U.S. patent number RE42,096 [Application Number 11/091,011] was granted by the patent office on 2011-02-01 for oral pulsed dose drug delivery system.
This patent grant is currently assigned to Shire LLC, USA. Invention is credited to Beth A. Burnside, Rong-Kun Chang, Richard A. Couch, Kimberly Fiske, Xiaodi Guo, Charlotte M. McGuiness, Edward M. Rudnic, Donald J. Treacy.
United States Patent |
RE42,096 |
Burnside , et al. |
February 1, 2011 |
**Please see images for:
( Certificate of Correction ) ( PTAB Trial Certificate
) ** |
Oral pulsed dose drug delivery system
Abstract
A multiple pulsed dose drug delivery system for pharmaceutically
active amphetamine salts, comprising an immediate-release component
and an enteric delayed-release component wherein (1) the enteric
release coating has a defined minimum thickness and/or (2) there is
a protective layer between the pharmaceutically active amphetamine
salt and the enteric release coating and/or (3) there is a
protective layer over the enteric release coating. The product can
be composed of either one of a number of beads in a dosage form,
including either capsule, tablet, or sachet method for
administering the beads.
Inventors: |
Burnside; Beth A. (Bethesda,
MD), Guo; Xiaodi (Apex, NC), Fiske; Kimberly
(Downingtow, PA), Couch; Richard A. (Bryn Mawr, PA),
Chang; Rong-Kun (Rockville, MD), Treacy; Donald J.
(Woodbine, MD), McGuiness; Charlotte M. (Bethesda, MD),
Rudnic; Edward M. (North Potomac, MD) |
Assignee: |
Shire LLC, USA (N/A)
|
Family
ID: |
22644775 |
Appl.
No.: |
11/091,011 |
Filed: |
March 24, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
09176542 |
Oct 21, 1998 |
06322819 |
Nov 27, 2001 |
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Current U.S.
Class: |
424/494; 424/472;
424/480 |
Current CPC
Class: |
A61K
9/5078 (20130101); A61P 25/00 (20180101); A61K
31/137 (20130101); A61P 25/28 (20180101); A61K
9/5047 (20130101); A61K 9/5026 (20130101) |
Current International
Class: |
A61K
9/16 (20060101) |
Field of
Search: |
;424/451,452,464,465,474,481,489,490,494,472 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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109438 |
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Jan 1940 |
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AU |
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640 337 |
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Mar 1995 |
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EP |
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59-082311 |
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May 1984 |
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JP |
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03-148215 |
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Jun 1991 |
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JP |
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07-061922 |
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Mar 1995 |
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JP |
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09-249557 |
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Sep 1997 |
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JP |
|
09-267035 |
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Oct 1997 |
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JP |
|
10-081634 |
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Mar 1998 |
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JP |
|
WO87/00044 |
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Jan 1987 |
|
WO |
|
WO90/09168 |
|
Aug 1990 |
|
WO |
|
97/03673 |
|
Feb 1997 |
|
WO |
|
98/14168 |
|
Apr 1998 |
|
WO |
|
WO 99/03471 |
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Jan 1999 |
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WO |
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WO 00/25752 |
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May 2000 |
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WO |
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WO 00/35450 |
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Jun 2000 |
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WO |
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Other References
US 6,034,101, 3/2000, Gupta et al. (withdrawn) cited by other .
Conte, et al., "Press-coated tablets for time-programmed release of
drugs," Biomaterials, 14(13):1017-1023 (1993). cited by other .
Gazzaniga, et al., "Time-dependent oral delivery systems for colon
targeting," S.T.P. Pharma Sciences, 5(1):83-88 (1995). cited by
other .
Gazzaniga, et al., "Oral Chronotopic Drug Delivery Systems:
Achievement of Time and/or Site Specificity," Eur. J. Pharm.
Biopharma 40(3):246-250 (1994). cited by other .
Pozzi, et al, The Time Clock system: a new oral dosage form for
fast and complete release of drug after a predetermined lag time,:
Journal of Controlled Release, 31:99-108 (1994). cited by other
.
Walia et al., "Preliminary Evaluation of an Aqueous Wax Emulsion
for Controlled-Release Coating," Pharmaceutical Development and
Technology, 3(1):103-113-(1998). cited by other .
Wilding, et al., "Gastrointestinal Transit and Systemic Absorption
of Captopril from a Pulsed-Release Formulation," Pharmaceutical
Research, 9(5):654-657 (1992). cited by other .
Xin Xu and Ping I. Lee, "Programmable Drug Delivery from an
Erodible Association Polymer System," Pharmaceutical Research,
10(8):1144-1152 (1993). cited by other .
Barr Laboratories Inc.'s Objections and Responses to Shire
Laboratories Inc.'s Second Set of Interrogatories (Nos. 8-11),
dated Feb. 18, 2004. cited by other .
Barr Laboratories' Objections and Responses to Plaintoff Shire
Laboratories Inc.'s Fourth Set of Interrogatories (Nos. 15-16),
dated Jul. 9, 2004. cited by other .
Barr Laboratories' Supplemetal Objections and Responses to
Plaintiff Shire Laboratories Inc.'s Third Set of Interrogatories
(Nos. 12-14 Redacted), dated Aug. 27, 2004. cited by other .
Barr Laboratories' Objections and Responses to Plaintiff Shire
Laboratories Inc.'s Fifth Set of Interrogatories (No. 17), dated
Sep. 3, 2004. cited by other .
Barr Laboratories' Memorandum In Support of its Motion to Amend its
Pleadings and exhibits thereto, dated Sep. 10, 2004. cited by other
.
Deposition transcript of Honorable Gerald J. Mossinghoff and
exhibits thereto, dated Jun. 8, 2005. cited by other .
Impax Laboratories Inc.'s First Amended Answer and Affirmative
Defenses, dated May 2, 2005. cited by other .
Barr Laboratories' Memorandum in Support of its Motion to Compel
Production, dated Sep. 13, 2004. cited by other .
Complaint for Declaratory Judgment, Impax Laboratories Inc. v.
Shire International Laboratories, Inc. (Civ. Action No. 05772) and
Exhibits attached thereto, dated Nov. 9, 2005. cited by other .
Angrist et al., Early Pharmacokinetics and Clinical Effects of Oral
D-Amphetamine in Normal Subjects, Biol. Psychiatry 1987, 22:
1357-1368. cited by other .
Brauer et al., Acute Tolerance to Subjective but not Cardiovascular
Effects of d-Amphetamine in normal, Healthy Men, Journal of
Clinical Psychopharmacology, 1996; 16(1):73-76. cited by other
.
Brown et al., Behavior and Motor Activity Response in Hyperactive
Children and Plasma Amphetamine Levels Following a Sustained
Release Preparation, Journal of the American Academy of Child
Psychiatry, 19:225-239, 1980. cited by other .
Brown et al., Plasma Levels of d-Amphetamine in Hyperactive
Children, Psychopharmacology 62, 133-140, 1979. cited by other
.
R. Bianchini & C. Vecchio, Oral Controlled Release Optimization
of Pellets Prepared by Extrusion-Spheronization Processing, IL
Farmaco 44(6), 645-654, 1989. cited by other .
Burns et al., A study of Enteric-coated Liquid-filled Hard Gelatin
Capsules with Biphasic Release Characteristics, International
Journal of Pharmaceutics 110 (1994) 291-296. cited by other .
Bodmeier et al., The Influence of Buffer Species and Strength on
Diltiazem HCl Release from Beads Coated with the Aqueous Catinoc
Polymer Dispensions, Eudragit RS, RL 30D, Pharmaceutical Research
vol. 13, No. 1, 1996, 52-56. cited by other .
Cody et al., Amphetamine Enantiomer Excretion Profile Following
Administration of Adderall, Journal of Analytical Toxicology, vol.
2, Oct. 2003, 485-492. cited by other .
Rong-Kun Chang, A Comparison of Rheological and Enteric Properties
among Organic Solutions, Ammonium Salt Aqueous Solutions, and Latex
Systems of Some Enteric Polymers, Pharmaceutical Technology, Oct.
1990. cited by other .
Chang et al., Preparation and Evaluation of Shellac Pseudolatex as
an Aqueous Enteric Coating Systems for Pellets, International
Journal of Pharmaceuticals, 60 (1990) 171-173, 1990. cited by other
.
Daynes, Treatment of Noctural Enuresis with Enteric-Coated
Amphetamine, The Practitioner, No. 1037, vol. 173, Nov. 1954. cited
by other .
Garnett et al., Pharmacokinitic Evaluation of Twice-Daily
Extended-Release Carbamazepine (CBZ) and Four-Times-Daily
Immediate-Release CBZ in Patients with Epilepsy, Epilepsia
39(3):274-279, 1998. cited by other .
Goodhart et al., An Evaluation of Aqueous Film-Forming Dispersions
for Controlled Release, Pharmaceutical Technology, Apr. 1984. cited
by other .
Greenhill et al., A Pharmacokinetic/Pharmacodynamic Study Comparing
a Single Morning Dose of Adderall to Twice-Daily Dosing in Children
with ADHD. J. Am. Acad. Adolesc. Psychiatry, 42:10, Oct. 2003.
cited by other .
