M A Y / J U N E 1 9 9 8
`
`I N T E R N A T I O N A L J O U R N A L
`
`of
`PHARMACEUTICAL
`COMPOUNDING
`
`C O M P O U N D I N G O P H T H A L M I C S
`
`Page 184 Compounding Ophthalmic Preparations
`Page 196 Ophthalmic Solutions in Cataract Surgery
`Page 214 An Automated Process for Batch
`Preparation of Epidural Solutions
`
`Page 221 Formulations
`Page 240 Making Capsules Using a Solid Oral Dosage
`Form of a Different Strength
`Page 249 Sorption of Benzalkonium Chloride to
`Filters Used in Processing Ophthalmics
`
`V O L U M E 2 N O . 3
`
`MYLAN Ex. 1006, Page 1
`
`

`
`T A B L E O F C O N T E N T S
`
`M A Y / J U N E
`
`1
`
`9
`
`9
`
`8
`
`I N T E R N A T I O N A L J O U R N A L
`
`of
`PHARMACEUTICAL
`COMPOUNDING
`
`D E P A R T M E N T S
`
`178 Letters to the Editor
`179 PreScription – From the Editor
`180 News
`180 Calendar of Events
`182 Web Reviews
`252 Continuing Education Questions
`253 Index of Advertisers
`254 Instructions for Authors
`255 Cumulative Index
`256 Formulation Contest Instructions
`
`F O R M U L A T I O N S
`
`222 Acetylcysteine 15% Ophthalmic
`Solution
`223 Amphotericin B 2-mg/mL Ophthalmic
`Solution
`224 Ascorbic Acid 10% Ophthalmic
`Solution
`225 Calcium Gluconate 1% Ophthalmic
`Irrigation Solution
`226 Cyclosporine 2% Ophthalmic Solution
`227 Dexamethasone Sodium Phosphate
`0.05% Ophthalmic Ointment
`228 Fluconazole 0.2% Ophthalmic
`Solution
`229 Fortified Gentamicin Ophthalmic
`Solution
`230 Glucose 40% Ophthalmic Ointment
`231 Idoxuridine 0.5% Ophthalmic
`Ointment
`232 Idoxuridine 0.1% Ophthalmic Solution
`233 Lissamine Green 0.5% Ophthalmic
`Solution
`234 Ophthalmic Lubricant
`235 Rose Bengal 1% Ophthalmic Solution
`236 Vancomycin 25-mg/mL Ophthalmic
`Solution
`
`C O V E R P H O T O G R A P H B Y J E F F R E Y M Y E R S ©
`
`Page 184
`
`Page 208
`
`Page 221
`
`Page 203
`
`O P H T H A L M I C C O M P O U N D I N G
`184 Compounding Ophthalmic Preparations – The importance of using non-
`irritating, compatible ingredients cannot be overemphasized.
`189 Ophthalmic Compounding: Techniques for Achieving Sterility – In all cases,
`err on the conservative side. – Charles W. Leiter, PharmD
`190 Buffer Solutions for Ophthalmic Preparations
`191 Anatomy of the Eye
`192 Preservation, Sterilization, and Sterility Testing of Ophthalmic Preparations
`196 Ophthalmic Solutions in Cataract Surgery – The formulation of preservative-
`free intraocular solutions is crucial to the success of surgical procedures. – Nicole
`J. Anderson, MD; Henry F. Edelhauser, PhD
`203 A Glimpse into the Future – Many new ophthalmic drug-delivery systems are
`being developed to facilitate administration and increase efficacy.
`205 An Eye to Success – Two pharmacists began compounding sterile ophthalmic
`products to fill a market vacuum. The rest is history.
`206 Ophthalmic Compounding for Animals – Two Equine Ophthalmic Ointments
`– Paul W. Franck, RPh; and Treatment of Epithelial Calcification of the Cornea
`with EDTA 1% – Randy S. Carr, RPh; Nancy Cottrill, DVM, DACVO
`208 Eyecups: The Beginning of Eye Irrigation and Treatment – Dating from the
`16th century, these historical artifacts are now collectors’ items.
