(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2015/0140085A1
`Goldstein
`(43) Pub. Date:
`May 21, 2015
`
`US 2015O140085A1
`
`(54) FORMULATIONS COMPRISING IBRUTINIB
`(71) Applicant: PRINCIPLA BIOPHARMA INC.,
`South San Francisco, CA (US)
`
`(72) Inventor: David Michael Goldstein, Redwood
`City, CA (US)
`
`(73) Assignee: Principia Biopharma Inc., South San
`Francisco, CA (US)
`
`(21) Appl. No.:
`
`14/403,927
`
`(22) PCT Filed:
`(86). PCT No.:
`
`Jun. 26, 2013
`PCT/US2013/047958
`
`7.) Nov. 25, 2014
`
`O
`O
`Related U.S. Application Data
`(60) Provisional application No. 61/666,562, filed on Jun.
`29, 2012.
`
`Publication Classification
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A619/28
`A647/32
`A 6LX 9/50
`A6II 45/06
`A 6LX3/59
`469/48
`(52) U.S. Cl.
`CPC ............. A61K 9/2846 (2013.01); A61 K3I/519
`(2013.01); A61 K9/4825 (2013.01); A61 K
`9/4808 (2013.01); A61K 9/5026 (2013.01);
`A61 K9/4891 (2013.01); A61K 45/06
`(2013.01); A61 K47/32 (2013.01)
`ABSTRACT
`(57)
`Oral pharmaceutical formulations of ibrutinib and/or a phar
`maceutically acceptable salt thereof, methods for their
`administration, process of their production, and use of these
`formulations
`the treatment S. diseases treatable by ibru
`tinib Such as cancer, inflammatory diseases, and autoimmune
`diseases.
`
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`FORMULATIONS COMPRISING BRUTINIB
`0001. The present disclosure provides certain oral phar
`maceutical formulations of ibrutinib, certain methods for
`their administration, certain processes of their production,
`and certain uses of these formulations for the treatment of
`diseases treatable by ibrutinib Such as cancer, inflammatory
`diseases, and autoimmune diseases.
`0002 Bruton's tyrosine kinase (BTK) is a member of the
`Tec tyrosine kinase family. BTK is expressed in most hemato
`poietic cells such as B cells, mast cells, and macrophages, but
`not in T cells, natural killer cells, and plasma cells. BTK plays
`a role in the development and activation of B cells. Mutations
`in the human BTK gene cause the inherited disease X-linked
`agammaglobulinemia (XLA), with lack of peripheral B cells
`and low levels of serum Ig. In XLA, the primary immune
`deficit is B cell specific. The development of drugs which
`inhibit BTK can have therapeutic significance in the treat
`ment of both B cell-related hematological cancers (e.g. non
`Hodgkin lymphoma (NHL) and B cell chronic lymphocytic
`leukemia (B-CLL), and autoimmune diseases (e.g. rheuma
`toid arthritis, Sjogrens syndrome, IBD, lupus, and asthma).
`0003 PCI-32765 (ibrutinib) is disclosed in U.S. Pat. No.
`7.514,444, issued on Apr. 7, 2009, and has the following
`Structure:
`
`0004 Ibrutinib is an orally available drug that targets Bru
`ton's tyrosine kinase (BTK). Ibrutinib is an irreversible small
`molecule BTK inhibitor that is in PhIb/II of clinical trials in
`a variety of B-cell malignancies including chronic lympho
`cytic leukemia (CLL), Small lymphocytic lymphoma (SLL).
`mantle cell lymphoma (MCL), diffuse large B-cell lym
`phoma (DLBCL) and multiple myeloma (cancer of plasma
`cells, a type of white blood cell present in bone marrow). At
`present ibrutinib is administered orally in clinical trials, via
`the gastrointestinal tract, at high clinical doses (420 mg/day
`or 840 mg/day) to patients with CLL and SLL to obtain the
`desired thereapeutic effect. The need for such high doses of
`ibrutinib may be due to low bioavailability (the oral bioavail
`ability of ibrutinib is reported to be 22.8% in rats) and may be
`responsible for the adverse side effects associated with the
`use of ibrutinib Such as nausea or emesis, dizziness and diar
`rhea. Moreover, low bioavailability results in more variable
`absorption and potential variability of the desired therapeutic
`response.
