`
`(51) International Patent Classification 7 :
`A61K 31/00
`
`A2
`
`ORLD INTELLECfUAL PROPERTY ORGANIZ.
`International Bureau
`•
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`wo 00/66099
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`9 November 2000 (09.11.00)
`
`(21) International Application Number:
`
`PCT/US00/11129
`
`(22) International Filing Date:
`
`26 April 2000 (26.04.00)
`
`(30) Priority Data:
`60/132,036
`
`30 April 1999 (30.04.99)
`
`us
`
`(71) Applicant (for all designated States except US): LILLY ICOS
`LLC [US/US]; 1209 Orange Street, Wilmington, DE 19801
`(US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): PULLMAN, William,
`Ernest [US/US]; 3004 Towne Drive, Carmel, IN 46032
`(US). WlllTAKER, John, Steven [US/US]; 19340 162nd
`Avenue, Woodinville, WA 98072 (US).
`
`{74) Agent: NAPOLI, James, J.; Marshall, O'Toole, Gerstein,
`Murray & Borun, 6300 Sears Tower, 233 South Wacker
`{~:,;
`Drive, Chicago, IL 60606 (US).
`
`(81) Designated States: AE, AG, AL, AM, AT, AU, AZ, BA, BB,
`BG,BR,BY,CA,CH,CN,CR,CU,CZ,DE,DK,DM,
`DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL,
`IN, IS, JP, KE. KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU,
`LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT,
`RO, RU, SD, SE, SG, Sl, SK, SL, TJ, TM, TR, TT, TZ,
`UA, UG, US, UZ, VN, YU, ZA, ZW, ARIPO patent (GH,
`GM, KE, LS, MW, SD, SL, SZ, 1Z, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
`IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published
`Without international search report and to be republished
`upon receipt of that report.
`
`~) Title: UNIT DOSAGE FORM
`
`{?J)Abstract
`
`The present invention relates to highly selective phosphodiesterase (PDE) enzyme inhibitors and to their use in pharmaceutical
`..
`~ides of manufacture. In particular, the present invention relates to potent inhibitors of cyclic guanosine 3' ,5'-monophosphate specific
`iiiiosphodiesterase type 5 (PDE5) that when incorporated into a pharmaceutical product at about 1 to about 20 mg unit dosage are useful
`~ the treatment of sexual dysfunction .
`
`..
`
`INTELGENX 1024, pg. 1
`
`
`
`F0&\1 PT0-1390 (Modified)
`U.S. DEPARTMENT OF COMMERCE PATENT AND TRADEMARK OFFICE
`(REV ll-2000)
`TRANSMITTAL LETTER TO THE UNITED STATES
`DESIGNATED/ELECTED OFFICE (DO/EO/US)
`CONCERNING A FILING UNDER 35 U.S.C. 371
`INTERNATIONAL APPLICATION NO.
`PCT/US00/11129
`ifiTLE OF INVENTION
`UNIT DOSAGE FORM
`
`I INTERNATIONAL Fll.lNG DATE
`
`26 April 2000
`
`ru
`
`S
`
`NUMBER"
`
`.._,....,
`
`29342/36206A
`
`PRIORITY DATE CLAIMED
`30 April 1999
`
`~PLICANT(S) FOR DO/EO/US
`PULLMAN, William Ernest and WHITAKER, John Steven
`
`[Applicant herewith submits to the United States Designated/Elected Office (DO/EO/US) the following items and other information:
`
`jgl
`1.
`0
`2.
`3 .. 0
`
`4.
`5.
`
`ZJ
`jgl.
`
`,!f: 0
`
`==.~
`
`~' 0
`jgl
`~91
`till
`0
`
`This is a FIRST submission of items concerning a filing under 35 U.S.C. 371.
`This is a SECOND or SUBSEQUENT submission of items concerning a filing under 35 U.S. C. 371.
`This is an express request to begin national examination procedures (35 U.S.C. 371(f)). The submission must include itens (5), (6),
`(9) and (24) indicated below.
`The US has been elected by the expiration of 19 months from the priority date (Article 31 ).
`A copy of the International Application as filed (35 U.S. C. 371 (c) (2))
`a 0
`is attached hereto (required only if not communicated by the International Bureau).
`-b.
`has been communicated by the International Bureau.
`jgl
`c.
`is not required, as the application was filed in the United States Receiving Office (RO/US).
`jgl
`An English language translation of the International Application as filed (35 U.S.C. 371(c)(2)).