`
`G E N E R A L I N T E R E S T
`212 Nutraceuticals: New Opportunities for Pharmacists –Allen M. Kratz, PharmD
`214 An Automated Process for Batch Preparation of Epidural Solutions Contain-
`ing Bupivacaine Hydrochloride and Fentanyl Citrate – Stephen P. Rice, PRh
`216 Basic Statistical Concepts for Evaluating the Pharmaceutical Compounding
`Literature, Part 4: Student’s t-test and One-way Analysis of Variance
`Nancy M. Fenn Buderer, MS
`219 Profile of a Practice: Office Practice Facilitates Compounding and Patient
`Counseling
`
`C O M P O U N D I N G S U P P O R T & Q U A L I T Y C O N T R O L
`237 Featured Excipient: Edetic Acid and Its Salts
`240 Making Capsules Using a Solid Oral Dosage Form of a Different Strength
`Andrew Glasnapp, RPh; Yen-Tuyet-Hua
`241 Calculations – Shelly J. Prince, PhD, RPh
`242 Standard Operating Procedure for General Aseptic Procedures Used
`at a Laminar Airflow Workbench
`
`P E E R - R E V I E W E D S T U D I E S
`243 Paclitaxel Compatibility with the IV Express™ Filter Unit – Quanyun A. Xu,
`PhD; Lawrence A. Trissel, FASHP; Yanping Zhang
`246 Stability of Milrinone Lactate in 5% Dextrose Injection and 0.9% Sodium
`Chloride Injection at Concentrations of 400, 600 and 800 µg/mL
`Dana Nguyen, PharmD; Mark A. Gill, PharmD, FASHP, FCCP
`249 Sorption of Benzalkonium Chloride to Various Filters Used in Processing
`Ophthalmics - Shelly J. Prince, PhD, RPh; Loyd V. Allen, Jr., PhD, RPh
`
`International Journal of Pharmaceutical Compounding
`Vol.2 No.3 May/June 1998
`
`177
`
`MYLAN Ex. 1006, Page 2
`
`

`
`L E T T E R S
`
`Letters
`
`■ Congratulations on an exceptionally fine
`journal and web page.
`I would like to comment on the mortar and
`pestle article from the March-April 1997
`issue. I have a nice collection of mortars
`and pestles and want to comment on one of
`the mortar and pestles; I think it’s the third
`one from the end of the article - the mor-
`tar has 1914-1916 printed on the side. I
`bought this mortar and pestle at an antique
`show in Portland last summer. The other side
`has the crest of Austria and the words Aus
`grosser Zeit - literally translated “for the
`big time.” The story is that the mortar and
`pestle was given to the citizens of Austria for
`their donations of gold and silver to the
`war effort (World War I). I wrote to the
`Austrian National Library for additional
`information and they were only able to tell
`me the company that made it, an R. (Rudold
`or Richard) Ditmar in Znaim, Austria, which
`
`operated from the early 1900s. Unfortu-
`nately, the pestle shown in the photos is
`not the pestle that came with the mortar. The
`one in your photo is wedgwood (probably
`not the wedgwood brand), while the
`mortar is ceramic. I have the matched
`mortar and pestle and my pestle is, no doubt,
`the correct one.
`I enjoyed the article very much and look
`forward to our subscription to your journal.
`Col. Allen F. Almquist
`Director, Department of Pharmacy
`Madigan Army Medical Center
`Tacoma, WA
`■ Congratulations on your success with the
`IJPC. It is a beautifully realized publica-
`tion, and I have heard many comments
`on its excellence.
`Ron Teeter
`Senior Editor, JAPhA
`■ Thank you for publishing such a fine
`journal. The future of compounding is
`looking better.
`I would like to share a few thoughts with
`
`178 International Journal of Pharmaceutical Compounding
`Vol.2 No.3 May/June 1998
`
`you. A number of formulations contain as-
`partame as an ingredient. We who have a nu-
`tritional practice dislike that product. We
`would much rather use stevia or even sucrose.
`Many clients cannot tolerate aspartame.
`This last issue had a couple of formulations
`containing peanut oil. Many people are al-
`lergic to peanut products. Why not use a more
`hypoallergenic oil such as olive oil or rice
`bran oil? We have made many changes in our
`compounds since our entry into nutrition and
`natural pharmacy. We never use lactose as
`a filler. We use natural substances to color
`capsules. There is a whole new world out
`there for compounders who are more aware
`of the needs and wishes of clients for more
`natural compounds.
`Don Bottoni, RPh, FIACP, FACA
`Peoples Pharmacies, Austin, TX
`I tried to access “The Diabetes Page,” Vol.
`1, No. 6, page 371, using the Internet ad-
`dresses you supplied, using several servers,
`but was unable to make contact.
`Could you please explain how I may
`contact “The Diabetes Page” using the
`Internet, without having a Notre Dame
`personal server?
`Dan Spera
`Via email (location unknown)
`Thank you for making us aware of this
`problem. We, too, were disappointed to learn
`that this web address is no longer available.
`We had no way of knowing that this webpage
`would be removed from the Internet, but we
`will try to prevent this from happening again
`and apologize for any inconvenience this may
`have caused you.
`■ This is the first time I have sat down to
`do the Continuing Education (CE) for the
`Journal. I was very favorably impressed with
`it. It makes us go and dig and learn instead
`of regurgitating what we can look on the
`page and see.
`You might also want to consider includ-
`ing problems from the Calculations Sec-
`tion. It is amazing how many pharmacists have
`problems with basic math.
`Bill Wills, RPh, FAICP
`Owner, Grandpa’s Compounding
`Pharmacy, Placerville, CA
`Thank you for your kind letter concerning the
`Journal. We are trying to approach CE from
`a little different angle. The CE questions may
`come from the entire journal and we are try-
`ing to continually incorporate more problem-
`solving questions rather than the straight-answer
`type. We will be working on this even more in
`future issues and hope you continue to enjoy it.
