(12) United States Patent
`Stra b et al
`
`u
`
`.
`
`(54) POROUS DRUG MATRICES AND METHODS
`OF MANUFACTURE THEREOF
`
`(75) Inventors: Julie Straub, Winchester; Howard
`Bernstein, Cambridge; Donald E.
`Chickering, III, Framingham; SarWat
`Khattak, Cambridge; Greg Randall,
`Stonehanh an of MA (Us)
`_
`_
`(73) Assignee: Acusphere, Inc., Cambridge, MA (US)
`( * ) Notice:
`Subject to any disclaimer, the term of this
`-
`-
`patent is extended or adJusted under 35
`U S C 154(k)) by 0 days
`
`This patent is subject to a terminal dis-
`Claimer-
`
`(21) Appl. N0.: 09/433,486
`
`(22) Filed:
`
`Nov. 4, 1999
`
`Related US Application Data
`(60) Provisional application No. 60/136,323, ?led on May 27,
`1999, and provisional application No, 60/158,659, ?led on
`00L 8, 1999
`(51) Int. c1.7 ........................ .. A61K 9/14; A61K 47/02;
`1329B 9 /00
`_
`(52) US. Cl. .......................................... .. 424/489 264/5
`
`424/465 400
`(58) Field of Search
`""""""
`’
`’
`424/484’ 489’ 428/402’ 264/5’ 9’ 114431’
`
`(56)
`
`.
`References Clted
`[)3 PATENT DOCUMENTS
`
`’
`
`’
`
`??lnow 1
`2 11/
`1 er et a '
`/
`(List Continued on next page)
`
`CA
`DE
`EP
`
`FOREIGN PATENT DOCUMENTS
`2 136 704
`5/1995
`37 13 326 A1 10/1987
`0 655 237 A1
`5/1995
`
`120 _
`
`US006395300B1
`
`(10) Patent N0.:
`45 Date of Patent‘
`
`.
`
`US 6,395,300 B1
`*Ma 28 2002
`
`,
`
`GB
`W0
`W0
`W0
`
`3/1972
`1 265 615
`7/1998
`WO 98/31346 A1
`WO 98/51282 A1 11/1998
`WO 99/56731 A1 11/1999
`
`OTHER PUBLICATIONS
`Adeyeye & Price, “Chemical, dissolution stability and
`microscopic evaluation of suspensions of ibuprofen and
`sustained release ibuprofen—Wax microspheres,” J. M icroen
`CaPSuL 14(3):357_77 (1997)
`Ahn’ et a1" ‘f Enhancement of bloavallablgty of ketoprofen
`usmg dry el1x1r as a novel dosage form, Drug Dev. Ind.
`Pharm. 24(7):697—701 (1998).
`
`List continued on next a e.
`(
`p g )
`Primary Examiner—EdWard J. Webman
`(74) Attorney, Agent, or Firm—Holland & Knight LLP
`(57)
`ABSTRACT
`
`,
`,
`,
`.
`Drugs, espec1allyloW aqueous solubility drugs, are provided
`in a porous matrix form, preferably microparticles, Which
`enhances dlssolunon of the drug 1_n aqueous medla- The drug
`matrices preferably are made using a process that includes
`dissolving a drug, preferably a drug having loW aqueous
`5011911194 in a Volatile Solvent to form a drug 501111109 (ii)
`combmmg at least one pore formmg agent With the drug
`so ut1on to orm an emu s1on, sus ens1on, or secon
`1
`'
`f
`1 '
`P
`'
`d
`
`remtpving tlhe volatile solvent and porge1
`iolution, and
`ormmg agent rom t e emu s1on, suspension, or secon
`solution to yield the porous matrix of drug. The pore forming
`agent can be either a volatile liquid that is immiscible With
`the drug solvent or a volatile solid compound, preferably a
`volatile salt. In a preferred embodiment, spray drying is used
`to remove the solvents and the pore forming agent. The
`resulting porous matrix has a faster rate of dissolution
`folloWing administration to a patient, as compared to non
`porous matrix forms of the drug. In a preferred embodiment,
`microparticles of the porous drug matrix are reconstituted
`With an aqueous medium and administered parenterally, or
`processed using standard techniques into tablets or capsules
`for oral administration.
`
`7 Claims, 4 Drawing Sheets
`
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`Exhibit 1034
`ARGENTUM
`IPR2018-00080
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`000001
`
`

`

`US 6,395,300 B1
`Page 2
`
`US. PATENT DOCUMENTS
`
`5,470,583 A 11/1995 Na et 81.
`5,500,331 A
`3/1996 CZekai et 81.
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`4/1996 Bosch et 81.
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`5/1996 CZekai et 81.
`5,518,187 A
`5/1996 Bruno et 81.
`5,518,738 A
`5/1996 Eickhoff et 81.
`5,534,270 A
`7/1996 De Castro
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`9/1996 Liversidge et 81.
`5,560,932 A 10/1996 Bagchi et 81.
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`4/1997 Wong
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`000002
`
`

`

`US 6,395,300 B1
`Page 3
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`000003
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`