Husson et al., Influence of Size Polydispersity on Drug Release
from Coated Pellets, International Journal of Pharmaceutics, 86
(1992) 113-121, 1992. cited by other .
Ishibashi et al., Design and Evaluatin of a New Capsule-type Dosage
Form for Colon-Targeted Delivery of Drugs, International Journal of
Pharmaceutics 168, (1998) 31-40, 1998. cited by other .
Kao et al., Lag Time Method to Delay Drug Release to Various Sites
in the Gastrointestinal Tract, Journal of Controlled Release
44(1997) 263-270. cited by other .
Kiriyama et al., The Bioavailability of Oral Dosage Forms of a New
HIV-1 Protease Inhibitor, KNI-272, in Beagle Dogs, Biopharmaceutics
& Drug Disposition, vol. 17 125-234 (1996). cited by other
.
Hans-Martin Klein & Rolf W. Gunther, Double Contrast Small
Bowell Follow-Through with an Acid-Resistant Effervescent Agent,
Investigative Radiology vol. 28, Jul. 1993. cited by other .
Krowczynski & Brozyna, Extended-Release Dosage Forms, pp.
123-131 (1987). cited by other .
Hall HS and Pondell RE, Controlled Release Technologies: Method,
Theory, and Applications, pp. 133-154 (Agis F. Kydonieus ed. 1980).
cited by other .
Treatise on Controlled Drug Delivery, pp. 185-199 (Agis Kydonieus
ed. 1992). cited by other .
Leopold & Eikeler, Eudragit E as Coating Material for the
pH-Controlled Drug Release in the Topical Treatment of Inflammatory
Bowel Disease (IBD), Journal of Drug Targeting, 1998, vol. 6, No.
2, pp. 85-94. cited by other .
Klaus Lehmann, Coating of Multiparticulates Using Polymeric
Solutions, Multiparticulate Oral Drug Delivery (Swarbrick and
Sellassie ed., 1994). cited by other .
Lin & Cheng, In-vitro Dissolution Behaviour of Spansule-type
Micropellets Prpared by Pan Coating Method, Pharm. Ind. 51 No. 5
(1989). cited by other .
C. Lin et al., Biovailability of d-pseudoephedrine and Azatadine
from a Repeat Action Tablet Formulation, J Int Med Res (1982),
122-125. cited by other .
C. Lin et al., Comparative Biovailability of d-pseudoephedrine from
a Conventional d-pseudoephedrine Sulfate Tablet and from a Repeat
Action Tablet, J Int Med Res (1982) 10, 126-128. cited by other
.
Rosen et al., Absorption and Excretion of Radioactively Tagged
Dextroamphetamine Sulfate from a Sustained-Release Preparation,
Jama, vol. 194, No. 11, Dec. 13, 1965, 145-147. cited by other
.
Liu et al., Comparative Release of Phenylprepanolamine ECl from
Long-Acting Appetite Suppressant Product: Acutrim vs. Dexatrim,
Drug Development and Industrial Pharmacy, 10(10), 1639-1661 (1984).
cited by other .
Marcotte et al., Kinetics of Protein Diffusion from a
Poly(D,L-Lactide) Reservoir System, Journal of Pharmaceutical
Sciences vol. 79, No. 5, May 1990. cited by other .
Mathir et al., In vitro characterization of a controlled-release
chlorpheniramine maleate delivery system prepared by the
air-suspension technique, J. Microencapsulation, vol. 14, No.
6,743-751 (1997). cited by other .
Mehta et al., Evaluation of Fluid-bed Processes for Enteric Coating
Systems, Pharmaceutical Technology, Apr. 1986. cited by other .
McGough et al., Pharmacokinetics of SL1381 (Adderall XR), an
Extended-Release Formulation of Adderall, Journal of the American
Academy of Child & Adolescent Psychiatry, vol. 42, No. 6, Jun.
2003. cited by other .
Harris et al., Aqueous Polymeric Coating for Modified-Release
Pellets, Aqueous Polymeric Coating for Pharmaceutical Dosage Forms
(McGinity ed., 1989). cited by other .
Kennerly S. Patrick & John S. Markowitz, Pharmacology of
Methylphenidate, Amphetamine Enantiomers and Pemoline in
Attention-Deficit Hyperactivity Disorder, Human Psychopharmacology,
vol. 12, 527-546 (1997). cited by other .
Pelham et al., A Comparison of Morning-Only and Morning/Late
Afternoon Adderall to Morning-Only, Twice-Daily, and Three
Times-Daily Methylphenidate in Children with
Attention-Deficit/Hyperactivity Disorder, Pediatrics, vol. 104, No.
6, Dec. 1999. cited by other .
American Chemical Society, Polymer Preprints, pp. 633-634, vol. 34,
No. 1, Mar. 1993. cited by other .
Rambali, et al., Using experimental design to optimize the process
parameters in fluidized bed granulation on a semi-full scale,
International Journal of Pharmaceutics 220 (2001) 149-160. cited by
other .
Charles S.L. Chlao amd Joseph R. Robinson, Sustained-Release Drug
Delivery Systems, Remington: The Science and Practice of Pharmacy,
Tenth Edition (1995) 1660-1675. cited by other .
Rosen, et al., Absorption and Excretion of Radioactively Tagged
Dextroamphetamine Sulfate From a Sustained-Release Preparation,
Journal of the American Medical Association, Dec. 13, 1965, vol.
194, No. 11, 1203-1205. cited by other .
Scheiffele, et al., Studies Comparing Kollicoat MAE 30 D with
Commercial Cellulose Derivatives for Enteric Coating on Caffiene
Cores, Drug Development and Industrial Pharmacy, 24(9), 807-818
(1998), 807-818. cited by other .
Serajuddin, et al., Selection of Solid Dosage Form Composition
through Drug-Excipient Compatibility Testing, Journal of
Pharmaceutical Sciences vol. 88, No. 7, Jul. 1999, 696-704. cited
by other .
Sheen et al., Aqueous Film Coating Studies of Sustained Release
Nicotinic Acid Pellets: An In-Vitro Evaluation, Drug Development
and Industrial Pharmacy, 18(8), 851-860 (1992). cited by other
.
Slattum, et al., Comparison of Methods for the Assessment of
Central Nervous System Stimulant Response after Dextroamphetamine
Administration to Healthy Male Volunteers, J. Clin Pharmacol 1996;
36: 1039-1050. cited by other .
Sriamornsak, et al., Development of sustained release theophylline
pellets coated with calcium pectinate, Journal of Controlled
Release 47 (1997) 221-232. cited by other .
Edward Stempel, Prolonged Drug Action, HUSA's Pharmaceutical
Dispensing, Sixth Edition, 1966, 464, 481-485. cited by other .
Stevens, et al., Controlled, Multidose, Pharmacokinetic Evaluation
of Two Extended-Release Carbamazepine Formulations (Carbatrol and
Tegretol-XR), Journal of Pharmaceutical Sciences vol. 87, No. 12,
Dec. 1998, 1531-1534. cited by other .
J. Sjogren, Controlled release oral formulation technology, Rate
Control in Drug Therapy, (1985) 38-47. cited by other .
Agyilirah GA and Bauker SB, Polymers for Enteric Coating
Applications, Polymers for Controlled Drug Delivery (Peter J.
Tarcha ed. 1991) 39-66. cited by other .
Leon Lachman, Herbert A. Lieberman, Joseph L. Kanig, The Theory and
Practice of Industrial Pharmacy, Second Edition (1976) 371-373.
cited by other .
Remington's Pharmaceutical Sciences, Fifteenth Edition (1975)
1624-1625. cited by other .
Tulloch, et al., SL1381 (Adderall XR), a Two-component,
Extended-Release Formulation of Mixed Amphetamine Salts:
Bioavailability of Three Test formulations and Comparison of
Fasted, Fed, and Sprinkled Administration, PHARMACOTHERAPY vol. 22,
No. 11. (2002), 1405-1415. cited by other .
Vasilevska, et al., Preparation and Dissolution Characteristics of
Controlled Release Diltiazem Pellets, Drug Development and
Industrial Pharmacy, 18(15), 1649-1661 (1992). cited by other .
Watano, et al., Evaluation of Aqueous Enteric Coated Granules
Prepared by Moisture Control Method in Tumbling Fluidized Bed
Process, Chem. Pharm. Bull. 42(3) 663-667 (1994). cited by other
.
Wesdyk, et al., Factors affecting differences in film thickness of
beads coated in fluidized bed units, International Journal of
Pharmaceutics, 93 101-109, (1993). cited by other .
Wouessidjewe, Aqueous polymethacrylate Dispersions as Coating
Materials for Sustained and Enteric Release Systems, S.T.P. Pharma
Sciences 7(6) 469-475 (1997). cited by other .
Ansel, et al., Rate Controlled Dosage Forms and Drug Delivery
Systems, Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th
Ed. (1995), 213-222. cited by other .
Bauer, et al., Cellulose Acetate Phthalate (CAP) and Trimellitate
(CAT), Coated Pharmaceutical Dosage Forms (1998), 102-104. cited by
other .
Chan, New Polymers for Controlled Release Products, Controlled
Release Dosage Forms Proceedings of the International Symposium
held on 29th to 31st of Jan. 1987 (The Bombay College of Pharmacy
1988) 59-67. cited by other .