`The Editor
`
`MYLAN Ex. 1006, Page 3
`
`■
`

`
`Some pharmacists are involved in com-
`pounding sterile ophthalmic solutions for
`intracameral, intravitreal and retinal drug
`delivery. Ophthalmic compounding ranges
`from the relatively simple to the highly
`complex; some products are diluted, some
`are fortified and some are formulated from
`raw materials. Many currently used thera-
`pies, such as periocular and intraocular so-
`lutions, are not commercially available or
`are not approved by the Food and Drug Ad-
`ministration; consequently, these products
`must be individually prepared. Periocular
`injections are those injected below the con-
`junctiva or Tenon’s capsule, given to either
`prolong administration or to increase pen-
`etration of the drug into the eye. The in-
`traocular injections are used to treat serious
`infections and inflammatory conditions.
`Guidelines for ophthalmic compound-
`ing are published in the U.S. Pharmacopeia
`and as an American Society of Health-Sys-
`tems Pharmacists Technical Assistance Bulletin
`on Pharmacy-Prepared Ophthalmic Products.
`Ophthalmic preparations should be pre-
`pared by qualified, aseptic compounding
`pharmacists using certified laminar airflow
`hoods in a clean room and, if applicable, a
`certified biohazard hood.
`A number of compounding pharmacists
`specialize in the preparation of sterile oph-
`thalmic injectables, irrigating solutions and
`ophthalmic topicals. An organization of
`compounding ophthalmic pharmacists, the
`Pharmacists in Ophthalmic Practice, was
`founded by Clement A. Weisbecker, long-
`time director of pharmacy at Wills Eye
`Hospital, Philadelphia, PA.
`These pharmacists routinely formulate
`topical solutions, irrigation solutions, sub-
`conjunctival injections and intravitreal in-
`jections. The organization has published a
`formulary entitled, Extemporaneous Oph-
`thalmic Preparations, a very good resource
`
`for compounding ophthalmic preparations.
`Thinking about ophthalmics, one some-
`times wonders why:
`● The eye is constantly exposed to dust, but
`we make our solutions particulate free.
`● The eye is constantly exposed to airborne
`bacteria, fungi and molds; but we make
`our solutions sterile.
`● The eye is exposed to hypotonic water dur-
`ing swimming, bathing and showering; but
`we make our solutions isotonic.
`● The eye works to remove any foreign
`material it encounters, but we formulate
`our ophthalmic products to remain in
`the eye as long as possible.
`● The eye is somewhat isolated for its func-
`tion, but medications administered can
`produce a systemic effect throughout
`the body.
`Ophthalmic compounding requires the ut-
`most in accuracy and precision, as a pa-
`tient’s eyesight is at stake. It must be done
`only by pharmacists who are willing, who
`are trained in this highly technical and crit-
`ical type of formulation and who have in-
`vested in the proper equipment.
`In this issue, Henry Edelheiser, PhD, a
`leader in the formulation of ophthalmic
`solutions for ophthalmic surgery, and a
`coworker, Nicole Anderson, MD, have pre-
`pared an indepth discussion of the devel-
`opment of ophthalmic solutions used in
`cataract surgery, based on many years of work
`with their research team, surgeons and
`pharmacists. In addition to 15 ophthalmic
`formulations, this issue contains a brief
`history of a successful corporation, founded
`by two compounding pharmacists; special
`articles by some compounding pharma-
`cists; and several technique-oriented arti-
`cles on preparing ophthalmic prescriptions.
`Continuing the series on the use of statis-
`tics in evaluating pharmacy literature, Nancy
`Buderer discusses the Student’s t-test and
`
`F R O M T H E E D I T O R
`
`PreScription
`
`one-way analysis of variance. The featured
`excipient is the widely used and often
`misunderstood edetic acid and its salts, a
`family of chelating agents widely used as
`excipients that also has therapeutic appli-
`cations. Also discussed are potential new de-
`livery systems for ophthalmic drugs in the
`future, some of which may be compounded
`by pharmacists. We would be well advised
`to keep our eyes on these new up-and-com-
`ing opportunities.
`
`Loyd V. Allen, Jr.
`PhD, RPh, FACA, FAPhA
`
`The International Journal of Pharmaceutical Compounding (IJPC) is published bimonthly by IJPC, 122 N. Bryant, Edmond, OK
`73034-6301 USA, (405) 330-0094, (800) 757-4572.
`Periodical postage pending paid at Edmond, OK, and additional mailing offices in Fulton, MO.
`Address changes, subscription service or orders should be mailed to IJPC at above address. Change-of-address notices should
`include old as well as new address with zip or postal code. Allow 30 days for change of address.
`Postmaster: Send address changes to IJPC. (Address above)
`
`SUBSCRIPTION RATES
`North America – 1 year, $95; 2 years, $170.
`Institutional: 1 year, $120; 2 years, $215.
`All other continents – 1 year, $190; 2 years, $340; ; Institu-
`tional: 1 year, $215; 2 years, $390. Credit cards only.
`Student – 1 year North America, $30.
`Back issues are available at $15 per issue to subscribers only.
`Minimum order, 10 issues.