`a 0
`is attached hereto.
`b. 0
`has been previously submitted under 35 U.S.C. l54(d)(4).
`Amendments to the claims of the International Application under PCT Article 19 (35 U.S. C. 371 (c}(3))
`a. 0
`are attached hereto (required only if not communicated by the International Bureau).
`b. 0
`have been communicated by the International Bureau.
`c. 0
`have not been made; however, the time limit for making such amendments has NOT expired.
`d.
`have not been made and will not be made.
`jgl
`An English language translation of the amendments to the claims under PCT Article 19 (35 U.S.C. 371(c)(3)).
`An oath or declaration of the inventor(s) (35 U.S.C. 371 (c)(4)).
`An English language translation of the annexes to the International Preliminary Examination Report under PCT
`Article 36 (35 U.S.C. 371 (c)(5)).
`
`11.
`12.
`
`jgl
`
`jgl
`
`A copy of the International Preliminary Examination Report (PCT/IPEA/409).
`A copy ofthe International Search Report (PCT/ISA/210).
`
`Items 13 to 20 below concern document(s) or information included:
`0 An Information Disclosure Statement under 37 CFR 1.97 and 1.98.
`13.
`14. Q An assignment document for recording. A separate cover sheet in compliance with 37 CFR 3.28 and 3.31 is included.
`jgl
`A FIRST preliminary amendment.
`15.
`0
`16.
`A SECOND or SUBSEQUENT preliminary amendment.
`0
`17.
`A substitute specification.
`0
`A change of power of attorney and/or address letter.
`18.
`0
`A computer-readable form of the sequence listing in accordance with PCT Rule 13ter.2 and 35 U.S.C. 1.821 - 1.825.
`19.
`0
`20.
`A second copy of the published international application under 35 U.S.C. 154(d)(4).
`0
`21.
`A second copy of the English language translation of the international application under 35 U.S.C. 154(d)(4).
`jgl
`Certificate of Mailing by Express Mail
`22.
`Other items or information:
`23.
`
`jgl
`
`Return receipt postcard
`
`Page 1 of2
`
`PCTUS1/REV03
`
`INTELGENX 1024, pg. 2
`
`
`
`. ..
`
`•
`u.s. APPLICATIOTU'l,""'1ES75~
`
`j
`
`_ _.
`
`INTER.!'lATIONAL APPI.iCATIO~"'N'I).- • -
`PCT/US00/11129
`
`~1 Dof''fi PM"!~,.~ 19 OCT.20fl1
`I AITORNEY'S DOCKET NUMBER
`
`29342/36206A
`
`g)
`
`D
`
`D
`
`D
`
`$1040.00
`
`$890.00
`
`$740.00
`
`$710.00
`
`CALCULATIONS PTOUSEONLY
`
`$890.00
`
`$0.00
`
`$0.00
`$0.00
`$0.00
`$890.00
`
`$0.00
`
`$890.00
`
`$0.00
`
`$890.00
`
`$0.00
`$890.00
`Amount to be:
`refunded
`charged
`
`$
`
`$
`
`The following fees are submitted:.
`24.
`BASIC NATIONAL FEE ( 37 CFR 1.492 (a) (1)- (5)):
`D Neither international preliminary examination fee (37 CFR 1.482) nor
`international search fee (37 CFR 1.445(a)(2)) paid to USPTO
`and International Search Report not prepared by the EPO or JPO ............
`International preliminary examination fee (37 CFR 1.482) not paid to
`USPTO but International Search Report prepared by the EPO or JPO ........
`International preliminary examination fee (37 CFR 1.482) not paid to USPTO
`but international search fee (37 CFR 1.445(a)(2)) paid to USPTO ... ~ ........
`International preliminary examination fee (37 CFR 1.482) paid to USPTO
`but all claims did not satisfy provisions ofPCT Article 33(1)-(4) ............
`International preliminary examination fee (37 CFR 1.482) paid to USPTO
`$100.00
`and all claims satisfied provisions ofPCT Article 33(1)-(4) ..........
`ENTER APPROPRIATE BASIC FEE AMOUNT=
`D 30
`D 20
`Surcharge of $130.00 for furnishing the oath or declaration later than
`months from the earliest claimed priority date (37 CFR 1.492 (e)).
`CLAIMS
`NUMBER EXTRA
`NUMBER FILED
`0
`0
`
`RATE
`$18.00
`Total claims
`17
`-20=
`- 3=
`$84.00
`2
`Independent claims
`D
`Multiple Dependent Claims (check if applicable).