Chan, Materials Used for Effective Sustained-Release Products,
Proceedings of the International Symposium held on 29th to 31st of
Jan. 1987 (The Bombay College of Pharmacy 1988), 69-84. cited by
other .
Moller, Dissolution Testing of Delayed Release Preparations,
Proceedings of the International Symposium held on 29th to 31st of
Jan. 1987 (The Bombay College of Pharmacy 1988), 85-11. cited by
other .
Fukumori, Coating of Multiparticulates Using Polymeric Dispersions,
Multiparticulate Oral Drug Delivery (Swarbrick and Selassie eds.
1994), 79-110. cited by other .
Handbook of Pharmaceutical Excipients: Ethylcellulose,
Polymethacrylates, (4th ed. (2003), 237-240, 462-468. cited by
other .
Handbook of Pharmaceutical Excipients: Plymethacrylates, (2nd ed.
1994), 361-366. cited by other .
Hawley's Condensed Chemical Dictionary 13th Ed. 1997, 584, 981.
cited by other .
Jarowski, The Pharmaceutical Pilot Plant, Pharmaceutical Dosage
Forms: Tablets, vol. 3, 2nd Ed. (1990), 303-367. cited by other
.
McGraw-Hill Dictionary of Scientific and Technical Terms, 5th Ed.
(1994), 97, 972. cited by other .
Physicians' Desk Reference: Adderall, 51st Ed. (1997). cited by
other .
Physicians' Desk Reference: Adderall, 56th Ed. (2002). cited by
other .
Physicians' Desk Reference: Dexedrine 56th Ed. (2002). cited by
other .
Physicians' Desk Reference: Ritalin, 56th Ed. (2002). cited by
other .
Remington: The Science and Practice of Pharmacy, Basic
Pharmacokinetics, 16th Ed. (1980), 693. cited by other .
Remington: The Science and Practice of Pharmacy, Elutriation, 20th
Ed. (2000), 690. cited by other .
Rong-Kun Chang and Joseph R. Robinson, Sustained Drug Release from
Tablets and Particles Through Coating, Pharmaceutical Dosage Forms:
Tablets (Marcel Dekker, Inc. 1990), 199-302. cited by other .
Shargel;. Pharmacokinetics of Oral Absorption, Applied
Biopharmaceutics & Pharmacokinetics. 5th Ed. (2005), 164-166.
cited by other .
Sprowls' American Pharmacy: An Introduction to Pharmaceutical
Techniques and Dosage Forms, 7th Ed. (1974), 387-388. cited by
other .
The Merck Index: Amphetamine, 12th Ed., 620. cited by other .
The Merck Index: Amphetamine, 13th Ed., (2001), 97, 1089. cited by
other .
The United States Pharmacopeia 23, National Formulary 18 (1995) pp.
1791-1799. cited by other .
The United States Pharmacopeia 26, National Formulary 21 (2003) pp.
2157-2165. cited by other .
The United States Pharmacopeia 27, National Formulary 22 (2004) pp.
2302-2312. cited by other .
Answering Expert Report of Dr. Alexander Klibanov, Apr. 25, 2005.
cited by other .
Answering Expert Report of Robert Langer, Apr. 25, 2005. cited by
other .
Expert Report of Dr. Joseph R. Robinson and exhibits thereto, Feb.
28, 2005. cited by other .
Expert Report of the Honorable Gerald J. Mossinghoff and exhibits
thereto, Mar. 16, 2005. cited by other .
Impax Laboratories, Inc.'s Memorandum in Support of the Motion to
Amend its Answer dated Feb. 25, 2005 and exhibits thereto. cited by
other .
Impax Laboratories, Inc.'s Reply Memorandum in Support of the
Motion to Amend its Answer dated Mar. 18, 2005 and exhibit thereto.
cited by other .
Impax Laboratories, Inc.'s First Supplemental Responses to Shire
Laboratories Inc.'s First Set of Interrogatories (Nos. 11-12).
cited by other .
Opening Expert Report of Dr. Michael Mayersohn and exhibits
thereto, Mar. 12, 2005. cited by other .
Opening Expert Report of Dr. Walter Chambliss and exhibits thereto,
Mar. 15, 2005. cited by other .
Couch Deposition Transcript, Sep. 8, 2004. cited by other .
Fiske Deposition Transcript, Sep. 17, 2004. cited by other .
Guo Deposition Transcript, Jul. 26, 2004. cited by other .
McGuiness Deposition Transcript, Aug. 6, 2004. cited by other .
Rudnic Deposition Transcript, Jul. 28, 2004. cited by other .
Chang Deposition Transcript, Sep. 8, 2004. cited by other .
Burnside Deposition Transcript, Feb. 2, 2005. cited by other .
Treacy Deposition Transcript, Aug. 31, 2004. cited by other .
Harrington Deposition Transcript, Jul. 27, 2005. cited by other
.
Schaffer Deposition Transcript, Aug. 17, 2005. cited by other .
Burnside Deposition Transcript, Feb. 3, 2005. cited by other .
Guo Deposition Transcript, Jan. 24, 2005. cited by other .
Chang Deposition Transcript, Jan. 20, 2005. cited by other .
Adderall XR Package Inset, Sep. (2004). cited by other .
Freedom of Information Request Results for--Dexadrine (SmithKline
Beecham): May 20, 1976 Disclosable Approval Information. cited by
other .
Guidance for Industry: Extended Release Oral Dosage Forms:
Development, Evaluation, and Application of In Vitro/In Vivo
Correlations (1997). cited by other .
Guidance for Industry: Food-Effext Bioavailability and Fed
Bioequivalence Studies (2002). cited by other .
Guidance for Industry: SUPAC-MR: Modified Release Solid Oral Dosage
Forms (1997). cited by other .
Holt, Bioequivalence Studies of Ketoprofen: Product formulation,
Pharmacokinetics, Deconvolution, and In Vitro-In Vivo correlations,
Thesis submitted to Oregon State University, Aug. (1997). cited by
other .
Teva Notice letter: Feb. 21, 2005. cited by other .
Teva Notice letter: Jun. 1, 2005. cited by other .
PDR Drug Information for Ritalin LA Capsules, Apr. (2004). cited by
other .
Prescribing Information: Dexedrine, brand of dextroamphetamine
sulfate (2001). cited by other .
Shire Laboartories Inc.'s Opposition to Barr Laboratories' Motion
to Amend Its Answers and Counterclaims, Sep. 15, 2004. cited by
other .
Notice of Allowance U.S. Appl. No. 11/091,010 filed dated Dec. 22,
2008. cited by other .
Interview Summary U.S. Appl. No. 11/091,010 filed date Dec. 22,
2008. cited by other .
Wigal, et al., Evaluation of Individual Subjects in the Analog
Classroom Setting; II. Effects of dose of amphetamine (Adderall),
Psychopharmacology Bulletin, vol. 34, No. 4, pp. 833-838, 1998.
cited by other .
Judgment and Order of Permanent Injunction in Shire LLC v. Teva
Pharmaceutical Industries Ltd. in the United States District Court
for the Eastern District of Pennsylvania, Civil Action No.
06-952-SD, Mar. 6, 2008. cited by other .
Notice of Allowance in U.S. Appl. No. 11/091,011 dated Jul. 20,
2007. cited by other .
Petition to Withdraw Application from Issue Pursuant to 37 CFR
1.313(c)(2) dated Oct. 16, 2007. cited by other .
Transcrip of Richard A. Couch 30(b)(6) Deposition in Shire LLC vs.
Sandoz Inc. in the United States District Court for the District of
Colorado, Dec. 14, 2007. cited by other .
Transcript of Beth A. Burnside Deposition in Shire LLC vs. Sandoz
Inc. in the United States District Court for the District of
Colorado, Case No. 07-CV-001197-EWN-CBS, Nov. 30, 2007. cited by
other .
Transcript of Kimberly Fiske Farrand Deposition in Shire, LLC v.
Sandoz, Inc. in the United States District Court of Colorado, Dec.
4, 2007. cited by other .
Defendant Sandoz, Inc.'s Answers and Objections to Plaintiff Shire
LLC's Interrogatories (No. 1-9), in the United States District
Court for the District of Colorado, Case No. 07-CV-001197-EWN-CBS,
Jun. 18, 2007. cited by other .
Defendant Sandoz, Inc.'s Answers and Objections to Plaintiff Shire
LLC's Second Set of Interrogatories (No. 10-19), in the United
States District Court for the District of Colorado, Case No.
07-CV-001197-EWN-CBS, Nov. 20, 2007. cited by other .
Defendant Sandoz, Inc.'s Answers and Objections to Plaintiff Shire
LLC's Second Set of Interrogatories (No. 20-25) and Supplement to
Answers to Interrogatories 8 and 9, in the United States District
Court for the District of Colorado, Case No. 07-CV-001197-EWN-CBS,
Dec. 10, 2007. cited by other .
Expert Report of Arthur J. Steiner in Shire LLC v. Colony
Pharmaceuticals, Inc., in the United States District Court for the
District of Maryland, case No. 1:07-cv-00718, Dec. 20, 2007. cited
by other .
Supplemental Expert Report of Harry G. Brittain, PhD, FRSC in Shire
LLC v. Colony Pharmaceuticals, Inc., in the United States District
Court for the District of Maryland, Case No. 1:07-cv-00718, Feb.
