IP Library › Granted Patent US 12,642,798
Granted Patent B2
US 12,642,798 · App. 17/450,683 · Granted Jun 2, 2026

Aripiprazole prodrug composition

Inventors: Philip Cresswell (Athlone, IE); Magali Hickey (Westwood, MA); Kristopher Perkin (Athlone, IE); Greg Smith (Norton, MA); Elaine Liversidge (Charlestown, MA); Brian Steinberg (Arlington, MA); David Manser (Keenagh, IE); Tarek Zeidan (Waltham, MA)
Assignee: Alkermes Pharma Ireland Limited
A61K31/496A61K9/0019A61K45/06A61K47/26
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,642,798
App. No.
17/450,683
Granted
Jun 2, 2026
Kind
B2
Abstract

Described is a composition comprising (a) a population of particles of an aripiprazole prodrug having a volume based particle size (Dv50) of less than 1000 nm and (b) at least one surface stabilizer comprising an adsorbed component which is adsorbed on the surface of the aripiprazole prodrug particles and a free component available for solubilisation of the aripiprazole prodrug. The surface stabilizer to prodrug ratio provides the optimal quantity of free surface stabilizer for the purposes of producing a lead-in formulation. Also described are methods of treatment using the aforementioned composition.

Claims (28)

1 . A method of preparing a composition comprising

(a) a population of particles of an aripiprazole prodrug having a volume based particle size (Dv50) of between 50 and 700 nm as determined by light scattering techniques; and

(b) at least one surface stabilizer comprising an adsorbed component which is adsorbed on the surface of the aripiprazole prodrug particles and a free component available for solubilisation of the aripiprazole prodrug, wherein the ratio of aripiprazole prodrug to the at least one surface stabilizer is between 10:1 and 26:1, and wherein the aripiprazole prodrug has the formula:

where n is 10,

wherein the at least one surface stabilizer is selected from the group consisting of carboxymethyl cellulose and a polyoxyethylene sorbitan fatty acid ester;

the method comprising the following steps:

(a) calculating a quantity of at least one surface stabilizer to be added to the composition in order to ensure that both an adsorbed component and a free component of the stabilizer are present in the composition,

(b) producing a population of aripiprazole prodrug particles having a volume based particle size (Dv50) of between 50 and 700 nm as determined by light scattering,

(c) combining the quantity of the at least one surface stabilizer with the population of aripiprazole prodrug particles, such that the adsorbed component of the at least one surface stabilizer is adsorbed on the surface of the aripiprazole prodrug particles.

2 . The method of claim 1 , wherein step (b) and step (c) are performed simultaneously by milling the aripiprazole prodrug with the at least one stabilizer present.

3 . The method of claim 1 , further comprising:

(d) retaining a sample of the composition for testing the quantity of the free component of the at least one surface stabilizer,

(e) separating the aripiprazole lauroxil particles and the at least one surface stabilizer adsorbed thereto from the dispersion medium in the sample to form a supernatant, and

(f) measuring the quantity of the at least one surface stabilizer in the supernatant using a high performance liquid chromatography (HPLC) apparatus.

4 . The method of claim 1 , further comprising the step of:

(g) combining the aripiprazole prodrug particles and the at least one surface stabilizer with a dispersion medium to form a dispersed aripiprazole prodrug composition.

5 . The method of claim 4 , further comprising:

(i) filling the dispersed aripiprazole prodrug composition into an injection device.

6 . The method of claim 5 , wherein the injection device is a prefilled syringe, an auto-injector, a needleless syringe, or a dual chambered syringe.

7 . The method of claim 6 , further comprising the step of

(g) filling the aripiprazole prodrug composition into one chamber of the dual chambered syringe, and filling the other chamber of the dual chamber syringe with a second composition.

8 . The method of claim 1 , wherein step (b) is carried out by milling the population of the aripiprazole prodrug.

9 . The method of claim 1 , wherein the ratio of aripiprazole prodrug to the at least one surface stabilizer is between about 15:1 and about 20:1.

