EP2124949A1 - Pharmaceutical formulation - Google Patents
Pharmaceutical formulationInfo
- Publication number
- EP2124949A1 EP2124949A1 EP08730525A EP08730525A EP2124949A1 EP 2124949 A1 EP2124949 A1 EP 2124949A1 EP 08730525 A EP08730525 A EP 08730525A EP 08730525 A EP08730525 A EP 08730525A EP 2124949 A1 EP2124949 A1 EP 2124949A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- dispersion
- amide
- bis
- 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- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- 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
Definitions
- the present invention relates to forms of (2R,4S)-Quinoline-4-carboxylic acid [ 1 - (3.5-bis-trifluoromelhyl-benzoyl)-2-(4-chloiOben7>l)-piperidin-4-yl] amide, or an active 10 metabolite thereof, or (2R,4S)-Quinazoline-4-carboxylic acid [l -(3,5-bis-trifluoromethyl- benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide and methods of making and using the same.
- Water-insoluble drugs present many challenging aspects to the formulation scientist in the development of a suitable dosage form for oral administration.
- the solubility, dissolution, and permeability of a compound all contribute to the bioavailability of a drug.
- incorporation of certain excipients into formulations for permeability enhancement has been studied, results are inconclusive and not widely
- Micronization of drug substance is an established technology platform which improves dissolution, and thus potentially bioavailability, through reduction of particle size and an associated increase in surface area. Processing and physical stability, e.g. excessive flocculation or agglomeration, are challenges that exist for the micronization platform
- (2R.4S)-Quinoline-4-carboxylic acid [1 -(3.5-bis-trifluoromethyl-benzoyl)-2-(4- chlorobcnzyl)-piperidin-4-yl] amide, or an active metabolite thereof
- (2R,4S)- Quinazoline-4-carboxylic acid [l -(3,5-bis-trifluoiOmethyl-benzoyl)-2-(4-chlorobenzyl)- piperidin-4-yl] amide provide desirable qualities, including solubility, bioavailability, and stability (e.g., physical and chemical stability).
- the invention features a solid dispersion comprising a compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [l -(3,5-bis-lrifluoromethyl- benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide, or an active metabolite thereof, or (2R,4S)-Quinazoline-4-carboxylic acid [l-(3,5-bis-trifluoromcthyl-benzoyl)-2-(4- chlorobenzyl)-piperidin-4-yl] amide and HPMCAS.
- a compound of formula I preferably (2R,4S)-Quinoline-4-carboxylic acid [l -(3,5-bis-lrifluoromethyl- benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide, or an active metabolite thereof, or (2R,4S)
- the active metabolite is (2R,4S)-Quinoline-N-oxide-4- carboxylic acid [l -(3,5 -bis-lrifluoromethy]-ben/,oyl) ⁇ 2-(4-ch]orobenzyl) ⁇ piperidin -4-yl] amide or (2R,4S)-2-Hydroxy-quinoline 4 -carboxylic acid [1 -(3,5 -bis-trifluoromelhyI- bcnzoyl)-2 -(4 -chlorobcnzy])-piperidin-4-ylJ amide.
- the ratio of the compound of formula I preferably
- (2R,4S)-Quinoline-4- carboxylic acid [1 -(3,5 ⁇ bis ⁇ trifluoiOmethyl-benzoy])-2-(4- chlorobenzyl)-piperidin-4-yl] amide,, or active metabolite thereof, or (2R.4S) Quinazoline-4-carboxylic acid [l-(3,5-bis-trifluoromethy]-benzoyl) ⁇ 2 -(4-chlorobenzyl) ⁇ piperidin-4-yl] amide to HPMCAS is from about 1 :5 to about 5: 1 , for example, from about 1 :3 to about 3: 1 , exemplary ratios include about 1 : 1 or about 3: 1.
- the dispersion is substantially homogeneous. In some embodiments, the dispersion has a single T g . In some embodiments, the dispersion maintains a single T g at 25 0 C. 60% relath e humidity for at least two weeks In some embodiments, the dispersion maintains a single T 2 at 40 "C. 75% relative humidity for at least two weeks. In some embodiments, the dispersion maintains a single T 2 at 25 0 C. 90% relative humidity for at least two weeks.
- the T 2 is at least about 5OK greater than 25 0 C at from about 50% to about 90% relative humidity. In some embodiments, the T 2 is at least about 50K greater than 25 0 C at from about 60% to about 75% rclati ⁇ e humidity. In some embodiments, the T g is from about 98 0 C to about 102 0 C at 25 0 C, 60% relative humidity.
- the dispersion comprises at least one non-homogeneous region enriched with the compound of formula I, preferably (2R,4S)-Quinoline-4- carboxylic acid [l -(3,5-bis-trifluoiOmethy]-benzoyl)-2-(4-chlorobenzyl)-piperidm-4-yl] amide, or active metabolite thereof, or (2R.4S)-Quinazoline-4-carboxylic acid [l-(3,5- bis-tri ⁇ uoromethyl-bcnzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.
- the dispersion comprises at least one non-homogeneous region enriched with (2R,4S)-Quinoline-4-carboxylic acid [ l -(3,5-bis-trifluoromethyl- benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.
- At least about 50% of the compound of formula I preferably (2R,4S)-Quinohne-4-carboxyhc acid [ 1 -(3,5 bis-trifluoiOmethy)-benzoyl)-2 (4-chlorobenzyl)-piperidin- 4-yl] amide or active metabolite thereof, or (2R,4S) • Quinazoline-4-carboxylic acid [ 1 -(3.5 bis lrifluoromethyl-benzoyl)-2 -(4-chlorobcnzyl)- pipe ⁇ din-4 yl] amide withm the solid dispersion is amorphous, for example, at least about 75% of the compound of formula I, preferably (?R,4S) Quinoline-4 carboxylic acid [I -(3,5 bis-trifluoroinethyl-benzoyl)-?
- the HPMCAS dissolves at pH > 5.5, e.g.. at pH > 6.0, or at pH > 6.5.
- the HPMCAS is HPMCAS-LF.
- the dispersion further comprises a surfactant.
- the surfactant is an anionic surfactant.
- the surfactant is present in the dispersion from an amount of from about 0.1% to about 20%, for example, from about 1 % to about 10%.
- the surfactant is selected from sodium lauryl sulfate and docusate sodium.
- the dispersion further comprises a plurality of surfactants.
- the dispersion comprises an additional polymer, for example, a water soluble polymer such as PVP.
- the ratio of HPMCAS to PVP is from about 5: 1 to about 1 :5, for example about from about 3: 1 to 1 :3, or 1 : 1.
- the dispersion comprises (2R,4S)-Quinoline-4-carboxylic acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.
- the dispersion is substantially free of active metabolite of (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2-(4- chlorobenzyl)-piperidin-4-yl] amide.
- the AUC of the compound of formula I preferably
- (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2 ⁇ (4- chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)-Quinazoline 4-carboxylic acid [ 1 -(3,5--bis-trifluoromelhyl-benzoyl)-2 -(4-chlorobcnzyl)-piperidin ⁇ 4-yl] amide when dosed in a subject is at least about 1.25 times the AUC of compound of formula I, preferably (2R,4S) ⁇ Quinoline-4-carboxylic acid [1 -(3,5-bis-lrifluorometbyl- benzoyl)-2-(4-chloiObenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R.4S)-Quinazoline-4-carboxy
- the compound of formula I preferably (2R,4S)-Quinoline- 4-carboxylic acid [ 1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloiObenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R.4S)-Quinazoline-4-carboxylic acid [ 1 -(3,5-bis- trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is substantially amorphous and remains substantially amorphous for 2 weeks at 40 °C/75% relative humidity for 2 weeks.
- the compound of formula I preferably (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2-(4- chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)-Quinazoline- 4-carboxylic acid [l -(3.5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is substantially amoiphous and remains substantially amorphous for 2 weeks at 25 °C/90% relative humidity for 2 weeks.
- the invention features a solid dispersion comprising a compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl- benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R.4S)-Quinazoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2-(4- chlorobenzyl)-piperidin-4-yl] amide and PVP, wherein the weight percent of the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis- trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-
- the active metabolite is (2R,4S) Quinoline-N-oxide-4 carboxyljc acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2 (4-chlorobenzyl)-piperidin 4-yl] amide or (2R,4S) -2-Hydroxy-quinoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl- benzoyl)-2-(4-chlorobenzyl) piperidin-4-yl] amide.
- the ratio of the compound of formula I, preferably (2R,4S)-Quinoline ⁇ 4-carboxylic acid [1 -(3,5-bis-trifluoromelhyl-benzoyl)-2-(4- chlorobenzyl)-piperidin-4-yl] amide to PVP is from about 1 : 1 to about 5: 1, e.g., from about 2: 1 to about 4: 1 , exemplary ratios include about 1 :1 or about 3.5: 1.
- the dispersion is substantially homogeneous
- the T g is at least about 5OK greater than 25 0 C at from about 50% to about 90% relativ e humidity, for example, the T 2 is at least about 50K greater than 25 0 C at from about 60% to about 75% relative humidity.
- the T P is at least about 100 0 C at 25 0 C and 60% relative humidity, for example, the T g is from about 1 15 0 C to about 155 0 C.
- the dispersion has a single T ⁇ . In some embodiments, the dispersion maintains a single T ⁇ at 25 0 C, 60% relative humidity for at least two weeks. In some embodiments, the dispersion maintains a single T g at 40 0 C, 75% relative humidity for at least two weeks. In some embodiments, the dispersion maintains a single To at 25 0 C. 90% relativ e humidity for at least two w eeks.
