Thus, because of patient-to-patient variability, dosages are a guideline only and the physician may adjust doses of the compounds to achieve the level of effective treatment that the physician considers appropriate for the patient. In considering the degree of treatment desired, the physician must balance a variety of factors such as the age of the patient and the presence of other diseases or pre-existing conditions.
- the pharmaceutical composition may be administered to a mammal.
- the mammal is a human.
- the pharmaceutical formulation is administered to treat erectile dysfunction.
- Treating,” “treated,” and “treatment” means at least one of the following: reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, or improvement or remediation of damage.
- the present method of "treating" erectile dysfunction thus encompasses both prevention of the disorder in a predisposed individual and treatment of the disorder in a clinically symptomatic individual.
- the solid composites of the invention and pharmaceutical compositions including them preferably allow for the rapid absorption and onset of the PDE inhibitor tadalafil in a mammal.
- tadalafil is preferably released from the solid composite or a pharmaceutical formulation including the solid composite with sufficient solubility for gastro-intestinal absorption in the slightly acidic to neutral pH regions.
- At least 80 wt% of the tadalafil dissolves within about 10 minutes.
- at least 60 wt%, more preferably at least 70 wt%, of the tadalafil dissolves within about 5 minutes under these conditions.
- such dissolution rates are also achieved when composites containing 20 mg of tadalafil are tested at conditions at least as stringent as those exemplified by Table 1 (e.g. the conditions set forth in Table 1).
- solid composites and pharmaceutical formulations or dosage forms comprising the solid composites can be coated (with, e.g., a polymeric coating), generally, when dissolution rates are tested, the solid composites are uncoated.
- compositions of the invention can also include mixtures of the solid composite of the invention, together with tadalafil in free drug form.
- the particles of the tadalafil in free drug form have a particle size distribution such that the d(0.9) value is greater than 40 ⁇ m so that intermediate rates of dissolution are achieved without using micronized tadalafil.
- the skilled artisan will know to vary the ratio of solid composite and tadalafil in free drug form to obtain the desired dissolution rate.
- the skilled artisan can achieve a dissolution rate that matches Cialis ® - i.e., preferably 50 wt% of the tadalafil in the composition dissolves within about 5 minutes and 70 wt% of the tadalafil in the composition dissolves within about 10 minutes when a sample of a composition containing 20 mg of tadalafil tested in conditions at least as stringent as those exemplified by Table 1 (e.g. the conditions set forth in Table 1).
- a Mini-Glatt model 7069 fluidized bed drier operated under the following conditions, was used to remove solvent in the Examples described herein:
- Atomizing press 1.5-2 bar
- Product temperature 30°C-35°C
- Dissolution profiles described herein were determined in a dissolution vessel using a USP Apparatus 2 (Paddles) under the conditions described in Table 1. Samples were analyzed on-line by a UV detector.
- Example 1 Tadalafil Solid Solution (Ratio of Active Drug : Carrier 1:5)
- the term d(0.9) ⁇ (about) 50 ⁇ m refers to the fact that at least about 90% of the particles have a particle size of less than about 50 ⁇ m.
- the dissolution profiles of the samples were determined according to the conditions in Table 1.
- the samples were analyzed on-line by UV detection, and were compared.
- Figure 2 illustrates the averages of the samples for each drug.
- 900 mg of hydroxypropyl methylcellulose is dissolved in the solution using a sonicator.
- Ethanol is evaporated from the solution using a fluidized bed dryer to obtain dry powder. The dry powder is collected and may be combined in a pharmaceutical formulation.
- Example 5 Tadalafil Solid Solution (Ratio of Active Drug : Carrier 1:7 s )
- 2100 mg of polyethylene glycol is dissolved in the solution using a sonicator.
- Ethanol is evaporated from the solution using a fluidized bed dryer to obtain dry powder.
- the dry powder is collected and may be combined in a pharmaceutical formulation.