10 . The method of claim 1 , wherein the weight ratio of aripiprazole prodrug to the at least one surface stabilizer is 17:1.

11 . The method of claim 1 , wherein the at least one surface stabilizer is polysorbate 20.

12 . The method of claim 1 , wherein the composition comprises

(a) a population of particles of an aripiprazole prodrug having a volume based particle size (Dv50) of about 200 nm as determined by light scattering techniques; and

(b) the at least one surface stabilizer is polysorbate 20 comprising an adsorbed component which is adsorbed on the surface of the aripiprazole prodrug particles and a free component available for solubilisation of the aripiprazole prodrug, wherein the ratio of aripiprazole prodrug to polysorbate 20 is about 17:1, and wherein the aripiprazole prodrug has the formula:

Assignments (6)
SECURITY INTEREST Recorded Feb 13, 2026
From: ALKERMES PHARMA IRELAND LIMITED
To: JPMORGAN CHASE BANK, N.A. AS ADMINISTRATIVE AGENT
Reel/Frame 074858/0405 →
RELEASE OF SECURITY INTEREST IN PATENTS PREVIOUSLY RECORDED AT REEL/FRAME (073213/0302) Recorded Feb 13, 2026
From: JPMORGAN CHASE BANK, N.A., AS ADMINISTRATIVE AGENT
To: ALKERMES PHARMA IRELAND LIMITED
Reel/Frame 074858/0429 →
SECURITY INTEREST Recorded Oct 23, 2025
From: ALKERMES PHARMA IRELAND LIMITED
To: JPMORGAN CHASE BANK, N.A. AS ADMINISTRATIVE AGENT
Reel/Frame 073213/0302 →
RELEASE OF PATENT SECURITY AGREEMENTS Recorded Dec 24, 2024
From: MORGAN STANLEY SENIOR FUNDING, INC.
To: ALKERMES PHARMA IRELAND LIMITED
Reel/Frame 069771/0701 →
SECURITY AGREEMENT Recorded Jul 17, 2023
From: ALKERMES PHARMA IRELAND LIMITED
To: MORGAN STANLEY SENIOR FUNDING, INC.
Reel/Frame 064286/0821 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 11, 2022
From: CRESSWELL, PHILIP; HICKEY, MAGALI; PERKIN, KRISTOPHER; SMITH, GREG; LIVERSIDGE, ELAINE; STEINBERG, BRIAN; MANSER, DAVID; ZEIDAN, TAREK
To: ALKERMES PHARMA IRELAND LIMITED
Reel/Frame 059563/0274 →
Continuity (6)
Continuation 16904246 · Jun 17, 2020
Continuation 16416818 · May 20, 2019
Continuation 16024729 · Jun 29, 2018
Division 14828229 · Aug 17, 2015
Provisional Application 62038665 · Aug 18, 2014
Related Publication 20220079939A1 · Mar 17, 2022
References Cited (89)
US 5145684A · Liversidge et al. · 1992 [cited by applicant]
US 5470583A · Na et al. · 1995 [cited by applicant]
US 5510118A · Bosch et al. · 1996 [cited by applicant]
US 5518187A · Bruno et al. · 1996 [cited by applicant]
US 5534270A · De Castro · 1996 [cited by applicant]
US 5543133A · Swanson et al. · 1996 [cited by applicant]
US 5560932A · Bagchi et al. · 1996 [cited by applicant]
US 5662883A · Bagchi et al. · 1997 [cited by applicant]
US 5665331A · Bagchi et al. · 1997 [cited by applicant]
US 5718388A · Czekai et al. · 1998 [cited by applicant]
US 5862999A · Czekai et al. · 1999 [cited by applicant]
US 6406718B1 · Cooper · 2002 [cited by applicant]
US 8431576B2 · Remenar · 2013 [cited by applicant]