- the dispersion comprises at least one non-homogeneous region enriched with the compound of formula I, preferably (2R,4S)-Quinoline-4- carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloiObenzyl)-pipcridin-4-yl] amide or an active metabolite thereof or (2R.4S)-Quinazoline-4-carboxylic acid [ l -(3.5- bis-trifluoiOmethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.
- the dispersion comprises at least one non-homogeneous region enriched with the (2R,4S)-Quinoline-4-carboxylic acid [1 -(3, 5 -bis trilluoromclhyl-benzoyl)-2-(4 -chlorobenzyl)-piperidin-4-yl] amide. In some embodiments, at least about 50% of the compound of formula I.
- (2R,4S)-Quinoline-4-carboxy)ic acid [ 1 (3,5 -bis- trifluoromethyl- benzoyl) 2 (4 cbJorobenzyl)-piperidin 4-yl] amide or active metabolite thereof or (2R,4S) Quinazoline 4 carboxylic acid [1 (3,5 bis trifluoromethyl -benzoyl) -2 (4 chlorobcnzyl) piperidin 4 -yl ) amide within the solid dispersion is amorphous, for example, at least about 75% of the compound of formula I, preferably (2R,4S) Quinoline 4 carboxylic acid [ l -(3,5 -bis-trifluoromelhyl-benzoyl)-2- (4-ch]orobenzyl)-pjperidin 4 -yl] amide or active metabolite thereof or (2R.4S) Quinazoline- 4 carboxylic acid [1 (3.5 bis- lri ⁇ u
- the PVP is K29/32. In some embodiments, the PVP has a molecular weight of from about 30,000 to about 100,000 daltons.
- the dispersion further comprises a surfactant, for example, an anionic surfactant. In some embodiments, the surfactant is present in the dispersion from an amount of from about 0.1 % to about 20% by weight, e.g.. from an amount of from about 1 % to about 10% by weight. In some embodiments, the surfactant is selected from sodium lauryl sulfate and docusate sodium. In some embodiments, the dispersion comprises a plurality of surfactants.
- the dispersion further comprises an additional polymer, for example, a water soluble polymer such as HPMCAS.
- an additional polymer for example, a water soluble polymer such as HPMCAS.
- the dispersion comprises (2R,4S)-Quinoline ⁇ 4-carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.
- the dispersion is substantially free of active metabolite of
- the AUC of the compound of formula I preferably (2R,4S)-Quinoline-4 carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoyl)-2-(4- chloiObcnzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)-Quinazoline- 4-carboxylic acid [] -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloiObeny,yl)-piperidin 4 yl] amide when dosed in a subject is al least about 1 .25 times the AUC of compound of formula I, preferably (2R,4S)-Quinoline 4 -carboxylic acid [ 1 (3,5 bis tnfluorometliyl benzoyl) 2 -(4 chlorobenzyl) piperidin 4 yl] amide or active metabolite thereof o
- the compound of formula I preferably (2R,4S)-Quinoline- 4-carboxylic acid [ l -(3,5 -bis-trifluoromethyl benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [l -(3,5-bis- lrifluoromethyl-bcnzoyl)-2-(4-chlorobenzyl)-pipcridin-4-yl] amide is substantially amorphous and remains substantially amorphous at 40 °CV75% relative humidity for 2 weeks.
- the compound of formula 1 is substantially amorphous and remains substantially amorphous at 40 °CV75% relative humidity for 2 weeks.
- the invention features a solid dispersion of compound of formula I, preferably (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [l-(3,5-bis-trifluoromethyl- benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or (2R,4S)-2-Hydroxy-quinoline-4- carboxylic acid [ 1 -(3,5 ⁇ bis-trifluoromethyl-benzoyl)-2-(4-chloiObenzyl)-piperidin-4-yl] amide and a polymer.
- compound of formula I preferably (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [l-(3,5-bis-trifluoromethyl- benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or (2R,4S)-2-Hydroxy-quinoline-4- carboxylic
- the dispersion comprises (2R,4S)-Quinoline-N-oxide-4- carboxylic acid [1 -(3.5-bis-trifluoroinethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.
- the dispersion comprises (2R,4S)-2-Hydroxy-quinoline-4 ⁇ carboxylic acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloiObenzyl)-piperidin-4-yl] amide.
- the polymer is a water soluble polymer, for example, HPMCAS or PVP.
- the dispersion is substantially homogeneous.
- the T g is at least about 5OK greater than 25 0 C at from about 50% to about 90% relative humidity. In some embodiments, the T g is at least about 50K greater than 25 0 C at from about 60% to about 75% relative humidity.
- the dispersion has a single T g . In some embodiments, the dispersion maintains a single T g at 25 0 C, 60% relative humidity for at least two weeks. In some embodiments, the dispersion maintains a single T e at 40 0 C, 75% relative humidity for at least two weeks.
- the dispersion maintains a single T g at 25 0 C, 90% relative humidity for at least two weeks.
- the dispersion comprises at least one non-homogeneous region enriched with (2R,4S)-Quinoline-N-oxide-4 ⁇ carboxylic acid [l-(3,5-bis- lrifluoromethyl-benzoyl)-2-(4-chloiObenzyl)-piperidin-4-yl] amide.
- the dispersion comprises at least one non-homogeneous region enriched with (2R,4S)-2-Hydroxy-quinoline-4-carboxylic acid [ l -(3,5-bis-trifluoi omethyl- benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.
- At least about 50% of the (2R,4S)-Quinoline-N-oxide-4- carboxylic acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloiObenzyl)-piperidin-4-yl] amide within the solid dispersion is amorphous, e.g., at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or substantially all of the (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [l -(3,5-bis-trifluoromcthyl-benzoyl)-2-(4- chlorobenzyl)-piperidin-4-yl] amide within the solid dispersion is amorphous.
- At least about 50% of the (2R,4S)-2-Hydroxy-quinoline-4- carboxylic acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-pipcridin-4-yl] amide within the solid dispersion is amorphous, e.g., at least about 55%.
- the dispersion further comprises a surfactant, for example, an anionic surfactant such as sodium lauryl sulfate or docusate sodium.
- a surfactant for example, an anionic surfactant such as sodium lauryl sulfate or docusate sodium.
- the surfactant is present in the dispersion from an amount of from about 0.1 % to about 20%. for example, from about 1 % to about 10%.
- the dispersion comprises a plurality of surfactants.
- the dispersion further comprises an additional polymer, for example, a water soluble polymer.
- the AUC of the (2R,4S)-Quinoline N-oxide-4-carboxylic acid f 1 -(3,5-bis-trifluoiOmethyl-bcnzoyl)-2-(4-chlorobcn/yl)-pipcridin-4-yl] amide when dosed in a subject is at least about 1.25 times the AUC of (2R,4S)-Quinoline-N-oxide-4- carboxylic acid [1 -(3,5 -bis-trifluoromethyl-benzoyl)-2-(4-chlorobcnzyl)-piperidin-4-yl] amide in an undispersed preparation, for example, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 4 times, at least about 5 times, or at least about 10 times.
- the AUC of the (2R,4S)-2-Hydroxy-quinoline-4- carboxylic acid [l-(3,5-bis-trifluoiOmethyl-benzoyl)-2-(4-ch]orobenzy])-piperidin-4-yl] amide when dosed in a subject is at least about 1.25 times the AUC of (2R,4S)-2- Hydroxy-quinoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2-(4- chlorobenzyl)-piperidin-4-yl] amide in an undispersed preparation, for example, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 4 times, at least about 5 times, or at least about 10 times.
- the (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [l-(3,5- bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is substantially amorphous and remains substantially amoiphous for 2 weeks at 40 °C/75% relative humidity for 2 weeks.
- the (2R,4S)-2-Hydroxy-quinoline-4- carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is substantially amorphous and remains substantially amorphous for 2 weeks at 40 °C/75% relative humidity for 2 weeks.
- the invention features a solid dosage form of a dispersion described herein, for example a dispersion of a compound of formula I.
- the invention features a particle coated with a compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2- (4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)- Quinazoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl) ⁇ piperidin-4-yl] amide and a polymer.
- a compound of formula I preferably (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2- (4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)- Quinazoline-4-carboxylic acid [l-(3,5-bis
- the particle is a non-pariel, a lactose prill, microcrystalline cellulose, or starch.
- the active metabolite is (2R,4S)--Quinolinc-N-oxide-4- carboxylic acid [l-(3,5-bis-trifluoiOmethyl-benzoyl) ⁇ 2-(4-chlorobenzyl)-pipcridin-4-yl] amide.
- the active metabolite is (2R,4S)-2-Hydroxy-quinoline-4- carboxylic acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-y]] amide.
- al least a portion of the compound of formula I preferably (2R,4S)-Quinoline-4-carboxylic acid [ 1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4- chloroben/yl)-piperidin-4-yl] amide or active metabolite thereof is dispersed in a polymer.
- the dispersion is substantially homogeneous.
- the T 6 of the dispersion is at least about 4OK greater than RT at from about 60% to about 75% relative humidity.
- the T g of the dispersion is from about 65 0 C to about 155 0 C.
- the dispersion has a single T g .
- the compound of formula I preferably (2R,4S)-Quinoline-4- carboxylic acid [1 -(3,5-bis-trifluoromcthyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof is substantially amorphous and the dispersion has a single T ⁇ at 25 0 C 60% relative humidity for at least 15 months.