15,2008. cited by other .
Ozturk et al., "Kinetics of Release from Enteric-Coated Tablets,"
Pharmacutical Research 1988;5:550-565. cited by other .
Ghebre-Sellassie et ., "Evaluation of acrylic-based
modified-release film coatings," International Journal of
Pharmaceutics, 1987;37:211-218. cited by other .
Order and Memorandum Denying Colony's Motion for Partial Summary
Judgment of Noninfringement of the '819 and '300 Patents in Shire
LLC v. Colony Pharmaceuticals, Inc., in the United States District
Court for the District of Maryland, Case No. CCB-07-718, Jan. 2,
2008. cited by other .
Plaintiff Shire LLC's Responses to Interrogatories No. 1-13 in
Shire LLC v. Colony Pharmaceuticals, Inc., in the United States
District Court for the District of Maryland, Case No.
1:07-cv-00718-CCB, Jun. 6, 2007. cited by other .
Transcript of Richard A. Couch Deposition in Shire LLC v. Colony
Pharmaceuticals, Inc., in the United States District Court for the
District of Maryland, Case No. 1:07-cv-00718-CCB, Nov. 15, 2007.
cited by other .
Transcript of Beth A. Burnside Deposition in Shire LLC v. Colony
Pharmaceuticals, Inc., in the United States District Court for the
District of Maryland, Case No. 1:07-cv-00718-CCB, Nov. 9, 2007.
cited by other .
Transcript of richard Rong-Kun Chang in Shire LLC v. Colony
Pharmaceuticals, Inc., in the United States District Court for the
District of Maryland, Case No. 1:07-cv-00718-CCB, Nov. 20, 2007.
cited by other .
Second Amended Complaint for Patent Infringement and Declaratory
Relief in Shire Laboratories, Inc. v. Andrx Pharmaceuticals, LLC,
in the United States District Court for the Southern District of
Florida, Miami Division, Case No. 07-22201-CIV-Cooke/Brown, Nov.
15, 2007. cited by other .
Answer and Counterclaims in Shire Laboratories, Inc. v. Andrx, LLC,
in the United States District Court for the Southern District of
Florida, Miami Division, Case No. 07-22201-CIV-Cooke/Brown, Aug.
31, 2007. cited by other .
Plaintiffs Shire Laboratories, Inc.'s and Shire LLC's Reply to
Defendant Andrx Pharmaceuticals, LLC's Counterclaims, in the United
States District Court for the Southern District of Florida, Miami
Division, Case No. 07-22201-CIV-Cooke/Brown, Sep. 24, 2007. cited
by other .
Judgment and Order of Permanent Injuunction in Shire Laboratories,
Inc. v. Andrx Pharmaceuticals, LLC, in the United States District
Court for the Southern District of Florida, Miami Division, Case
No. 07-22201-CIV-Cooke/Brown, Nov. 19, 2007. cited by
other.
|
Primary Examiner: Tran; S.
Attorney, Agent or Firm: McDermott Will & Emery LLP
Claims
What is claimed is:
1. A pharmaceutical composition for delivery of one or more
pharmaceutically active amphetamine salts, comprising: (a) one or
more pharmaceutically active amphetamine salts covered with an
immediate release coating; and (b) one or more pharmaceutically
active amphetamine salts that are covered with an enteric release
coating that provides for delayed pulsed enteric release, wherein
said enteric release coating releases essentially all of said one
or more pharmaceutically active amphetamine salts coated with said
enteric coating within about 60 minutes after initiation of said
delayed pulsed enteric .[.release.]. .Iadd.release; wherein the
pharmaceutically active amphetamine salts in (a) and (b) comprise
mixed amphetamine salts..Iaddend.
2. .[.The composition of claim 1.]. .Iadd.A pharmaceutical
composition for delivery of one or more pharmaceutically active
amphetamine salts, comprising: (a) one or more pharmaceutically
active amphetamine salts covered with an immediate release coating;
and (b) one or more pharmaceutically active amphetamine salts that
are covered with an enteric release coating that provides for
delayed pulsed enteric release, wherein said enteric release
coating releases essentially all of said one or more
pharmaceutically active amphetamine salts coated with said enteric
coating within about 60 minutes after initiation of said delayed
pulsed enteric release; .Iaddend.wherein said enteric release
coating has a thickness of at least 25.mu..
3. The pharmaceutical composition of claim 1 wherein the one or
more pharmaceutically active amphetamine salts are coated onto a
core.
4. The pharmaceutical composition of claim 1 wherein the one or
more pharmaceutically active amphetamine salts are incorporated
into a core.
5. .[.The pharmaceutical composition of claim 1.]. .Iadd.A
pharmaceutical composition for delivery of one or more
pharmaceutically active amphetamine salts, comprising: (a) one or
more pharmaceutically active amphetamine salts covered with an
immediate release coating; and (b) one or more pharmaceutically
active amphetamine salts that are covered with an enteric release
coating that provides for delayed pulsed enteric release, wherein
said enteric release coating releases essentially all of said one
or more pharmaceutically active amphetamine salts coated with said
enteric coating within about 60 minutes after initiation of said
delayed pulsed enteric release; .Iaddend.wherein the one or more
pharmaceutically active amphetamine salts covered with an immediate
release coating and the one or more pharmaceutically active
amphetamine salts covered with an enteric release coating are
present on a single core.
6. The pharmaceutical composition of claim 1 wherein the one or
more pharmaceutically active amphetamine salts covered with an
immediate release coating and the one or more pharmaceutically
active amphetamine salts covered with an enteric release coating
are present on different cores.
7. The composition of claim 1 wherein said enteric release coating
is a non-pH dependent enteric release coating.
8. A pharmaceutical composition for delivery of at least one
amphetamine salt, comprising: (a) at least one pharmaceutically
active amphetamine salt covered with an immediate release coating;
and (b) at least one pharmaceutically active amphetamine salt
covered with an enteric release coating, said component (a)
providing for an immediate release of amphetamine salt to provide a
first blood level of amphetamine salt and component (b) providing a
delayed pulse enteric release of amphetamine salt that increases
the blood level of amphetamine salt to a second level that is
greater than the first level provided by component (a), wherein
said enteric release coating releases essentially all of said one
or more pharmaceutically active amphetamine salts coated with said
enteric coating within about 60 minutes after initiation of said
delayed pulsed enteric release.Iadd.; wherein the pharmaceutically
active amphetamine salts comprise mixed amphetamine salts in (a)
and (b) comprise mixed amphetamine salts.Iaddend..
9. The pharmaceutical composition of claim 8 wherein the one or
more pharmaceutically active amphetamine salts are coated onto a
core.
10. The pharmaceutical composition of claim 8 wherein the one or
more pharmaceutically active amphetamine salts are incorporated
into a core.
11. .[.The pharmaceutical composition of claim 8.]. .Iadd.A
pharmaceutical composition for delivery of at least one amphetamine
salt, comprising: (a) at least one pharmaceutically active
amphetamine salt covered with an immediate release coating; and (b)
at least one pharmaceutically active amphetamine salt covered with
an enteric release coating, said component (a) providing for an
immediate release of amphetamine salt to provide a first blood
level of amphetamine salt and component (b) providing a delayed
pulse enteric release of amphetamine salt that increases the blood
level of amphetamine salt to a second level that is greater than
the first level provided by component (a), wherein said enteric
release coating releases essentially all of said one or more
pharmaceutically active amphetamine salts coated with said enteric
coating within about 60 minutes after initiation of said delayed
pulsed enteric release; and .Iaddend.wherein the one or more
pharmaceutically active amphetamine salts covered with an immediate
release coating and the one or more pharmaceutically active
amphetamine salts covered with an enteric release coating are
present on a single core.
12. The pharmaceutical composition of claim 8 wherein the one or
more pharmaceutically active amphetamine salts covered with an
immediate release coating and the one or more pharmaceutically
active amphetamine salts covered with an enteric release coating
are present on different cores.
13. A pharmaceutical composition for delivering one or more
pharmaceutically active amphetamine salts comprising: (a) one or
more pharmaceutically active amphetamine salts covered with an
immediate release coating; (b) one or more pharmaceutically active
amphetamine salts that are covered with an enteric release coating
that provides for delayed pulsed enteric release, wherein said
enteric release coating releases essentially all of said one or
more pharmaceutically active amphetamine salts coated with said
enteric coating within about 60 minutes after initiation of said
delayed pulsed enteric release; and (c) a protective layer over the
enteric release coating.
14. The pharmaceutical composition of claim 13 wherein the one or
more pharmaceutically active amphetamine salts are coated onto a
core.
15. The pharmaceutical composition of claim 13 wherein the one or
more pharmaceutically active amphetamine salts are incorporated
into a core.
16. The pharmaceutical composition of claim 13 wherein the one or
more pharmaceutically active amphetamine salts covered with an
immediate release coating and the one or more pharmaceutically
active amphetamine salts covered with an enteric release coating
are present on a single core.
17. The pharmaceutical composition of claim 13 wherein the one or
more pharmaceutically active amphetamine salts covered with an
immediate release coating and the one or more pharmaceutically
active amphetamine salts covered with an enteric release coating
are present .[.On.]. .Iadd.on .Iaddend.different cores.