`US 6,395,300 B1
`Page 4
`
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`
`* cited by examiner
`
`000004
`
`

`

`U.S. Patent
`
`May 28, 2002
`
`Sheet 1 0f 4
`
`US 6,395,300 B1
`
`120_
`
`25;?“
`
`__:-:_.___"_,___T__T___—___TT_________§
`$
`
`—-9—BULK PREDISONE POWDER
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`

`

`U.S. Patent
`
`May 28,2002
`
`Sheet 2 0f 4
`
`US 6,395,300 B1
`
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`000006
`
`

`

`U.S. Patent
`
`May 28, 2002
`
`Sheet 3 0f 4
`
`US 6,395,300 B1
`
`120
`
`100-:
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`ill _' '
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`000007
`
`

`

`U.S. Patent
`
`May 28,2002
`
`Sheet 4 0f 4
`
`US 6,395,300 B1
`
`120
`
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`
`000008
`
`

`

`US 6,395,300 B1
`
`1
`POROUS DRUG MATRICES AND METHODS
`OF MANUFACTURE THEREOF
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`Priority is claimed to US. provisional applications Ser.
`No. 60/136,323, ?led May 27, 1999, and Ser. No. 60/158,
`659, ?led Oct. 8, 1999.
`
`BACKGROUND OF THE INVENTION
`This invention generally relates to formulations of drugs,
`especially drugs having loW solubility, and more particularly
`to methods of making formulations of such drugs to enhance
`their rate of dissolution.
`The bioavailability of a drug can be limited by poor
`dissolution of the drug into aqueous bodily ?uids following
`administration. This rate-limiting step may therefore be
`critical to rapidly attaining therapeutically effective drug
`levels.
`Traditional approaches to parenteral delivery of poorly
`soluble drugs include using large volumes of aqueous
`diluents, solubiliZing agents, detergents, non-aqueous
`solvents, or non-physiological pH solutions. These
`formulations, hoWever, can increase the systemic toxicity of
`the drug composition or damage body tissues at the site of
`administration.
`Other approaches have focused on the physical form of
`the drug itself. Since the dissolution rate of a drug particle
`is directly related to its surface area available to contact the
`aqueous media at the site of administration or site of
`absorption, methods of preparing drugs in nanoparticulate
`form have been developed in an effort to maximize the drug
`surface area, as described, for example, in US. Pat. No.
`5,534,270 to De Castro and US. Pat. No. 5,587,143 to
`Wong. Nanoparticles, hoWever, can be difficult to produce
`and maintain in a stable form due to the tendency of the
`nanoparticles to ?occulate or agglomerate, particularly With
`out the presence of surface modifying agents adsorbed or
`coated onto the particles. Furthermore, milling or Wet grind
`ing techniques, Which are typically employed for
`nanoniZation, can be undesirable, as it can take several days
`to process a single batch, scaling-up of the milling or
`grinding process can be difficult and/or costly, the process
`can be difficult to conduct aseptically, and it is difficult to
`eliminate shedding of milling media into the product.
`Other efforts directed at enhancing the rate of dissolution
`have focused on delivering the drug as a dispersion in a
`Water-soluble or biodegradable matrix, typically in the form
`of polymeric microparticles. For example, the dissolution
`rate of dexamethasone reportedly Was improved by entrap
`ping the drug in chitosan microspheres made by spray
`drying (Genta, et al., S. TR Pharma Sciences 5(3):202—07
`(1995)). Similarly, others have reported enhanced dissolu
`tion rates by mixing a poorly soluble drug poWder With a
`Water-soluble gelatin, Which purportedly makes the surface
`of the drug hydrophilic (Imai, et al., J Pharm. Pharmacol,
`42:615—19 (1990)).
`Related efforts have been directed to forming relatively
`large, porous matrices of loW solubility drugs. For example,
`Roland & Paeratakul,“Spherical Agglomerates of Water
`Insoluble Drugs,” J Pharma. Sci., 78(11):964—67 (1989)
`discloses preparing beads having a loW solubility drug
`content up to 98%, Wherein the beads have a porous internal
`structure. Such large beads, hoWever, are unsuitable for
`parenteral administration, and the beads have less surface
`area and sloWer dissolution rates than smaller particles.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`2
`It is therefore an object of the present invention to provide
`compositions enhancing the dissolution rate of drugs, espe
`cially drugs having loW aqueous solubility, and to provide
`methods of making such compositions.
`It is another object of the present invention to provide
`compositions providing enhanced dissolution of drugs, espe
`cially drugs of loW aqueous solubility, in a formulation
`suitable for administration by a variety of routes, including,
`but not limited to, parenteral, mucosal, oral, and topical
`administration, for local, regional, or systemic effect.
`It is further object of the present invention to provide
`compositions for administration as a bolus injection instead
`of by infusion.
`SUMMARY OF THE INVENTION
`Drugs are provided in a porous matrix form Wherein the
`dissolution rate of the drug is enhanced When the matrix is
`contacted With an aqueous medium. In a preferred
`embodiment, loW aqueous solubility drugs are provided in a
`porous matrix form Which forms microparticles When the
`matrix is contacted With an aqueous medium. The porous
`matrix With loW aqueous solubility drugs yields upon con
`tact With an aqueous medium microparticles having a mean
`diameter betWeen about 0.1 and 5 pm and a total surface area
`greater than about 0.9 m2/mL. The dry porous matrix is in
`a dry poWder form having a TAP density less than or equal
`to 1.0 g/mL and/or having a total surface area (sum of
`internal and external surface area) of greater than or equal to
`0.2 m2/g. The porous matrices that contain the drug are
`preferably made using a process that includes
`dissolving
`a drug in a volatile solvent to form a drug solution, (ii)
`combining at least one pore forming agent With the drug
`solution to form an emulsion, suspension, or second
`solution, and (iii) removing the volatile solvent and pore
`forming agent from the emulsion, suspension, or second
`solution to yield the dry porous matrix of drug. The resulting
`porous matrix has a faster rate of dissolution folloWing
`administration to a patient, as compared to non-porous
`matrix forms of the drug. The pore forming agent can be
`either a volatile liquid that is immiscible With the drug
`solvent or a volatile solid compound, preferably a volatile
`salt. If the pore forming agent is a liquid, the agent is
`emulsi?ed With the drug solution. If the pore forming agent
`is a solid, the agent is
`dissolved in the drug solution, (ii)
`dissolved in a solvent that is not miscible in the drug solvent
`and then emulsi?ed With the drug solutions or iii suspended
`as solid particulates in the drug solution. Optionally, hydro
`philic excipients, Wetting agents, and/or tonicity agents may
`be added to the drug solvent, the pore forming agent solvent,
`or both. The solution, emulsion, or suspension of the pore
`forming agent in the drug solution is then processed to
`remove the drug solvent and the pore forming agent, as Well
`as any pore forming agent solvent. In a preferred
`embodiment, spray drying, optionally folloWed by
`lyophiliZation, ?uid bed drying, or vacuum drying, is used to
`remove the solvents and the pore forming agent.
`An advantage of the formulations is that they can be
`administered as a bolus, When the drug normally must be
`infused to avoid precipitation of the drug. By avoiding
`precipitation of drug in vivo, the formulations can also be
`administered parenterally. An additional advantage is the
`formulations can be administered in reduced volumes.
`In one embodiment, the matrix further includes a pegy
`lated excipient, such as pegylated phospholipid, With the
`drug. The pegylated excipient shields the drug from mac
`rophage uptake, Which prolong its half-life or enhance
`bioavailability of the drug.
`
`000009
`
`