- the dispersion comprises at least one non-homogeneous region enriched with the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [l -(3,5-bis- trifluoromelhyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof, or (2R,4S)-Quinazoline-4-carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoyl)- 2-(4-chlorobenzyl)-piperidin-4-yl] amide
- the dispersion comprises at least one non-homogeneous region enriched with (2R,4S)-Quinoline-4- carboxylic acid [ 1 -(3,5-bis-u'ifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.
- At least about 50% of the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoyl)-2 - (4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)- Quinazoline-4-carboxylic acid [1 -(3,5-bis ⁇ trifluoromethyl-benzoyl)-2-(4-chlorobenzyl) piperidin-4-yI] amide within the dispersion is amorphous e.g., at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or substantially all of the compound of formula J, preferably (2R,4S)-Quinoline-4-carboxylic acid [1 -(3,5 bis- trifluoromethyl
- the dispersion further comprises a surfactant, for example, an anionic surfactant such as sodium lauryl sulfate and docusate sodium.
- a surfactant for example, an anionic surfactant such as sodium lauryl sulfate and docusate sodium.
- the surfactant is present in the dispersion from an amount of from about 0.1 % to about 20%, for example, from about 1 % to about 10%.
- the dispersion comprises a plurality of surfactants,
- the AUC of the compound of formula I preferably (2R,4S)-Quinoline-4-carboxylic acid [ l ⁇ (3,5 ⁇ bis-trifluoromethyl-benzoyl) ⁇ 2-(4 ⁇ chloiObenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)-Quinazoline ⁇ 4-carboxylic acid [1 -(3.5-bis4rifluoromethyl-benzoyl)-2-(4-chlorobenzyl) ⁇ piperidin ⁇ 4 ⁇ yl] amide when dosed in a subject is at least about 1 .25 times the AUC of compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [l -(3,5-bis-trifluoromethyl- benzoyl) ⁇ 2-(4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4
- the polymer is HPMCAS.
- the ratio of the compound of formula I, preferably (2R,4S)-Quinoline ⁇ 4-carboxylic acid [1 -(3,5- bis-trifluoromethyl"benzoyl)"2 ⁇ (4"ChloiObenzyl)"piperidin-4-yl] amide or active metabolite thereof to HPMCAS within the dispersion is from about 1 .5 to about 5: 1 , e.g., from about 1 :3 to about 3: 1 ; exemplary ratios include about 1 : 1 , or about 3 : 1.
- the HPMCAS dissolves at pH > 5.5, for example, at pH > 6.0, or at pH > 6.5
- the HPMCA S is HPMCAS LF.
- the particle is further coated by an additional polymer, such as a water soluble polymer.
- the polymer is PVP
- l -(3,5-bis-triOuoromelhyl-benzoyJ)-2 (4-chlorobenzyl)-piperidin-4-yl] amide to PVP within the dispersion is from about 1 :5 to about 5: 1 , e.g., from about 1 :3 to about 3: 1 ; exemplary ratios include about 1 : 1 , or about 3: 1.
- the weight percent of compound of formula I preferably (2R,4S)-Quinoline-4-carboxylic acid [l -(3,5-bis-trifluoromcthyl-benzoyl)-2-(4- chlorobcnzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S) ⁇ Quinazoline-4-carboxylic acid [l -(3,5-bis-trifluoromethyl-bcnzoyl)-2-(4-chloiObenzyl)- piperidin-4-yl] amide within the solid dispersion is at least about 50%, e.g., at least about 55%, at least about 60%, at least about 65%, at least about 70%, or at least about 75%.
- the ratio of the compound of formula I, preferably (2R,4S)- Quinoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)- piperidin-4-yl] amide to PVP is from about 1 : 1 to about 5: 1 , e.g., from about 2: 1 to about 4: 1 : exemplary ratios include about 1 : 1 or about 3.5: 1.
- the PVP is K29/32.
- the particle comprises (2R,4S)-Quinoline-4-carboxylic acid [ l -(3,5-bis-lrifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.
- the particle is substantially free of active metabolite of (2R,4S)-Quinoline-4-carboxylic acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4- chlorobenzyl)-piperidin-4-yl] amide.
- the compound of formula I preferably (2R,4S) ⁇ Quinoline- 4-carboxylic acid [l -(3,5-bis-trifluoromelhyl-benzoy])-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [l-(3,5-bis- trifluoromelhyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is substantially amorphous and remains substantially amorphous for 2 weeks at 40 °C/75% relative humidity for 2 weeks.
- the compound of formula I preferably (2R,4S)-Quinoline-4-carboxylic acid [1 -(3,5 ⁇ bis--trifluoromethyl-benzoyl)-2-(4 - ch)orobenzyl)-piperidin -4-yl] amide or active metabolite thereof or (2R,4S) -Quinazoline 4-carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoy])"2-(4 ⁇ chlorobenzyl)-piperidin-4-ylJ amide is substantially amorphous and remains substantially amorphous for 2 weeks at 25 °C/90% relative humidity for 2 weeks.
- the invention features a solid dosage formulation comprising a particle described herein a dispersion described herein.
- the formulation further comprises one or more of an excipient, a diluent, a binder, a disintegrant, a glidant, a lubricant, and/or a surfactant.
- the dosage formulation is a tablet. In some embodiments, the dosage formulation is a capsule.
- the dosage formulation further comprises a coating, for example, an enteric polymer such as a cellulosic polymer.
- solid dosage formulation comprises about 20 mg of the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis- trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.
- solid dosage formulation comprises about 40 mg of the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis-ti ⁇ fluoromethyl- benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide. In some embodiments, solid dosage formulation comprises about 160 mg of the compound of formula I, preferably (2R,4S)-
- solid dosage formulation comprises about
- solid dosage formulation comprises
- the (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis- trifluoromcthyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-ylJ amide and
- PVP form a solid dispersion
- solid dosage formulation comprises from about 20 to about 30 % by weight (2R,4S) ⁇ Quinoline-4-carboxylic acid [l-(3,5-bis- trifluoiOmethyl-bcnzoyl)-2-(4-chlorobcnzyl)-piperidin-4-yl] amide; from about 20 to about 30 % by weight PVP; fiom about 0 2 to about 1 0 % by weight DOSS, fiom about 30 to about 50 % by weight croci ystallmc cellulose, fiom about 5 to about 10 % by w eight cioscaimellose, fiom about 0 5 to about 3 % by weight SLS, and fiom about 1 to about 2 % by weight magnesium steaiate
- solid dosage foimulation comprises about 25 % by weight (2R,4S)-Qumolmc-4-caiboxylic acid [l -(3,5-bis-t ⁇ fluoiomethyl- benzoyl)-2 ⁇ (4-chloiobenzyl)-pipe ⁇ dm-4-yl] amide, about 25 % by weight PVP, about 0 6 % by weight DOSS, about 40 % by weight crociystalline cellulose, about 7 5 % by weight cioscaimellose, about 1 % by weight SLS, and about 1 5 % by weight magnesium stearate
- HPMCAS granulfate cellulose
- dicalcmm phosphate cioscarmellose a maltiated cellulose
- HPMCAS a maltiated cellulose
- dicalcmm phosphate cioscarmellose a maltiated cellulose
- HPMCAS a maltiated cellulose
- dicalcmm phosphate cioscarmellose a maltiated cellulose
- HPMCAS a maltiated cellulose
- dicalcmm phosphate cioscarmellose dicalcmm phosphate cioscarmellose
- the (2R,4S) Qumolme 4 caiboxyhc acid [ l-( 3,5-bis tnfluoiomethyl-benzoyl) 2-(4 chloiobenzyl) pipciidm 4 yl] amide and
- solid dosage formulation compiises from about 20 to about 30 % by weight (2R,4S)-Qumoline-4-caiboxyhc acid [l-(3,5-bis- t ⁇ fluoiomethyl-benzoyl)-2-(4-chloiobenzyl)-pipe ⁇ d 1 n-4-yl] amide, fiom about 20 to about 30 % by weight HPMCAS, from about 15 to about 25 % by weight microcrystallinc cellulose; from about 15 to about 25 % by weight dicalcium phosphate from about 2 to about 8 % by weight croscarmellosc. from about 0.2 to about 0.8 % by weight SLS; from about 0.2 to about 0.8 % by weight silicon dioxide; and from about 1 to about 2 % by weight magnesium stearate.
- solid dosage formulation comprises about 25 % by weight (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl- benzoyl)-2-(4-chlorobenzyl)-pipcridin-4-yl] amide; about 25 % by weight HPMCAS; about 2 1 % by weight microcrystalline cellulose; about 21 % by weight dicalcium phosphate about 5 % by weight croscarmellosc; about 0.5 % by weight SLS; about 0.5 % by weight silicon dioxide; and about 1.5 % by weight magnesium stearate.
- solid dosage formulation comprises
- the (2R,4S) Quinolinc-4-carboxylic acid [1 -(3.5 bis- trifluoromethyl -benzoyl) 2 (4 chlorobenzyl) piperidin-4 yl] amide and PVP arc coated onto the microcrystalline cellulose
- l - (3.5-bis- trifluoromcthyl benzoyl)- 2-(4-chlorobenzyl)-piperidin-4 yl ] amide and PVP form a solid dispersion.
- solid dosage fo ⁇ nulation comprises from about 20% to about 30% by weight (2R,4S)-Quinoline-4-carboxylic acid [l -(3,5- bis-trifluoiOmcthyl-benzoyl)-2-(4-chlorobcnzyl)-piperidin-4-yl] amide; from about 7% to about 10% by weight PVP; from about 0.1 % to about 0.5% by weight DOSS; from about 60% to about 70% by weight microcrystalline cellulose; and from about 0.2% to about 0.8% by weight SLS.