`
`0005. As stated above, at presentibrutinib is administered
`orally, via the gastrointestinal tract, at high clinical doses (420
`mg/day or 840 mg/day) to patients to obtain the desired clini
`cal benefit. It is presently disclosed that when ibrutinib is
`administered intraduodenally versus via the gastrointestinal
`tract in rats, the oral bioavailability of ibrutinib unexpectedly
`increased from 21% to 100% as determined by AUC. This
`unexpected increase in oral bioavailability of ibrutinib can
`translate into a number of desirable practical benefits. The
`increase in oral bioavailability should enable administration
`of ibrutinib at a significantly lower therapeutically effective
`dose than is currently being used. The lower variability asso
`ciated with this greater bioavailability should lead to a more
`reliable therapeutic response as well as more predictable drug
`absorption. And avoidance of exposure of Ibtrutinib to the
`stomach and/or use of lower therapeutically effective dose of
`ibrutinib can reduce or altogether eliminate potential adverse
`side effects of this drug Such as diahrrea, nausea or emesis,
`and dizziness. U.S. Pat. No. 7,514,444, mentioned above,
`discloses administration of 0.02-5000 mg/kg and 1-1500 mg
`ofibrutinib/per day and in clinical trials 420 or 840 mg/day of
`ibrutinib is being administered to the patients with CLL and
`SLL. There is no reasonable expectation in the art that ibru
`tinib can be adminstered orally at lower efficacious doses to
`the patients with CLL and SLL, particularly as evidenced by
`the 420 or 840 mg/day of ibrutinib being administered in
`clinical trials to those patients. Moreover, other than for active
`agents that are unstable in the stomachoratacidic pH delivery
`of any active agent with low bioavailability further along in
`the gastrointestinal tract reduces the path length for drug
`absorption and would be expected to reduce bioavailability.
`Therefore, it was unexpected to achieve delivery of ibruntinib
`directly to the small intestine with greater bioavailability.
`0006. Accordingly, in one aspect, the present disclosure
`provides a Solid oral dosage form comprising:
`0007 (i) ibrutinib and/or a pharmaceutically acceptable
`salt thereof
`0008 (ii) means for release of ibrutinib in the intestine;
`and
`0009 (iii) at least one pharmaceutically acceptable excipi
`ent
`0010. In one embodiment of above aspect, ibrutinib and/or
`a pharmaceutically acceptable salt thereof is released in the
`small intestine. In another embodiment, ibrutinib and/or a
`pharmaceutically acceptable salt thereof is released to a
`region of the intestine in which the pH is about 5, or 5, or
`greater than 5. In another embodiment, said ibrutinib and/or a
`pharmaceutically acceptable salt thereof is released to a
`region of the intestine in which the pH is about 5.5, or greater
`than about pH 5.5. For example, the release is in one or more
`of the duodenum, jejunum, ileum, and colon. In one embodi
`ment, the release is in one or more of the duodenum, jejunum,
`or ileum. In one embodiment, the release to the above regions
`of the intestine is achieved by coating ibrutinib and/or a
`pharmaceutically acceptable salt thereof or the dosage form
`containing ibrutinib and/or a pharmaceutically acceptable
`salt thereof with at least one coating chosen from enteric
`coatings and non-enteric time-delayed release coatings. In
`one embodiment, the release to the above regions of the
`intestine is achieved by coatingibrutinib and/or a pharmaceu
`tically acceptable salt thereof or the dosage form containing
`ibrutinib and/or a pharmaceutically acceptable salt thereof
`with at least one coating chosen from enteric coatings. In one
`embodiment, the release to the above regions of the intestine
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`is achieved by coating ibrutinib and/or a pharmaceutically
`acceptable salt thereof or the dosage form containing ibru
`tinib and/or a pharmaceutically acceptable salt thereof with at
`least one coating chosen from enteric coatings wherein the
`enteric coatings are chosen from polymeric coatings. In
`another embodiment, the enteric coating is is an anionic poly
`mer Such as polymethacrylates (e.g., methacrylic acid
`ethacrylate poly, methacrylic acid methyl methacrylate poly);
`cellulose-based polymers (e.g., cellulose acetate phthalate
`(CAP), cellulose acetate trimellitate (CAT), cellulose acetate
`succinate (CAS), hydroxypropylmethyl-cellulose phthalate
`(HPMCP), and hydroxypropylmethylcellulose acetate succi
`nate (HPMCAS)) or polyvinyl derivatives such as polyvinyl
`acetate phthalate (PVAP). When a non-enteric coating is
`employed, the time-delayed release dosage forms are admin
`istered in fasted State and the time-delayed release coating is
`designed to erode, burst, or become hightly permeable in
`about 0.3 to about 3 hours or in about 0.5 to about 2 hours after
`administration to release ibrutinib and/or a pharmaceutically
`acceptable salt thereof.
