111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`us 20060204588Al
`
`(19) United States
`(12) Patent Application Publication
`Liversidge et al.
`
`(10) Pub. No.: US 2006/0204588 Al
`Sep. 14,2006
`(43) Pub. Date:
`
`(S4) FORMULATIONS OF A NANOPARTICULATE
`FINASTERIDE, DUTASTERIDE OR
`TAMSULOSIN HYDROCHLORIDE, AND
`MIXTURES THEREOF
`
`(7S)
`
`Inventors: Gary Liversidge, Westchester, PA (US);
`Scott Jenkins, Downingtown, PA (US)
`
`Correspondence Address:
`ELAN DRUG DELIVERY, INC.
`CIO FOLEY & LARDNER LLP
`3000 K STREET, N.W.
`SUITE 500
`WASHINGTON, DC 20007-5109 (US)
`
`(73) Assignee: Elan Pharma International Limited
`
`(21) Appl. No.:
`
`111372,227
`
`(22) Filed:
`
`Mar. 10, 2006
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/660,229, filed on Mar.
`10, 200S.
`
`Publication Classification
`
`(Sl)
`
`Int. Cl.
`A61K 9/50
`(2006.01)
`(2006.01)
`A61K 9/16
`(S2) U.S. Cl. ............................................ 424/490; 9771906
`
`(S7)
`
`ABSTRACT
`
`Described are nanoparticulate compositions of finasteride,
`dutasteride, tamsulosin hydrochloride, or a combination
`thereof. The formulations exhibit unexpectedly prolonged
`release and can be maintained in a depot for release to a
`patient for a period of up to six months.
`
`LUPIN EX. 1019
`Lupin v. iCeutica
`US Patent No. 8,999,387
`
`Page 1
`
`

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`US 2006/0204588 Al
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`Sep.14,2006
`
`1
`
`FORMULATIONS OF A NANOPARTICULATE
`FINASTERIDE, DUTASTERIDE OR TAMSULOSIN
`HYDROCHLORIDE, AND MIXTURES THEREOF
`
`prostatectomy. Physician's Desk Reference 58th Edition
`(Thompson PDR, Montvale, N.J., 2004) pp. 10, 325 and
`2070-73.
`
`BACKGROUND OF THE INVENTION
`
`[0009] 2. Dutasteride
`
`[0001] 1. Field of the Invention
`
`[0002] The invention is directed to a nanoparticulate for(cid:173)
`mulations of finasteride, dutasteride, or tamsulosin hydro(cid:173)
`chloride, or any combination thereof. The compositions of
`the invention, which surprisingly can be formulated into
`injectable depot dosage forms, are particularly useful in the
`treatment of benign prostatic hyperplasia. The invention also
`comprises methods of making and using such formulations.
`
`[0003] 2. Description of the Related Art
`
`A. Background Regarding the Compounds of the Invention
`and Methods of Treatment
`
`[0004]
`
`I. Finasteride
`
`[0005] Finasteride is a synthetic androgen inhibitor used
`primarily in men for the treatment of benign prostatic
`hyperplasia and androgenetic alopecia (hairloss). Finas(cid:173)
`teride, a synthetic, 4-azasteroid compound, is a specific
`inhibitor of steroid Type II 5a-reductase, an intracellular
`enzyme that converts the androgen testosterone into 5a-di(cid:173)
`hydrotestosterone.
`
`[0006] The compound is known chemically as (5alpha,
`1 7beta)-N -(1, I-dimethy lethyl)-3-oxo-4-azaandrost -I-ene-
`17 -carboxamide. Finasteride is insoluble in water and
`soluble in chloroform and alcohol. The empirical formula of
`finasteride is C23H36N202 and its molecular weight is
`372.55. Finasteride has the following structure:
`
`o
`
`[0007] Finasteride is a white crystalline powder with a
`melting point near 250 0 C. It is freely soluble in chloroform
`and in lower alcohol solvents, but is practically insoluble in
`water. Finasteride is commercially available under the trade
`name PROSCAR®. PROSCAR® tablets (Merck & Co., Inc.
`(West Point, Pa.)) for oral administration are film-coated and
`contain 5 mg of finasteride and the following inactive
`ingredients: hydrous lactose, microcrystalline cellulose,
`pregelatinized starch, sodium starch glycolate, hydroxypro(cid:173)
`pyl cellulose LF, hydroxypropylmethyl cellulose, titanium
`dioxide, magnesium stearate, talc, docusate sodium, FD&C
`Blue 2 aluminum lake and yellow iron oxide.