- solid dosage formulation comprises about 27% by weight (2R,4S)-Quinoline-4-carboxylic acid [l -(3,5-bis-trifluoromethyl- benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide; about 8% by weight PVP; about 0.3% by weight DOSS; about 64% by weight microcrystalline cellulose; and about 0.5% by weight SLS.
- solid dosage formulation comprises (2R.4S)-Quinoline-4-carboxylic acid [l -(3.5-bis-trifluorornethyl-benzoyl)-2-(4- chlorobenzyl)-piperidin-4-yl] amide;
- PVP polyvinyl styrene
- croscarmellose lactose
- crospovidone lactose
- magnesium stearate magnesium stearate
- solid dosage formulation comprises from about 25% to about 35% by weight (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5- bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide; from about 3% to about 5% by weight DOSS: from about 1 % to about 3% by weight SLS; from about 7% to about 1 1 % by weight PVP; from about 8% to about 12% by weight croscarmellose; from about 25% to about 45% by weight lactose; from about 5% to about 9% by weight crospovidone; and from about 0.2% to about 0.8% by weight magnesium stearate.
- DOSS from about 1 % to about 3% by weight SLS
- PVP from about 8% to about 12% by weight croscarmellose
- lactose from about 5% to about 9% by weight crospovidone
- magnesium stearate from about 0.2% to about 0.8%
- solid dosage formulation comprises about 29% by weight (2R.4S)-Quinoline-4-carboxylic acid [l -(3.5-bis-trifluoromethyl- benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide; about 4% by weight DOSS; about 2% by weight SLS; about 9% by weight PVP ; about 10% by weight croscarmellose; about 38% by weight lactose; about 7% by weight crospovidone; and about 0.5% by weight magnesium stearate.
- the invention features a method of making a carrier coated with a compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1 -(3,5 -bis trif)uoromethyl-benzoyl)-2-(4-chlorobcnzyl)-piperidin-4-yl] amide or an active metabolite thereof oi (2R,4S)-Quinazoline-4-carboxylic acid [ 1 (3,5-bis-trifluoromethyl- benzoyl)-2-(4-chlorobenzyl) ⁇ piperidin-4-yl] amide, the method comprising providing particles comprising the compound of formula I, preferably (2R,4S)
- the compound of formula I preferably (2R,4S)-Quinoline- 4-carboxylic acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is substantially amorphous.
- the solvent is methanol.
- the water soluble polymer is PVP.
- the water soluble polymer is HPMCAS.
- the earner comprises lactose particles. In some embodiments, the earner comprises microcrystalline cellulose.
- the invention features a method of making particles comprising the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis- trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl ⁇ benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide, the method comprising dissolving the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis-lrifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-
- the polymer in the dispersion is PVP. In some embodiments, the polymer in the dispersion is HPMCAS. In some embodiments, the solvent dissolving the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoyl)-2- (4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)- Quinazoline-4-carboxylic acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)- piperidin-4-yl] amide and polymer is selected from the group consisting of ethyl acetate, methanol, acetone, and ethanol.
- the solvent dissolving the compound of formula I preferably (2R,4S)-Quinoline-4-carboxylic acid [l -(3,5-bis-trifluorornethyl-benzoyl)-2- (4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)- Quinazoline-4-carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)- pjperidin-4-yl] amide and polymer is a methanol or ethanol.
- the solvent dissolving the compound of formula I preferably (2R,4S)-Quinoline-4-carboxylic acid [l -(3,5-bis-trifluoiOmethyl-benzoyl)-2- (4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)- Quinazoline-4-carboxylic acid [ 1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)- piperidin-4-yl] amide and polymer is a mixture of organic solvents.
- the resulting particles have a bulk density of from about 0.20 g/ml to about 0.30 g/ml.
- the resulting particles have a D 50 of less than about 1 ⁇ ni.
- the T 011 , of the spray dryer is from about 70 0 C to about 150 0 C.
- the solids load of the compound of formula I preferably (2R.4S)-Quinoline-4-carboxylic acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4- chlorobenzyl)-pipcridin-4-yl] amide or an active metabolite thereof or (2R,4S)- Quinazoline-4-carboxylic acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)- piperidin-4-yl] amide and polymer in solution is from about 1 % to about 20% by weight, for example, about 5% by weight.
- the invention features a method of treating an NK- I related disorder, the method comprising administering to a subject a particle or dispersion described herein.
- the compound of formula I preferably (2R.4S)-Quinoline- 4-carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazolin ⁇ -4-carboxylic acid [1 -(3,5- bis-tiifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is administered to a subject who has eaten.
- the invention features a the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [l -(3,5-bis-trifluorornethyl-benzoy1)-2- (4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-
- the compound of formula I preferably (2R,4S)-Quinoline ⁇ 4-carboxylic acid [1 -(3,5-bis-trifluoromethyl-bcnzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1 -(3,5- bis-trifluoromethyl-benzoyl)-2-(4-chloiObenzyl)-piperidin-4-yl] amide is administered to a subject who has eaten within 60 minutes prior to administration or eats within 120 minutes after administration.
- the method comprises administering a dose comprising from about 1 to about 1000 mg of the compound of formula T, preferably (2R,4S)- Quinoline-4-carboxylic acid [l -(3,5-bis-trifJuoromethyl-benzoyl)-2-(4-chlorobenzyl)- piperidin 4-yl] amide or an active metabolite thereof, or (2R,4S)-Quinazoline ⁇ 4 - carboxylic acid [1 -(3,5 bis-trifluoromethyl-benzoyl) 2-(4-chlorobenzyl)-pjperidin-4-yl] amide.
- the method comprises administering a dose comprising about 40 mg of the compound of formula I, preferably (2R.4S)-Quinoline-4-carboxylic acid [l-(3,5-bis-trifluoromelhyl-bcnzoyl)-2-(4-chloiObenzyl)-piperidin-4-yl] amide or an active metabolite thereof, or (2R,4S)-Quinazoline-4-carboxylic acid [l -(3,5-bis- lrifluoromelhyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.
- the method comprises administering a dose comprising about 320 mg of the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [l -(3,5-bis-trifluoiOmethyl-benzoyl)-2-(4-chloiObenzyl)-piperidin-4-yl] amide or an active metabolite thereof, or (2R,4S)-Quinazoline-4-carboxylic acid [l -(3,5-bis- trifluoromethyl -benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.
- the compound of formula I preferably (2R,4S)-Quinoline ⁇ 4 ⁇ carboxylic acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1 -(3,5- bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is administered once daily.
- the compound of formula I preferably (2R.4S)-Quinoline- 4-carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1 -(3,5- bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is administered twice daily.
- the compound of formula I preferably (2R,4S)-Quinoline- 4-carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1 -(3,5- bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is administered three times daily.
- the compound of formula I preferably (2R,4S)-Quinoline- 4-carboxylic acid [1 (3,5 -bis-trifluoromethyl -benzoyl) -2 •(4-chlorobenzyl)-piperidi ⁇ -4-yl
- the compound of formula I preferably (2R,4S)-Quinoline- 4-carboxylic acid f 1 -(3,5-bis-trifluoiOmethyl-benzoyl)-2-(4-chloiObenzyl)-piperidin-4 yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [ J -(3,5- bis-trifIuoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide and the additional therapeutic agent are administered in a combined dosage form.
- the compound of formula I preferably (2R,4S)-Quinoline- 4-carboxylic acid [l -(3,5-bis-trifluoromcthyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1 -(3,5- bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-pipcridin-4-yl] amide is administered orally.
- the compound of formula I preferably (2R,4S)-Quinoline- 4-carboxylic acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1 -(3,5- bis-trifluoromethyl-benzoyl)-2-(4-chlorobcnzyl)-piperidin-4-yl] amide is administered topically.
- An amorphous form of a drug may exhibit different properties than the crystalline form.
- a polymer or polymeric mixture can be used to form an amorphous solid dispersion system together with the drug.
- a "solid solution" which is a system which will not phase separate over time, or a solid dispersion can be formulated in which the recrystallization of the drug is limited or slowed during a pharmaceutically significantly long period (e.g., two years) at ambient temperature.
- Solid dispersions of the compound of formula I preferably (2R,4S)-Quinoline ⁇ 4- carboxylic acid [1 -(3,5-bis-trifluoromelhyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide can provide improved bioavailability orally administered relative to the administration of undispered compound of formula I, preferably (2R,4S)-Quinoline-4- carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoyl)-2 (4-chlorobenzyl)-piperidin 4-yl] amide, e.g., crystalline compound of formula J, preferably (2R,4S)-Quinoline-4 carboxylJc acid [1 -(3,5 -bis-trifluoromelhyl-ben/oyl)-2 -(4-chlorobenzyl)-pipcridin-4 yl] amide.
- these solid dispersions are in a solid state that can be conveniently stored and administered.
- the manufacture of the solid dispersions can be conducted and scaled up successfully by selecting an organic solvent or solvent mixture (for example, methanol, acetone, etc.).
- solid dispersions can have improved chemical and physical stability.
- the solid dispersions can be chemically and/or physically stable for at least a year, e.g., at least 15 months, 18 months, two years, or longer at conventional storage conditions (room temperature).
- solid dispersions herein include a compound of formula I, or pharmaceutically acceptable salts or solvates thereof
- X is CH, N, or N-O; Y is CH, N, or N-O; Z is halogen, preferably chloro; and R is H or OH.