- PVP k-30 povidone
- Example 7 Tadalafil Solid Solution (Ratio of Active Drug : Carrier 1:10)
- 3000 mg of povidone (PVP k-30) is dissolved in the solution using a sonicator.
- Ethanol is evaporated from the solution using a fluidized bed dryer to obtain dry powder. The dry powder is collected and may be combined in a pharmaceutical formulation.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Gynecology & Obstetrics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2008016569A MX2008016569A (en) | 2006-07-07 | 2006-11-09 | Solid compositions comprising tadalafil and at least one carrier. |
JP2009518090A JP2009542648A (en) | 2006-07-07 | 2006-11-09 | Solid composition comprising tadalafil and at least one carrier |
CN2006800551991A CN101500572B (en) | 2006-07-07 | 2006-11-09 | Solid compositions comprising tadalafil and at least one carrier |
BRPI0621852-0A BRPI0621852A2 (en) | 2006-07-07 | 2006-11-09 | solid compounds consisting of tadalafil and at least one vehicle |
CA002654902A CA2654902A1 (en) | 2006-07-07 | 2006-11-09 | Solid compositions comprising tadalafil and at least one carrier |
IL196272A IL196272A0 (en) | 2006-07-07 | 2008-12-30 | Solid compositions comprising tadalafil and at least one carrier |
NO20090610A NO20090610L (en) | 2006-07-07 | 2009-02-09 | Solid preparations comprising tadalafil and at least one carrier |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US81921506P | 2006-07-07 | 2006-07-07 | |
US60/819,215 | 2006-07-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2008005039A1 true WO2008005039A1 (en) | 2008-01-10 |
Family
ID=37733988
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2006/043664 WO2008005039A1 (en) | 2006-07-07 | 2006-11-09 | Solid compositions comprising tadalafil and at least one carrier |
Country Status (12)
Country | Link |
---|---|
US (2) | US20080009502A1 (en) |
EP (1) | EP1875914A1 (en) |
JP (1) | JP2009542648A (en) |
KR (1) | KR101140110B1 (en) |
CN (1) | CN101500572B (en) |
BR (1) | BRPI0621852A2 (en) |
CA (1) | CA2654902A1 (en) |
IL (1) | IL196272A0 (en) |
MX (1) | MX2008016569A (en) |
NO (1) | NO20090610L (en) |
RU (1) | RU2009103660A (en) |
WO (1) | WO2008005039A1 (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2238979A1 (en) | 2009-04-06 | 2010-10-13 | LEK Pharmaceuticals d.d. | Active pharmaceutical ingredient adsorbed on solid support |
DE102009033396A1 (en) | 2009-07-16 | 2011-01-20 | Ratiopharm Gmbh | An aqueous solution and gelatinized composition comprising a phosphodiesterase 5 inhibitor and methods and use thereof |
WO2012085927A2 (en) * | 2010-12-02 | 2012-06-28 | Mylan Laboratories, Limited | Tadalafil compositions |
WO2012107092A1 (en) | 2011-02-10 | 2012-08-16 | Synthon Bv | Pharmaceutical composition comprising tadalafil and a cyclodextrin |
WO2012107090A1 (en) | 2011-02-10 | 2012-08-16 | Synthon Bv | Granulated composition comprising tadalafil and a disintegrant |
WO2012107541A1 (en) | 2011-02-10 | 2012-08-16 | Synthon Bv | Pharmaceutical composition comprising tadalafil and a cyclodextrin |
WO2015000853A1 (en) * | 2013-07-05 | 2015-01-08 | Synthon B.V. | Pharmaceutical composition comprising a solid dispersion of tadalafil |
US9238007B2 (en) | 2007-06-22 | 2016-01-19 | Ratiopharm Gmbh | Method for the production of a medicament containing tadalafil |