`
`[0008] PROSCAR® is recommended for the treatment of
`symptomatic benign prostatic hyperplasia in men with an
`enlarged prostate to: improve symptoms; reduce the risk of
`acute urinary retention; reduce the risk of the need for
`surgery, including transurethral resection of the prostate and
`
`[0010] Dutasteride is a synthetic 4-azasteroid compound
`which is an antiandrogen which inhibits the conversion of
`testosterone into dihydrotestosterone. Clinical studies have
`found it to be more effective than finasteride in doing so, as
`it inhibits both isoforms of steroid 5-alpha reductase (5AR),
`an intracellular enzyme that converts testosterone to dihy(cid:173)
`drotestosterone (DHT). Dutasteride is indicated for the treat(cid:173)
`ment of symptomatic BPH in men with an enlarged prostate
`to: improve symptoms, reduce the risk of acute urinary
`retention, and reduce the risk of the need for BPH-related
`surgery. Dutasteride is currently in trial phase for the treat(cid:173)
`ment of alopecia (hairloss).
`
`[0011] Dutasteride is known chemically as (5a, 17~)-(2,5
`bis-(trifluoromethyl)phenyl)-3-oxo-4-azaandrost-I-ene-17 -
`carboxamide. The empirical formula is C27H30F 6N202' rep(cid:173)
`resenting a molecular weight of 528.5. The compound has
`the following structure:
`
`F
`
`o
`
`[0012] Dutasteride is a white to pale yellow powder with
`a melting point of 242 0 C. to 2500 C. It is soluble in ethanol
`(44 mg/mL), methanol (64 mg/mL) and polyethylene glycol
`400 (3 mg/mL), but it is insoluble in water.
`
`[0013] Dutasteride is commercially available under the
`trade name AVODART®. AVODART® Soft Gelatin Cap(cid:173)
`sules (GlaxoSmithKline (Research Triangle Park, N.C.)) for
`oral administration contain 0.5 mg of the active ingredient
`dutasteride in yellow capsules with red print. Each capsule
`contains 0.5 mg dutasteride dissolved in a mixture of mono(cid:173)
`di-glycerides of caprylic/capric acid and butylated hydroxy(cid:173)
`toluene. The inactive excipients in the capsule shell are
`gelatin (from certified BSE-free bovine sources), glycerin,
`and ferric oxide (yellow). The soft gelatin capsules are
`printed with edible red ink.
`
`[0014] AVODART® (dutasteride) is a synthetic 4-azaster(cid:173)
`oid compound that is a selective inhibitor of both the type 1
`and type 2 isoforms of steroid 5a-reductase (5AR), an
`intracellular enzyme that converts testosterone to 5a-dihy(cid:173)
`drotestosterone. Physician's Desk Reference, 58th Ed.
`(Thompson PDR, Montvale, N.J., 2004) pp. 316 and 1456-
`59.
`
`[0015] 3. Tamsulosin Hydrochloride
`
`[0016] Tamsulosin hydrochloride is an antagonist of
`alpha
`adrenoceptors in the prostate. This drug is used
`
`lA
`
`Page 2
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`

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`US 2006/0204588 Al
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`Sep.14,2006
`
`2
`
`clinically as an oral medication to ameliorate the dysuria
`associated with prostatic hypertrophy.
`[0017] Tamsulosin hydrochloride is known chemically as
`(-)-(R)-5-[2-[[2-(0-ethoxyphenoxy) ethyl]amino ]propyl]-2-
`methoxybenzenesulfonamide, monohydrochloride. Tamsu(cid:173)
`losin hydrochloride occurs as white crystals that melt with
`decomposition at approximately 230 0 C. It is sparingly
`soluble in water and in methanol, slightly soluble in glacial
`acetic acid and in ethanol, and practically insoluble in ether.
`The compound has the following structure:
`
`·Hel
`
`The empirical formula of tamsulosin hydrochloride is
`C2oH28N20sS.HCI. The molecular weight of tamsulosin
`hydrochloride is 444.98.
`[0018] Tamsulosin hydrochloride is commercially avail(cid:173)
`able under the trade name FLOMAX®. FLOMAX® cap(cid:173)
`sules (Boehringer Ingelheim (Ridgefield, Conn.)) for oral
`administration contain tamsulosin hydrochloride 0.4 mg,
`and the following inactive ingredients: methacrylic acid
`copolymer, microcrystalline cellulose, triacetin, polysorbate
`80, sodium lauryl sulfate, calcium stearate, talc, FD&C blue
`No.2, titanium dioxide, ferric oxide, gelatin, and trace
`amounts of shellac, industrial methylated spirit 74 OP,
`n-butyl, alcohol, isopropyl alcohol, propylene glycol, dim(cid:173)
`ethylpolysiloxane, and black iron oxide EI72.