`0011. In a second aspect, the present disclosure provides a
`Solid oral dosage form comprising:
`0012 (i) ibrutinib and/or a pharmaceutically acceptable
`salt thereof
`0013 (ii) means for increasing the oral bioavailability of
`ibrutinib, as measured by the area under the curve (AUC), as
`compared to when said ibrutinib and/or said pharmaceuti
`cally acceptable salt thereofare administered in an immediate
`release dosage form; and
`0014 (iii) at least one pharmaceutically acceptable excipi
`ent.
`0015. In one embodiment of the second aspect, the
`increase in the oral bioavailability of ibrutinib and/or a phar
`maceutically acceptable salt thereof is due to the release of the
`ibrutinib and/or a pharmaceutically acceptable salt thereof in
`the intestine. In another embodiment of the second aspect, the
`increase in the oral bioavailability of ibrutinib and/or a phar
`maceutically acceptable salt thereof is due to the release of the
`ibrutinib and/or a pharmaceutically acceptable salt thereof in
`the small intestine. In another embodiment of the second
`aspect, ibrutinib and/or a pharmaceutically acceptable salt
`thereof is released in one or more of the duodenum, jejunum,
`or ileum. In one embodiment, the release to the above regions
`of the intestine is achieved by coating ibrutinib and/or a
`pharmaceutically acceptable salt thereof or a a dosage form
`containing ibrutinib and/or a pharmaceutically acceptable
`salt thereof with at least one coating chosen from enteric
`coatings and a non-enteric time-delayed release coatings.
`When the delayed release dosage forms are administered in
`fasted State, the time-delayed release coating is designed to
`erode, burst, or become very permeable in about 0.3 to about
`3 hours or in about 0.5 to about 2 hours after administration to
`release ibrutinib and/or a pharmaceutically acceptable salt
`thereof. When the dosage form comprised of said compound
`is coated with a non-enteric coating, it is generally adminis
`tered in the fasted state to avoid variability or delays in gastric
`emptying with meals and the resulting variability in the ini
`tiation of efficacious plasma levels.
`0016. In a third aspect, the present disclosure provides a
`Solid oral dosage form comprising:
`0017 (i) ibrutinib and/or a pharmaceutically acceptable
`salt thereof
`0.018
`(ii) at least one coating chosen from enteric coatings
`and non-enteric time-delayed release coatings; and
`0019 (ii) at least one pharmaceutically acceptable excipi
`ent.
`
`0020. In one embodiment, the said at least one coating is
`chosen from enteric coatings. In one embodiment, the said at
`least one coating is chosen from polymeric coatings. In one
`embodiment, the said at least one coating is chosen from
`enteric coatings where the enteric coating is a polymer which
`erodes to release ibrutinib and/or a pharmaceutically accept
`able salt thereofat about pH 5 and above. In another embodi
`ment, ibrutinib and/or a pharmaceutically acceptable salt
`thereof is released at about pH 5.5 and above or from about
`5.5 to about 6.5. In yet another embodiment of the third
`aspect, ibrutinib and/or a pharmaceutically acceptable salt
`thereof is released in one or more of the duodenum, jejunum,
`or ileum. In one embodiment of the third aspect and embodi
`ments contained therein the dosage form is coated. In one
`embodiment of the third aspect and embodiments contained
`therein said ibrutinib and/or said pharmaceutically acceptable
`salt thereof are coated.
`0021. In a fourth aspect, the present disclosure provides a
`Solid oral dosage from comprising:
`0022 (i) about 20 mg to about 450 mg of ibrutinib and/or
`a pharmaceutically acceptable salt thereof.