EP3466951A1 (en) | 2014-07-23 | 2019-04-10 | KRKA, d.d., Novo mesto | A process for the preparation of cgmp-phosphodiesterase inhibitor and oral pharmaceutical formulation comprising tadalafil co-precipitates |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2405787T3 (en) * | 2007-04-25 | 2013-06-03 | Teva Pharmaceutical Industries Ltd. | Solid dosage forms |
DE102009035211A1 (en) * | 2009-07-29 | 2011-02-17 | Ratiopharm Gmbh | A coprecipitate comprising a phosphodiesterase-5 inhibitor (PDE-5 inhibitor) and a pharmaceutically acceptable carrier, their preparation and use |
WO2011030351A2 (en) | 2009-09-03 | 2011-03-17 | Rubicon Research Private Limited | Taste - masked pharmaceutical compositions |
US10610528B2 (en) * | 2009-12-08 | 2020-04-07 | Intelgenx Corp. | Solid oral film dosage forms and methods for making same |
US20110136815A1 (en) * | 2009-12-08 | 2011-06-09 | Horst Zerbe | Solid oral film dosage forms and methods for making same |
US20110263606A1 (en) * | 2010-04-26 | 2011-10-27 | Horst Zerbe | Solid oral dosage forms comprising tadalafil |
WO2012095151A1 (en) | 2010-12-23 | 2012-07-19 | Zaklady Farmaceutyczne Polpharma Sa | Solid pharmaceutical dosage forms comprising tadalafil and methods of preparation thereof |
PL2797599T3 (en) * | 2011-12-26 | 2019-03-29 | Tritech Biopharmaceuticals Co. Ltd. | Method and improved pharmaceutical composition for enhancing transdermal delivery of pde-5 inhibitor |
WO2014003678A1 (en) * | 2012-06-28 | 2014-01-03 | Xspray Microparticles Ab | Pharmaceutical compositions comprising ambrisentan and solid dispersion particles containing tadalafil |
WO2014003677A1 (en) * | 2012-06-28 | 2014-01-03 | Xspray Microparticles Ab | Pharmaceutical compositions comprising solid dispersion particles containing tadalafil |
WO2014027981A2 (en) | 2012-08-17 | 2014-02-20 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Effervescent tablet formulations of dapoxetine and a pde5 inhibitor |
US20150231092A1 (en) | 2012-08-17 | 2015-08-20 | Sanovell IIac Sanayi Ve Ticaret Anonim Sirketi | Novel effervescent sachet formulations of dapoxetine and a pde5 inhibitor |
WO2014027979A2 (en) | 2012-08-17 | 2014-02-20 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Tablet formulations comprising tadalafil and dapoxetine |
US20160000720A1 (en) * | 2013-02-14 | 2016-01-07 | Aurobindo Pharma Limited | Pharmaceutical compositions comprising Tadalafil |
CN104188912B (en) * | 2014-07-17 | 2017-12-22 | 山东大学 | Tadalafei solid dispersions and its tablet |
KR101712524B1 (en) * | 2014-08-21 | 2017-03-08 | 동국제약 주식회사 | Combinatory formulation comprising tadalafil and dutasteride and the method for preparing thereof |
KR101538985B1 (en) * | 2014-09-02 | 2015-07-24 | 주식회사 서울제약 | Tadalafil Orally Disintegrating Film and Precess For Producing thereof |
KR20160138796A (en) | 2015-05-26 | 2016-12-06 | 삼아제약 주식회사 | Novel fast disintegrating fine granule formulation containing tadalafil as an active ingredient |
KR101634382B1 (en) | 2015-10-20 | 2016-06-28 | 미래제약 주식회사 | Oral liquid formulation of tadalafil |
WO2017104862A1 (en) * | 2015-12-16 | 2017-06-22 | 동국제약 주식회사 | Composite preparation composition comprising tadalafil and dutasteride and preparation method thereof |
CN107303284A (en) * | 2016-04-25 | 2017-10-31 | 湖北生物医药产业技术研究院有限公司 | Prepare the method and Tadalafei tablet of Tadalafei tablet |
CN110035756A (en) * | 2016-11-30 | 2019-07-19 | 成药技术Ip控股有限公司 | Medicament preparation containing Tadalafei |