`TOTAL OF ABOVE CALCULATIONS =
`[J, AppliMIDt claims small entity status. See 37 CFR 1.27). The fees indicated above are
`:: reduced by 1/2.
`
`X
`
`X
`
`Pmcessing fee of $130.00 for furnishing the English translation later than
`~ths from the earliest claimed priority date (37 CFR 1.492 (f)).
`i.l
`TOTAL NATIONAL FEE
`F~for recording the enclosed assignment (37 CFR 1.21(h)). The assignment must be
`attbmpanied by an appropriate cover sheet (37 CFR 3.28, 3.31) (check if applicable).
`TOTAL FEES ENCLOSED
`
`SUBTOTAL =
`D 30
`D 20
`
`+
`
`=
`
`lo
`
`=
`
`f:-
`
`~
`
`~- _:;
`
`'
`
`~o,&
`
`eil-
`
`~;;b.
`
`181 A check in the amount of
`0
`Please charge my Deposit Account No.
`A duplicate copy of this sheet is enclosed.
`
`$890.00
`
`to cover the above fees is enclosed.
`
`in the amount of
`
`to cover the above fees.
`
`c.
`
`181
`The Commissioner is hereby authorized to charge any additional fees which may be required, or credit any overpayment
`to Deposit Account No.
`A duplicate copy of this sheet is enclosed.
`13-2855
`d. ·o Fees are to be charged to a credit card. WARNING: Information on this form may become public. Credit card
`information should not be included on this form. Provide credit card information and authorization on PT0-2038.
`
`NOTE: "Where an appropriate time limit under 37 CFR 1.494 or 1.495 has not been met, a petition to revive (37 CFR
`1.137(a) or (b)) must be filed and granted to restore the application to pending status.
`
`SEND ALL CORRESPONDENCE TO:
`
`NAPOLI, James J.
`Customer No. 04743
`Marshall, Gerstein & Borun
`6300 Sears Tower
`233 South Wacker Drive
`Chicago, Illinois 60606
`United States of America
`
`- ~
`
`--h.<e&<J2
`SIGNATURE
`
`James J. Napoli
`NAME
`
`32,361
`
`REGISTRATION NUMBER
`
`19 October 2001
`
`DATE
`
`Page 2 of2
`
`INTELGENX 1024, pg. 3
`
`
`
`10/031556
`19 OCT 2001
`
`PATENT
`
`IN THE UNITED STATES PATENT
`AND TRADEMARK OFFICE
`
`Applicants:
`
`WILLIAM E. PULLMAN ET AL.
`
`U.S. National Phase of
`PCT/US00/11129 filed April 26,
`2000
`
`Filed: Herewith
`
`For: UNIT DOSAGE FORM
`
`Group Art Unit: Unassigned
`
`Examiner: Unassigned
`
`Attorney Docket No. 29342/36206A
`
`"EXPRESS MAIL" mailing label
`No. EK657817671US
`
`Date of Deposit:
`October 19, 2001
`
`I hereby certify that this
`paper (or fee) is being
`deposited with the United
`States Postal Service "EXPRESS
`MAIL POST OFFICE TO ADDRESSEE"
`service under 37 CFR §1.10 on
`the date indicated above and is
`addressed to:
`Assistant Commissioner for
`Patents, Washington, D.C.
`20231.
`
`PRELIMINARY AMENDMENT
`ACCOMPANYING APPLICATION TRANSMITTAL
`
`Commissioner of Patents
`Washington/ D.C.
`20231
`
`Sir:
`
`Please amend the above-identified application
`as follows:
`
`IN THE SPECIFICATION:
`
`Page 1 1 after the title, please delete the
`CROSS-REFERENCE TO RELATED APPLICATION in its entirety
`and insert therefor:
`
`INTELGENX 1024, pg. 4
`
`
`
`10/J3155b
`19 OCT 2001
`531 Rec5d ~;-,·· "-
`
`--CROSS-REFERENCE TO RELATED APPLICATIONS
`
`This is the U.S. national phase application of
`International Application No. PCT/US00/11129, filed on
`April 26, 2000, which claims the benefit of provisional
`
`patent application Serial No. 60/132,036, filed April 30,
`
`1999.--
`
`IN THE CLAIMS:
`
`Cancel claims 18 and 19 without prejudice.
`Amend claims 7-9 as follows:
`
`(Amended) The dosage form of claim 1, 2,
`7.