`[0019] Tamsulosin, an alphal adrenoceptor blocking
`agent, exhibits selectivity for alphal receptors in the human
`prostate. At least three discrete alphal-adrenoceptor sub(cid:173)
`types have been identified: alpha lA' alphalB and alphalD ;
`their distribution differs between human organs and tissue.
`Approximately 70% of the alphal-receptors in the human
`prostate are of the alphalA subtype. Physician's Desk Ref(cid:173)
`erence, 58 th Edition (Thompson PDR, Montvale, N.J., 2004)
`pp. 4, 310 and 1006.
`[0020] 4. Treatment of Prostatic Hyperplasia
`[0021] The prostate gland is located around the tube which
`empties urine from the bladder (urethra). As the prostate
`gland enlarges, usually after 50 years of age, it can obstruct
`or partially block the urine flow. This leads to symptoms
`which include dribbling of urine, narrow stream, problems
`starting urine flow, interruption while urinating, and a feel(cid:173)
`ing of incomplete emptying. Other symptoms include wet(cid:173)
`ting and staining of clothes, urinary burning, and urgency.
`[0022] Prostate gland enlargement (Benign Prostatic
`Hyperplasia or BPH), is directly dependent on DHT (a
`hormone converted from the male hormone testosterone).
`Finasteride inhibits the enzyme necessary for the conversion
`of testosterone to DHT in the prostate. Therefore, adminis(cid:173)
`tration offinasteride lowers blood and tissue DHT levels and
`helps reduce the size of the prostate gland.
`[0023] The symptoms associated with benign prostatic
`hyperplasia are related to bladder outlet obstruction, which
`
`is comprised of two underlying components: static and
`dynamic. The static component is related to an increase in
`prostate size caused, in part, by a proliferation of smooth
`muscle cells in the prostatic stroma. However, the severity of
`benign prostatic hyperplasia symptoms and the degree of
`urethral obstruction do not correlate well with the size of the
`prostate. The dynamic component is a function of an
`increase in smooth muscle tone in the prostate and bladder
`neck leading to constriction of the bladder outlet. Smooth
`muscle tone is mediated by the sympathetic nervous stimu(cid:173)
`lation of alphal adrenoceptors, which are abundant in the
`prostate, prostatic capsule, prostatic urethra, and bladder
`neck. Blockade of these adrenoceptors can cause smooth
`muscles in the bladder neck and prostate to relax, resulting
`in an improvement in urine flow rate and a reduction in
`symptoms of benign prostatic hyperplasia.
`
`[0024] Treatment of benign prostatic hyperplasia is gen(cid:173)
`erally required over the remaining life of a patient. Current
`pharmaceutical compositions used in such treatment which
`are typically in the form of tablets or capsules taken daily,
`are inconvenient as they require ongoing patient compli(cid:173)
`ance. The administration of such dosages may be forgotten,
`which lessens the efficacy of the treatment. Alternative
`dosage forms of drugs useful in treating BPH are therefore
`desirable.
`
`B. Background Regarding Nanoparticulate Active Agent
`Compositions
`
`[0025] Nanoparticulate active agent compositions, first
`described in U.S. Pat. No. 5,145,684 ("the '684 patent"), are
`particles consisting of a poorly soluble therapeutic or diag(cid:173)
`nostic agent having adsorbed onto or associated with the
`surface thereof a non-crosslinked surface stabilizer. The
`'684 patent does not describe nanoparticulate compositions
`of finasteride, dutasteride, or tamsulosin hydrochloride.
`
`[0026] Methods of making nanoparticulate active agent
`compositions are described in, for example, U.S. Pat. Nos.
`5,518,187 and 5,862,999, both for "Method of Grinding
`Pharmaceutical Substances;" U.S. Pat. No. 5,718,388, for
`"Continuous Method of Grinding Pharmaceutical Sub(cid:173)
`stances;" and U.S. Pat. No. 5,510,118 for "Process of
`Preparing Therapeutic Compositions Containing Nanopar(cid:173)
`ticles."