CN107334736A (en) * | 2017-07-21 | 2017-11-10 | 广州中医药大学 | Tadalafei solid dispersion system and preparation method thereof |
CN110812336B (en) * | 2018-08-07 | 2021-09-10 | 迪沙药业集团有限公司 | Tadalafil tablet composition |
KR102195162B1 (en) | 2019-01-30 | 2020-12-24 | 단국대학교 천안캠퍼스 산학협력단 | Tadalafil-containing solid dispersion and method for preparation the same |
WO2021145831A1 (en) * | 2020-01-16 | 2021-07-22 | Pharmacti̇ve İlaç Sanayi̇ Ve Ti̇caret A.Ş. | Pharmaceutical compositions comprising tadalafil and relevant excipients |
KR20220057077A (en) | 2020-10-29 | 2022-05-09 | 대화제약 주식회사 | Orally disintegrating film comprising tadalafil |
EP4272733A1 (en) * | 2020-12-31 | 2023-11-08 | Dong Kook Pharm. Co., Ltd | Pharmaceutical composition comprising tadalafil or pharmaceuticallly acceptable salt thereof and dutasteride or pharmaceuticallly acceptable salt thereof exhibiting novel dissolution rate |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004037262A2 (en) * | 2002-10-22 | 2004-05-06 | Vivus, Inc. | Immediate release topical pharmaceutical formulation for enhancement of female sexual desire and responsiveness |
WO2005065308A2 (en) * | 2003-12-29 | 2005-07-21 | Jason Mcdevitt | Compositions and methods to treat recurrent medical conditions |
US20050196418A1 (en) * | 2004-03-04 | 2005-09-08 | Yu Ruey J. | Bioavailability and improved delivery of alkaline pharmaceutical drugs |
WO2006108519A1 (en) * | 2005-04-13 | 2006-10-19 | Bayer Healthcare Ag | Therapeutic combination in case of benign prostate hyperplasia |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU171662B (en) * | 1975-07-18 | 1978-02-28 | Richter Gedeon Vegyeszet | Process for preparing new optically active derivatives of apovincaminol and acid addition salts thereof |
CA1146866A (en) * | 1979-07-05 | 1983-05-24 | Yamanouchi Pharmaceutical Co. Ltd. | Process for the production of sustained release pharmaceutical composition of solid medical material |
GB9401090D0 (en) * | 1994-01-21 | 1994-03-16 | Glaxo Lab Sa | Chemical compounds |
GB9511220D0 (en) * | 1995-06-02 | 1995-07-26 | Glaxo Group Ltd | Solid dispersions |
GB9514464D0 (en) * | 1995-07-14 | 1995-09-13 | Glaxo Lab Sa | Medicaments |
US7182958B1 (en) * | 1999-08-03 | 2007-02-27 | Lilly Icos Llc. | β-carboline pharmaceutical compositions |
US6821975B1 (en) * | 1999-08-03 | 2004-11-23 | Lilly Icos Llc | Beta-carboline drug products |
EP1239844B1 (en) * | 1999-12-20 | 2005-06-08 | Nicholas J. Kerkhof | Process for producing nanometer particles by fluid bed spray-drying |
PL372290A1 (en) * | 2002-02-07 | 2005-07-11 | Pharmacia Corporation | Pharmaceutical dosage form for mucosal delivery |
US20050019641A1 (en) * | 2003-06-18 | 2005-01-27 | Toshiyuki Aoyama | Fuel tank for fuel-cell and fuel cell system |
US20050096418A1 (en) | 2003-10-31 | 2005-05-05 | Baranek Todd M. | High density metal oxide fillers in rubber compounds |
US20060276442A1 (en) * | 2004-09-08 | 2006-12-07 | Woodward John R | Methods of female sexual enhancement |
US8367105B2 (en) * | 2004-11-10 | 2013-02-05 | Teva Pharmaceutical Industries, Ltd. | Compressed solid dosage form manufacturing process well-suited for use with drugs of low aqueous solubility and compressed solid dosage forms made thereby |
US20070009589A1 (en) * | 2005-07-07 | 2007-01-11 | Kandarapu Raghupathi | Extended release compositions |
ES2405787T3 (en) * | 2007-04-25 | 2013-06-03 | Teva Pharmaceutical Industries Ltd. | Solid dosage forms |