- X is CH or N (e.g., CH); Y is N or N-O and R is H.
- X is CH, N. Y is CH, N, or N- O; Z is halogen;, preferably chloro and R OFI.
- Formula I includes compounds which can be formed in the body via a metabolic pathway, and are also included herein as components of the solid dispersions described herein.
- Exemplary active metabolites include (2R,4S) ⁇ Quinoline- N-oxide-4-carboxylic acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)- piperidin-4-yl] amide and (2R,4S)-2-Hydroxy-quinolinc-4-carboxylic acid [1 -(3,5-bis- tri ⁇ uoromethyl-ben/,oyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.
- Preferred compounds of fo ⁇ nula I include the following: (2R,4S)-Quinoline-4- carboxylic acid [1 -(3,5-bis-trifluoiOmethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide; (2R,4S)-Quinazoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2-(4- chlorobenzyl)-piperidin-4-yl] amide, (2R,4S)-Quinolinc-N-oxide-4-carboxylic acid [1 - (3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide(2R,4S)- Quinoline-N-oxide-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2-(4- chlor
- the compounds described herein include various solid forms thereof, including polymorphic forms, solvates and salts thereof.
- the compounds described herein also include tautomeric forms thereof.
- Described herein are dispersions including a compound of Formula I, or an active metabolite thereof, and a polymer, such as a water soluble polymer.
- Preferred polymers include HPMCAS and PVP.
- dispersion refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle).
- the size of the discrete units of the dispersed phase can vary considerably (e.g. a single molecule, to colloidal particles of nanometer dimension, to multiple microns in size).
- the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids.
- a solid dispersion can include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase), or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase).
- an amorphous solid dispersion includes the polymer constituting the dispersed phase, and the drag constitute the continuous phase.
- amorphous solid dispersion generally refers to a solid dispersion of two or more components, usually a drag and polymer or combination of polymers, but possibly containing other components such as surfactants or other pharmaceutical excipients, where the drug is in the amorphous phase (e.g., wherein substantially all of the drug is in the amorphous phase), and the physical stability and/or dissolution and/or solubility of the amorphous drug is enhanced by the other components.
- An exemplary solid dispersion is a co-precipitate or a co-melt of (2R,4S) ⁇ Quinoline-4-carboxylic acid [1 -(3,5 bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)- piperidin 4 yJJ amide with HPMCAS or PVP
- a "Co precipitate” is a product after dissolving a drag and a polymer in a solvent or solvent mixture followed by the removal of the solvent or solvent mixture. Sometimes the polymer can be suspended in the solvent or solvent mixture.
- the solvent or solvent mixture includes organic solvents and supercritical fluids.
- the solid dispersions arc prepared by adding a solution of a drug and a solid polymer followed by mixing and removal of the solvent.
- vacuum drying, spray drying, tray drying, lyophilization, and other drying procedures may be applied.
- Applying any of these methods using appropriate processing parameters, according to this invention, would provide (2R,4S)- Quinoline-4-carboxylic acid [l-(3,5-bis ⁇ t ⁇ fluoromethyl-benzoyl)-2-(4-chlorobenzyl)- piperidin-4-yl] amide in an amorphous state in the final solid dispersion product.
- Dispersions including HPMCAS and/or PVP can have any form suitable for pharmaceutical use.
- the solid dispersions can be in the form of a powder, or a coating on a substrate (e.g., the solid dispersion can be spray coated onto a particle such as lactose or macrocrystalline cellulose).
- the ratio of polymer to the compound of formula I affects the properties of the solid dispersion. For example, if the ratio of polymer to the compound of formula 1 is relatively high, the compound of formula 1 will tend to form a molecular dispersion or a dispersion having very small domains of the water-insoluble drug dispersed in the water- soluble polymer phase. However, if the ratio of polymer to the compound of formula I is higher, the concentration of water-insoluble drug in the solid dispersion will be low, thereby requiring large amounts of the solid dispersion in pharmaceutical compositions comprising the solid dispersion. In addition, the low concentration of the compound of formula I can reduce the rate of absorption of the compound of formula I in a patient.
- the ratio of polymer to the compound of formula I is relatively low, the compound of formula I will tend to form dispersions of domains of the compound of formula I in the polymer phase, rather than the molecular dispersions of the compound of formula I in polymer. However, if the ratio polymer to compound of formula I is too low, the dispersed domains of the compound of formula 1 will be so large that dissolution and absorption of the drug in a patient will be reduced, thereby reducing the bioavailability of the compound of formula I.
- the appropriate ratio of polymer to compound of formula I will depend on the compound, the polymer, the intended use.
- An exemplary solid dispersion includes a compound of formula I, such as (2R,4S)-Quinoline-4-carboxylic acid [1 -(3.5-bis-trifluoiOmethyl-benzoyl)-2-(4- chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)- Quinazoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)- piperidin- 4-yl] amide, and HPMCAS.
- the amount of compound of formula I to HPMCAS can vary.
- the dispersion can be predominantly compound of formula I, predominantly HPMCAS, or a relatively even balance of compound of formula I and HPMCAS.
- the ratio of compound of formula I to polymer can be varied to alter the characteristics of the solid dispersion. For example, in some embodiments, it is preferred to have a ratio of compound of formula 1 to polymer to provide a homogeneous dispersion, whereas in some embodiments the ratio of compound of formula I to polymer to provide regions enriched for the compound of formula I.
- Exemplary ratios of the compound of formula I to HPMCAS include from about 1 :20 to about 5: 1 , for example, from about 1 :4 to about 4: 1 , from about 1 :2 to about 3: 1 , e.g., about 1 : 1.
- the composition of the solid dispersion may include the compound of formula I and a combination or polymers such as HPMCAS and PVP.
- exemplary ratios of HPMCAS:PVP include about 5: 1 , 4: 1 , 3: 1 , 2: 1 , 1.5: 1, 1 : 1 , 1 : 1.5, 1 :2, 1 :3, 1 :4, or 1 :5.
- the polymer ratio may be adjusted to optimize the physical stability and/or the manufacturability (i.e. flow, compaction, etc) of the solid dispersion.
- Another exemplary solid dispersion includes a compound of formula I, such as (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis4rifluoromethyl-benzoyl)-2-(4- chloroben7yl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)- Quinazoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)- 2-(4-chlorobenzyl)- piperidin-4-ylJ amide, and PVP, wherein the amount of compound of formula I within the dispersion is at least about 25%, e.g., at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or greater
- ratios of the compound of formula I to PVP include from about 1 :2 to about 5: 1, e.g., from about 1 : 1 to about 4: 1 .
- the compound of formula I and PVP are present in a ratio of about 1 : 1 or about 3.5: 1
- Dispersions including a compound of formula I and a polymer, such as a water soluble polymer are included here.
- a dispersion of (2R,4S) Quinoline-N ⁇ oxide-4-carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)- piperidin-4-ylJ amide and a polymer or a dispersion of (2R,4S)-2-HydiOxy-quinoline-4- carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloiObenzyl)-piperidin-4-yl] amide and a polymer are disclosed herein.
- Exemplary polymers include a water soluble polymer.
- water-soluble polymer refers to any polymer, natural or synthetic, which has an apparent viscosity of less than 100 mPs-s measured for a 2% aqueous solution of the water-soluble polymer at 20 0 C.
- suitable water-soluble polymers include cellulose ethers such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose. hydroxybutylcellulose, hydroxyethyl methylcellulose.
- cellulose esters such as hydroxypropylmethylcellulose acetate succinate (H PMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP); starches; pectines such as sodium carboxymethylamylopectine; chitin derivates such as chitosan; polysaccharides such as alginic acid, and alkali metal and ammonium salts thereof; carrageenans; galactomannans; tragacanth; agar-agar; gummi arabicum; guar gummi; xanthan gummi; polyacrylic and polymethacrylic acids and salts thereof; acrylate and methacryl
- Ratios of compound for formula 1 and potymci include those ratios described above, for example the dispersions above including HPMCAS and/or PVP. AddiiiOna]jLompj)neQts
- surfactant is generally present in the dispersion in an amount from about 0.1 to about 20% by weight, for example, from about 1 to about 15% by weight (e.g., about 9%). e.g., from about 0.5 to about 10%, from about 0.5 to about 5%, or from about 1 to about 2%.
- the weight ratio of compound of formula I to surfactant ranges from about 300: 1 to about M . for example, about 50: 1 to about 20: 1 , e.g., about 25: 1 or about 4: 1.
- Suitable surfactants include anionic surfactants, cationic surfactants, and non- ionic surfactants.
- Anionic surfactants are amphiphilic molecules having a negative charge.
- suitable anionic surfactants include alkyl, aryl, or aryl alkyl carboxylates, sulfonates, sulfates, phosphates, or acylated protein hydrolysates.
- Suitable carboxylated surfactants include, for example, soaps (i.e., fatty acid salts), bile salts, polyalkoxycarboxylates and N-acylsarcosinates.
- Suitable sulfonated surfactants include, for example alkylsulfonates, alkylbenzenesulfonates, alkylarenesulfonates, short- chain lignosulfates. naphthalenesulfonates, ⁇ -olefinsulfonates, petroleum sulfonates, and sulfonates with ester, amide, or ether linkages.
- Suitable sulfated surfactants include, for example sulfate esters of fatty alcohols, sulfated alkylphenols, sulfated acids, amides, and esters, and sulfated natural oils and fats.
- Suitable phosphonated surfactants include fatty alcohol mono- and diesters of orthophosphoric acid.