18. A pharmaceutical composition for delivery of one or more
pharmaceutically active amphetamine salts comprising: (a) one or
more pharmaceutically active amphetamine salts covered with an
immediate release coating; (b) one or more pharmaceutically active
amphetamine salts that are covered with an enteric release coating
that provides for delayed pulsed enteric release, wherein said
enteric release coating releases said one or more pharmaceutically
active amphetamine salts coated with said enteric coating within
about 60 minutes after initiation of said delayed pulsed enteric
release; and (c) a protective layer between the at least one
pharmaceutically active amphetamine salt and the enteric release
coating.
19. The pharmaceutical composition of claim 18 wherein The delayed
pulsed release is from 4 to 6 hours after administration of the
pharmaceutical composition.
20. The pharmaceutical composition of claim 18 wherein the delayed
pulse enteric release, releases the amphetamine salt in about 30 to
60 minutes after initiation of the release.
21. The pharmaceutical composition of claim 18 wherein the one or
more pharmaceutically active amphetamine salts are coated onto a
core.
22. The pharmaceutical composition of claim 18 wherein the one or
more pharmaceutically active amphetamine salts are incorporated
into a core.
23. The pharmaceutical composition of claim 18 wherein the one or
more pharmaceutically active amphetamine salts covered with an
immediate release coating and the one or more pharmaceutically
active amphetamine salts covered with an enteric release coating
are present on a single core.
24. The pharmaceutical composition of claim 18 wherein the one or
more pharmaceutically active amphetamine salts covered with an
immediate release coating and the one or more pharmaceutically
active amphetamine salts covered with an enteric release coating
are present on different cores.
.Iadd.25. The pharmaceutical composition of any one of claims 2, 13
or 18 to 20 wherein the pharmaceutically active amphetamine salt in
(a) and (b) comprises mixed amphetamine salts..Iaddend.
Description
This invention pertains to a multiple dosage form delivery system
comprising one or more amphetamine salts for administering the
amphetamine salts to a recipient.
BACKGROUND OF THE INVENTION
Traditionally, drug delivery systems have focused on
constant/sustained drug output with the objective of minimizing
peaks and valleys of drug concentrations in the body to optimize
drug efficacy and to reduce adverse effects. A reduced dosing
frequency and improved patient compliance can also be expected for
the controlled/sustained release drug delivery systems, compared to
immediate release preparations. However, for certain drugs,
sustained release delivery is not suitable and is affected by the
following factors:
First pass metabolism: Some drugs, such as .beta. blockers,
.beta.-estradiol, and salicylamide, undergo extensive first pass
metabolism and require fast drug input to saturate metabolizing
enzymes in order to minimize pre-systemic metabolism. Thus, a
constant/sustained oral method of delivery would result in reduced
oral bioavailability.
Biological tolerance: Continuous release drug plasma profiles are
often accompanied by a decline in the pharmacotherapeutic effect of
the drug, e.g., biological tolerance of transdermal
nitroglycerin.
Chronopharmacology and circadian rhythms: Circadian rhythms in
certain physiological functions are well established. It has been
recognized that many symptoms and onset of disease occur during
specific time periods of the 24 hour day, e.g., asthma and angina
pectoris attacks are most frequently in the morning hours
(1,2).
Local therapeutic need: For the treatment of local disorders such
as inflammatory bowel disease, the delivery of compounds to the
site of inflammation with no loss due to absorption in the small
intestine is highly desirable to achieve the therapeutic effect and
to minimize side effects.
Gastric irritation or drug instability in gastric fluid: For
compounds with gastric irritation or chemical instability in
gastric fluid, the use of a sustained release preparation may
exacerbate gastric irritation and chemical instability in gastric
fluid.
Drug absorption differences in various gastrointestinal segments:
In general, drug absorption is moderately slow in the stomach,
rapid in the small intestine, and sharply declining in the large
intestine. Compensation for changing absorption characteristics in
the gastrointestinal tract may be important for some drugs. For
example, it is rational for a delivery system to pump out the drug
much faster when the system reaches the distal segment of the
intestine, to avoid the entombment of the drug in the feces.
Pulsed dose delivery systems, prepared as either single unit or
multiple unit formulations, and which are capable of releasing the
drug after a predetermined time, have been studied to address the
aforementioned problematic areas for sustained release
preparations. These same factors are also problematic in pulsed
dose formulation development. For example, gastrointestinal transit
times vary not only from patient to patient but also within
patients as a result of food intake, stress, and illness; thus a
single-unit pulsed-release system may give higher variability
compared to a multiple unit system. Additionally, drug layering or
core making for multiple unit systems is a time-consuming and
hard-to-optimize process. Particularly challenging for formulation
scientists has been overcoming two conflicting hurdles for
pulsatile formulation development, i.e., lag time and rapid
release.
Various enteric materials, e.g., cellulose acetate phthalate,
hydroxypropyl methylcellulose phthalate, polyvinyl acetate
phthalate, and the EUDRAGIT.RTM. acrylic polymers, have been used
as gastroresistant, enterosoluble coatings for single drug pulse
release in the intestine (3). The enteric materials, which are
soluble at higher pH values, are frequently used for colon-specific
delivery systems. Due to their pH-dependent attributes and the
uncertainty of gastric retention time, in-vivo performance as well
as inter- and intra-subject variability are major issues for using
enteric coated systems as a time-controlled release of drugs.
A retarding swellable hydrophilic coating has been used for oral
delayed release systems (4,5). It was demonstrated that lag time
was linearly correlated with coating weight gain and drug release
was pH independent.
Hydroxypropyl methylcellulose barriers with erodible and/or
gellable characteristics formed using press coating technology for
tablet dosage forms have been described to achieve time-programmed
release of drugs (6). Barrier formulation variables, such as grade
of hydroxypropyl methylcellulose, water-soluble and water-insoluble
excipients, significantly altered the lag time and the release rate
from the center cores.
Special grades of hydroxypropyl methylcellulose, e.g.,
METOLOSE.RTM. 60SH, 90SH (Shin-Etsu Ltd., Japan), and METHOCEL.RTM.
F4M (Dow Chemical Company, USA), as a hydrophilic matrix material
have been used to achieve bimodal drug release for several drugs,
i.e., aspirin, ibuprofen, and adinazolam (7). Bimodal release is
characterized by a rapid initial release, followed by a period of
constant release, and finalized by a second rapid drug release.
Tablets or capsules coated with a hydrophobic wax-surfactant layer,
made from an aqueous dispersion of carnauba wax, beeswax,
polyoxyethylene sorbitan monooleate, and hydroxypropyl
methylcellulose have been used for rapid drug release after a
predetermined lag time. For example,. However, even though a
two-hour lag time was achieved for the model drug theophylline at a
higher coating level (60%), three hours were required for a
complete release of theophylline after the lag time. (8)
A sustained-release drug delivery system is described in U.S. Pat.
No. 4,871,549. When this system is placed into dissolution medium
or the gastrointestinal tract, water influx and the volume
expansion of the swelling agent cause the explosion of the water
permeable membrane. The drug thus releases after a predetermined
time period.
The OROS.RTM. push-pull system (Alza Company) has been developed
for pulsatile delivery of water-soluble and water-insoluble drugs (
a specific site (e.g., colon) in the gastrointestinal tract (11).
The drug formulation is contained within a water-insoluble capsule
body and is sealed with a hydrogel plug. Upon oral administration,
the capsule cap dissolves in the gastric juice and the hydrogel
plug swells. At a controlled and predetermined time point, the
swollen plug is ejected from the PULSINCAP.RTM. dosage form and the
encapsulated drug is released. A pulsatile capsule system
containing captopril with release after a nominal 5-hr period was
found to perform reproducibly in dissolution and gamma scintigraphy
studies. However, in the majority of subjects, no measurable
amounts of the drug were observed in the blood, possibly due to
instability of the drug in the distal intestine. (12)
ADDERAL.RTM. comprises a mixture of four amphetamine sulfate salts
which, in combination is indicated for treatment of Attention
Deficit of age. One disadvantage of current treatment is that a
tablet form is commonly used which many young children have
difficulty in swallowing. Another disadvantage of current
treatments is that two separate doses are administered, one in the
morning and one approximately 4-6 hours later, commonly away from
home under other than parental supervision. This current form of
treatment, therefore, requires a second treatment which is
time-consuming, inconvenient and may be problematic for those
children having difficulties in swallowing table t
formulations.
SUMMARY OF THE INVENTION
Accordingly, in view of a need for successfully administering a
multiple pulsed dose of amphetamine salts and mixtures thereof, the
present invention provides an oral multiple pulsed dose delivery
system for amphetamine salts and mixtures thereof. FIG. 1
illustrates the desired target plasma level profile of the
pharmaceutical active contained within the delivery system.
In accordance with a preferred embodiment of the present invention,
there is provided a pharmaceutical composition for delivering one
or more pharmaceutically active amphetamine salts that includes:
(a) one or more pharmaceutically active amphetamine salts that are
covered with an immediate release coating, and (b) one or more
pharmaceutically active amphetamine salts that are covered with an
enteric release coating wherein (1) the enteric release coating has
a defined minimum thickness and/or (2) there is a protective layer
between the at least one pharmaceutically active amphetamine salt
and the enteric release coating and/or (3) there is a protective
layer over the enteric release coating.