`0023 (ii) at least one coating chosen from an enteric coat
`ing and/or a non-enteric time-delayed release coating; and
`0024 (iii) at least one pharmaceutically acceptable excipi
`ent
`0025 wherein said oral dosage form increases the oral
`bioavailability, as measured by the area under the curve
`(AUC), of said ibrutinib and/or said pharmaceutically accept
`able salt thereof by at least 20% as compared to the bioavail
`ability obtained from an immediate release solid oral dosage
`form comprising the same dose of said ibrutinib and/or said
`pharmaceutically acceptable salt thereof and said at least one
`pharmaceutically acceptable excipient under the same condi
`tions. In one embodiment, the increase in bioavailability is at
`least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,
`75%, 80%, 85%, 90%, 95%, or 100%. In another embodi
`ment the increase in bioavailability is independently at least
`70%, or 75%, or 80%, or 85%, or 90%, 95% or 100%.
`0026. In one embodiment of the first to fourth aspect and
`embodiments contained therein, the dosage form contains
`from about 20 mg to about 450 mg of said ibrutinib and/or
`said pharmaceutically acceptable salt thereof. In another
`embodiment of the fourth aspect and embodiments contained
`therein, the dosage form contains from about 20 mg to about
`420 mg of said ibrutinib and/or said pharmaceutically accept
`able salt thereof. In another embodiment of the fourth aspect
`and embodiments contained therein, the dosage form con
`tains from about 20 or 30 mg to about 300 or 350 mg of said
`ibrutinib and/or said pharmaceutically acceptable salt
`thereof. In another embodiment of the fourth aspect and
`embodiments contained therein, the dosage form contains
`from about 50 mg to about 200, or 220, or 250 mg of said
`ibrutinib and/or said pharmaceutically acceptable salt
`thereof.
`0027. In one embodiment, the solid oral dosage forms
`disclosed above are coated with at least one coating chosen
`from enteric coatings and non-enteric time-delayed release
`coatings. Within this embodiment, in one embodiment, the at
`least one coating is chosen from enteric coatings. Within the
`above embodiments, the enteric coatings are chosen from
`polymeric coatings.
`0028. In another embodiment, the solid oral dosage form
`disclosed above comprise ibrutinib and/a pharmaceutically
`acceptable salt thereofthat are coated with at least one coating
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`chosen from enteric coatings and non-enteric time-delayed
`release coatings. Within this embodiment, in one embodi
`ment, the at least one coating is chosen from enteric coatings.
`Within the above embodiments, the enteric coatings are cho
`sen from polymeric coatings. Within the above embodiments,
`the enteric coating is an anionic polymer Such as poly
`methacrylates (e.g., methacrylic acid ethacrylate poly, meth
`acrylic acid methyl methacrylate poly); cellulose-based poly
`mers (e.g., cellulose acetate phthalate (CAP), cellulose
`acetate trimellitate (CAT), cellulose acetate succinate (CAS),
`hydroxypropylmethyl-cellulose phthalate (HPMCP), and
`hydroxypropylmethylcellulose acetate succinate (HPM
`CAS)) or polyvinyl derivatives such as polyvinyl acetate
`phthalate (PVAP).
`0029. In one embodiment, the solid oral dosage forms are
`a tablet or capsule. When the dosage form is capsule, ibrutinib
`and/or a pharmaceutically acceptable salt thereof can be
`present in a non-solid form. In another embodiment, the Solid
`oral dosage form disclosed above comprises ibrutinib.
`0030. The therapeutically effective amount of ibrutinib
`and/or a pharmaceutically acceptable Salt thereof when
`administered into the intestine by bypassing the stomach can
`be from about 20 mg per day to about 450 mg/day, or 20
`mg/day to about 420 mg/day; or about 20 mg/day or 30
`mg/day to about 300 or 350 mg/day; or about 30 or 50 mg/day
`to about 200, or 220 or 250 mg/day; or about 30 or 50 mg/day
`to about 100 or 150 mg/day and can be administered in single
`or multiple doses. Accordingly, any of the formulations dis
`closed herein can contain from about 5, 10, 15, 20, 25, 30, 35,
`40, 45, 50, 55, 60, 65, 70, 75, 80, 85,90, 95, 100, 110, 115,
`120, 125, 130, 135, 140, 145, 150, 155, 160, 175, 170, 175,
`180, 185, 190, 195, 200, 225, 250, 300, 325, 350,375,400,
`425, or 450 milligrams of ibrutinib or a pharmaceutically
`acceptable salt thereof. In one embodiment, the tablets or
`capsules can contain about 20, 25, 30, 50, 75, 100, 150, 200,
`or 220 milligrams of ibrutinib and/or a pharmaceutically
`acceptable salt thereof.