`IJPC provides information for professional use only. The individual professionals must determine the validity and appropriateness of any information contained in this journal for their specific
`patients and/or applications. The opinions, statements and views expressed by contributors to the Journal are the authors’ and do not necessarily reflect those of the publisher, editor-in-chief, editors,
`Editorial Board, staff or Board of Directors. Letters to the Editor may be edited for content or style.
`The appearance of advertising in the Journal does not necessarily constitute endorsement of the advertiser, its products or services.
`Copyright 1998 by the International Journal of Pharmaceutical Compounding. ISSN No. 1092-4221. The International Journal of Pharmaceutical Compounding is a registered trademark of the Interna-
`tional Journal of Pharmaceutical Compounding, Inc. All rights reserved. None of the contents of this publication may be reproduced without prior written permission. The International Journal of
`Pharmaceutical Compounding or any part thereof may not be reproduced, stored in a retrieval system, or transcribed in any form or by any means, electronic or mechanical, including photocopying
`and recording, without the prior written permission of the Editor. Permission, however, is granted for libraries and others registered with the Copyright Clearance Center, Inc., 222 Rosewood
`Drive, Danvers, MA. 01923 USA, to photocopy articles for a base fee of $5 per copy of the article plus $2 per page. Requests for bulk orders should be addressed to the Editor.
`
`PHOTO BY PAUL SCHMIDT ©
`
`International Journal of Pharmaceutical Compounding
`Vol.2 No.3 May/June 1998
`
`179
`
`MYLAN Ex. 1006, Page 4
`
`

`
`N E W S
`
`I N T E R N A T I O N A L J O U R N A L
`
`of
`PHARMACEUTICAL
`COMPOUNDING
`
`Loyd V. Allen, Jr., PhD, RPh Editor-in-Chief
`Sonora Hudson Managing Editor
`Carolyn Rose Art Director
`Leslie Ross Advertising Director/
`Associate Publisher
`Andy Bernick Circulation Director
`Elene Ragan Assistant to the
`Editor-in-Chief
`
`Editorial Board
`Marianna Foldvari, PhD, RPh
`University of Saskatchewan, Canada
`Peter R. Ford, RPh, FIACP
`Moncton, New Brunswick, Canada
`Paul F. Grassby, PhD, MRPharmS
`Penarth, South Glamorgan, UK
`Hetty A. Lima, RPh, FASHP, Baltimore, MD, USA
`George Malmberg, RPh, FACA, FIACP
`Sewell, NJ, USA
`George Roentsch, RPh, FIACP, Keene, NH, USA
`M. Lou Stiles, RPh, MS, Oklahoma City, OK, USA
`Evelyn Timmons, RPh, FACA, FIACP
`Paradise Valley, AZ, USA
`Neil Thompson, RPh, Minneapolis, MN, USA
`Larry Trissel, RPh, FASHP, Houston, TX, USA
`David J. Woods, MPharm, MRPharmS, FHPA
`Dunedin, New Zealand
`
`Board of Directors
`
`Dick Holm, RPh
`Bob Scarbrough, RPh
`Blair Lundberg, RPh
`Pat Downing, RPh
`Alice Marks
`Mike Collins, RPh
`Tom Marks, RPh
`Eldon Armstrong, RPh
`Joe Musick, RPh
`Jake Beckel, RPh
`Jim Palmieri, RPh
`Shelly Schluter Capps
`Gene Ragazzo, RPh
`Jim Cammack, RPh
`Larry Smith, RPh
`Charlie Chapman, RPh
`Scott Snyder, RPh
`Thomas Denson, RPh
`Ken Turner, RPh
`Anne Marie Ford, RPh
`Gene Woo, RPh
`Ben Fry, RPh
`John A. Yakim, RPh
`Sam Georgiou, RPh
`John G. Yakim, RPh
`
`Editorial
`
`122 N. Bryant, Edmond, OK 73034-6301 USA
`1-800-757-4572, 405-330-0094, Fax: 405-330-5622
`
`Advertising Sales
`
`Leslie Ross, email: lross@ijpc.com
`P.O. Box 820148, Houston, TX 77282-0148 USA
`Tel: 800-661- 4572 Fax: 800-494-4572
`
`Circulation
`
`Andy Bernick, 1-888-588-4572
`
`Federal
`
`HCFA Proposes to Remove
`Requirement for Pharmacists
`The Health Care Financing Administra-
`tion (HCFA) has proposed changes to the
`conditions of participation for hospitals
`that participate in Medicare and Medicaid.
`The proposed changes would eliminate the
`requirement for “pharmacists” to develop,
`supervise and coordinate the pharmacy ser-
`vices of the hospital. Instead, HCFA pro-
`poses “…that before medications are
`administered, a licensed nurse, or a physi-
`cian…review the patient’s information and
`the drug order.” In the proposal HCFA
`says that the nurse could report any po-
`tential errors to the physician. These revi-
`sions were published in the December 19,
`1997, Federal Register and can be found in
`full on the Government Printing Office’s
`website at www.gpo.gov. Comments on the
`proposed changes were due the middle of
`April, after which time HCFA will prepare
`a response.