`

`US 6,395,300 B1
`
`3
`In a preferred embodiment, the porous drug matrix is
`reconstituted With an aqueous medium and administered
`parenterally, such as intramuscularly, isubcutaneously, or
`intravenously. Alternatively, the porous drug matrix can be
`further processed using standard techniques into tablets or
`capsules for oral administration or into rectal suppositories,
`delivered using a dry poWder inhaler for pulmonary
`administration, or mixed/processed into a cream or ointment
`for topical administration.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a graph of the in vitro dissolution rate (percent
`dissolved versus time) for non-formulated prednisone and
`prednisone in porous matrix form.
`FIG. 2 is a graph of the in vitro dissolution rate (percent
`dissolved versus time) for non-formulated griseofulvin and
`griseofulvin in porous matrix form.
`FIG. 3 is a graph of the in vitro dissolution rate (percent
`dissolved versus time) for non-formulated nifedipine and
`nifedipine in porous matrix form.
`FIG. 4 is a graph of the in vitro dissolution rate (percent
`dissolved versus time) for non-formulated naproxen and
`naproxen in a porous matrix form.
`FIG. 5 is a graph of the in vitro dissolution rate (percent
`dissolved versus time) for non-formulated paclitaxel and
`paclitaxel in a porous matrix form.
`FIG. 6 is a graph of the in vitro dissolution rate (percent
`dissolved versus time) for various porous matrix forms of
`nifedipine.
`FIG. 7 is a graph of the in vitro dissolution rate (percent
`dissolved versus time) for various porous matrix forms of
`griseofulvin.
`FIG. 8 is a graph of nifedipine plasma levels versus time
`post intravenous administration of reconstituted nifedipine
`matrix in dogs.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The rate of dissolution of drugs can be enhanced by
`making the drug into a porous matrix form, substantially
`increasing the surface area of the drug available to contact
`aqueous biological ?uids at the site of administration of the
`drug composition. In a preferred embodiment, the drug has
`loW aqueous solubility.
`I. Drug Matrix Compositions
`The porous drug matrix is at least 1 to 95%, preferably at
`least about 10%, and more preferably betWeen about 10 and
`60%, drug by Weight. The matrices also may contain hydro
`philic excipients such as Water soluble polymers or sugars,
`Wetting agents such as surfactants, and tonicity agents.
`The form of the drug matrix (drug poWder) is critical to
`the dissolution rate. The matrix must contain microparticles
`of drug, Which preferably have a diameter betWeen about
`100 nm and 5 pm, more preferably betWeen about 500 nm
`and 5 pm