`
`[0027] Nanoparticulate active agent compositions are also
`described, for example, in U.S. Pat. No. 5,298,262 for "Use
`of Ionic Cloud Point Modifiers to Prevent Particle Aggre(cid:173)
`gation During Sterilization;" U.S. Pat. No. 5,302,401 for
`"Method to Reduce Particle Size Growth During Lyophiliza(cid:173)
`tion;" U.S. Pat. No. 5,318,767 for "X-Ray Contrast Com(cid:173)
`positions Useful in Medical Imaging;" U.S. Pat. No. 5,326,
`552 for "Novel Formulation For Nanoparticulate X-Ray
`Blood Pool Contrast Agents Using High Molecular Weight
`Non-ionic Surfactants;" U.S. Pat. No. 5,328,404 for
`"Method of X-Ray Imaging Using Iodinated Aromatic Pro(cid:173)
`panedioates;" U.S. Pat. No. 5,336,507 for "Use of Charged
`Phospholipids to Reduce Nanoparticle Aggregation;" U.S.
`Pat. No. 5,340,564 for "Formulations Comprising Olin 10-G
`to Prevent Particle Aggregation and Increase Stability;" U.S.
`Pat. No. 5,346,702 for "Use of Non-Ionic Cloud Point
`Modifiers to Minimize Nanoparticulate Aggregation During
`Sterilization;" U.S. Pat. No. 5,349,957 for "Preparation and
`Magnetic Properties of Very Small Magnetic-Dextran Par(cid:173)
`ticles;" U.S. Pat. No. 5,352,459 for "Use of Purified Surface
`
`Page 3
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`

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`US 2006/0204588 Al
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`Sep.14,2006
`
`3
`
`Modifiers to Prevent Particle Aggregation During Steriliza(cid:173)
`tion;" u.s. Pat. Nos. 5,399,363 and 5,494,683, both for
`"Surface Modified Anticancer Nanoparticles;" u.s. Pat. No.
`5 401 492 for "Water Insoluble Non-Magnetic Manganese
`P~rticles as Magnetic Resonance Enhancement Agents;"
`U.S. Pat. No. 5,429,824 for "Use of Tyloxapol as a Nano(cid:173)
`particulate Stabilizer;" U.S. Pat. No. 5,447,710 for "Method
`for Making Nanoparticulate X-Ray Blood Pool Contrast
`Agents Using High Molecular Weight Non-ionic Surfac(cid:173)
`tants;" U.S. Pat. No. 5,451,393 for "X-Ray Contrast Com(cid:173)
`positions Useful in Medical Imaging;" U.S. Pat. No. 5,466,
`440 for "Formulations of Oral Gastrointestinal Diagnostic
`X-Ray Contrast Agents in Combination with Pharmaceuti(cid:173)
`cally Acceptable Clays;" U.S. Pat. No. 5,470,583 for
`"Method of Preparing Nanoparticle Compositions Contain(cid:173)
`ing Charged Phospholipids to Reduce Aggregation;" U.S.
`Pat. No. 5,472,683 for "Nanoparticulate Diagnostic Mixed
`Carbamic Anhydrides as X-Ray Contrast Agents for Blood
`Pool and Lymphatic System Imaging;" U.S. Pat. No. 5,500,
`204 for "Nanoparticulate Diagnostic Dimers as X-Ray Con(cid:173)
`trast Agents for Blood Pool and Lymphatic System Imag(cid:173)
`ing;" U.S. Pat. No. 5,518,738 for "Nanoparticulate NSAID
`Formulations;" U.S. Pat. No. 5,521,218 for "Nanoparticu(cid:173)
`late Iododipamide Derivatives for Use as X-Ray Contrast
`Agents;" U.S. Pat. No. 5,525,328 for "Nanoparticulate Diag(cid:173)
`nostic Diatrizoxy Ester X-Ray Contrast Agents for Blood
`Pool and Lymphatic System Imaging;" U.S. Pat. No. 5,543,
`133 for "Process of Preparing X-Ray Contrast Compositions
`Containing Nanoparticles;" U.S. Pat. No. 5,552,160 for
`"Surface Modified NSAID Nanoparticles;" U.S. Pat. No.
`5 560931 for "Formulations of Compounds as Nanoparticu(cid:173)
`I~te Dispersions in Digestible Oils or Fatty Acids;" U.S. Pat.
`No. 5,565,188 for "Polyalkylene Block Copolymers as
`Surface Modifiers for Nanoparticles;" U.S. Pat. No. 5,569,
`448 for "Sulfated Non-ionic Block Copolymer Surfactant as
`Stabilizer Coatings for Nanoparticle Compositions;" U.S.