`FDA Calls for Chemicals for Compounding
`Section 127 of the Food and Drug Ad-
`ministration (FDA) Modernization Act of
`1997 requires the FDA to list bulk drug
`substances that may be used in pharmacy
`compounding. The agency has posted a
`notice on its webpage (www.fda.gov) for
`“interested groups and individuals” to “begin
`considering” chemicals for inclusion on
`this list. The posting promises to print a more
`detailed notice in an upcoming Federal Reg-
`ister that will list requirements for inclusion
`of chemicals.
`Calendar
`
`■ American College for Advancement in
`Medicine, 1998 Spring Conference
`Ft. Lauderdale, FL
`April 30 - May 3, 1998
`800-532-3688
`
`■ Canadian Pharmacists Association
`86th Annual Conference
`St. John’s, Newfoundland, Canada
`May 24-26,1998
`800-917-9489
`■ Natural Pharmacy West
`Marriott’s Rancho Las Palmas Resort
`Rancho Mirage, CA
`May 29-31, 1998
`1-800-5-BIOCON
`■ National Community Pharmacist’s
`Association Rx Expo/NHIA/ACA
`Midyear Meeting
`Pittsburgh, PA
`May 6-9, 1998
`800-544-7447
`■ American Society of Health-System
`Pharmacists Annual Convention
`Baltimore, MD
`May 30 - June 4, 1998
`301-657-4383
`International Academy of
`Compounding Pharmacists*
`Compounders On Capitol Hill
`Washington Court Hotel
`Washington, D.C.
`June 17-18, 1998
`800-927-4227
`■ World Congress of Pharmacy &
`Pharmaceutical Sciences/ International
`Pharmaceutical Students
`Federation Annual Congress
`Cairo, Egypt
`August 16-26, 1998
`www.pharmweb/pharmweb/fip.html
`■ American Society of Health-System
`Pharmacists Home Care ‘98
`Chicago, IL
`August 22-24, 1998
`301-657-4383
`1998 American College of
`Apothecaries Annual Conference
`Four Seasons Hotel
`Toronto, Ontario, Canada
`August 26-30, 1998
`800-828-5933
`■ National Community Pharmacist’s
`Association Annual Convention
`St. Louis, MO
`
`180 International Journal of Pharmaceutical Compounding
`Vol.2 No.3 May/June 1998
`
`MYLAN Ex. 1006, Page 5
`
`■
`■
`

`
`W E B R E V I E W S
`
`October 17-21, 1998
`703-683-8200
`■ Parenteral Drug Association
`Annual Meeting and Exhibition
`Washington, D.C.
`November 9-11, 1998
`301-986-0293
`■ American College of Clinical Pharmacy
`Annual Meeting
`Cincinnati, OH
`November 9-12, 1998
`816-531-2177
`■ National Hospice Organization 20th
`Annual Symposium and Exposition
`Adams Mark Hotel
`Dallas, TX
`November 14-17, 1998
`703-243-5900
`
`■ American Association of Pharmaceutical
`Scientists Annual Meeting and Exposition
`Moscone Convention Center
`San Francisco, CA
`November 15-19, 1998
`703-548-3000
`■ Medtrade 1998 Healthcare Conference
`Atlanta, GA
`November 18-21, 1998
`770-641-8181
`■ American Society of Health-System
`Pharmacists Mid-Year Clinical Meeting
`Las Vegas, NV
`December 6-10, 1998
`301-657-4383
`
`*Offering continuing education in
`compounding
`
`T h a n k s t o . . .
`The International Journal of
`Pharmaceutical Compounding
`would like to thank the Uni-
`versity of Houston College of
`Pharmacy for allowing us to
`borrow and photograph the
`mortars and pestles that
`appeared on the cover of our March/April issue.
`
`We would also like to thank
`Lawson Kloesel, RPh, for loan-
`ing us the 19th century mortar
`and pestle that appears on
`the cover of this issue. The
`cast-iron mortar is 8 1⁄2 x 8 1⁄2
`inches and the pestle is 11
`inches long.
`
`International Journal of Pharmaceutical Compounding
`Vol.2 No.3 May/June 1998
`
`181
`
`MYLAN Ex. 1006, Page 6
`
`

`
`W E B R E V I E W S
`
`Web Reviews
`
`Eurekalert
`www.eurekalert.org
`This where-to-get-started site for con-
`ducting research caters to journalists re-
`searching various medical and scientific
`topics and has up-to-date and comprehen-
`sive information. The page is corporate
`sponsored and offers links to research in-
`stitutions and medical associations, as well
`as a medical dictionary and directory of
`on-line medical resources. The directory of
`medical links is extensive, including uni-
`versities, government listings, museums
`and corporations. Medical research journals
`
`are also available here, for example, The
`Lancet, JAMA, and the New England Jour-
`nal of Medicine.
`HMS Beagle
`www.biomednet.com/hmsbeagle
`While a slow site to download and navi-
`gate, the HMS Beagle, a BioMedNet mag-
`azine, is another site conducive to research.