`3 1 4, 5, or 6 wherein the unit dose is in a form selected
`from the group consisting of a liquid, a tablet, a cap(cid:173)
`sule, and a gelcap.
`
`(Amended) The dosage form of claim 1, 2,
`8.
`3, 4, 5, or 6 wherein the unit dose is in the form of a
`tablet.
`
`9.
`
`(Amended) The dosage form of
`(Amended)
`claim 1, 2, 3, 4, 5, or 6 for use in treating a condition
`wherein inhibition of PDE5 is desirable.
`
`- 2
`
`-
`
`INTELGENX 1024, pg. 5
`
`
`
`531 Rec'd PGT/1 ..
`
`19 OCT 2001
`
`REMARKS
`
`Claims 1-19 are pending in the application.
`Claims 18 and 19 have been cancelled. Therefore, claims
`1-17 are at issue in this application.
`The amendments are described in more detail
`below. Pursuant to 37 C.F.R. §1.121, a marked-up version
`of the changes made to the claims by the present amend(cid:173)
`ment is attached hereto following the signature page of
`this amendment. The first page of the marked-up version
`of the changes is captioned "Version With Markings to
`Show Changes Made.n
`This preliminary amendment adds no new matter.
`The specification has been amended to insert a cross(cid:173)
`reference to a related application. Claims 7-9 have been
`amended to improve the form of the claims.
`It is submitted that the amendment should be
`entered, and that the claims are of a proper form and
`scope for allowance. An early and favorable action on
`the merits is respectfully requested.
`Should the examiner wish to discuss the fore(cid:173)
`going, or any matter of form in an effort to advance this
`application toward allowance, the examiner is urged to
`telephone the undersigned at the indicated number.
`
`-
`
`3
`
`-
`
`INTELGENX 1024, pg. 6
`
`
`
`Respectfully submitted/
`
`MARSHALL, GERSTEIN & BORUN
`
`By
`
`(Registration No. 32,361)
`Attorneys for Applicants
`6300 Sears Tower
`233 South Wacker Drive
`Chicago, Illinois 60606
`(312) 474-6300
`
`Chicago, Illinois
`October 19, 2001
`
`- 4
`
`-
`
`INTELGENX 1024, pg. 7
`
`
`
`10/031~56
`10 ~:~T lfln1
`5'31 Rec~aP~f~,.
`Version With Markings to Show Changes Made
`(U.S. National Stage of PCT/US00/11129
`filed October 191 2001)
`
`IN THE SPECIFICATION:
`
`The following cross-reference to related
`application has been inserted into the specification:
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`This is the U.S. national phase application
`of International Application No. PCT/US00/11129, filed
`on April 26, 2000, which claims the benefit of
`provisional patent application Serial No. 60/132,036,
`filed April 30, 1999.
`
`IN THE CLAIMS:
`
`Claims 18 and 19 have been cancelled without
`prejudice.
`Claims 7-9 have been amended as follows:
`
`(Amended) The dosage form of [claims 1
`7.
`through 6] claim 1, 2, 3, 4, 5, or 6 wherein the unit
`dose is in a form selected from the group consisting of
`a liquid, a tablet, a capsule, and a gelcap.
`
`(Amended) The dosage form of [claims 1
`8.
`through 6] claim 1, 2, 3, 4, 5, or 6 wherein the unit
`
`dose is in the form of a tablet.
`
`-
`
`1
`
`-
`
`INTELGENX 1024, pg. 8
`
`
`
`(Amended) The dosage form of [claims 1
`9.
`through 6] claim 1, 2, 3, 4, 5, or 6 for use in treat(cid:173)
`
`ing a condition wherein inhibition of PDE5 is desir(cid:173)
`able.
`
`- 2
`
`-
`
`INTELGENX 1024, pg. 9
`
`
`
`W000/66099
`
`fTG/7·~:-r ~-~, · 19 OCT 2001
`1 0 pfr~l~lltl;> 5 6
`
`-
`
`1
`
`-
`
`UNIT DOSAGE FORM
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`This application claims the benefit of
`provisional patent application Serial No.
`60/132,036, filed April 30, 1999.
`
`FIELD OF THE INVENTION
`
`The present invention relates to a highly
`selective phosphodiesterase (PDE) enzyme inhibitor
`and to its use in a pharmaceutical unit dosage form.