-
2006
- 2006-11-09 KR KR1020097000700A patent/KR101140110B1/en not_active IP Right Cessation
- 2006-11-09 RU RU2009103660/15A patent/RU2009103660A/en unknown
- 2006-11-09 MX MX2008016569A patent/MX2008016569A/en not_active Application Discontinuation
- 2006-11-09 CA CA002654902A patent/CA2654902A1/en not_active Abandoned
- 2006-11-09 EP EP06255751A patent/EP1875914A1/en not_active Withdrawn
- 2006-11-09 JP JP2009518090A patent/JP2009542648A/en active Pending
- 2006-11-09 WO PCT/US2006/043664 patent/WO2008005039A1/en active Application Filing
- 2006-11-09 BR BRPI0621852-0A patent/BRPI0621852A2/en not_active IP Right Cessation
- 2006-11-09 CN CN2006800551991A patent/CN101500572B/en not_active Expired - Fee Related
- 2006-11-09 US US11/595,481 patent/US20080009502A1/en not_active Abandoned
-
2008
- 2008-12-30 IL IL196272A patent/IL196272A0/en unknown
-
2009
- 2009-02-09 NO NO20090610A patent/NO20090610L/en not_active Application Discontinuation
- 2009-12-23 US US12/646,733 patent/US20100099687A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004037262A2 (en) * | 2002-10-22 | 2004-05-06 | Vivus, Inc. | Immediate release topical pharmaceutical formulation for enhancement of female sexual desire and responsiveness |
WO2005065308A2 (en) * | 2003-12-29 | 2005-07-21 | Jason Mcdevitt | Compositions and methods to treat recurrent medical conditions |
US20050196418A1 (en) * | 2004-03-04 | 2005-09-08 | Yu Ruey J. | Bioavailability and improved delivery of alkaline pharmaceutical drugs |
WO2006108519A1 (en) * | 2005-04-13 | 2006-10-19 | Bayer Healthcare Ag | Therapeutic combination in case of benign prostate hyperplasia |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9238007B2 (en) | 2007-06-22 | 2016-01-19 | Ratiopharm Gmbh | Method for the production of a medicament containing tadalafil |
EP2238979A1 (en) | 2009-04-06 | 2010-10-13 | LEK Pharmaceuticals d.d. | Active pharmaceutical ingredient adsorbed on solid support |
WO2010115886A1 (en) | 2009-04-06 | 2010-10-14 | Lek Pharmaceuticals D.D. | Active pharmaceutical ingredient adsorbed on solid support |
DE102009033396A1 (en) | 2009-07-16 | 2011-01-20 | Ratiopharm Gmbh | An aqueous solution and gelatinized composition comprising a phosphodiesterase 5 inhibitor and methods and use thereof |
WO2011006596A2 (en) | 2009-07-16 | 2011-01-20 | Ratiopharm Gmbh | Aqueous solution and gelatinized composition comprising a phosphodiesterase-5 inhibitor and corresponding methods and use |
WO2012085927A2 (en) * | 2010-12-02 | 2012-06-28 | Mylan Laboratories, Limited | Tadalafil compositions |
WO2012085927A3 (en) * | 2010-12-02 | 2012-09-07 | Mylan Laboratories, Limited | Tadalafil compositions |
WO2012107092A1 (en) | 2011-02-10 | 2012-08-16 | Synthon Bv | Pharmaceutical composition comprising tadalafil and a cyclodextrin |
WO2012107090A1 (en) | 2011-02-10 | 2012-08-16 | Synthon Bv | Granulated composition comprising tadalafil and a disintegrant |
WO2012107541A1 (en) | 2011-02-10 | 2012-08-16 | Synthon Bv | Pharmaceutical composition comprising tadalafil and a cyclodextrin |
WO2015000853A1 (en) * | 2013-07-05 | 2015-01-08 | Synthon B.V. | Pharmaceutical composition comprising a solid dispersion of tadalafil |
EP3466951A1 (en) | 2014-07-23 | 2019-04-10 | KRKA, d.d., Novo mesto | A process for the preparation of cgmp-phosphodiesterase inhibitor and oral pharmaceutical formulation comprising tadalafil co-precipitates |