`0031. In one embodiment, any of the formulations dis
`closed herein contain, unless stated otherwise, one or more
`pharmaceutically acceptable excipient(s) such as glidants,
`polymers, binders, Surfactants, disintegrants, diluents, buff
`ering agents, antiadherents, retardants, Solubilizers, antioxi
`dants, antifoaming agents, fillers, flavors, colors, lubricants,
`sorbents, plasticizers, or Sweeteners, preservatives, or mix
`tures thereof, which facilitate processing of ibrutinib and/or a
`pharmaceutically acceptable salt thereof or into preparations
`which can be used pharmaceutically. Any of the well-known
`techniques and excipients may be used as Suitable and as
`understood in the art, see for example, Remington: The Sci
`ence and Practice of Pharmacy, Twenty-first Ed., (Pharma
`ceutical Press, 2005); Liberman, H. A., Lachman, L., and
`Schwartz, J. B. Eds. Pharmaceutical Dosage Forms, Vol. 1-2
`Taylor & Francis 1990; and R. I. Mahato, Ansel's Pharma
`ceutical Dosage Forms and Drug Delivery Systems, Second
`Ed. (Taylor & Francis, 2012).
`0032. In certain embodiments, the formulations may
`include one or more pH adjusting agents or buffering agents,
`for example, acids such as acetic, boric, citric, lactic, phos
`phoric and hydrochloric acids; bases such as sodium hydrox
`ide, Sodium phosphate, Sodium borate, Sodium citrate,
`Sodium acetate, Sodium lactate and tris-hydroxymethylami
`nomethane; and buffers such as citrate/dextrose, sodium
`bicarbonate, ammonium chloride, and the like. The acids,
`
`bases, and buffers are added in an amount required to main
`tain pH of the composition in an acceptable range.
`0033. In certain embodiments, the formulations may also
`include one or more salts in an amount that is required to bring
`osmolality of the composition into an acceptable range. Such
`salts include those having Sodium, potassium, or ammonium
`cations and chloride, citrate, ascorbate, borate, phosphate,
`bicarbonate, sulfate, thiosulfate, or bisulfite anions. Suitable
`salts include Sodium chloride, potassium chloride, sodium
`thiosulfate, sodium bisulfite, and ammonium sulfate.
`0034. In certain embodiments, the formulations may also
`include one or more antioxidants, such as non-thiol antioxi
`dants, e.g., ascorbic acid, butylated hydroxytoluene (BHT),
`butylated hydroxyanisole, sodium ascorbate, and tocopherol
`or derivatives thereof. In certain embodiments, antioxidants
`enhance chemical stability where required.
`0035. In certain embodiments, the formulations may also
`include one or more antifoaming agents. The foaming agent
`(s) are added to reduce foaming during processing which can
`result in coagulation of aqueous dispersions, bubbles in the
`finished film, or generally impair processing. Examples of
`Suitable anti-foaming agents include silicon emulsions or
`Sorbitan Sesquoleate.
`0036. In certain embodiments, the formulations may also
`include one or more preservatives. Preservatives are used to
`inhibit microbial activity. Suitable preservatives include mer
`cury-containing Substances such as merfen and thiomersal,
`stabilized chlorine dioxide, and quaternary ammonium com
`pounds such as benzalkonium chloride, cetyltrimethylammo
`nium bromide, and cetylpyridinium chloride.