`Pat. No. 5,571,536 for "Formulations of Compounds as
`Nanoparticulate Dispersions in Digestible Oils or Fatty
`Acids;" U.S. Pat. No. 5,573,749 for "Nanoparticulate Diag(cid:173)
`nostic Mixed Carboxylic Anydrides as X-Ray Contrast
`Agents for Blood Pool and Lymphatic System Imaging;"
`U.S. Pat. No. 5,573,750 for "Diagnostic Imaging X-Ray
`Contrast Agents;" U.S. Pat. No. 5,573,783 for "Redispers(cid:173)
`ible Nanoparticulate Film Matrices With Protective Over(cid:173)
`coats;" U.S. Pat. No. 5,580,579 for "Site-specific Adhesion
`Within the GI Tract Using Nanoparticles Stabilized by High
`Molecular Weight, Linear Poly(ethylene Oxide) Polymers;"
`U.S. Pat. No. 5,585,108 for "Formulations of Oral Gas(cid:173)
`trointestinal Therapeutic Agents in Combination with Phar(cid:173)
`maceutically Acceptable Clays;" U.S. Pat. No. 5,587,143 for
`"Butylene Oxide-Ethylene Oxide Block Copolymers Sur(cid:173)
`factants as Stabilizer Coatings for Nanoparticulate Compo(cid:173)
`sitions;" U.S. Pat. No. 5,591,456 for "Milled Naproxen with
`Hydroxypropyl Cellulose as Dispersion Stabilizer;" U.S.
`Pat. No. 5,593,657 for "Novel Barium Salt Formulations
`Stabilized by Non-ionic and Anionic Stabilizers;" U.S. Pat.
`No. 5,622,938 for "Sugar Based Surfactant for Nanocrys(cid:173)
`tals;" U.S. Pat. No. 5,628,981 for "Improved Formulations
`of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents
`and Oral Gastrointestinal Therapeutic Agents;" U.S. Pat. No.
`5,643,552 for "Nanoparticulate Diagnostic Mixed Carbonic
`Anhydrides as X-Ray Contrast Agents for Blood Pool and
`Lymphatic System Imaging;" U.S. Pat. No. 5,718,388 for
`"Continuous Method of Grinding Pharmaceutical Sub-
`
`stances;" u.s. Pat. No. 5,718,919 for "Nanoparticles Con(cid:173)
`taining the R( - )Enantiomer of Ibuprofen;" U.S. Pat. No.
`5,747,001 for "Aerosols Containing Beclomethasone Nano(cid:173)
`particle Dispersions;" U.S. Pat. No. 5,834,025 for "Reduc(cid:173)
`tion ofIntravenously Administered Nanoparticulate Formu(cid:173)
`lation Induced Adverse Physiological Reactions;" U.S. Pat.
`No. 6,045,829 "Nanocrystalline Formulations of Human
`Immunodeficiency Virus (HIV) Protease Inhibitors Using
`Cellulosic Surface Stabilizers;" U.S. Pat. No. 6,068,858 for
`"Methods of Making Nanocrystalline Formulations of
`Human Immunodeficiency Virus (HIV) Protease Inhibitors
`Using Cellulosic Surface Stabilizers;" U.S. Pat. No. 6,153,
`for "Injectable Formulations of Nanoparticulate
`225
`Naproxen;" U.S. Pat. No. 6,165,506 for "New Solid Dose
`Form of Nanoparticulate Naproxen;" U.S. Pat. No. 6,221,
`400 for "Methods of Treating Mammals Using Nanocrys(cid:173)
`talline Formulations of Human Immunodeficiency Virus
`(HIV) Protease Inhibitors;" U.S. Pat. No. 6,264,922 for
`"Nebulized Aerosols Containing Nanoparticle Dispersions;"
`U.S. Pat. No. 6,267,989 for "Methods for Preventing Crystal
`Growth and Particle Aggregation in Nanoparticle Compo(cid:173)
`sitions;" U.S. Pat. No. 6,270,806 for "Use of PEG-Deriva(cid:173)
`tized Lipids as Surface Stabilizers for Nanoparticulate Com(cid:173)
`positions;" U.S. Pat. No. 6,316,029
`for
`"Rapidly
`Disintegrating Solid Oral Dosage Form," U.S. Pat. No.
`6375 986 for "Solid Dose Nanoparticulate Compositions
`Com;rising a Synergistic Combination of a Polymeric Sur(cid:173)
`face Stabilizer and Dioctyl Sodium Sulfosuccinate;" U.S.
`Pat. No. 6,428,814 for "Bioadhesive Nanoparticulate Com(cid:173)
`positions Having Cationic Surface Stabilizers;" U.S. Pat.