Also Published As
Publication number | Publication date |
---|---|
CN101500572A (en) | 2009-08-05 |
US20080009502A1 (en) | 2008-01-10 |
US20100099687A1 (en) | 2010-04-22 |
IL196272A0 (en) | 2009-09-22 |
MX2008016569A (en) | 2009-01-30 |
KR101140110B1 (en) | 2012-06-04 |
CN101500572B (en) | 2013-08-21 |
CA2654902A1 (en) | 2008-01-10 |
NO20090610L (en) | 2009-02-09 |
EP1875914A1 (en) | 2008-01-09 |
RU2009103660A (en) | 2010-08-20 |
KR20090021380A (en) | 2009-03-03 |
JP2009542648A (en) | 2009-12-03 |
BRPI0621852A2 (en) | 2011-12-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1875914A1 (en) | Solid compositions comprising tadalafil and at least one carrier | |
EP2101741B1 (en) | Solid dispersion comprising a poorly water soluble drug | |
US20110112136A1 (en) | Novel process for the manufacture of pharmaceutical preparations | |
EP2436377B1 (en) | Microspheres with improved bioavailability containing poorly water-soluble drugs, and method for preparing same | |
JP2003518038A (en) | Method for producing nanoparticles by fluidized bed spray drying | |
US20100168247A1 (en) | Solid composites of a calcium receptor-active compound | |
EP1940364A2 (en) | Capsule formulation of pirfenidone and pharmaceutically acceptable excipients | |
CN101827585A (en) | Solid dispersion product containing N-aryl urea-based compound | |
EA028009B1 (en) | Pharmaceutical composition with improved bioavailability | |
TWI380829B (en) | Solid dispersion composition of pranlukast with improved bioavailibility and the method of preparing the solid dispersion | |
US20030077322A1 (en) | Solid dispersion system of pranlukast with improved dissolution and method for preparing the same | |
US20170072058A1 (en) | Pharmaceutical composition containing tacrolimus and preparation methods thereof | |
CN114126712A (en) | Amorphous spartan (SPARSENTAN) compositions | |
WO2009034409A2 (en) | Pharmaceutical compositions of rhein or diacerein | |
KR20090118982A (en) | Pharmaceutical formulation | |
EP3831381A1 (en) | Solid dispersion of hydantoin derivative | |
JP5106119B2 (en) | Drug for oral administration containing cyclooxygenase-2 inhibitor and method for preparing the same | |
AU2013201986A1 (en) | Capsule Formulation Of Pirfenidone And Pharmaceutically Acceptable Excipients | |
Kavitha | Enhancement of Solubility of Repaglinide Through Solid Dispersion Methods | |
Shetty et al. | FAST DISSOLVING TABLETS OF PHENYTOIN BY HOLE TECHNOLOGY | |
JPH05170649A (en) | Trithione derivative composition |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200680055199.1 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 06827676 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2654902 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10198/DELNP/2008 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2008/016569 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 196272 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009518090 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020097000700 Country of ref document: KR |
|
ENP | Entry into the national phase |
Ref document number: 2009103660 Country of ref document: RU Kind code of ref document: A |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 06827676 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: PI0621852 Country of ref document: BR Kind code of ref document: A2 Effective date: 20090106 |