US 20050148597A1 · Kostanski et al. · 2005 [cited by applicant]
US 20070148100A1 · Jenkins et al. · 2007 [cited by applicant]
US 20110003828A1 · Blumberg et al. · 2011 [cited by applicant]
US 20120238552A1 · Perry et al. · 2012 [cited by applicant]
US 20120238553A1 · Peters et al. · 2012 [cited by applicant]
US 20130267503A1 · Perry et al. · 2013 [cited by applicant]
US 20130267504A1 · Perry et al. · 2013 [cited by applicant]
US 20130267505A1 · Perry et al. · 2013 [cited by applicant]
US 20140088115A1 · Perry et al. · 2014 [cited by applicant]
US 20150265529A1 · Hickey et al. · 2015 [cited by applicant]
US 20160045495A1 · Cresswell et al. · 2016 [cited by applicant]
US 20160051546A1 · Morales et al. · 2016 [cited by applicant]
CA 2885196A1 · 2013 [cited by applicant]
CN 105012236A · 2015 [cited by applicant]
KR 20070118225A · 2007 [cited by applicant]
WO WO9714407 · 1997 [cited by applicant]
WO 03030872A2 · 2003 [cited by applicant]
WO WO2005041937A2 · 2005 [cited by applicant]
WO WO2006085747A1 · 2006 [cited by applicant]
WO 2007035348A2 · 2007 [cited by applicant]
WO 2012129156A1 · 2012 [cited by applicant]
WO WO2016026822A1 · 2016 [cited by applicant]
U.S. Appl. No. 13/423,606 / 2012/0238552 / U.S. Pat. No. 9,034,867, Mar. 19, 2012 / Sep. 20, 2012 / May 19, 2015, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 14/714,621 / 2015/0258115 / U.S. Pat. No. 9,351,976, May 18, 2015 / Sep. 17, 2015 / May 31, 2016, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 14/688,050 / 2016/0038508 /, Apr. 16, 2015 / Feb. 11, 2016, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 15/154,562, filed May 13, 2016, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 15/388,554 / 2017/0196856 / U.S. Pat. No. 10,226,458, Dec. 22, 2016 / Jul. 13, 2017 / Mar. 12, 2019, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 16/248,259 / 2019/0216805, Jan. 15, 2019 / Jul. 18, 2019, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 13/801,025 / 2013/0267503 / U.S. Pat. No. 10,004,807, Mar. 13, 2013 / Oct. 10, 2013 / Jun. 26, 2018, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 13/801,167 / 2013/0267504 / U.S. Pat. No. 9,993,556, Mar. 13, 2013 / Oct. 10, 2013 / Jun. 12, 2018, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 13/801,344 / 2013/0267505 / U.S. Pat. No. 9,999,670, Mar. 13, 2013 / Oct. 10, 2013 / Jun. 19, 2018, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 14/031,842 / 2014/0088115 / U.S. Pat. No. 9,861,699, Sep. 19, 2013 / Mar. 27, 2014 / Nov. 24, 2015, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 14/882,069 / 2016/0136279 / U.S. Pat. No. 9,861,699, Oct. 13, 2015 / May 19, 2016 / Jan. 9, 2018, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 15/705,237 / 2018/0000944, Sep. 14, 2017 / Jan. 4, 2018, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 16/425,150 / 2019/0275155 / U.S. Pat. No. 10,639,376, May 29, 2019 / Sep. 12, 2019 / May 5, 2020, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 16/834,565 / 2020/0268891 / U.S. Pat. No. 11,097,006, Mar. 30, 2020 / Aug. 27, 2020 / Aug. 24, 2021, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 17/398,801, filed Aug. 10, 2021, Jason M. Perry. [cited by applicant]