`Compiled here from various journals are
`medical research news, breakthroughs and
`drug updates, all available through a search
`engine. This site is updated daily with news
`relating to biological sciences, medicine/
`health and biotech/pharmacy. The great
`thing about this site is that it gives a syn-
`opsis and then navigates beyond to journal
`home pages, contents, and abstracts, pro-
`viding researchers with full text articles,
`
`182 International Journal of Pharmaceutical Compounding
`Vol.2 No.3 May/June 1998
`
`when they’re available, without the hassle
`of having to browse another journal’s web-
`site. To have full access to this site, you
`have to register. Registration is free but
`requires personal information.
`American Academy of Ophthalmology
`www.eyenet.org
`This is the webpage for the American
`Academy of Ophthalmology (AAO) and a
`good starting point for basic information on
`eye diseases, treatments and structure. The
`site is geared for the public, as well as the
`health care practitioner. There is enter-
`taining information, such as history and
`trivia, and an on-line museum of eyewear
`– pictures included. One of the site fea-
`tures is “Find An Ophthalmologist.” When
`a city and state are entered, every member
`of the AAO in that area appears in alpha-
`betical order. The site’s ophthalmology
`links are also user friendly and searchable
`by topic.
`Wilmer Eye Institute
`http://www.wilmer.jhu.edu/
`This is the Wilmer Eye Institute at John
`Hopkins. The Wilmer Institute is known
`throughout the world, not only for research
`but also for management of complex and se-
`rious eye cases. American physicians have
`ranked Wilmer the country’s No. 1 eye de-
`partment in the U.S. News & World Report
`physician survey this year and for six of the
`previous seven years. Check out the eye
`structure and glossary linked to this page
`at http://webeye.ophth.uiowa.edu/coms/
`booklet/book1.htm. This is a place to go to
`find current clinical trials and studies.
`Medical Matrix
`http://www.medmatrix.org/Index.asp
`Medical Matrix is a ranked, peer-reviewed,
`annotated, updated, clinical medicine
`resource, with free registration with no so-
`licitation clause if access to full text is de-
`sired. It has more than 3,000 medical listings
`by topics such as disease, education, pro-
`fession, literature, etc. Links are starred to
`indicate ranking, much like a listing of
`movies. This is one of the most extensive list-
`ings of medical sites on the worldwide web.
`
`MYLAN Ex. 1006, Page 7
`
`

`
` '1.
`-Jninlgs need diéfary suppurt,
`especially fur pimple with
`nste:1arthriti3*,
`
`1
`
`i-I .-.' .r:--n.:- I'II:'i.'I:|
`HIE
`'.~.'-._."~. '1-.
`'.'.'-'- |1I.'-'- I::.| 1!
`'_II.'
`|'I'._‘.'.
`-.
`. :I'|I:
`
`I1 .'
`
`'|..'
`
`I.
`
`|'- ‘I-E I."I '!_E |I-|..4.'iII-E EIII. ..|I.:I-Cllli-I. '\=..'|.'|I.'|'III..'.:.'Z
`
`|!'.III|'r um." '-I;T'|'|:|III.'l-'.I i:-. Ill:-|IE|1I'.'-\.'l .1I'.-J :|iI1i|.T|":.' Trr-an L1‘. '
`i:r. r.-.:.
`'|..' -.p.. -'. n':|r|-.'..-.1.-:|[H-.'| -|:I| ;|:|:.;-. -a_-.'.l
`'-
`:-:J-
`:-:r -',.- .'
`'.' h:.'2I."-'
`
`-
`
`'. |‘E.'| I-..:.'1~E.'III-I:| "- |.":'._I.t'.||.":'..IrIIIiI.1'I. fi]II:IIImIi.-..' !"Iu||'iI~:.
`
`|'.1I.I.'II':
`||1I.'
`TIII: |_"'I'-IHII ‘in ‘i1:
`|-'-'|-.'.|E|!u'
`."!:1-.-'.'h;-'-::I.':'-I.-Iu.'.-..I.I'u.'.-. !'i.,.-I'.I-.-I'= :I:-. .--.'.-.
`III' -..'I:.!
`. :-.'.|
`I- - '-:I--:"-.-'I.'i|:
`III :II'.
`.":.II1-E"..'I: I.|iII.-.'.|. '-J:|.:I'.|-
`'.'.-.I'."-I.'. '-.I'||' -|.:.'II.'I|':.
`i.'I|.-.'I:_:.|'::|II-..'I'|| ."||
`.|.-I; _-1: |'| -'.'
`|'I:'...'|I.I'I.I II‘
`I
`I5-E.| EI";'.r- .'.I:'|'5.'I!! T.‘-Z2 |.'|.|-.I 1 .'."I'|! :'IIIIZJ|I. H
`
`__
`
`3.'J|Ir I.11I".':I.I.-..':.'J'III'.'I'_"_I.'|2I:I'rIr..'.II'
`
`|'..I |ml'I!_|':II'n.' nu.-h'.51_.|r.
`
`|1I.I-.|'!'.'.'n::.'I '-. '.'I.'
`
`|'I'.
`
`" ‘-2 Il'_''
`
`3-
`
`''u_ 1..-
`
`'..!- |"II:-.I.'I.".'
`|n'a.'|I-I.IE |.': H.I.|ZJ 1-3:‘.-r;I'I.
`J::.!