`No. 6,431,478 for "Small Scale Mill;" U.S. Pat. No. 6,432,
`381 for "Methods for Targeting Drug Delivery to the Upper
`and/or Lower Gastrointestinal Tract," U.S. Pat. No. 6,592,
`903 for "Nanoparticulate Dispersions Comprising a Syner(cid:173)
`gistic Combination of a Polymeric Surface Stabilizer and
`Dioctyl Sodium Sulfosuccinate," U.S. Pat. No. 6,582,285
`for "Apparatus for sanitary wet milling;" U.S. Pat. No.
`6 656 504 for "Nanoparticulate Compositions Comprising
`Amo~hous Cyclosporine;" U.S. Pat. No. 6,742,734 for
`"System and Method for Milling Materials;" 6,745,962 for
`"Small Scale Mill and Method Thereof;" U.S. Pat. No.
`6811,767 for "Liquid droplet aerosols of nanoparticulate
`d~gs;" and U.S. Pat. No. 6,908,626 for "Compositions
`having a combination of immediate release and controlled
`release characteristics;" U.S. Pat. No. 6,969,529 for "Nano(cid:173)
`particulate compositions comprising copolymers of vinyl
`pyrrolidone and vinyl acetate as surface stabilizers;" U.S.
`Pat. No. 6,976,647 for "System and Method for Milling
`Materials," all of which are specifically incorporated by
`reference.
`In addition, U.S. Patent Application No.
`20020012675 AI, published on Jan. 31, 2002, for "Con(cid:173)
`trolled Release Nanoparticulate Compositions," describes
`nanoparticulate compositions, and is specifically incorpo(cid:173)
`rated by reference. None of these patents describe nanopar(cid:173)
`ticulate formulations of dutasteride or tamsulosin hydro(cid:173)
`Patent Application No.
`although U.S.
`chloride,
`20020012675 Al refers to controlled release formulations of
`finasteride. Moreover, none of the patents or patent publi(cid:173)
`cations describe injectable depot dosage forms of nanopar(cid:173)
`ticulate dutasteride, tamsulosin hydrochloride, or finas(cid:173)
`teride.
`
`[0028] Amorphous
`small particle compositions are
`described, for example, in U.S. Pat. No. 4,783,484 for
`"Particulate Composition and Use Thereof as Antimicrobial
`
`Page 4
`
`

`
`US 2006/0204588 Al
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`Sep.14,2006
`
`4
`
`Agent;" U.S. Pat. No. 4,826,689 for "Method for Making
`Uniformly Sized Particles from Water-Insoluble Organic
`Compounds;" U.S. Pat. No. 4,997,454 for "Method for
`Making Uniformly-Sized Particles From Insoluble Com(cid:173)
`pounds;" U.S. Pat. No. 5,741,522 for "Ultrasmall, Non(cid:173)
`aggregated Porous Particles of Uniform Size for Entrapping
`Gas Bubbles Within and Methods;" and U.S. Pat. No.
`5,776,496, for "Ultrasmall Porous Particles for Enhancing
`Ultrasound Back Scatter."
`
`[0029] Because finasteride, dutasteride, and tamsulosin
`hydrochloride are poorly water soluble, and because these
`drugs are useful in treating chronic conditions requiring long
`term and periodic treatment, improved dosage forms having
`increased bioavailability and prolonged activity are desir(cid:173)
`able. The present invention satisfies these needs.
`
`SUMMARY OF THE INVENTION
`
`It is an object of the invention to provide compo(cid:173)
`[0030]
`sitions comprising nanoparticulate finesteride, nanoparticu(cid:173)
`late dutasteride, nanoparticulate tamsulosin hydrochloride,
`or a combination thereof, wherein the nanoparticulate fines(cid:173)
`teride, dutasteride, and/or tamsulosin hydrochloride have an
`effective average particle size ofless than about 2000 llill. It
`is preferred that the active agent have adsorbed onto or
`associated with the surface of the active agent at least one
`surface stabilizer.
`
`It is another object of the invention to provide
`[0031]
`formulations comprising a pharmaceutically effective nano(cid:173)
`particulate finesteride, dutasteride, and/or tamsulosin hydro(cid:173)
`chloride composition for the treatment of benign prostatic
`hyperplasia in mammals, in particular, in human patients.
`
`It is a further object of the invention to provide
`[0032]
`methods of making a formulation for the treatment of benign
`prostatic hyperplasia.
`
`It is a further object of the invention that the
`[0033]
`compositions of the invention be sufficiently stable so that a
`depot comprising one quantity or batch of the composition
`can provide continuous intramuscular or subcutaneous
`release of the composition to a patient or subject for up to
`about six months. In other embodiments of the invention, the
`release of the active agent is over alternative periods of time,
`such as up to about one week, up to about two weeks, up to
`about three weeks, up to about one month, up to about two
`months, up to about three months, up to about four months,
`or up to about five months.