`0037. In certain embodiments, the formulations may also
`include one or more binders. Binders impart cohesive quali
`ties. Exemplary binders include, e.g., alginic acid and salts
`thereof; cellulose derivatives, such as carboxymethylcellu
`lose, methylcellulose (e.g., Methocel(R), hydroxypropylm
`ethylcellulose, hydroxyethylcellulose, hydroxypropylcellu
`lose (e.g., Kiucel(R), ethylcellulose (e.g., Ethocel(R), and
`microcrystalline cellulose (e.g., Avicel(R); microcrystalline
`dextrose; amylose; magnesium aluminum silicate; polysac
`charide acids; bentonites; gelatin: polyvinyl-pyrrolidone/vi
`nyl acetate copolymer, crosspoVidone; poVidone; starch;
`pregelatinized starch; tragacanth, dextrin, a Sugar, Such as
`Sucrose (e.g., Dipac.R.), glucose, dextrose, molasses, manni
`tol, Sorbitol. Xylitol (e.g., XylitabR), and lactose; a natural or
`Synthetic gum Such as acacia, tragacanth, ghatti gum muci
`lage of isapol husks, polyvinylpyrrolidone (e.g., Polyvi
`done(R) CL, Kollidon R CL, PolyplasdoneR XL-10), larch
`arabogalactan, Veegum(R), polyethylene glycol, polyethylene
`oxide, waxes, Sodium alginate, and the like. In general, binder
`levels of about 10 to about 70% are used in powder-filled
`gelatin capsule formulations. Binder usage level in tablet
`formulations varies on whether direct compression, wet
`granulation, or roller compaction process is used to make the
`tablet, and/or on types of other excipients used to make the
`formulation e.g., fillers which itself can act as moderate
`binder.
`0038. In certain embodiments, the formulations may also
`include dispersing agents and/or viscosity modulating agents.
`Dispersing agents and/or viscosity modulating agents include
`materials that control the diffusion and homogeneity of a drug
`through liquid media or a granulation method or blend
`method. In some embodiments, these agents also facilitate the
`effectiveness of a coating or eroding matrix. Exemplary dif
`fusion facilitators/dispersing agents include, e.g., hydrophilic
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`polymers, electrolytes, Tween R60 or 80, PEG, polyvinylpyr
`rolidone (PVP; commercially known as Plasdone(R), and the
`carbohydrate-based dispersing agents, for example, hydrox
`ypropyl celluloses (e.g., HPC, H-PC-SL, and HPC-L),
`hydroxypropyl methylcelluloses (e.g., HPMC K100, RPMC
`K4M, HPMC K15M, and HPMC K100M), carboxymethyl
`cellulose sodium, methylcellulose, hydroxyethyl-cellulose,
`hydroxypropylcellulose,
`hydroxypropylmethylcellulose
`phthalate, hydroxypropyl-methylcellulose acetate Stearate
`(HPMCAS), noncrystalline cellulose, magnesium. alumi
`num silicate, triethanolamine, polyvinyl alcohol (PVA), vinyl
`pyrrolidone/vinyl acetate copolymer (S630), 4-(1,1,3,3-tet
`ramethylbutyl)-phenol polymer with ethylene oxide and
`formaldehyde (also known as tyloxapol), polyethylene oxide
`(e.g., PolyOX or PEO), poloxamers which are block copoly
`mers of ethylene oxide and propylene oxide (e.g., Pluronics
`F68(R), F88(R), and F108(R); and poloxamines (e.g., Tetronic
`908(R), also known as Poloxamine 908R, which is a block
`copolymer derived from sequential addition of propylene
`oxide and ethylene oxide to ethylenediamine (BASF Corpo
`ration, Parsippany, N.J.)), polyvinylpyrrolidone K12, K17,
`K25, or K30, polyvinylpyrrolidone/vinyl acetate copolymer
`(S-630), polyethylene glycol, e.g., the polyethylene glycol
`can have a molecular weight of about 300 to about 6000, or
`about 3350 to about 4000, or about 5400 to about 7000,
`polysorbate-80, Sodium alginate, gums, such as, e.g., gum
`tragacanth and gum acacia, guar gum, Xanthans, including
`Xanthan gum, Sugars, polyethoxylated Sorbitan monolaurate,
`polyethoxylated Sorbitan monolaurate, povidone, carbomers,
`polyvinyl alcohol (PVA), alginates, chitosans, and combina
`tions thereof. Dispersing agents particularly useful in liposo
`mal dispersions and self-emulsifying dispersions are
`dimyristoyl phosphatidylcholine, natural phosphatidylcho
`line from eggs, natural phosphatidylglycerol from eggs, cho
`lesterol, and isopropyl myristate.
`0039. In certain embodiments, the formulations may also
`include one or more "diluents' which refers to chemical
`compounds that are used to dilute the compound of interest
`prior to delivery. Diluents can also be used to stabilize com
`pounds because they can provide a more stable environment.