U.S. Appl. No. 14/633,042 / 2015/0265529 / U.S. Pat. No. 9,452,131, Mar. 19, 2015 / Sep. 24, 2015 / Sep. 27, 2016, Magali B. Hickey. [cited by applicant]
U.S. Appl. No. 15/164,473 / 2016/0263111 / U.S. Pat. No. 9,526,726, May 25, 2016 / Sep. 15, 2016 / Dec. 27, 2016, Magali B. Hickey. [cited by applicant]
U.S. Appl. No. 15/349,243 / 2017/0157117 / U.S. Pat. No. 10,085,980, Nov. 11, 2016 / Jun. 8, 2017 / Oct. 2, 2018, Magali B. Hickey. [cited by applicant]
U.S. Appl. No. 16/116,652 / 2018/0369239 / U.S. Pat. No. 10,238,651, Aug. 29, 2018 / Dec. 27, 2018 / Mar. 26, 2019, Magali B. Hickey. [cited by applicant]
U.S. Appl. No. 16/271,248 / 2019/0167673 / U.S. Pat. No. 10,813,928, Feb. 8, 2019 / Jun. 6, 2019 / Oct. 27, 2020, Magali B. Hickey. [cited by applicant]
U.S. Appl. No. 16/889,528 / 2020/0289504, Jun. 1, 2020 / Sep. 17, 2020, Magali B. Hickey. [cited by applicant]
U.S. Appl. No. 14/833,638 / 2016/0051546 / U.S. Pat. No. 10,064,859, Aug. 24, 2015 / Feb. 25, 2016 / Sep. 4, 2018, Wilfredo Morales. [cited by applicant]
U.S. Appl. No. 16/043,721 / 2019/0015408 / U.S. Pat. No. 10,478,434, Jul. 24, 2018 / Jan. 17, 2019 / Nov. 19, 2019, Wilfredo Morales. [cited by applicant]
U.S. Appl. No. 16/595,608 / 2020/0108063 / U.S. Pat. No. 10,973,816, Oct. 8, 2019 / Apr. 9, 2020 / Apr. 13, 2021, Wilfredo Morales. [cited by applicant]
U.S. Appl. No. 17/211,352 / 2021/0205302, Mar. 24, 2021 / Jul. 8, 2021, Wilfredo Morales. [cited by applicant]
U.S. Appl. No. 12/823,007 / 2011/0015156 / U.S. Pat. No. 8,431,576, Jun. 24, 2010 / Jan. 20, 2011 / Apr. 30, 2013, Julius F. Remwnar. [cited by applicant]
U.S. Appl. No. 13/607,066 / 2013/0096089 / U.S. Pat. No. 8,796,276, Sep. 7, 2012 / Apr. 18, 2013 / Aug. 5, 2014, Julius F. Remenar. [cited by applicant]
U.S. Appl. No. 14/297,195 / 2014/0350254, Jun. 5, 2014 / Nov. 27, 2014, Julius F. Remenar. [cited by applicant]
U.S. Appl. No. 14/677,333 / 2015/0274670, Apr. 2, 2015 / Oct. 1, 2015, Julius F. Remenar. [cited by applicant]
U.S. Appl. No. 15/147,021 / 2016/0318869 / U.S. Pat. No. 10,023,537, May 5, 2016 / Nov. 3, 2016 / Jul. 17, 2018, Julius F. Remenar. [cited by applicant]
U.S. Appl. No. 15/875,478 / 2018/0162816 / U.S. Pat. No. 10,112,903, Jan. 19, 2018 / Jun. 14, 2018 / Oct. 30, 2018, Julius F. Remenar. [cited by applicant]
U.S. Appl. No. 16/131,773 / 2019/0084937 /, Sep. 14, 2018 / Mar. 21, 2019, Julius F. Remenar. [cited by applicant]
U.S. Appl. No. 16/425,119 / 2019/0276406 / U.S. Pat. No. 10,822,306, May 29, 2019 / Sep. 12, 2019 / Nov. 3, 2020, Julius F. Remenar. [cited by applicant]
U.S. Appl. No. 17/020,499 / 2020/0407320, Sep. 14, 2020 / Dec. 31, 2020, Julius F. Remenar. [cited by applicant]