- an anionic surfactant is preferred.
- exemplary anionic surfactants include, for example, fatty acid salts such as sodium caproate, sodium caprylate, sodium caprate, sodium lauratc, sodium myristate, sodium myristolate, sodium palmitate, sodium palmitoleate, sodium oleate, sodium ricinoleate, sodium linoleate, sodium linolenate, sodium stearate, sodium lauryl sulfate (SLS), sodium tetradecyl sulfate, sodium lauryl sarcosinate, sodium dioctylsulfosuccinate, etc.; bile salts such as sodium chelate, sodium larocbolate, sodium glycocholate, sodium deoxycholate, sodium taurodeoxycholate, sodium glycodeoxycholate, sodium ursodeoxycholate, sodium chemodeoxycholate, sodium glycochemodeoxycholate, sodium cholylsarcosinate, sodium N methyl taurocho
- Preferred surfactants include sodium lauryl sulfate and sodium docusate, which can be used alone, or in combination. For example, a mixture of sodium lauryl sulfate and sodium docusate.
- two or more surfactants are used in combination. If the compositions of the present invention include a mixture of two or more surfactants, the two or more surfactants can be selected from the same class of surfactant (e.g., the two or more surfactants can each be anionic surfactants), or can be selected from different classes of surfactant (e.g., one of the two or more surfactants can be any non-ionic surfactant, and at least one other surfactant can be an anionic surfactant).
- the weight ratio of the two surfactants can range from about 5: 1 to about 1 : 1.
- the weight ratio of the two surfactants can be about 5: 1 , 4: 1 , 3: 1 , 2: 1 , or 1 : 1. Additional polymers
- a dispersion described herein includes a compound of formula I and two or more polymers.
- the dispersion e.g., the dispersion of the compound of formula 1 and HPMCAS or the dispersion of the compound of formula I and PVP
- the two polymers are chosen for their complementary properties, such as solubility, compressability, flowability ease of handling, cost, etc.
- the ratio of the first polymer: second polymer can vary and generally ranges from about 1 :4 to about 4: 1 , e.g., from about 1 :3 to about 3: 1 , from about 1 :2 to about 2: 1 , e.g., about 1 : 1.
- Characteristics of dispersions As described above, the dispersion can be homogeneous or can be non- homogeneous, for example having a region rich in the compound of formula 1.
- the size distribution of the domains of the enriched region (e.g. discontinuous phase) distributed within the dispersion phase can be unimodal, or bimodal.
- more than 90% of domains of the compound of formula I dispersed in the polymer have a size ranging from 10 nm to 1000 nm, or 100 nm to 800 nm, or 100 nm to 500 nm.
- the compound of formula I, within the dispersion is substantially amorphous (e.g., at least about 50% of compound of formula I is amorphous, at least about 55% of compound of formula I is amorphous, at least about 60% of compound of formula I is amorphous, at least about 65% of compound of formula I is amorphous, at least about 70% of compound of formula I is amorphous, at least about 75% of compound of formula I is amorphous, at least about 80% of compound of formula I is amorphous, at least about 85% of compound of formula I is amorphous, at least about 90% of compound of formula I is amorphous, at least about 95% of compound of formula I is amorphous, at least about 98% of compound of formula I is amorphous, at least about 99% of compound of formula I is amoipbous, or substantially all of compound of formula I is amorphous.
- amorphous refers to a solid material having no long range order in the position of its atoms.
- Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner so that there is no well- defined arrangement and no long range order.
- Amorphous solids are generally isotropic, i.e. exhibit similar properties in all directions and do not have definite melting points.
- an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern.
- XRPD X-ray power diffraction
- crystalline solids refers to compounds or compositions where the structural units are arranged in fixed geometric patterns or lattices, so that crystalline solids have rigid long range order.
- the units that constitute the crystal structure can be atoms, molecules, or ions. Crystalline solids show definite melting points.
- the dispersion has a single glass transition temperature ("T 2 "1 ).
- T 2 is a characteristics temperature where a glassy material, upon heating, undergoes a rapid physical change from a glassy state to a rubbery state.
- the T 2 can be determined by several commonly accepted techniques such as differential scanning calorimetry (DSC) or by a dynamic mechanical analyzer (DMA). It is preferable that the T g of the dispersion is generally at least about 5OK greater than the storage conditions at room temperature and relative humidity conditions (e.g., 25 0 C, 60% RH).
- the T 2 of the dispersion at room temperature/humidity conditions is generally from about 98 0 C to about 102 0 C (e.g., about 100 0 C or 101 0 C).
- the T g of the dispersion at room temperature/humidity conditions is generally from about 130 0 C to about 135 0 C. It is well understood that the T 2 of a dispersion is dependent upon many factors such as the components (i.e. their structures, interactions, etc.) their weight fraction of the dispersion, and the equilibrium solvent and/or moisture content of the dispersion to name a few.
- the T g of a homogeneous blend of amorphous components can be estimated in many cases by the Gordon-Taylor Equation in which the weight fractions of each component and their respective T g 's are used to estimate the T 2 of the dispersion.
- the ratio of formula I to polymer in the dispersion is such that a sufficient therapeutic amount of formula 1 can be manufactured into a conventional dosage form of conventional size (i.e. 650 mg preferable to 1300 mg), using common techniques (e.g. roller compaction, wet granulation, etc) and that the dispersion has a single T g of at least 5OK greater than the anticipated storage conditions.
- Solid dispersions described herein are generally stable, e.g. chemically and physically stable.
- the solid dispersion is both chemically and physically stable under accelerated storage conditions such as 40 °C/75 % and/or 25 °C/90% for at least 2 weeks.
- the physical stability of the dispersion can be evaluated for content of amorphous form of compound of formula I via XRPD, DSC, and/or microscope observations.
- the T g at room temperature/humidity conditions is generally from about 130 0 C to about 135 0 C
- the T g of the same dispersion at 40 0 C 1 IS 0 A storage for two weeks remains at about 130 °C to about 135 0 C
- the T g of the same dispersion at 25 °C/90% storage for at least two weeks is about 130 0 C to about 135 0 C.
- a dispersion of PVP and the compound in formula I coated onto lactose and subsequently blended with common excipients and filled into a gelatin capsules is stable for at least 15 months at room temperature and relative humidity conditions (e.g., 25 0 C, 60% RH).
- the solid dispersions described herein can be used as a component in a pharmaceutical composition, for example as a component as a powder for oral suspension, tablet, capsule, etc.
- the solid dispersions described herein have a bulk density of from about 0.20 g/ml to about 0.30 g/ml, and a tap density of from about 0.34 g/ml to about 0.40 g/ml.
- the solid dispersions generally have a D 5 o of less than about 1 ⁇ m.
- a composition of compound formula I consists of solid dispersion that is present in sufficient amount such that following an administration of the composition containing a solid dispersion to an animal, the level of compound of formula I in the blood of the animal is at least about 20% higher than seen with an administration of compound of formula I which does not include a solid dispersion, for example, at least about 25% higher, at least about 50% higher, at least about 100% higher, at least about 200% higher, at least about 300% higher or at least about 400% higher.
- the composition of the present invention provides an increased bioavailability of at least 1.25 fold, fold, ! .50 fold, or at least 2.0 fold over the bioavailability of non -formulated water insoluble drag.
- Particles of the compound of formula I aie described herein pariicles comprising amorphous compound of formula I are described herein, e.g.. particles containing substantially amorphous compound of formula I are described herein.
- Amorphous compound of formula 1 can be made, for example, by spray drying the compound of formula I to provide particles of compound of formula I suitable for formulation into a pharmaceutical composition such as an oral dosage formulation.
- the compound of formula I and dispersions including the compound of formula I described herein can be used as a component in a pharmaceutical composition.
- the dispersion is formulated directly into the composition.
- the compound of formula I e.g.. a dispersion including a compound of formula I as described herein, is coated onto a particle, which particle is formulated onto the pharmaceutical composition.
- the compound of formula I e.g.. amorphous compound of formula I
- a dispersion described herein is coated onto the surface of a particle.
- Exemplary particles useful for coating with a dispersion described herein include non-pariels such as lactose or microcrystallinc cellulose or starch.
- a compound of formula I or a dispersion described herein can be coated onto the surface of the particle in a spray coating process, for example, by providing a suspension or slurry of the compound of formula I, for example amorphous compound of formula I or a dispersion described herein, and particle and spraying the suspension or slurry to provide a particle coated with the compound of formula I.
- the surface of the particle can also be coated with additional ingredients, for example an enteric coating.
- the coated particles can then be formed into a suitable dosage form, for example by encapsulation.
- the coated substrate can be mixed with one or more additional ingredients as disclosed herein, using processes known in the pharmaceutical field, such as wet or dry granulation, milling, etc. and then formed into a suitable dosage form, for example by encapsulation, tablctting, or palletization.
- any method for obtaining solid dispersions could be used in connection with this the dispersions described herein.
- methods that could be used include those that involve rapid removal of solvent from a mixture or cooling a molten sample. Such methods include, but are not limited to, rotational evaporation, freeze-drying (i.e., lyophilization), vacuum drying, melt congealing, and melt extrusion.
- a preferred embodiment of this invention involves amorphous solid dispersion obtained by spray-drying. Accordingly, in another embodiment, this invention provides drying the product obtained by spray drying to remove the solvent.
- Preparations disclosed herein can be obtained by spray-drying a mixture comprising a compound of formula I, HPMCAS and/or PVP, and an appropriate solvent (e.g., acetone).