`I-'.
`'..': I'll
`.'
`.'I..
`.'III I-:' I_.'|II.' I-.I::'I:I.'
`"Jrr-.'
`I‘-.
`' "'1: ' =.|'|-I-I _ '-II I
`. -c' r '.'
`-._'-
`
`I'J~I.'.1
`'1.
`'I..'.
`
`- '..-.Z:.II.'
`'.'-'--'
`I I-.':
`
`|:.::rlE|:.|_:r
`|.'-£l.'|-|:'!TJ.|:|:'
`|:|i.'.|ii:-:l|J5' pr-:I-.'u.u1 1:-:I
`::|I' I-.I|' '.'. II:I: J'I- -..i|::. :'-\.'.":I:'. 2'3I:|'-|I.' :I- ...'I.-."r.~I.'.'I ..'_'.':..|-. '. .:-..!
`.-J'l'.:-
`I Ji: I|'-:|- I. *- d.I. :r 'I- ‘u|H‘.- :I.'|'.I.r.r:-..1|;|.,'
`|I- I.'I.|_ . .I -'-.
`.
`:-.'!.'.5|
`I-'|.'- 'i|III'I I.'."I. |.'.I."- J.'Z||£.I|I
`|I.'.:'.|'.|lI.' 2|".
`|.|II::J;|:.'.
`
`._'_J..'
`|..'..':'I -.'..'
`':!1-.' -.i"...'.-I |'n'- .'i:I-.|
`|'IIr'h.'
`II|I.'rI.' .|:::. |:I..|'
`'II|'r.'.'.'..|
`"I. .'..'.'r.u-I
`.".-"uir .'_.' -:'|I'II.'
`-.|"|':I|_' 1I|.| r.-.'|
`l|'| .-.-.-.'.
`-5 1|-.' .'."I'|'.l"I'|-."-I.'J..'-r'L'. ;.-J: -:I:---"':Iu.--..:":::-:.:::-I
`
`IIJ--'. JII J!:II'I'1I.I"II '.'.-\.' .II'|.'-'- II-:.':' I3
`
`'.'._' ..:n =.|'.'.-
`'--.' _-'. .'|n.|- I‘: -'-..' II'II'-\:|:.J'_|-'J.II ' -'.._'
`._
`l'-'
`I-I. ;.'I--. ;I |.I f."-.ICf:-
`|.: L‘-.I I-I"I'I.."."':'I|:.'I'. .-.-
`|I:I'I'.I.""..I III.-
`:':.:‘-
`I"- '.'.‘-II
`|.' ELI. ‘II’-
`
`I.!.|lv;lr1I'lIr:I.'I-D-1I.'J
`'I'.-.'.- .'| |!:.'“.'
`I' IE".'
`3..-."'.:.'lI
`II.‘-:III'_ .'I II.'! I.'I|::r\.'.'.'.
`-I L: I:: !I:'III-I.'. '-J..'.- -.-"
`El."-.::-rI'-.
`|'|II |I'I|' '..'IIII-I in.-.I.Z-I - -.'. II '
`:""' "' -' "' "'7' "'I'T""'|""' "“' """ f'""""”"""""E |'|"'"" 1:"
`---.-.|-.|.I1‘-5|-.:';.-.!I-::lI.'1IL'I.
`-'-..uI:'p.'-l:.'ruE'I-.::u:r:l.-1:‘;
`-|.lvlIIl:'-:|-..'.'a. "I..I.I:I|:-!I.:.|i.J.-. I.I|I:' 5|-:r:.I'II: IIIIJIIIJI '.~.'
`.1.'.
`-.'
`.'
`'- -.|||-..'...'.-.:.'u_- II-JII:
`'|.'.|n|n'
`'-'1-'|-|':'.II-.'~._-.1r.r--.-r._
`-in-'3' -'- 'I|Ji'-:Eu-'-!'-'.
`-"'-:'-'- '--'I-'-l|'-"-'-I'--'
`'-' 3'|'"5= |'=I!-.:'
`'
`.'.-..~.'
`I i.5II::":".'I IIu:I'»,'r'..'I".. mI:In_:_-'r.|I.'r
`.'.'iI:Ii.1:-.'-.
`
`I
`|5 .:|I-_..3.:-
`'_|"_I-"_. I:hE_'_.,“.
`.\_- --:|1_- ."_-:-,-_-.J|_-.-_|_-[1-..-"
`_:--\.I_ H_ II.
`|"_-.._.-_- :|- 1|.-'1'--_--.: ||-_:
`-|:“ ._ ._: "r_,_ _ |.“__";._.|
`-_.;|,_- __|_-_.“|___- I-I-, ._.__- .
`_'I|-:_1_,_H_'I|”r_:u 31'.
`|.'|.:-.-n.|'..'n-- .IlJ:'. Ir :'|..'..':. ..||I] SIJIII 55.‘!
`I.‘!"I\'.|
`"
`
`'.'-.. u. -,-_ n._.u |I-._;;-'
`
`|._.r._-H.-_-, ,_- .--
`
`-I ..r|.--.|-..'I -:I ;|'-:r.1.':--'-.'.-.'--..m..;. -:.-.' -.- :::: .'...'-.---.;:u..'.-.
