WO2014143935A4 - Rapidly dispersible dosage form of oxcarbazepine - Google Patents

Rapidly dispersible dosage form of oxcarbazepine Download PDF

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Publication number
WO2014143935A4
WO2014143935A4 PCT/US2014/028125 US2014028125W WO2014143935A4 WO 2014143935 A4 WO2014143935 A4 WO 2014143935A4 US 2014028125 W US2014028125 W US 2014028125W WO 2014143935 A4 WO2014143935 A4 WO 2014143935A4
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WO
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Prior art keywords
particle size
drug
matrix
particles
microns
Prior art date
Application number
PCT/US2014/028125
Other languages
French (fr)
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WO2014143935A1 (en
Inventor
Jules Jacob
Kelly CAPUTO
Micael Guillot
Kenneth J. Sultzbaugh
Thomas G. West
Original Assignee
Aprecia Pharmaceuticals Company
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to MX2015012136A priority Critical patent/MX364381B/en
Priority to ES14763545T priority patent/ES2761265T3/en
Priority to EP14763545.2A priority patent/EP2968354B1/en
Priority to CN201480014727.3A priority patent/CN105050604B/en
Priority to JP2016502709A priority patent/JP6463333B2/en
Priority to AU2014228063A priority patent/AU2014228063B2/en
Priority to CA2906107A priority patent/CA2906107C/en
Application filed by Aprecia Pharmaceuticals Company filed Critical Aprecia Pharmaceuticals Company
Publication of WO2014143935A1 publication Critical patent/WO2014143935A1/en
Publication of WO2014143935A4 publication Critical patent/WO2014143935A4/en
Priority to US14/837,493 priority patent/US9314429B2/en
Priority to HK16101293.4A priority patent/HK1213472A1/en
Priority to US15/045,711 priority patent/US9616018B2/en
Priority to HK16102379.9A priority patent/HK1214173A1/en
Priority to US15/437,966 priority patent/US10028909B2/en
Priority to AU2017203365A priority patent/AU2017203365B2/en
Priority to US16/015,552 priority patent/US20180296479A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • A61K9/1694Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2009Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • A61K9/2018Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
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    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
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    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • AHUMAN NECESSITIES
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    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2095Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/08Antiepileptics; Anticonvulsants
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29CSHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C64/00Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
    • B29C64/10Processes of additive manufacturing
    • B29C64/165Processes of additive manufacturing using a combination of solid and fluid materials, e.g. a powder selectively bound by a liquid binder, catalyst, inhibitor or energy absorber
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B33ADDITIVE MANUFACTURING TECHNOLOGY
    • B33YADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y10/00Processes of additive manufacturing
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B33ADDITIVE MANUFACTURING TECHNOLOGY
    • B33YADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y70/00Materials specially adapted for additive manufacturing
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B33ADDITIVE MANUFACTURING TECHNOLOGY
    • B33YADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00Products made by additive manufacturing
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1611Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • A61K9/1623Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1635Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007Drug-containing films, membranes or sheets
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29KINDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2105/00Condition, form or state of moulded material or of the material to be shaped
    • B29K2105/0005Condition, form or state of moulded material or of the material to be shaped containing compounding ingredients
    • B29K2105/0035Medical or pharmaceutical agents
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29KINDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2105/00Condition, form or state of moulded material or of the material to be shaped
    • B29K2105/0058Liquid or visquous
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29KINDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2105/00Condition, form or state of moulded material or of the material to be shaped
    • B29K2105/25Solid
    • B29K2105/251Particles, powder or granules

Abstract

A high dose orodispersible dosage form of oxcarbazepine is provided. Drug-containing particles of oxcarbazepine are included within a porous bound matrix. The dosage form disperses in saliva or water in less than 15 sec and it has sufficient hardness to withstand handling and storage. It can be used to treat diseases or disorders that are therapeutically responsive to oxcarbazepine or a derivative thereof.