`In particular, the present invention relates to a
`potent inhibitor of cyclic guanosine 3',5'-mono(cid:173)
`phosphate specific phosphodiesterase type 5
`(PDES)
`that when incorporated into a pharmaceutical product
`is useful for the treatment of sexual dysfunction.
`The unit dosage form described herein is character-
`ized by selective PDE5 inhibition, and accordingly,
`provides a benefit in therapeutic areas where
`inhibition of PDES is desired, with minimization or
`elimination of adverse side effects resulting from
`inhibition of other phosphodiesterase enzymes.
`
`BACKGROUND OF THE INVENTION
`
`The biochemical, physiological, and
`clinical effects of cyclic guanosine 3',5'-mono-
`phosphate specific phosphodiesterase (cGMP-specific
`PDE} inhibitors suggest their utility in a variety
`of disease states in which modulation of smooth
`muscle, renal, hemostatic, inflammatory, and/or
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`INTELGENX 1024, pg. 10
`
`
`
`W000/66999
`
`PCT IUSD0/11129
`
`-
`
`2
`
`-
`
`endocrine function is desired. Type 5 cGMP-specific
`phosphodiesterase {PDE5) is the major cGMP hydro(cid:173)
`lyzing enzyme in vascular smooth muscle, and its
`expression in penile corpus cavernosum has been
`reported (Taher et al., J. Urol., ~49, p. 285A
`(1993)). Thus, PDES is an attractive target in the
`treatment of sexual dysfunction {Murray, DN&P 6(3),
`pp. 150-56 {1993)).
`A pharmaceutical product, which provides a
`PDE5 inhibitor/ is currently available and marketed
`®
`under the trademark VIAGRA
`. The active ingredient
`®
`in VIAGRA
`is sildenafil. The product is sold a·s an
`article of manufacture including 25, 50, and 100 mg
`tablets of sildenafil and a package insert. The
`package insert provides that sildenafil is a more
`potent inhibitor of PDES than other known phospho(cid:173)
`diesterases (greater than 80 fold for PDEl inhibi(cid:173)
`tion, greater than 1,000 fold for PDE2, PDE3, and
`PDE4 inhibition} . The IC50 for sildenafil against
`PDE5 has been reported as 3 nM (Drugs of the Future,
`22(2), pp. 138-143 {1997)) and as 3.9 nM (Boolel et
`al., Int. J. of Impotence, 8, pp. 47-52 {1996)).
`Sildenafil is described as having a 4,000-fold
`selectivity for PDE5 versus PDE3, and only a 10-fold
`selectivity for PDE5 versus PDE6.
`Its relative lack
`of selectivity for PDE6 is theorized to be the basis
`for abnormalities related to color vision.
`While sildenafil has obtained significant
`commercial success, it has fallen short due to its
`significant adverse side effects, including facial
`flushing (10% incidence rate) . Adverse side effects
`limit the use of sildenafil in patients suffering
`from vison abnormalities, hypertension, and, most
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`INTELGENX 1024, pg. 11
`
`
`
`W000/66099
`
`PCT/US00/11129
`
`-
`
`3
`
`-
`
`significantly, by individuals who use organic
`nitrates (Welds et al., Amer. J. of Cardiology,
`8 3 ( 5A) I pp . 2 1 (c) - 2 8 (c)
`( 19 9 9) ) .
`The use of sildenafil in patients taking
`organic nitrates causes a clinically significant
`drop in blood pressure which could place the patient
`in danger. Accordingly, the package label for
`sildenafil provides strict contraindications against
`its use in combination with organic nitrates (e.g.,
`nitroglycerin, isosorbide mononitrate, isosorbide
`nitrate, erythrityl tetranitrate} and other nitric
`oxide donors in any form, either regularly or
`intermittently, because sildenafil potentiates the
`hypotensive effects of nitrates. See C.R. Conti et
`al., Amer. J. of Cardiology, 83(5A), pp. 29C-34C
`{1999) . Thus, even with the availability of
`sildenafil, there remains a need to identify
`improved pharmaceutical products that are useful in
`treating sexual dysfunction.
`Daugan U.S. Patent 5,859,006 discloses
`certain tetracyclic derivatives that are potent
`inhibitors of cGMP-specific PDE, or PDE5. The IC50
`of the compounds disclosed in U.S. Patent No.
`5,859,006 is reported in the range of 1 nM to 10 pM.
`The oral dosage for such compounds is 0.58 mg daily
`for an average adult patient (70 kg) . Thus, unit
`dosage forms (tablets or capsules) are reported as
`0.2 to 400 mg of active compound. Significant
`adverse side effects attributed to compounds
`disclosed in U.S. Patent No. 5,859,006 are not
`disclosed.