`Salts dissolved in buffered solutions (which also can provide
`pH control or maintenance) are utilized as diluents in the art,
`including, but not limited to a phosphate buffered saline solu
`tion. In certain embodiments, diluents increase bulk of the
`composition to facilitate compression or create Sufficient bulk
`for homogenous blend for capsule filling. Such compounds
`include e.g., lactose, starch, mannitol, Sorbitol, dextrose,
`microcrystalline cellulose such as Avicel(R: dibasic calcium
`phosphate, dicalcium phosphate dihydrate; tricalcium phos
`phate, calcium phosphate; anhydrous lactose, spray-dried
`lactose; pregelatinized starch, compressible Sugar, Such as
`Di-PacR (Amstar); hydroxypropyl-methylcellulose, hydrox
`ypropylmethylcellulose acetate Stearate. Sucrose-based dilu
`ents, confectioner's Sugar, monobasic calcium Sulfate mono
`hydrate, calcium sulfate dihydrate; calcium lactate trihydrate,
`dextrates; hydrolyzed cereal Solids, amylose; powdered cel
`lulose, calcium carbonate; glycine, kaolin; mannitol, Sodium
`chloride; inositol, bentonite, and the like.
`0040. In certain embodiments, the formulations may also
`include one or more “disintegrants' which facilitate the
`breakup or disintegration of the dosage form when it comes in
`contact with the gastrointestinal fluid. Examples of disinte
`gration agents include a starch, e.g., a natural starch Such as
`corn starch or potato starch, a pregelatinized starch Such as
`
`National 1551 or sodium starch glycolate such as Promo
`gel R. or Explotab(R), a cellulose such as a wood product,
`methylcrystalline cellulose, e.g., Avicel(R), Avicel(R) PH101,
`Avice1(R) PH 102, Avice1(R) PH105, Elceme(R) P100, Emco
`cel(R), Vivacel(R), and Solka-FlocR, methylcellulose, croscar
`mellose, or a cross-linked cellulose, such as cross-linked
`sodium carboxymethyl-cellulose (Ac-Di-SolR), cross-linked
`carboxymethylcellulose, or cross-linked croScarmellose, a
`cross-linked starch Such as Sodium starch glycolate, a cross
`linked polymer Such as crosspovidone, a cross-linked poly
`vinylpyrrolidone, alginate Such as alginic acid or a salt of
`alginic acid Such as Sodium alginate, a clay Such as Veegum R
`HV (magnesium aluminum silicate), a gum Such as agar,
`guar, locust bean, Karaya, pectin, or tragacanth, Sodium
`starch glycolate, bentonite, a natural sponge, a surfactant, a
`resin Such as a cation-exchange resin, citrus pulp, sodium
`lauryl Sulfate, Sodium lauryl Sulfate in combination starch,
`and the like.
`0041. In certain embodiments, the formulations may also
`include erosion facilitators which include materials that con
`trol the erosion of a particular material in gastrointestinal
`fluid. Exemplary erosion facilitators include, e.g., hydro
`philic polymers, electrolytes, proteins, peptides, and amino
`acids.
`0042. In certain embodiments, the formulations may also
`include one or more filling agents which include compounds
`Such as lactose, Xylitol, lactitol, mannitol, Sorbitol, calcium
`carbonate, calcium phosphate, dibasic calcium phosphate,
`calcium sulfate, microcrystalline cellulose, cellulose powder,
`dextrose, dextrates, dextran, starches, pregelatinized starch,
`Sucrose, Sodium chloride, polyethylene glycol, and the like.
`0043. In certain embodiments, the formulations may also
`include one or more flavoring agents and/or 'sweeteners'
`e.g., acacia syrup, acesulfame K, alitame, anise, apple, aspar
`tame, banana, orange, pear, peach, peppermint, peppermint
`cream, Powder, raspberry, root beer, rum, Saccharin, Safrole,
`Sorbitol, spearmint, spearmint cream, Strawberry, Strawberry
`cream, Stevia, Sucralose, Sucrose, Sodium saccharin, saccha
`rin, aspartame, acesulfame potassium, mannitol, talin, Sylitol,
`Sucralose, Sorbitol, tagatose, tangerine, thaumatin, Vanilla,
`walnut, watermelon, wild cherry, Xylitol, or any combination
`of thereof. these flavoring ingredients, e.g., anise-menthol,
`cherry-anise, cinnamon-orange, cherry-cinnamon, choco
`late-mint, honey-lemon, lemon-lime, lemon-mint, menthol
`eucalyptus, orange-cream, Vanilla-mint, and mixtures
`thereof. The flavoring agent may be incorporated with or
`without a polymeric coating or may be mixed directly in a
`formulation or first incorporated into one or more polymers.