Claims

AMENDED CLAIMS received by the International Bureau on 25 September 2014 (25.09.2014)
1) A rapidly dispersible solid dosage form comprising a porous non-compressed three-dimensionally printed bound matrix comprising :
drug-containing particles having an effective particle size and comprising a first grade of oxcarbazepine (OXC) particles having a first native particle size, a second grade of OXC particles having a second native particle size, at least one disintegrant, at least one surfactant, and at least one binder;
at least one disintegrant; and
at least one binder; wherein
the dosage form disperses in 15 sec or less when placed in 15 ml of aqueous fluid; and the ratio of effective particle size to first native particle size is >1 : 1 to 5 : 1 , and the ratio of effective particle size to second native particle size is 20:1 to 50:1.
2) A rapidly dispersible three-dimensionally printed porous non-compressed bound matrix comprising:
a first grade of OXC particles having a first native particle size, a second grade of OXC particles having a second native particle size, at least one sweetener, at least one binder, at least one disintegrant, at least one surfactant, and at least one glidant; wherein .
the matrix comprises particles bound by binder;
the matrix disperses in less than 15 sec in a volume of 15 ml of aqueous fluid;
the OXC particles are included in drug-containing particles having an effective particle size and comprising the OXC particles and at least one pharmaceutical excipient as carrier;
the content of OXC in the matrix ranges from 35-60 % wt based upon the total weight of the matrix; and
the ratio of effective particle size to first native particle size is >1 :1 to 5:1, and the ratio of effective particle size to second native particle size is 20:1 to 50:1.
3) The invention according to any one of the above claims, wherein: a) OXC particles possess a bi-modal or multi-modal particle size distribution; b) the drug- containing particles possess a mono-modal bi-modal or multi-modal particle size distribution; or c) a combination of one or more of the above.
4) The invention according to claim 1 or 2, wherein: a) the at least one surfactant is present in an amount ranging from 0.5- 7.0% wt based upon the final weight of the dosage form; b) the at least one sweetener is present in an amount ranging from 0.01- 2.0% based upon the final weight of the dosage form; c) the at least one binder is present in an amount ranging from 5-15% based upon the final weight of the dosage form; d) the at least one disintegrant is present in an amount ranging from 10-30% based upon the final weight of the dosage form; and/or e) the at least one glidant is present in an amount ranging from 0-2% based upon the final weight of the dosage form.
5) The invention according to claim 1 or 2, wherein: a) the hardness of the matrix ranges from about 1 to about 7 kiloponds (kp), about 1 to about 3 kp; b) the matrix disperses in 10 sec or less when placed in 15 ml of water or in saliva; c) binder is introduced into the matrix by way of printing fluid used to form the matrix; d) binder is introduced into the matrix by way of bulk powder used to form the matrix; e) the matrix comprises about 150 mg to about 600 mg of OXC; and/or f) the matrix comprises 10 to 40 three-dimensionally printed incremental layers.
6) The invention according to claim 1 or 2, wherein the drug-containing particles further comprise sweetener and/or flavorant,
7) The invention according to claim 1 or 2, wherein: a) the content of drug- containing particles in the matrix generally ranges from 55-85% wt, 60-80% wt or 65- 70% wt based upon the total weight of matrix in the final dosage form; b) the content of native particles of OXC in the drug-containing particles ranges from 55-85% wt, 60-80% wt or 65-70% wt, based upon the final weight of the drug-containing particles; c) the content of disintegrant in the drug-containing particles ranges from 0-30%, 1-15%, or 2-5 % wt, based upon the final weight of the drug-containing particles; d) the content of binder in the drug-containing particles ranges from 0-10%, 1-7%, or 2-5% wt, based upon the final weight of the drug-containing particles; e) the content of surfactant in the drug- containing particles ranges from 0-10%, 1-5%, or 1.4-4.2 % wt, based upon the final weight of the chug-containing particles; and/or f) the drug-containing particles are manufactured by wet granulation.