`
`In human therapy, it is important to provide a
`[0034]
`dosage form that delivers the required therapeutic amount of
`the active ingredient in vivo, and that renders the active
`ingredient bioavailable in a rapid and constant manner. The
`nanoparticulate formulations of the invention, which can be
`administered intramuscularly and subcutaneously, satisfy
`these needs.
`
`[0035] The objectives are accomplished by a composition
`comprising at least one of finasteride, dutasteride, and
`tamsulosin hydrochloride which are collectively referred to
`in the application as the "active ingredient." The formulation
`of the invention comprises the active ingredient having a
`surface stabilizer adsorbed on or associated with the surface
`of the active ingredient. In one embodiment of the invention,
`the surface stabilizer is a povidone polymer. In another
`embodiment of the invention, the active ingredient has an
`
`effective average particle size ofless than about 2000 llill. In
`yet other embodiments of the invention, the effective aver(cid:173)
`age particle size of the nanoparticulate active ingredient is
`less than about 1000 llill, less than about 600 llill, less than
`about 450 llill, less than about 300 llill, less than about 250
`llill, or less than about 100 llill.
`
`[0036] The invention provides for compositions compris(cid:173)
`ing concentrations of the active ingredient with rapid dis(cid:173)
`solution of the active ingredient upon administration.
`
`In another aspect of the invention there is provided
`[0037]
`a method of preparing a nanoparticulate formulation of the
`active ingredient. The method comprises: (1) dispersing the
`active ingredient in a liquid dispersion medium; and (2)
`mechanically reducing the particle size of the active ingre(cid:173)
`dient to an effective average particle size of less than about
`2000 llill. A surface stabilizer, such as a povidone polymer
`with a molecular weight of less than about 40,000 daltons,
`can be added to the dispersion media either before, during,
`or after particle size reduction. Preferably, the pH of the
`liquid dispersion medium is maintained within the range of
`from about 3 to about 8 during the size reduction process.
`
`[0038] Yet another aspect of the invention provides a
`method of treating a mammal, in particular, a human patient,
`for benign prostatic hyperplasia, comprising administering
`to the mammal a nanoparticulate active agent composition
`according to the invention. In yet another embodiment, the
`compositions of the invention are useful in treating alopecia.
`
`It is to be understood that both the foregoing
`[0039]
`general description and the following detailed description
`are exemplary and explanatory and are intended to provide
`further explanation of the invention as claimed. Other
`objects, advantages, and novel features will be readily
`apparent to those skilled in the art from the following
`detailed description of the invention.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`[0040] The present invention is directed to the surprising
`and unexpected discovery that the pharmaceutical formula(cid:173)
`tions or compositions of the invention for treatment of
`benign prostatic hyperplasia, or alopecia, can be intramus(cid:173)
`cularly or subcutaneously released continuously to a patient
`over a prolonged period of time, namely for up to about six
`months. The duration of release of the formulation is depen(cid:173)
`dent upon the particle size of the active ingredient. The
`effective average particle size of the active ingredient is less
`than about 2000 llill, although smaller particle sizes are
`described herein, such less than about 600 llill, less than
`about 450 llill, less than about 300 llill, less than about 250
`llill, or less than about 100 llill. The formulation comprises
`the nanoparticulate active ingredient with a surface stabilizer
`adsorbed onto or associated with the surface of the active
`ingredient particles. In one embodiment of the invention, the
`surface stabilizer is a povidone polymer having a molecular
`weight of not more than about 40,000 daltons.
`
`[0041] The compositions comprise nanoparticles of at
`least one of finasteride, dutasteride and tamsulosin hydro(cid:173)
`chloride. Alternatively, the composition can be described as
`comprising nanoparticles offinasteride, dutasteride and tam(cid:173)
`sulosin hydrochloride, and mixtures thereof. The referenced
`nanoparticles are sometimes collectively referred to herein
`as the "active ingredient."