`Applicants have discovered that one such
`tetracyclic derivative, (6R,12aR}-2,3,6,7,12,12a-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`INTELGENX 1024, pg. 12
`
`
`
`W000/66099
`
`PCTIUS00/11129
`
`-
`
`4
`
`-
`
`hexahydro-2-methyl-6-(3 14-methylenedioxyphenyl)(cid:173)
`pyrazino[2'11':6,l]pyrido[314-b]indole-1,4-dione,
`alternatively named (6R-trans)-6-(1,3-benzodioxol-5-
`yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino-
`[1',2' :1,6]pyrido[3,4-b]indole-1,4-dione, andre-
`ferred to herein as Compound (I}, can be admin(cid:173)
`istered in a unit dose that provides an effective
`treatment without the side effects associated with
`the presently marketed PDES inhibitor, sildenafil.
`Prior to the present invention such side effects
`were considered inherent to the inhibition of PDES.
`Significantly, applicants' clinical
`studies also reveal that an effective product having
`a reduced tendency to cause flushing in susceptible
`individuals can be provided. Most unexpectedly, the
`product also can be administered with clinically
`insignificant side effects associated with the com(cid:173)
`bined effects of a PDES inhibitor and an organic
`nitrate. Thus, the contraindication once believed
`necessary for a product containing a PDE5 inhibitor
`is unnecessary when Compound (I) is administered as
`a unit dose of about 1 to about 20 mg, as disclosed
`herein. Thus, the present invention provides an
`effective therapy for sexual dysfunction in indi-
`victuals who previously were untreatable or suffered
`from unacceptable side effects, including individ(cid:173)
`uals having cardiovascular disease, such as in
`individuals requiring nitrate therapy, having
`suffered a myocardial infarction more than three
`months before the onset of sexual dysfunction
`therapy, and suffering from class 1 congestive heart
`failure, or individuals suffering from vision ab(cid:173)
`normalities.
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`The present invention provides Compound
`the present
`(I) in a unit dosage form. That is 1
`invention provides a pharmaceutical unit dosage form
`suitable for oral administration comprising about 1
`to about 20 mg Compound (I) .
`
`SUMMARY OF THE INVENTION
`
`The present invention provides a pharma-
`ceutical dosage form for human pharmaceutical use,
`comprising about 1 to about 20 mg of (6R,12aR)-
`2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylene(cid:173)
`dioxyphenyl)pyrazino[2 1 ,1' :6,1]pyrido[3,4-b]indole-
`1,4-dione in a unit dosage form suitable for oral
`administration.
`The present invention further provides a
`method of treating conditions where inhibition of
`PDE5 is desired, which comprises administering to a
`patient in need thereof an oral dosage form con-
`taining about 1 to about 20 mg of a selective PDE5
`inhibitor 1 as neededr up to a total dose of 20 mg
`per day. The invention further provides the use of
`an oral dosage form comprising a selective PDE5
`inhibitor at a dosage of about 1 to about 20 mg for
`the treatment of sexual dysfunction.
`Specific conditions that can be treated by
`the present invention, include, but are not limited
`to, male erectile dysfunction and female sexual
`dysfunction, particularly female arousal disorder,
`also known as female sexual arousal disorder.
`In particular, the present invention is
`directed to a pharmaceutical unit dosage composition
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`comprising about 1 to about 20 mg of a compound
`
`having the structural formula:
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`said unit dosage form suitable for oral administra(cid:173)
`tion, and method of treating sexual dysfunction
`using the pharmaceutical unit dose composition.
`
`DETAILED DESCRIPTION
`
`For purposes of the present invention as
`disclosed and described herein, the following terms
`and abbreviations are defined as follows.
`The term ncontainer" means any receptacle
`and closure therefor suitable for storing, shipping,
`dispensing, and/or handling a pharmaceutical prod(cid:173)
`uct.
`
`is the measure of potency
`The term "IC50 "
`of a compound to inhibit a particular PDE enzyme
`(e.g., PDElc, PDE5, or PDE6). The IC50 is the con-
`centration of a compound that results in 50% enzyme
`inhibition in a single dose-response experiment.
`Determining the IC 50 value for a compound is readily
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`carried out by a known in vitro methodology
`
`generally described in Y. Cheng et al., Biochem.
`Pharmacal., 22, pp. 3099-3108 (1973}.