8) The invention according to claim 1 or 2, wherein the matrix comprises about 150 to about 1200 mg, about 150 mg, about 300 mg, about 450 mg, about 600 mg, about 750 mg, about 900 mg, about 1050 mg or about 1200 of OXC.
9) The invention according to claim 1 or 2, wherein the dosage form has been prepared by a three-dimensional printing process employing printing fluid, drug- containing particles and bulk powder of the following compositions:
Figure imgf000004_0001
10) The invention according to claim 1 or 2, wherein the dosage form has the following composition:
Figure imgf000005_0001
11) The invention according to claim 1, wherein the dosage form is shaped as a wafer, cylinder, ring, donut, tube, cube, spheroid, ellipsoid or rectangular box.
12) The invention according to claim 1 or 2, wherein: a) the binder is selected from the group consisting of polyvinylpyrrolidone (povidone), mannitol, hydroxypropylcellulose, and a combination thereof; b) the disintegrant is selected from the group consisting of microciystalline cellulose, a combination of two grades of miciOciystalhne celluse, croscarmellose, and a combination thereof; or b) a combination of the above.
13) A method of treating a disease, condition or disorder that is therapeutically responsive to oxcarbazepine comprising administering the dosage form of claim 1 or the matrix of claim 2 one to three times daily to a subject in. need thereof throughout a treatment period.
14) The invention according to claim 5, wherein the thickness (height) of an incremental layer ranges from 0.006 to 0.014 inches or 0.008 to 0.012 inches.
15) A rapidly dispersible solid matrix comprising a porous three-dimensionally printed bound matrix comprising;
drug-containing particles comprising at least one disintegrant, at least one binder, at least one surfactant and native particles of drug, wherein the drug-containing particles have an effective particle size and the native particles of drug have a native particle size, and the ratio of effective particle size to native particle size of >1 :1 to 200:1;
at least one disintegrant; and
at least one binder;
wherein the hardness of the matrix ranges from about 1 to about 7 kiloponds.
16) The matrix of claim 15, wherein the matrix disperses in 15 sec or less when placed in 15 ml of aqueous fluid.
17) The matrix of claim 15, wherein the average native particle size is such that 90%- 100% of the drug is <10 microns, and the ratio of effective particle size to native particle size is in the range of 10:1 to 200:1.
18) The matrix of claim 15, wherein the average native particle size is such that not more than 20% of the drug is <32 microns, 40-70% of the drug is <63 microns, 70-95% of the drug is <125 microns, and 100% of the drug is <250 microns, and the ratio of effective particle size to native particle size is in the range of >1 : 1 to about 10:1.
19) The matrix of claim 15, wherein the native particles of drag have an average, mean or median native particle size in the range of about 1 to about 90 microns, about 1 to about 75 microns, about 1 to about 50 microns, about 1 to about 30 microns, about 1 to about 15 microns, about 1 to about 10 microns, about 2 to about 14 microns, about 10 to about SO microns, about 20 to about 70 microns, about 20 to about 60 microns or about 30 to about 50 microns.
20) The matrix of claim 17, 18 or 19, wherein the drug-containing particles have an average, mean or median effective particle size in the range of about 50 to about 400 microns, about 50 to about 300 microns, about 50 to about 250 microns, about 60 to about 250 microns, about 60 to about 100 microns, or about 75 to about 250 microns.
21) The matrix of claim 15, 16, 17, 18 or 19, wherein the drag is poorly water soluble.
22) The matrix of claim 21 , wherein the drug is OXC,