In one embodiment, the immediate release and enteric release
portions of the composition are present on the same core.
In another embodiment, the immediate release and enteric release
components are present on different cores.
It is also contemplated that the composition may include a
combination of the hereinabove referred to cores (one or more cores
that include both components on the same core and one or more cores
that include only one of the two components on the core).
The present invention provides a composition in which there is
immediate release of drug and enteric release of drug wherein the
enteric release is a pulsed release and wherein the drug includes
one or more amphetamine salts and mixtures thereof.
The immediate release component releases the pharmaceutical agent
in a pulsed dose upon oral administration of the delivery
system.
The enteric release coating layer retards or delays the release of
the pharmaceutical active or drug for a specified time period ("lag
time") until a predetermined time, at which time the release of the
drug is rapid and complete, i.e., the entire dose is released
within about 30-60 minutes under predetermined environmental
conditions, i.e. a particular location within the gastrointestinal
tract.
The delay or lag time will take into consideration factors such as
transit times, food effects, inflammatory bowel disease, use of
antacids or other medicaments which alter the pH of the GI
tract.
In a preferred embodiment, the lag time period is only
time-dependent, i.e., pH independent. The lag time is preferably
within 4 to 6 hours after oral administration of the delivery
system.
In one aspect, the present invention is directed to a composition
that provides for enteric release of at least one pharmaceutically
active amphetamine salt, including at least one pharmaceutically
active amphetamine salt that is coated with an enteric coating
wherein (1) the enteric release coating has a defined minimum
thickness and/or (2) there is a protective layer between the at
least one pharmaceutically active amphetamine salt and the enteric
release coating and/or (3) there is a protective layer over the
enteric release coating.
In attempting to provide for enteric release of an amphetamine
salt, applicants found that use of an enteric release coating as
generally practiced in the art did not provide effective enteric
release.
Typical enteric coating levels did not meet the above requirements
for the desired dosage profile of amphetamine salts. Using the
typical amount of enteric coating (10-20 .mu.) resulted in
undesired premature leakage of the drug from the delivery system
into the upper gastrointestinal tract and thus no drug delivery at
the desired location in the gastrointestinal tract after the
appropriate lag time. Thus this coating did not meet the
requirements for the drug release profile to provide full
beneficial therapeutic activity at the desired time.
Surprisingly, applicants found that using a thicker application of
enteric coating on the formulation allowed for the second pulsed
dose to be released only and completely at the appropriate time in
the desired predetermined area of the gastrointestinal tract, i.e.,
in the intestine.
Th is was surprising because an increase in thickness of about 5-10
.mu.of enteric coatings above a minimum thickness of about 10-20
.mu.typically does not have a significant effect on release of d
rug from within such coatings. Enteric coatings typically are pH
dependent and will only dissolve/disperse when exposed to the
appropriate environment. Typically, application of a thicker
coating (greater than 20 .mu.) will only marginally increase the
time for complete release at the appropriate environmental
condition i.e., for a brief period of time (20 minutes). Using the
typical coating, applicants could not achieve the desired
result--rather, the coating leaked before the predetermined time in
an inappropriate environment resulting in significant loss of the
therapeutic agent.
Accordingly, in one aspect, the pulsed enteric release of the
amphetamine salts is accomplished by employing a certain minimum
thickness of the enteric coating .
In one embodiment of the invention, the pulsed dose delivery
comprises a composition which comprises one or more
pharmaceutically active amphetamine salts; an enteric coating over
the one or more pharmaceutically active amphetamine salts, wherein
the thickness of the enteric coating layer is at least 25 .mu.; a
further layer of one or more pharmaceutically active amphetamine
salts over the enteric coating layer; and an immediate release
layer coating. The thicker enteric coating surprisingly provides
the required delayed i m mediate release of the pharmaceutically
active amphetamine salt at the desire d time in the desired area of
the gastrointestinal tract. FIG. 2 illustrates a model of this
delivery system.
In this aspect, the one or more pharmaceutically active amphetamine
salts can be provided within or as a part of a core seed around
which the enteric coating is applied. Alternatively, a core seed
can be coated with one or more layers of one or more
pharmaceutically active amphetamine salts.
It has further been discovered that a delayed immediate release
drug delivery can also be accomplished by coating the drug first
with a protective layer prior to applying the enteric coating.
Thus, in another embodiment, the pulsed enteric release is
accomplished by employing a protective layer between the drug and
the enteric coating. When using a protective coating, the enteric
coating may be of an increased thickness or may be of lower
thickness.
Thus, in another aspect, the object of the invention is met by
providing a composition comprising one or more pharmaceutically
active amphetamine salts; a protective layer coating over the one
or more pharmaceutically active amphetamine salt layer(s), and an
enteric coating layer over the protective coating layer; a further
pharmaceutically active amphetamine salt layer and an immediate
release layer coating. In a preferred embodiment of this aspect,
the thickness of the enteric coating is at least 25 .mu., and the
protective layer comprises an immediate release coating.
With respect to this embodiment of the invention, the one or more
pharmaceutically active amphetamine salts can be provided within or
as a part of a core seed, during the core seed manufacturing
process, around which the protective coating is applied.
Alternatively, a core seed can be coated with one or more layers of
one or more pharmaceutically active amphetamine salts.
In another embodiment, the pulsed enteric release is accomplished
by employing a protective layer over the enteric coating.
Accordingly, in this embodiment of the present invention, there is
provided a pulsed dose release drug delivery system comprising one
or more pharmaceutically active amphetamine salts; an enteric
coating layer over the pharmaceutically active amphetamine salt
layer(s); and a protective layer over the enteric coating; a second
pharmaceutically active amphetamine salt layer; and an immediate
release layer coating.
In one aspect of this embodiment, the protective layer is comprised
of one or more components, which includes an immediate release
layer and a modifying layer. The modifying layer is preferably
comprised of a semi water-permeable polymer. Applicants have
surprisingly found that a semi-permeable polymer coating used in
combination with an immediate release layer coating provided a
delayed pulsed release drug delivery profile when layered over the
enteric coating.
Thus, in this embodiment, the protective layer comprises a
semi-permeable polymer and an immediate release coating layer. In a
preferred embodiment, the modifying layer comprises a first layer
of a semi-permeable polymer which is adjacent to the enteric
coating layer and a second coating layer over the semi-permeable
polymer coating layer comprising an immediate release polymer
coating layer.
In one aspect of this embodiment, a semi-permeable polymer, which
may comprise a low water-permeable pH-insensitive polymer, is
layered onto the outer surface of the enteric layer, in order to
obtain prolonged delayed release time. This semi-permeable polymer
coating controls the erosion of the pH-sensitive enteric polymer in
an alkaline pH environment in which a pH-sensitive polymer will
dissolve rapidly. Another pH-sensitive layer may be applied onto
the surface of a low water-permeability layer to further delay the
release time.
In a still further aspect of the invention, in addition to a
protective layer, the composition comprises an acid which is
incorporated into the pharmaceutical active layer or coated onto
the surface of the active layer to reduce the pH value of the
environment around the enteric polymer layer. The acid layer may
also be applied on the outer layer of the pH-sensitive enteric
polymer layer, followed by a layer of low water-permeability
polymer. The release of the active thus may be delayed and the
dissolution rate may be increased in an alkaline environment.
In a further embodiment, the protective coating may be used both
over the drug and over the enteric coating.
With respect to this embodiment of the invention, the one or more
pharmaceutically active amphetamine salts can be provided within or
as a part of a core seed, during the core seed manufacturing
process, around which the enteric coating is applied.
Alternatively, a core seed can be coated with one or more layers of
one or more pharmaceutically active amphetamine salts.
The drug delivery system of the present invention as described
herein preferably comprises one or a number of beads or beadlets in
a dosage form, either capsule, tablet, sachet or other method of
orally administering the beads.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates a multiple pulse drug delivery system target
plasma profile of the drug delivery system of the present
invention. The profile reflects an immediate-release component
followed by a delayed-release component.
FIG. 2 schematically illustrates the delayed-release system of the
present invention.
FIG. 2a graphically illustrates a pulsed dose delivery system.
FIGS. 2b and c graphically illustrate the drug release mechanism
from the proposed delivery system.
FIG. 3 is a plot of the percent drug released versus time from the
drug-loaded pellets described in Example 1 which exemplifies the
immediate release component of the present invention.
FIG. 4 is a plot of the percent drug released versus time from the
coated pellets described in Example 2 which exemplifies .[.the
immediate release component and.]. the delayed release components
of the present invention.
FIG. 5 is a plot of the percent drug released versus time from the
coated pellets .[.of.]. .Iadd.described in .Iaddend.Example 3 which
exemplifies .[.the immediate release component and.]. the delayed
release components of the present invention.
FIG. 6 illustrates the drug release profile of coated pellets
described in Example 4 which exemplifies .[.the immediate release
component and.]. the delayed release components of the present
invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention comprises a core or starting seed, either
prepared or commercially available product. The cores or starting
seeds can be sugar spheres; spheres made from microcrystalline
cellulose and any suitable drug crystals.