`The term "package insert" means informa-
`tion accompanying the product that provides a de(cid:173)
`scription of how to administer the product, along
`with the safety and efficacy data required to allow
`the physician/ pharmacist, and patient to make an
`informed decision regarding use of the product. The
`package insert generally is regarded as the "label"
`for a pharmaceutical product.
`The term "oral dosage form 11 is used in a
`general sense to reference pharmaceutical products
`administered orally. Oral dosage forms are recog-
`nized by those skilled in the art to include such
`forms as liquid formulations/ tablets, capsules, and
`gelcaps.
`
`The term nvision abnormalities" means ab(cid:173)
`normal vision characterized by blue-green vision
`believed to be caused by PDE6 inhibition.
`The term 11 flushing 11 means an episodic
`redness of the face and neck attributed to vaso(cid:173)
`dilation caused by ingestion of a drug/ usually
`accompanied by a feeling of warmth over the face and
`neck and sometimes accompanied by perspiration.
`The term "free drug" means solid particles
`of drug not intimately embedded in a polymeric
`coprecipitate.
`The presently claimed dosage form
`preferably is packaged as an article of manufacture
`for human pharmaceutical use, comprising a package
`insert, a container, and a dosage form comprising
`about 1 to about 20 mg of Compound (I)
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`The package insert provides a description
`of how to administer a pharmaceutical product, along
`with the safety and efficacy data required to allow
`the physician, pharmacist, and patient to make an
`informed decision regarding the use of the product.
`The package insert generally is regarded as the
`label of the pharmaceutical product. The package
`insert incorporated into the article of manufacture
`indicates that Compound (I) is useful in the
`treatment of conditions wherein inhibition of PDE5
`is desired. The package insert also provides
`instructions to administer one or more about 1 to
`about 20 mg unit dosage forms as needed, up to a
`maximum total dose of 20 mg per day. Preferably,
`the dose administered is about 5 to about 20 mg/day,
`more preferably about 5 to about 15 mg/day. Most
`preferably, a 10 mg dosage form is administered once
`per day.
`
`Preferred conditions to be treated include
`sexual dysfunction (including male erectile dysfunc(cid:173)
`tion; and female sexual dysfunction, and more
`preferably female arousal disorder (FAD)). The
`preferred condition to be treated is male erectile
`dysfunction.
`Significantly, the package insert supports
`the use of the product to treat sexual dysfunction
`in patients suffering from a retinal disease, for
`example, diabetic retinopathy or retinitis pig(cid:173)
`mentosa, or in patients who are using organic
`nitrates. Thus, the package insert preferably is
`free of contraindications associated with these
`conditions, and particularly the administration of
`the dosage form with an organic nitrate. More
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`preferably, the package insert also is free of any
`cautions or warnings both associated with retinal
`diseases, particularly retinitis pigmentosa, and
`associated with individuals prone to vision ab-
`normalities. Preferably, the package insert also
`reports incidences of flushing below 2%, preferably
`below 1%, and most preferably below 0.5%, of the
`patients administered the dosage form. The inci(cid:173)
`dence rate of flushing demonstrates marked improve-
`ment over prior pharmaceutical products containing a
`PDE5 inhibitor.
`The container used in the article of
`manufacture is conventional in the pharmaceutical
`arts. Generally, the container is a blister pack,
`foil packet, glass or plastic bottle and accompany(cid:173)
`ing cap or closure, or other such article suitable
`for use by the patient or pharmacist. Preferably,
`the container is sized to accommodate 1-1000 solid
`dosage forms, preferably 1 to 500 solid dosage
`forms, and most preferably, 5 to 30 solid dosage
`forms.
`
`Oral dosage forms are recognized by those
`skilled in the art to include, for example, such
`forms as liquid formulations, tablets, capsules, and
`gelcaps.
`Preferably the dosage forms are solid
`dosage forms, particularly, tablets comprising about
`1 to about 20 mg of Compound (I) . Any pharmaceut(cid:173)
`ically acceptable excipients for oral use are suit(cid:173)
`able for preparation of such dosage forms. Suitable
`pharmaceutical dosage forms include coprecipitate
`forms described, for example, in Butler U.S. Patent
`No. 5,985,326, incorporated herein by reference.
`In
`preferred embodiments, the unit dosage form of the
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`present invention is a solid free of a coprecipitate
`form of Compound (I), but rather contains solid
`Compound (I) as a free drug.