STATEMENT UNDER ARTICLE 19 (1 )

Claims now require non-compressed matrix comprising two different grades of OXC differing in particle size and further specify ranges for effective particle size and native drug particle size as well as for ratio thereof.

Examiner argues Sehgal discloses a rapidly dispersible dosage form containing oxcarbazepine and dissolving in <2 minutes. Examiner acknowledges Sehgal fails to suggest a 3DP dosage form exhibiting a dispersion time of 15 sec or less and relies upon Yoo as disclosing rapidly dispersible dosage forms exhibiting a dispersion time of 15 sec or less. Examiner relies upon Blau as disclosing formulations containing 35-60% of oxcarbazepine.

Neither Sehgal, Yoo nor Blau discloses use of two different grades of drug particles having different native particle sizes, None of the references discloses need to balance effective particle size and native drug particle size during 3DP.

Sehgal and Blau illustrate wide range of results when different drug particle sizes and granulation approaches are used with tabletting. All achieve much slow disintegration times.

Sehgal (Dl) only discloses a compressed dosage form and focuses on use of wetting agent to overcome the need for small particle size oxcarbazepine. ([0003], [0011], [0020]). Sehgal strongly suggests use of larger particles of oxcarbazepine (median particle size: 20-50 microns) in order to obtain "best results". Examples 1-4 ([0040]-[0048]) employ oxcarbazepine with median particle size of about 26 microns. Sehgal only suggests granulated particles and only achieves a "disintegration time in water <2 minutes."

Yoo's (D2) 3DP non-compressed matrices have a dispersion time of 15 sec or less; however, Yoo does not recognize the importance of balancing particle size of native drug versus that of drug-containing particles, Yoo does not contemplate granulation of small drug particles into larger drug-containing particles in order overcome problems caused by small drug particles during 3DP process. Yoo only achieves <15 sec disintegration time using ungranulated drug particles.

Blau (D3) discloses formulations containing granulated OXC having at least two different particle size populations. The granulated particles are used in compressed tablets and have a disintegration time of <30 mill- ([0025]) Proper combination of Sehgal, Yoo and Blau suggests that granulation of drug causes a slower rather than faster dMotegration time. There is no suggestion or enablement a priori that one can achieve dispersion in <15 sec in a 3DP matrix containing granulated particles comprising OXC particles of two different sizes. There is no certainty that a satisfactory dosage form, e.g. with suitable hardness and/or surface features, could even be produced by 3DP.

The instant specification discloses the "effective particle size" of OXC in the bulk powder must be increased without increasing the "actual particle size" of the drug ([0013]) for the purpose of facilitating three-dimensional printing of acceptable dosage forms while keeping the actual drug particle size small to facilitate drug absorption. ([0023], [0024], [004]).

Claimed invention provides preferred ranges for effective particle size and native drug particle size and for ratio thereof and requires combination of two different grades of OXC differing in particle size.

Respectfully submitted,

PCT/US2014/028125 2013-03-15 2014-03-14 Rapidly dispersible dosage form of oxcarbazepine WO2014143935A1 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
MX2015012136A MX364381B (en) 2013-03-15 2014-03-14 Rapidly dispersible dosage form of oxcarbazepine.
ES14763545T ES2761265T3 (en) 2013-03-15 2014-03-14 Rapidly dispersible oxcarbazepine dosage form
EP14763545.2A EP2968354B1 (en) 2013-03-15 2014-03-14 Rapidly dispersible dosage form of oxcarbazepine
CN201480014727.3A CN105050604B (en) 2013-03-15 2014-03-14 Fast dispersing dosage forms of oxcarbazepine
JP2016502709A JP6463333B2 (en) 2013-03-15 2014-03-14 Rapidly dispersible dosage form of oxcarbazepine
AU2014228063A AU2014228063B2 (en) 2013-03-15 2014-03-14 Rapidly dispersible dosage form of oxcarbazepine
CA2906107A CA2906107C (en) 2013-03-15 2014-03-14 Rapidly dispersible dosage form of oxcarbazepine
US14/837,493 US9314429B2 (en) 2013-03-15 2015-08-27 Rapidly dispersible dosage form of oxcarbazepine
HK16101293.4A HK1213472A1 (en) 2013-03-15 2016-02-04 Rapidly dispersible dosage form of oxcarbazepine
US15/045,711 US9616018B2 (en) 2013-03-15 2016-02-17 Rapidly dispersible dosage form of oxcarbazepine
HK16102379.9A HK1214173A1 (en) 2013-03-15 2016-03-02 Rapidly dispersible dosage form of oxcarbazepine
US15/437,966 US10028909B2 (en) 2013-03-15 2017-02-21 Rapidly dispersible dosage form of oxcarbazepine
AU2017203365A AU2017203365B2 (en) 2013-03-15 2017-05-19 Rapidly dispersible dosage form of oxcarbazepine
US16/015,552 US20180296479A1 (en) 2013-03-15 2018-06-22 Rapidly Dispersible Dosage Form with High Drug Content

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US10028909B2 (en) 2018-07-24
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US9314429B2 (en) 2016-04-19
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US20170172919A1 (en) 2017-06-22
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