`
`Page 5
`
`

`
`US 2006/0204588 Al
`
`Sep.14,2006
`
`5
`
`[0042] Advantages of the nanoparticulate finasteride,
`dutasteride,
`tamsulosin hydrochloride, or combination
`thereof formulations of the invention over conventional
`forms of the drugs include, but are not limited to: (1)
`increased water solubility; (2) increased bioavailability; (3)
`smaller dosage form size or volume due to enhanced bio(cid:173)
`availability; (4) lower therapeutic dosages due to enhanced
`bioavailability; (5) reduced risk of unwanted side effects; (6)
`enhanced patient convenience and compliance; (7) higher
`dosages possible without adverse side effects; (8) more
`effective BPH and/or alopecia treatment. A further advan(cid:173)
`tage of the injectable nanoparticulate finasteride, dutast(cid:173)
`eride, tamsulosin hydrochloride, or combination thereof
`formulations of the invention over conventional forms of the
`drugs is the elimination of the need to use a solubilizing
`agent such as ethanol, polysorbates (e.g., polysorbate 80),
`alcohol, isopropyl alcohol, toluene, or derivatives thereof
`(e.g., butylated hydroxy toluene) to increase the solubility of
`the drug(s).
`
`[0043] The present invention also includes nanoparticulate
`finasteride, dutasteride, tamsulosin hydrochloride, or com(cid:173)
`bination thereof formulations together with one or more
`non-toxic physiologically acceptable carriers, adjuvants, or
`vehicles, collectively referred to as carriers. The composi(cid:173)
`tions can be formulated for parenteral injection (e.g., intra(cid:173)
`venous, intramuscular, or subcutaneous), oral administration
`in solid, liquid, or aerosol form, vaginal, nasal, rectal, ocular,
`local (powders, ointments or drops), buccal, intracisternal,
`intraperitoneal, or topical administration, and the like. A
`preferred dosage form is an injectable depot dosage form.
`
`A. Definitions
`
`[0044] The present invention is described herein using
`several definitions, as set forth below and throughout the
`application.
`
`[0045] The term "effective average particle size of less
`than about 2000 nm," as used herein means that at least 50%
`of the finasteride, dutasteride, or tamsulosin hydrochloride
`particles have a size, by weight, of less than about 2000 nm,
`when measured by, for example, sedimentation field flow
`fractionation, photon correlation spectroscopy, light scatter(cid:173)
`ing, disk centrifugation, and other techniques known to
`those of skill in the art.
`
`[0046] As used herein, "about" will be understood by
`persons of ordinary skill in the art and will vary to some
`extent on the context in which it is used. If there are uses of
`the term which are not clear to persons of ordinary skill in
`the art given the context in which it is used, "about" will
`mean up to plus or minus 10% of the particular term.
`
`[0047] As used herein, a "stable" finasteride, dutasteride,
`or tamsulosin hydrochloride particle connotes, but is not
`limited to a finasteride, dutasteride, or tamsulosin hydro(cid:173)
`chloride particle with one or more of the following param(cid:173)
`eters: (1) the finasteride, dutasteride, or tamsulosin hydro(cid:173)
`chloride particles do not appreciably
`flocculate or
`agglomerate due to interparticle attractive forces or other(cid:173)
`wise significantly increase in particle size over time; (2) the
`physical structure of the finasteride, dutasteride, or tamsu(cid:173)
`losin hydrochloride particles is not altered over time, such as
`by conversion from an amorphous phase to a crystalline
`phase; (3) the finasteride, dutasteride, or tamsulosin hydro(cid:173)
`chloride particles are chemically stable; and/or (4) where the
`
`finasteride, dutasteride, or tamsulosin hydrochloride has not
`been subject to a heating step at or above the melting point
`of the finasteride, dutasteride, or tamsulosin hydrochloride
`in the preparation of the nanoparticles of the invention.
`
`[0048] The term "conventional" or "non-nanoparticulate"
`active agent or finasteride, dutasteride, or tamsulosin hydro(cid:173)
`chloride shall mean an active agent, such as finasteride,
`dutasteride, or tamsulosin hydrochloride, which is solubi(cid:173)
`lized or which has an effective average particle size of
`greater than about 2000 nm. Nanoparticulate active agents
`as defined herein have an effective average particle size of
`less than about 2000 nm.
`
`[0049] The phrase "poorly water soluble drugs" as used
`herein refers to drugs that have a solubility in water of less
`than about 30 mg/ml, less than about 20 mg/ml, less than
`about 10 mg/ml, or less than about 1 mg/m!.
`
`[0050] As used herein, the phrase "therapeutically effec(cid:173)
`tive amount" means the drug dosage that provides the
`specific pharmacological response for which the drug is
`administered in a significant number of subjects in need of
`such treatment. It is emphasized that a therapeutically effec(cid:173)
`tive amount of a drug that is administered to a particular
`subject in a particular instance will not always be effective
`in treating the conditions/diseases described herein, even
`though such dosage is deemed to b