- Spray drying is a method that involves atomization of a liquid mixture containing, e.g., a solid and a solvent, and removal of the solvent. Atomization may be done, for example, through a nozzle or on a rotating disk. Spray drying is a process that converts a liquid feed to a dried particulate form.
- a secondary drying process such as fluidized bed drying or vacuum drying, may be used to reduce residual solvents to pharmaceutically acceptable levels.
- spray-drying involves contacting a highly dispersed liquid suspension or solution, and a sufficient volume of hot air to produce evaporation and drying of the liquid droplets.
- the preparation to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that may be atomized using the selected spray-drying apparatus.
- the preparation is sprayed into a current of warm filtered air that evaporates the solvent and conveys the dried product to a collector (e.g., a cyclone).
- the spent air is then exhausted with the solvent, or alternatively the spent air is sent to a condenser to capture and potentially recycle the solvent.
- Commercially available types of apparatus may be used to conduct the spray-drying.
- commercial spray dryers are manufactured by Buchi Ltd. and Niro (e.g., the PSD line of spray driers manufactured by Niro) (see, US 2004/0105820; US 2003/0144257).
- Spray- drying typically employs solids loads of material from about 2% to about 25%, (i.e., compound of formula 1 and cxcipients) preferably at least about 4% or 5%.
- the upper limit of solids loads is governed by the viscosity of (e.g., the ability to pump) the resulting solution and the solubility of the components in the solution.
- the spray- drying is generally conducted with an outlet temperature of from about 70 0 C to about 150 ° C, for example from about 80 °C to about 1 10 C C.
- Preferred solvents are those solvents where the compound of formula I has a solubility of at least about 10 mg/ml (e.g., at least about 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 35 mg/ml, 40 mg/ml, 45 mg/ml, 50 mg/ml, 75 mg/ml, 100 mg/ml, 125 mg/ml, 150 mg/ml, 175 mg/ml, 200 mg/ml, or greater).
- a solubility of at least about 10 mg/ml (e.g., at least about 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 35 mg/ml, 40 mg/ml, 45 mg/ml, 50 mg/ml, 75 mg/ml, 100 mg/ml, 125 mg/ml, 150 mg/ml, 175 mg/ml, 200 mg/ml, or greater).
- Suitable solvents include esters, ketones, and alcohols.
- Exemplary solvents that could be used include ethyl acetate, methanol, acetone, and ethanol. Some preferred embodiments include ethyl acetate.
- a mixture of solvents is used.
- a common dissolves both the compound of formula I and the polymer (i.e., HPMCAS and/or PVP).
- Removal of the solvent may require a subsequent drying step, such as tray drying, fluid bed drying (e.g., from about room temperature to about 100 °C), vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying (e.g., from about room temperature to about 200 "C).
- a subsequent drying step such as tray drying, fluid bed drying (e.g., from about room temperature to about 100 °C), vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying (e.g., from about room temperature to about 200 "C).
- the resulting dispersed particles (e.g., after spray drying) generally have an average particle size of less than 1 ⁇ m, for example average particle sizes ranging from about 100 nm to about 900 nm, including average particle sizes of about 850 nm, about 800 nm, about 750 nm, about 700 nm, about 650 nm, about 600 nm, about 550 nm, about 500 nm, about 450 nm, about 400 nm, about 350 nm, about 300 nm, about 250 nm, about 200 nm, and about 150 nm, including all ranges and subranges therebetween.
- the particle size distribution of the dispersed particles can be essentially unimodal or bimodal.
- the particle size distribution is essentially unimodal, at least 50% of the particles have a particle size of less than 1 ⁇ m.
- at lease 50% of the particles have a particle size of less than 900 nm, 800 nm, 700 nm, 600 nm, 500 run, 400 nm, 300 nm, or 200 nm, including all ranges and subranges therebetween.
- a compound of fonnula (I) or a dispersion comprising a compound of formula (I) and a polymer is coated onto a carrier such as a solid particle, e.g., a particle such as lactose or microcrystallinc cellulose or starch.
- a carrier such as a solid particle, e.g., a particle such as lactose or microcrystallinc cellulose or starch.
- a compound of formula I, or a dispersion of the compound of formula I and a polymer as described herein is suspended in a solution of water and a water-soluble polymer (e g.. PVP).
- the suspension is layered onto a carrier such as solid particle such as lactose or a sphere of microcrystalline cellulose (e.g. Celsphere).
- the water soluble polymer is the same polymer as the polymer in the solid dispersion (or a polymer in the solid dispersion in examples of dispersions including more than one poly
- the solids load of the water-soluble polymer in the coating process is from about 10 to about 60 % by weight.
- compositions comprising a dispersion of a compound of formula I
- the solid dispersions described herein and particles coated with the solid dispersions described herein can be formulated with additional pharmaceutically acceptable excipients to provide dosage formulations for administration to a subject.
- the weight percentage of the compound of formula I in the compositions described herein can range from about 99 wt.% to about 15 wt.%.
- the weight percentage of water-insoluble drug can be about 99, about 95, about 90, about 85, about 80, about 75, about 70, about 65, about 60, about 55, about 50, about 45, about 40, about 35, about 30, about 25, about 20, and about 15 wt%.
- the unit dosage employed may be varied depending upon the requirements of the patient and the condition being treated For convenience, the total daily dosage may be divided and administered in portions during the day as required.
- the quantity of water- insoluble drag in the compositions of the present invention ranges from about i rag to about 500 mg per unit dose
- the quantity of water insoluble drug per unit dose of the compositions of the present invention can be about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 75 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 rag, 80 mg, 90 mg, 100 mg, 1 10 mg, 120 mg, 130 mg, 140 mg. 150 mg. 1 60 mg. 170 mg, 180 nig.
- the weight percentage of water-soluble polymer in the compositions of the present invention can range from about 90 to about 5 wt.%.
- the weight percent of water-insoluble polymer in the composition can be about 90, about 85, about 80, about 75, about 70, about 65, about 60, about 55, about 50, about 45, about 40, about 35, about 30, about 25. about 20, about 15, about 10, and about 5 wt.%.
- the weight percentage of the total amount of the one or more additional ingredients in the composition of the present invention can range from about 90 to about 5 wt.%.
- the weight percent of the total amount of one or more additional ingredients in the composition can be about 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, and 20 wt.%.
- Exemplary pharmaceutically acceptable excipients include diluents or fillers, drug complexing agents or solubilizers, disintegrants, binders, lubricants, glidants, pH modifiers, and surfactants.
- suitable diluents or fillers include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch.
- drug complexing agents or solubilizers include polyethylene glycols, caffeine, xanthene, gentisic acid, and cyclodextrins.
- disintegrants include sodium starch glycolate, sodium alginate, carboxymethylcellulose sodium, methylcellulose, croscarmellose sodium, and crospovidone, preferably croscarmellose sodium and/or crospovidone.
- binders include methylcellulose, povidone, microcrystalline cellulose, starch, hydroxypropyl cellulose, hydroxymethyl propyl cellulose, and gums such as guar and tragacanth, preferably povidone.
- lubricants include magnesium stearate, stearic acid, sodium stearyl fumurate..
- An example of a glidant is silicon dioxide.
- pH modifiers include acid such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and buffers comprising mixtures of any of the above-noted acids and their salts.
- the weight percentage of surfactant in the compositions of the present invention can range from about 0.1 wt.% to about 20 wt.%.
- the weight percent of surfactant in the composition can be about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 12, about 1 1 , about 10, about 9, about 8, about 7, about 6, about 5.5, about 5.0, about 4.5, about 4.0, about 3.5, about 3.0, about 2.5, about 2.0, about 1.5, about 1.0, about 0.9, about 0.8, about 0.7, about 0.6, about 0.5, about 0.4, about 0.3, about 0.2, about 0.1 wt.%,.
- compositions included herein can include e.g., one or more diluents or fillers and a disintegrant, a single diluent or filler and two or more disintegrants, a filler, a disintegrants, a binder, a lubricant, etc.
- compositions described herein include an additional therapeutic agent, for example to provide co-administration of the compound of formula I with a second therapeutic agent.
- therapeutic agent as used herein is used in its conventional sense, denoting a compound or any synthetic or naturally existing entity having beneficial prophylactic and/or therapeutic properties when administered to a mammal, especially a human
- suitable water-insoluble drugs include, for example, dings from a variety of known classes of drugs, including proteins, peptides, nucleotides, anti-obesity drugs, nutraceuticals, corticosteroids, elastase inhibitors, analgesics, anti-fungals, oncology therapies, anti-emetics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimy
- the particles of the solid dispersion can then be formed into a suitable dosage form, for example by encapsulation.
- the particles of solid dispersion can be mixed with one or more additional ingredients as disclosed herein, using unit processes known in the pharmaceutical field, such as wet or dry granulation, milling, etc., and then formed into a suitable dosage form, for example by encapsulation, pelletization, or tablctting.
- compositions of the present invention can be provided in any dosage form suitable for delivery of a therapeutically effective dose of the water-insoluble drug to a patient.
- suitable dosage forms include a mini capsule, a capsule, a tablet, and implant, a troche, a lozenge, a suspension, an ovule, a suppository, a wafer, a chewable tablet, a quick or fast dissolving tablet, an effervescent tablet, a buccal or sublingual solid, a granule, a film, a pellet, a bead, a pill, a powder, a strip, or a sachet.
- compositions of the present invention can be formulated for oral, sub-lingual, buccal, nasal, ocular, pulmonary, urethral, transmucosal, vaginal, topical, or rectal delivery.