The materials that can be employed in making drug-containing
pellets are any of those commonly used in pharmaceutics and should
be selected on the basis of compatibility with the active drug and
the physicochemical properties of the pellets. The additives except
active drugs are chosen below as examples:
Binders such as cellulose derivatives such as methylcellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl
acetate copolymer and the like.
Disintegration agents such as corn starch, pregelatinized starch,
cross-linked carboxymethylcellulose (AC-DI-SOL.RTM.), sodium starch
glycolate (EXPLOTAB.RTM.), cross-linked polyvinylpyrrolidone
(PLASDONE.RTM. XL), and any disintegration agents used in tablet
preparations.
Filling agents such as lactose, calcium carbonate, calcium
phosphate, calcium sulfate, microcrystalline cellulose, dextran,
starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium
chloride, polyethylene glycol, and the like.
Surfactants such as sodium lauryl sulfate, sorbitan monooleate,
polyoxyethylene sorbitan monooleate, bile salts, glyceryl
monostearate, PLURONIC.RTM. line (BASF), and the like.
Solubilizer such as citric acid, succinic acid, fumaric acid, malic
acid, tartaric acid, maleic acid, glutaric acid sodium bicarbonate
and sodium carbonate and the like.
Stabilizers such as any antioxidation agents, buffers, acids, and
the like, can also be utilized.
Methods of manufacturing the core include
a. Extrusion-Spheronization--Drug(s) and other additives are
granulated by addition of a binder solution. The wet mass is passed
through an extruder equipped with a certain size screen. The
extrudates are spheronized in a marumerizer. The resulting pellets
are dried and sieved for further applications.
b. High-Shear Granulation--Drug(s) and other additives are
dry-mixed and then the mixture is wetted by addition of a binder
solution in a high shear-granulator/mixer. The granules are kneaded
after wetting by the combined actions of mixing and milling. The
resulting granules or pellets are dried and sieved for further
applications.
c. Solution or Suspension Layering--A drug solution or dispersion
with or without a binder is sprayed onto starting seeds with a
certain particle size in a fluid bed processor or other suitable
equipment. The drug thus is coated on the surface of the starting
seeds. The drug-loaded pellets are dried for further
applications.
For purposes of the present invention, the core particles have a
diameter in the range of about .[.500-1500.]. .Iadd.100-1500
.Iaddend.microns; preferably 100-800 microns.
These particles can then be coated in a fluidized bed apparatus
with an alternating sequence of coating layers.
The core may be coated directly with a layer or layers of at least
one pharmaceutically active amphetamine salts and/or the
pharmaceutically active amphetamine salt may be incorporated into
the core material. Pharmaceutical active amphetamine salts
contemplated to be within the scope of the present invention
include amphetamine base, all chemical and chiral derivatives and
salts thereof; methylphenidate, all chemical and chiral derivatives
and salts thereof; phenylpropanolamine and its salts; and all other
compounds indicated for the treatment of attention deficit
hyperactivity disorder (ADHD).
A protective layer may be added on top of t he pharmaceutical
active containing layer and also may be provided between active
layers. A separation or protective layer may be added onto the
surface of the active-loaded core, and then the enteric layer is
coated thereupon. Another active layer may also be added to the
enteric layer to deliver an initial dose.
A protective coating layer may be applied immediately outside the
core, either a drug-containing core or a drug-layered core, by
conventional coating techniques such as pan coating or fluid bed
coating using solutions of polymers in water or suitable organic
solvents or by using aqueous polymer dispersions. Suitable
materials for the protective layer include cellulose derivatives
such as hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, polyvinylpyrrolidone,
polyvinylpyrrolidone/vinyl acetate copolymer, ethyl cellulose
aqueous dispersions (AQUACOAT.RTM., SURELEASE.RTM.), EUDRAGIT.RTM.
RL 30D, OPADRY.RTM. and the like. The suggested coating levels are
from 1 to 6%, preferably 2-4% (w/w).
The enteric coating layer is applied onto the cores with or without
seal coating by conventional coating techniques, such as pan
coating or fluid bed coating using solutions of polymers in water
or suitable organic solvents or by using aqueous polymer
dispersions. All commercially available pH-sensitive polymers are
included. The pharmaceutical active is not released in the acidic
stomach environment of approximately below pH 4.5, but not limited
to this value. The pharmaceutical active should become available
when the pH-sensitive layer dissolves at the greater pH; after a
certain delayed time; or after the unit passes through the stomach.
The preferred delay time is in the range of two to six hours.
Enteric polymers include cellulose acetate phthalate, Cellulose
acetate trimellitate, hydroxypropyl methylcellulose phthalate,
polyvinyl acetate phthalate, carboxymethylethylcellulose,
co-polymerized methacrylic acid/methacrylic acid methyl esters such
as, for instance, materials known under the trade name
EUDRAGIT.RTM. L12.5, L100, or EUDRAGIT.RTM. S12.5, S100 or similar
compounds used to obtain enteric coatings. Aqueous colloidal
polymer dispersions or re-dispersions can be also applied, e.g.
EUDRAGIT.RTM. L 30D-55, EUDRAGIT.RTM. L100-55, EUDRAGIT.RTM. S100,
EUDRAGIT.RTM. preparation 4110D (Rohm Pharma); AQUATERIC.RTM.,
AQUACOAT.RTM. CPD 30 (FMC); KOLLICOAT MAE.RTM. 30D and 30DP (BASF);
EASTACRYL.RTM. 30D (Eastman Chemical).
The enteric polymers used in this invention can be modified by
mixing with other known coating products that are not pH sensitive.
Examples of such coating products include the neutral methacrylic
acid esters with a small portion of trimethylammonioethyl
methacrylate chloride, sold currently under the trade names
EUDRAGIT.RTM. and EUDRAGIT.RTM. RL; a neutral ester dispersion
without any functional groups, sold under the trade names
EUDRAGIT.RTM. NE30D and EUDRAGIT.RTM. NE30; and other pH
independent coating products.
The modifying component of the protective layer used over the
enteric coating can include a water penetration barrier layer
(semipermeable polymer) which can be successively coated after the
enteric coating to reduce the water penetration rate through the
enteric coating layer and thus increase the lag time of the drug
release. Sustained-release coatings commonly known to one skilled
in the art can be used for this purpose by conventional coating
techniques such as pan coating or fluid bed coating using solutions
of polymers in water or suitable organic solvents or by using
aqueous polymer dispersions. For example, the following materials
can be used, but not limited to: Cellulose acetate, Cellulose
acetate butyrate, Cellulose acetate propionate, Ethyl cellulose,
Fatty acids and their esters, Waxes, zein, and aqueous polymer
dispersions such as EUDRAGIT.RTM. RS and RL 30D, EUDRAGIT.RTM. NE
30D, AQUACOAT.RTM., SURELEASE.RTM., cellulose acetate latex. The
combination of above polymers and hydrophilic polymers such as
Hydroxyethyl cellulose, Hydroxypropyl cellulose (KLUCEL.RTM.,
Hercules Corp.), Hydroxypropyl methylcellulose (METHOCEL.RTM., Dow
Chemical Corp.), Polyvinylpyrrolidone can also be used.
An overcoating layer can further optionally be applied to the
composition of the present invention. OPADRY.RTM., OPADRY II.RTM.
(Colorcon) and corresponding color and colorless grades from
Colorcon can be used to protect the pellets from being tacky and
provide colors to the product. The suggested levels of protective
or color coating are from 1 to 6%, preferably 2-3% (w/w).
Many ingredients can be incorporated into the overcoating formula,
for example to provide a quicker immediate release, such as
plasticizers; acetyltriethyl citrate, triethyl citrate,
acetyltributyl citrate, dibutylsebacate, triacetin, polyethylene
glycols, propylene glycol and the others; lubricants: talc,
colloidal silica dioxide, magnesium stearate, calcium stearate,
titanium dioxide, magnesium silicate, and the like.
The composition, preferably in beadlet form, can be incorporated
into hard gelatin capsules, either with additional excipients, or
alone. Typical excipients to be added to a capsule formulation
include, but are not limited to: fillers such as microcrystalline
cellulose, soy polysaccharides, calcium phosphate dihydrate,
calcium sulfate, lactose, sucrose, sorbitol, or any other inert
filler. In addition, there can be flow aids such as fumed silicon
dioxide, silica gel, magnesium stearate, calcium stearate or any
other material imparting flow to powders. A lubricant can further
be added if necessary by using polyethylene glycol, leucine,
glyceryl behenate, magnesium stearate or calcium stearate.
The composition may also be incorporated into a tablet, in
particular by incorporation into a tablet matrix, which rapidly
disperses the particles after ingestion. In order to incorporate
these particles into such a tablet, a filler/binder must be added
to a table that can accept the particles, but will not allow their
destruction during the tableting process. Materials that are
suitable for this purpose include, but are not limited to,
microcrystalline cellulose (A VICEL.RTM.), soy polysaccharide
(EMCOSOY.RTM.), pre-gelatinized starches (STARCH.RTM. 1500,
NATIONAL.RTM. 1551), and polyethylene glycols (CARBOWAX.RTM.). The
materials should be present in the range of 5-75% (w/w), with a
preferred range of 25-50% (w/w).