`Preferably, the tablets comprise pharma-
`ceutical excipients generally recognized as safe
`such as lactose, microcrystalline cellulose, starch,
`calcium carbonate, magnesium stearate, stearic acid,
`talc, and colloidal silicon dioxide, and are pre(cid:173)
`pared by standard pharmaceutical manufacturing tech-
`niques as described in Remington's Pharmaceutical
`Sciences, 18th Ed., Mack Publishing Co., Easton, PA
`(1990) . Such techniques include, for example, wet
`granulation followed by drying, milling, and com(cid:173)
`pression into tablets with or without film coatingi
`dry granulation followed by,milling, compression
`into tablets with or withou~ film coatingi dry
`blending followed by compre~sion into tablets, with
`or without film coating; molded tabletsi wet gran(cid:173)
`ulation, dried and filled into gelatin capsules; dry
`blend filled into gelatin capsules; or suspension
`and solution filled into gelatin capsules. Gener(cid:173)
`ally, the solid dosage forms have identifying marks
`which are debossed or imprinted on the surface.
`The present invention is based on detailed
`experiments and clinical trials, and the unexpected
`observations that side effects previously believed
`to be indicative of PDES inhibition can be reduced
`to clinically insignificant levels by the selection
`of a compound and unit dose. This unexpected obser-
`vation enabled the development of a unit dosage form
`that incorporates Compound (I) in about 1 to about
`20 mg per unit dosage forms that, when orally admin(cid:173)
`istered, minimizes undesirable side effects previ-
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`ously believed unavoidable. These side effects
`include facial flushing, vision abnormalities, and a
`significant decrease in blood pressure, when Com(cid:173)
`pound (I) is administered alone or in combination
`with an organic nitrate. The minimal effect of
`Compound (I), administered in about 1 to about 20 mg
`unit dosage forms, on PDE6 also allows the adminis(cid:173)
`tration of a selective PDES inhibitor to patients
`suffering from a retinal disease, like diabetic
`retinopathy or retinitis pigmentosa.
`Compound (I) has the following structural
`
`formula:
`
`{I)
`
`The compound of structural formula (I) was demon-
`strated in human clinical studies to exert a minimal
`impact on systolic blood pressure when administered
`in conjunction with organic nitrates. By contrast,
`sildenafil demonstrates a four-fold greater decrease
`in systolic blood pressure over a placebo, which
`®
`leads to the contraindications in the VIAGRA
`in-
`sert, and in warnings to certain patients.
`The following illustrates the PDE5 and
`PDE6 IC 50 values for the compound of structural
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`formula {I) determined by the procedures described
`herein.
`
`Compound
`
`PDES ICso
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`(nM)
`
`PDE6 IC50
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`(nM}
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`PDE6/PDE5
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`I
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`2.5
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`3400
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`1360
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`The compound of structural formula {I) additionally
`demonstrates an IC50 against PDE1c of 10,000, and a
`ratio of PDE1c/PDE5 of 4,000.
`
`PREPARATIONS
`
`Human PDES Preparation
`
`Recombinant production of human PDE5 was
`carried out essentially as described in·Example 7 of
`u.s. Patent No. 5,702,936, incorporated herein by
`reference, except that the yeast transformation
`vector employed, which is derived from the basic
`ADH2 plasmid described in V. Price et al., Methods
`in Enzymology, 1985, pages 308-318 (1990), incorpor(cid:173)
`ated yeast ADH2 promoter and terminator sequences
`rather than ADHl promoter and terminator sequences
`and the Saccharomyces cerevisiase host was the
`protease-deficient strain BJ2-54 deposited on August
`31, 1998 with the American Type Culture Collection,
`Manassas, Virginia, under accession number ATCC
`74465. Transformed host cells were grown in 2X SC-
`leu medium, pH 6.2, with trace metals, and vitamins.
`After 24 hours, YEP medium containing glycerol was
`added to a final concentration of 2X YEP/3% glycer(cid:173)
`ol. Approximately 24 hours later, cells were
`harvested, washed, and stored at -70°C.
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`Cell pellets (29 g) were thawed on ice
`with an equal volume of lysis buffer (25 mM Tris-Cl,
`pH 8, 5 mM MgCl 2 , 0.25 mM dithiothreitol, 1 mM
`benzamidine, and 10 ~M Zn804 } • Cells were lysed in
`a microfluidizer with N2 at 20,000 psi. The lysate
`was centrifuged and filtered through 0.45 ~m dis(cid:173)
`posable filters. The filt