- the compositions of the present invention are formulated so that it is suitable to be administered to a subject orally and taken into the subject system through, e.g., gastric/intestinal tract.
- a composition described herein is formulated for oral administration, for example as a tablet, a capsule, or a powder for oral suspension, preferably a tablet or a capsule.
- the capsule can be a hard or soft gelatin capsule, starch capsule, or cellulosic capsule.
- compositions of the present invention can also be coated with one or more coatings in order to control the rate of disintegration, e.g. in the digestive tract, in order to provide immediate release, pulsatile release, controlled release, extended release, delayed release, targeted release, synchronized release, or targeted delayed release properties.
- coatings can include an enteric coatings, film coatings, barrier coatings, compress coatings, fast disintegrating coatings, enzyme degradable coatings, etc.
- the compounds and solid dispersions, particles including the solid dispersions and compositions including the compounds and solid dispersions described herein can be used in therapy, for example to treat an NK-I related disorder.
- a therapeutically effective amount of a solid dispersion including a compound of formula I as described herein (and/or a particle including a solid dispersion and/or a composition including a solid dispersion) can be administered to a subject, for example a subject in need of such treatment, to treat an NK-I related disorder.
- terapéuticaally effective amount is an amount of water-insoluble drug which ides a clinically useful effect, e.g. reducing or alleviating symptoms, or preventing or ameliorating a disease or condition.
- NK-I related disorders include disorders such as depression, anxiety, cognitive and memory deficits, acute and chronic pain, allergic disorders, asthma, chronic obstructive pulmonary disease, dermatological disorders, incontinence, inflammation, emesis, irritable bowl syndrome, sleep disorders, substance withdrawal, immune system disorder, inflammatory disorders such as osteoarthritis, rheumatoid arthritis, and other arthritides, inflammatory bowel disease ,scleritis, visceral disorders such as pelvic inflammatory disorder, vesicultis and dyspareunia.
- a compound or dispersion described herein or a composition including a compound or dispersion described herein is administered to a subject for the treatment of social anxiety disorder, incontinence, and/or irritable bowl syndrome.
- a dispersion described herein is administered to a subject who has eaten within 2 hours of administration of the solid dispersion or will eat within an hour after administration of the solid dispersion.
- the frequency of dosing can vary depending on a number of factors, including the disorder being treated, the dosage formulation, the dosage amount, and the patient. Accordingly, a compound or dispersion described herein can be administered once daily, twice daily, three times daily, or four times daily
- Example 2 Stressed stability of solid dispersions including PVP or HPMCAS
- Exemplary solid dispersions from Table 1 were subjected to accelerated stability conditions, including 25 °C/90% RH for 2 weeks and 40 °C/75% RH for 2 weeks with the results presented in Table 3.
- the Tg " s were determined with mDSC. Further evaluation of the form of drug in the dispersions was performed by microscope assessment.
- the dispersions described herein can be prepared and further formulated into an oral dosage form such as a tablet or capsule.
- the solid dispersion may be formulated into a dosage form by coating onto lactose or an acceptable carrier first and subsequently processed into a capsule or tablet.
- compositions of Table 4. were prepared by dissolving dissolving (2R,4S)- Quinoline-4-carboxylic acid [1 -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)- piperidin-4-yl] amide and the chosen polymer (PVP or HPMCAS) in a common organic solvent.
- the resulting solution was spray-dried to provide nano-sized solid dispersion particles of which approximately 50% had a diameter of about 0.8 urn or less.
- the solid dispersions were further processed into tablet dosage forms by blending with diluents, a glidant, and a portion of a lubricant which was densified by slugging and subsequently milled. A disintegrant and the balance of the lubricant were added to the milled granulation and blended The lubricated granulation was compressed into tablets The tablets can also be coated with a functional or non-functional film coat
- the GMP#3 composition of Table 5 was prepared by dissolving (2R,4S)- Quinoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)- piperidin-4-yl] amide and docusate sodium in ethyl acetate. The resulting solution was spray-dried to provide nano-sizcd particles of (2R,4S)-Quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-ben/oyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide and docusate sodium.
- nano-sized particles Approximately 50% of the nano-sized particles had a diameter of about 0.8 ⁇ m or less.
- the nano-sized particles were then added to an aqueous solution of povidone and the resulting suspension was spray coated onto lactose prills.
- the dried, coated lactose prills were then dry blended with croscarmellose sodium, crospovidone, and sodium lauryl sulfate.
- Magnesium stearate was added to the mixture and blended and then subsequently encapsulated.
- X608PFCA003 was prepared in the same fashion as GMP#3 with the exceptions of the PVP:drug suspension being layered onto a microcrystalline cellulose (Celsphere) prior to encapsulation.
- Example 4 Stressed stability of formulated oral dosage forms
- Exemplary solid dispersions formulated into Drug Product were subjected to accelerated stability conditions, including 25 °C/90% RH for 2 weeks and 40 °C/75% RH for 2 weeks, 5 weeks, 3 months and 6 months.
- Table 6 illustrates the Tg ' s that were determined with mDSC for the 2 week timepoint analysis. Further evaluation of the form of drag in the dispersions was performed by microscope assessment.
- Tables '/., 8., and 9. show the appearance, assay, related substance, and dissolution results for formulations X608OCTA001 , X608OCTA002, and X608PFCA003, respectively, stored for various times at 40 °C/75%.
- the assay and impurity results demonstrate chemical stability for the formulations and the dissolution results, which when significantly depressed from initial are a suitable surrogate for the crystallization of the drug form, show minimal change.
- solid dispersion tablets A notable disadvantage of solid dispersion tablets is their extremely long disintegration and dissolution times. These prolonged times may lead to rate limited absorption in both humans and dogs. Since many of the water-soluble polymers are also used as binders, e.g. PVP, HPMC, HPC, etc., the slow disintegration and dissolution times are not unexpected. However, solid dispersion tablets comprised of HPMCAS or solid dispersion layered pellets comprised of PVP offer substantial improvements in dissolution time when compared to a solid dispersion tablet of PVP. This is apparent when examining the dissolution times listed in Tables 7.-9. for formulations listed in Tables 4. and 5.
- compositions of the last four formulations were presently previously in Tables 4. and 5.
- compositions of the other three formulations i.e. ' 10 V , WG#2 and WG#3 are presented in Table 1 1. Note that the PVP in formulations WG#2 and WG#3 was admixed and was not present as a dispersion.
- Example 7 Bioavailability of selected oral dosage formulations in humans.
- composition of GMP#3 an exemplary solid dispersion of (2R,4S)-Quinoline-4-carboxylic acid [1- (3,5-bis-lrifluorometliyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide and PVP along with a non-solid dispersion Control, GMP#2, are listed in Table 12.
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Abstract
Description
Claims
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US89127207P | 2007-02-23 | 2007-02-23 | |
PCT/US2008/054735 WO2008103914A1 (en) | 2007-02-23 | 2008-02-22 | Pharmaceutical formulation |
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EP2124949A1 true EP2124949A1 (en) | 2009-12-02 |
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EP08730525A Withdrawn EP2124949A1 (en) | 2007-02-23 | 2008-02-22 | Pharmaceutical formulation |
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EP (1) | EP2124949A1 (en) |
JP (1) | JP2010519312A (en) |
KR (1) | KR20090118982A (en) |
CN (1) | CN101668527A (en) |
AU (1) | AU2008218248A1 (en) |
CA (1) | CA2679028A1 (en) |
WO (1) | WO2008103914A1 (en) |
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TWI520732B (en) * | 2011-01-18 | 2016-02-11 | 輝瑞有限公司 | Solid molecular dispersion |
DK3278803T3 (en) | 2015-04-03 | 2022-08-29 | Impact Therapeutics Shanghai Inc | Solid pharmaceutical dosage form of PARP inhibitor, and use of solid pharmaceutical dosage form of PARP inhibitor |
AU2020408173A1 (en) * | 2019-12-20 | 2022-06-09 | Intervet International B.V. | A pharmaceutical composition of a pyrazole compound dispersed in a polymer matrix |
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CN1216598C (en) * | 1998-08-25 | 2005-08-31 | 诺瓦提斯公司 | Pharmaceutical use |
GB0220953D0 (en) * | 2002-09-10 | 2002-10-23 | Novartis Ag | Organic compounds |
MXPA06002067A (en) * | 2003-08-22 | 2006-08-11 | Johnson & Johnson | Stepwise delivery of topiramate over prolonged period of time. |
CA2569310A1 (en) * | 2004-06-08 | 2005-12-29 | Maura Murphy | Pharmaceutical compositions |
-
2008
- 2008-02-22 CA CA002679028A patent/CA2679028A1/en not_active Abandoned
- 2008-02-22 EP EP08730525A patent/EP2124949A1/en not_active Withdrawn
- 2008-02-22 KR KR1020097019681A patent/KR20090118982A/en not_active Application Discontinuation
- 2008-02-22 WO PCT/US2008/054735 patent/WO2008103914A1/en active Application Filing
- 2008-02-22 JP JP2009551032A patent/JP2010519312A/en not_active Withdrawn
- 2008-02-22 AU AU2008218248A patent/AU2008218248A1/en not_active Abandoned
- 2008-02-22 CN CN200880013347A patent/CN101668527A/en active Pending
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CN101668527A (en) | 2010-03-10 |
CA2679028A1 (en) | 2008-08-28 |
KR20090118982A (en) | 2009-11-18 |
JP2010519312A (en) | 2010-06-03 |
AU2008218248A1 (en) | 2008-08-28 |
WO2008103914A1 (en) | 2008-08-28 |
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