U.S. Appl. No. 12/823,102 / 2011/0003828 / U.S. Pat. No. 8,686,009, Jun. 24, 2010 / Jan. 6, 2011 / Apr. 1, 2014, Laura Cook Blumberg. [cited by applicant]
U.S. Appl. No. 14/172,391 / 2014/0221653 / U.S. Pat. No. 9,102,618, Feb. 4, 2014 / Aug. 7, 2014 / Aug. 11, 2015, Laura Cook Blumberg. [cited by applicant]
U.S. Appl. No. 14/755,412 / 2015/0376143, Jun. 30, 2015 / Dec. 31, 2015, Laura Cook Blumberg. [cited by applicant]
U.S. Appl. No. 15/227,117 / 2017/0015659 / U.S. Pat. No. 10,040,787, Aug. 3, 2016 / Jan. 19, 2017 / Aug. 7, 2018, Laura Cook Blumberg. [cited by applicant]
U.S. Appl. No. 16/023,887 / 2019/0031648 / U.S. Pat. No. 10,428,058, Jun. 29, 2018 / Jan. 31, 2019 / Oct. 1, 2019, Laura Cook Blumberg. [cited by applicant]
U.S. Appl. No. 16/540,802 / 2019/0367501/ U.S. Pat. No. 10,723,728, Aug. 14, 2019 / Dec. 5, 2019 / Jul. 28, 2020, Laura Cook Blumberg. [cited by applicant]
U.S. Appl. No. 14/828,229 / 2016/0045495 / U.S. Pat. No. 10,016,415, Aug. 17, 2015 / Feb. 18, 2016 / Jul. 10, 2018, Philip Cresswell. [cited by applicant]
U.S. Appl. No. 16/024,729 / 2018/0318293, Jun. 29, 2018 / Nov. 8, 2018, Philip Cresswell. [cited by applicant]
U.S. Appl. No. 16/416,818 / 2019/0269676 / U.S. Pat. No. 10,688,091, May 20, 2019 / Sep. 5, 2019 / Jun. 23, 2020, Philip Cresswell. [cited by applicant]
U.S. Appl. No. 16/904,246 / 2020/0316061, Jun. 17, 2020 / Oct. 8, 2020, Philip Cresswell. [cited by applicant]
International Search Report and Written Opinion issued in related International Patent Application No. PCT/EP2015/068872, completed Oct. 8, 2015. [cited by applicant]
Aulton, “Pharmaceutics: The Science of Dosage form Design,” pp. 569-580 (1988). [cited by applicant]
Haskell, Part II. Nanoparticle Characterization and Properties, “Physical Characterization of Nanoparticles,” pp. 103-138 (2006). [cited by applicant]
European Search Report issued in related European Patent Application No. 16 15 6356, dated Jul. 20, 2016. [cited by applicant]
Turncliff et al., “Relative Bioavailability and Safety of Aripiprazole Lauroxil, a Novel once-monthly, long-acting injectable atypical antipsychotic, following deltoid and gluteal administration in adult subjects with s… [cited by applicant]
Merisko-Liversidge et al., “Nanosizing: a Formulation Approach for Poorly-Water-Soluble Compounds”, European Journal of Pharmaceutical Sciences, vol. 18, pp. 113-120, 2003. [cited by applicant]
Nagarwal et al., “Nanocrystal Technology in the Delivery of Poorly Soluble Drugs: An Overview”, Current Drug Delivery, vol. 8, No. 4, pp. 398-406, 2011. [cited by applicant]
Remenar, “Making the Leap from Daily Oral Dosing to Long-Acting Injectables: Lessons from the Antipsychotics”, Molecular Pharmaceutics, vol. 11, pp. 1739-1749, Mar. 28, 2014. [cited by applicant]
Notice of Opposition in corresponding EP Patent No. 3182958, filed Nov. 27, 2019. [cited by applicant]
Chueshov et al., Nekapete Industrial Technology, vol. 2, Ed. prof. V. I. Chueshova, pp. 352-355. [cited by applicant]