`I-
`.__||;|._-_ _ .|
`j
`:-:!I_I _-'._=,3 :_=|'II_ 2- .“ _=| :.u
`
`E .'%LH' -_.-:I.'.'.".'
`
`.
`
`."_ 1'
`
`':'."'|'-'.L|-'.JI.""'.-:-a1'.
`
`H
`
`I
`
`-.-.
`
`.
`
`.
`
`.
`
`I
`
`'-
`
`.
`
`'-
`
`.
`
`_
`
`'
`
`I
`
`.
`
`
`
`MYLAN Ex. 1006, Page 8
`
`

`
`O P H T H A L M I C
`
`The impor tance
`
`of using
`
`nonirr itating,
`
`compatible
`
`ingredients
`
`cannot
`
`be over-
`
`emphasized.
`
`Compounding
`Ophthalmic
`Preparations
`
`Ophthalmic prepara-
`tions include solutions,
`ointments and suspen-
`sions. Ophthalmic so-
`lutions are sterile, free
`from foreign particles
`and especially prepared
`for instillation into the
`eye. Ophthalmic oint-
`ments are sterile prepa-
`rations of an ointment
`base with or without an
`active drug, designed
`for application to the
`eye. Ophthalmic sus-
`pensions are sterile liq-
`uid preparations that
`contain solid particles
`in a suitable vehicle in-
`tended for instillation
`into the eye.
`In addition to the ac-
`tive drugs, ophthalmic
`preparations contain a
`number of excipients,
`including vehicles,
`buffers, preservatives,
`tonicity-adjusting agents, antioxidants and viscosity enhancers.
`Important in the formulation process is the use of ingredients
`that are nonirritating and compatible with the eyes. When formulating
`ophthalmic preparations, what is appropriate for one formula
`may not work for another; each drug must be considered based
`on its properties and its compatibility and stability with
`various excipients.
`
`184 International Journal of Pharmaceutical Compounding
`Vol.2 No.3 May/June 1998
`
`MYLAN Ex. 1006, Page 9
`
`

`
`O P H T H A L M I C
`
`Preparation Methods and Techniques
`All work must be done in a clean-air environment by qualified,
`aseptic compounding pharmacists. The source of all ingredients
`must be the highest grade that can be reasonably obtained.
`Solutions
`
`1. Accurately weigh/measure each ingredient.
`2 Dissolve the ingredients in about three fourths of the quan-
`tity of sterile water for injection and mix well.
`3. Add sufficient sterile water for injection to volume and mix well.
`4. Determine the pH, clarity and other quality control factors from
`a sample of the solution and make any necessary adjustments.
`5. Filter through a sterile 0.2-µm filter into a sterile ophthalmic
`container.
`6. Package and label.
`7.
`If a large number are to be prepared, select a random sample
`to be checked for sterility and to be assayed.
`Suspensions – Two Methods
`
`1. Accurately weigh/measure each ingredient.
`2. Dissolve/mix the ingredients in about three fourths of the
`quantity of sterile water for injection and mix well.
`3. Add sufficient sterile water for injection to volume and mix well.
`4. Determine the pH, and other quality control factors from a sam-
`ple of the suspension and make any necessary adjustments.
`5. Package in a suitable container for autoclaving.
`6. Autoclave, cool and label.
`7.
`If a large number are to be prepared, select a random sample
`to be checked for sterility and to be assayed.
`
`Or
`1. Accurately weigh/measure each ingredient.
`2. Sterilize each of the ingredients by a suitable method.
`3. Dissolve/mix the ingredients in about three fourths of the
`quantity of sterile water for injection and mix well.
`4. Add sufficient sterile water for injection to volume and mix well.
`5. Determine the pH, and other quality control factors, from a
`sample of the suspension and make any necessary adjustments.
`6. Package and label.
`7.
`If a large number are to be prepared, select a random sample
`to be checked for sterility and to be assayed.
`Ointments
`
`1. Accurately weigh/measure each ingredient.
`2. Sterilize each of the ingredients by a suitable method.
`3. Mix each of the ingredients with the sterile vehicle.
`4. Determine the quality control factors from a sample of the
`product.
`5. Package and label.
`6.
`If a large number are to be prepared, select a random sample
`to be checked for sterility and to be assayed.
`
`Did you know?
`
`● The normal volume of fluid in the eye is about 10 µL;
`the volume of a drop is much larger, i.e., between 25 to
`50 µL. A dose of more than one drop delivered at the same
`time may be questionable.
`If more than one drop or more than one drug is to
`be administered, wait at least five minutes between
`doses to allow the drug to be distributed and absorbed.
`Immediately after instilling a drop into the eye, plac-
`ing pressure on the lacrimal sac for one to two minutes
`will help decrease systemic absorption of the drug that
`occurs when the drug is removed via the nasolacrimal duct.
`Individuals with baggy lower eyelids may actually
`have greater absorption of drugs from ophthalmic dosage
`forms because of the larger cul-de-sac that serves as a
`reservoir.
`● The bioav