In addition, disintegrants are added in order to disperse the beads
once the tablet is ingested. Suitable disintegrants include, but
are not limited to: cross-linked sodium carboxymethyl cellulose
(AC-DI-SOL.RTM.), sodium starch glycolate (EXPLOTAB.RTM.,
PRIMOJEL.RTM.), and cross-linked polyvinylpolypyrrolidone
(Plasone-XL). These materials should be present in the rate of
3-15% (w/w), with a preferred range of 5-10% (w/w).
Lubricants are also added to assure proper tableting, and these can
include, but are not limited to: magnesium stearate, calcium
stearate, stearic acid, polyethylene glycol, leucine, glyceryl
behanate, and hydrogenated vegetable oil. These lubricants should
be present in amounts from 0.1-10% (w/w), with a preferred range of
0.3-3.0% (w/w).
Tablets are formed, for example, as follows. The particles are
introduced into a blender along with AVICEL.RTM., disintegrants and
lubricant, mixed for a set number of minutes to provide a
homogeneous blend which is then put in the hopper of a tablet press
with which tablets are compressed. The compression force used is
adequate to form a tablet; however, not sufficient to fracture the
beads or coatings.
It will be appreciated that the multiple dosage form of the present
invention can deliver rapid and complete dosages of
pharmaceutically active amphetamine salts to achieve the desired
levels of the drug in a recipient over the course of about 8 hours
with a single oral administration.
In so doing, the levels of drug in blood plasma of the
pharmaceutically active amphetamine salts will reach a peak fairly
rapidly after about 2 hours, and after about 4 hours a second pulse
dose is released, wherein a second fairly rapid additive increase
of plasma drug levels occurs which slowly decreases over the course
of the next 12 hours.
The following examples are presented to illustrate and do not limit
the invention.
EXAMPLES
Example 1
Immediate release formulation
The following formulation was used to layer the drug onto sugar
spheres. Nonpareil seeds (30/35 mesh, Paulaur Corp., NJ), 6.8 kg
were put into a FLM-15 fluid bed processor with a 9'' Wurster
column and fluidized at 60.degree. C. The suspension of mixed
amphetamine salts (MAS) with 1% HPMC E5 Premium (Dow Chemical) as a
binder was sprayed onto the seed under suitable conditions. Almost
no agglomeration and no fines were observed with a yield of at
least 98%. The drug-loaded cores were used to test enteric coatings
and sustained release coatings.
TABLE-US-00001 TABLE 1 Ingredients Amount (%) Nonpareil seed 88.00
mixed amphetamine salts 11.40 METHOCEL .RTM. E5 Premium 0.60 Water
* *removed during processing
The drug release profile of the drug-loaded pellets of this example
is shown in FIG. 3.
Example 2
The following formulation was used to coat the mixed amphetamine
salts loaded (MASL) pellets from Example 1 with the EUDRAGIT.RTM. L
30D-55 (Rohm Pharma, Germany) coating dispersion. 2 kg of MASL
pellets were loaded into a fluid bed processor with a reduced
Wurster column equipped with a precision coater.[.(MP 2/3, Niro
Inc.).]. . The coating dispersion was prepared by dispersing
Triethyl citrate, Talc and EUDRAGIT.RTM. L 30D-55 into water and
mixing for at least 30 minutes. Under suitable fluidization
conditions, the coating dispersion was sprayed onto the fluidized
MASL pellets. The spraying was continued until the targeted coating
level was achieved.[.(20.mu.).]. . The coated pellets were dried at
30-35.degree. C. for 5 minutes before stopping the process. The
enteric coated .[.PPA.]. .Iadd.MASL .Iaddend.pellets were tested at
different pH buffers by a USP paddle method. The drug content was
analyzed using HPLC. The results showed that the enteric coating
delayed the drug release from the coated pellets until after
exposure to pH 6 or higher. (Reference # AR98I25-4)
TABLE-US-00002 TABLE 2 Ingredients Amount (%) MASL pellets
.[.40.00.]. .Iadd.70.00.Iaddend. EUDRAGIT .RTM. L 30D-55 24.88
Triethyl citrate 2.52 Talc 2.60 Water * *removed during
processing
The drug release profile of the coated pellets of this example is
shown in FIG. 4.
Example 3
The following formulation was used to coat the MASL pellets from
Example 1 with the EUDRAGIT.RTM. 4110D (Rohm Pharma, Germany)
coating dispersion. MASL pellets (2 kg) were loaded in a fluid bed
processor with a reduced Wurster column (GPGC-15 Glatt). The
coating dispersion was prepared by dispersing Triethyl citrate,
Talc and EUDRAGIT.RTM. 4110D into water and mixing for at least 30
minutes. Under suitable fluidization conditions, the coating
dispersion was sprayed onto the fluidized MASL pellets. The
spraying was continued until the targeted coating level was
achieved. The coated pellets were dried at 30-35.degree. C. for 5
minutes before stopping the process. The enteric coated MASL
pellets were tested u sing a USP paddle method at different pH
buffers. The drug content was analyzed using HPLC. The enteric
coating delayed the drug release for several hours from the coated
pellets until the pH value reached 6.8 or higher. (Reference #
AR98I25-3)
TABLE-US-00003 TABLE 3 Ingredients Amount (%) MASL pellets
.[.70.00.]. EUDRAGIT .RTM. 4110D .[.26.24.]. Triethyl citrate
.[.0.76.]. Talc .[.3.00.]. Water * *removed during processing
The drug release profile of coated pellets of this example is shown
in FIG. 5.
Example 4
The following formulation was selected to coat the enteric coated
MASL pellets. Coated MASL pellets from Example 2 or coated MASL
pellets from Example 3 (2 kg of either) were loaded into a fluid
bed processor with a reduced Wurster column (GPGC-1 5, Glatt). The
coating dispersion was prepared by mixing SURELEASE.RTM. (Colorcon)
and water for at least 15 minutes prior to spraying. Under suitable
fluidization conditions, the coating dispersion was sprayed onto
the fluidized pellets. The spraying was continued until the
targeted coating level was achieved. The coated pellets were coated
with a thin layer of OPADRY.RTM. white (Colorcon) (2%) to prevent
the tackiness of the coated pellets during storage. The coated
pellets were then dried at 35-40.degree. C. for 10 minutes before
discharging from the bed. The drug dissolution from both coated
pellets was performed using a USP paddle method at different pH
buffers. The drug content was analyzed using HPLC. The 8%
SURELEASE.RTM. coating slightly sustained the drug release from
EUDRAGIT.RTM. L 30D-55 coated pellets at pH 7.5 buffer, while the
SURELEASE.RTM. coating delayed the drug release up to 2 hours after
the buffer switched from pH 1 to pH 7.5. (Reference ##
AR98I25-1)
TABLE-US-00004 TABLE 4 Ingredients Amount.[., kg.].
.Iadd.(%).Iaddend. Enteric coated MASL pellets 90.00 SURLEASE .RTM.
8.00 OPADRY .RTM. white 2.00 Water * *removed during processing
The drug release profile of the coated pellets from this example is
shown in FIG. 6.
CITED LITERATURE
1. B.Lemmer, "Circadian Rhythms and Drug Delivery", J. Controlled
Release, 16, 63-74 (1991)
2. B. Lemmer, "Why are so many Biological Systems Periodic?" in
Pulsatile Drug Delivery: Current Applications and Future Trends, R
Gumy, HE Junginger and NA Peppas, eds. (Wissenschaftliche
Verlagsgesellschaft mbH Stuttgart, Germany 1993) pp.11-24
3. X. Xu and PI Lee, "Programmable Drug Delivery from an Erodible
Association Polymer System", Pharm. Res. 10(8), 1144-1152
(1993)
4. A. Gazzaniga, ME Sangalli, and F Giodano, "Oral Chonotropic Drug
Delivery Systems: Achievement of Time and/or Site Specificity", Eur
J Pharm. Biopharm., 40(4), 246-250 (1994)
5. A Gazzaniga, C Busetti, L Moro, ME Sangalli and F Giordano,
"Time Dependent Oral Delivery Systems for Colon Targeting", S. T.P.
Pharma Sciences5(1), 83-88 (1996)
6. U Conte, L Maggi, ML Torre, P Giunchedi and A Lamanna,
"Press-coated Tablets for Time programmed Release of Drugs",
Biomaterials, 14(13), 1017-1023 (1993)
7. AC Shah International Patent Application W098/00044
8. PS Walia, P Jo Mayer Stout and R Turton, "Preliminary Evaluation
of an Aqueous Wax Emulsion for Controlled Release Coating", Pharm
Dev Tech, 3(1), 103-113 (1998)
9. F Theeuwes, "OROS.RTM. Osmotic System Development", Drug Dev Ind
Pharm9(7), 1331-1357 (1983)
10. F Theeuwes, "Triggered, Pulsed and Programmed Drug Delivery" in
Novel Drug Delivery and its Therapeutic Application, LF Prescott
and WS Nimmos. eds. (Wiley, New York, 1989) pp. 323-340
11. M McNeil, A Rashid and H Stevens, "International Patent App
W090/09168
12. IR Wilding, SS Davis, M Bakhshaee, HNE Stevens, RA Sparrow and
J Brennan, "Gastrointestinal Transit and Systemic Absorption of
Captopril from a Pulsed Release Formulation", Pharm Res 9(5),
654-657 (1992)
* * * * *