`0044. In certain embodiments, the formulations may also
`include one or more plasticizers which are compounds used
`to soften the enteric or delayed release coatings to make them
`less brittle. Suitable plasticizers include, e.g., polyethylene
`glycols such as PEG 300, PEG 400, PEG 600, PEG 1450,
`PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic
`acid, triethyl citrate, dibutyl sebacate, triethyl cellulose, and
`triacetin. In some embodiments, plasticizers can also function
`as dispersing agents or wetting agents.
`0045. In certain embodiments, the formulations may also
`include one or more lubricants and glidants which are com
`pounds that prevent, reduce or inhibit adhesion or friction of
`materials. Exemplary lubricants include, e.g., Stearic acid,
`calcium hydroxide, talc, Sodium Stearyllumerate, a hydrocar
`bon Such as mineral oil, or hydrogenated vegetable oil such as
`hydrogenated Soybean oil, higher fatty acids and their alkali
`
`SAN EX 1002, Page 5
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`US 2015/O 140O85 A1
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`May 21, 2015
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`metal and alkaline earth metal salts, such as aluminum, cal
`cium, magnesium, Zinc, Stearic acid, Sodium Stearates, glyc
`erol, talc, waxes, boric acid, Sodium benzoate, sodium
`acetate, Sodium chloride, leucine, a polyethylene glycol (e.g.,
`PEG4000) or a methoxypolyethylene glycol such as Carbo
`wax R, Sodium oleate, Sodium benzoate, glyceryl behenate,
`polyethylene glycol, magnesium or sodium lauryl Sulfate,
`colloidal silica such as Syloid R. Cab-O-Sil.R., a starch such as
`corn Starch, silicone oil, a Surfactant, and the like.
`0046. In certain embodiments, the formulations may also
`include one or more solubilizers which include compounds
`Such as triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,
`sodium lauryl sulfate, sodium doccusate, vitamin E TPGS,
`dimethylacetamide, N-methylpyrrolidone, N-hydroxyeth
`ylpyrrolidone, polyvinylpyrrolidone, organic alcohols such
`as ethanol, n-butanol, isopropyl alcohol, hydroxypropylm
`ethyl cellulose, hydroxypropyl beta cyclodextrins for
`example Captisol R, cholesterol, bile salts, propylene glycol,
`polyethylene glycol 200-600, glycofurol, transcutol, dim
`ethyl isosorbide and the like. In one embodiment, the solubi
`lizer is vitamin ETPGS and/or Captisol(R). In certain embodi
`ments, the formulations may also include one or more
`Suspending agents which include compounds Such as cellu
`loses, such as, e.g., sodium carboxymethyl-cellulose, meth
`ylcellulose, hydroxypropylmethylcellulose, or hydroxyeth
`ylcellulose, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone
`K1 12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25,
`or polyvinylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate
`copolymer (S630), polyethylene glycol, e.g., the polyethyl
`ene glycol can have a molecular weight of about 300 to about
`6000, or about 3350 to about 4000, or about 5400 to about
`7000, hydroxymethylcellulose acetate stearate, polysorbate
`80, Sodium alginate, gums, such as, e.g., gum tragacanth and
`gum acacia, guar gum, Xanthans, including Xanthan gun,
`Sugars, polyethoxylated Sorbitan monolaurate, polyethoxy
`lated Sorbitan monolaurate, povidone and the like.
`0047. In certain embodiments, the formulations may also
`include one or more Surfactants which include compounds
`Such as Sodium lauryl Sulfate, Sodium docusate, Tween 60 or
`80, triacetin, vitamin ETPGS, sorbitan monooleate, polyoxy
`ethylene Sorbitan monooleate, polysorbates, polaxomers, bile
`salts, glyceryl monostearate, copolymers of ethylene oxide
`and propylene oxide, e.g., Pluronic R (BASF), and the like.
`Some other surfactants include polyoxyethylene fatty acid
`glycerides and vegetable oils, e.g., p