Opiant Exhibit 2041
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 1
`
`

`

`Ansel’s Pharmaceutical
` Dosage Forms and
`Drug Delivery Systems
`
`NINTH EDITION
`
`Loyd V. Allen, Jr., PhD
`Professor and Chair Emeritus
`Department of Medicinal Chemistry and Pharmaceutics
`College of Pharmacy
`University of Oklahoma
`Editor-in-Chief
`International Journal of Pharmaceutical Compounding
`
`Nicholas G. Popovich, PhD
`Professor and Head
`Department of Pharmacy Administration
`College of Pharmacy
`University of Illinois at Chicago
`
`Howard C. Ansel, PhD
`Professor and Dean Emeritus
`College of Pharmacy
`The University of Georgia
`
`FM.indd i
`
`10/22/2009 9:53:56 PM
`
`Opiant Exhibit 2041
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 2
`
`

`

`FM.indd ii
`
`10/22/2009 9:53:56 PM
`
`Opiant Exhibit 2041
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 3
`
`

`

`SECTION I
`INTRODUCTION TO DRUGS, DRUG DOSAGE FORMS,
`AND DRUG DELIVERY SYSTEMS
`
`CHAPTER
`
`1
`
`Introduction to Drugs
`and Pharmacy
`
`After reading this chapter, the student will be able to:
`1. Describe the development and purpose of the United States Pharmacopeia
`(USP) and the National Formulary (NF)
`2. Describe the central features of a typical drug monograph
`3. Compare and contrast signifi cant drug regulation and control federal laws
`and their impact on pharmacy
`4. Explain the concept of pharmaceutical care
`5. Summarize the Code of Ethics for Pharmacists of the American Pharmacists
`Association
`6. Summarize the Code of Ethics of the American Association of
` Pharmaceutical Scientists (AAPS)
`
`OBJECTIVES
`
`A drug is defi ned as an agent intended for use
`in the diagnosis, mitigation, treatment, cure, or
`prevention of disease in humans or in other
` animals (Food, Drug, and Cosmetic Act, 1938).
`One of the most astounding qualities of drugs is
`the diversity of their actions and effects on the
`body. This quality enables their selective use in
`the treatment of a range of common and rare
`conditions involving virtually every body organ,
`tissue, and cell.
`Some drugs selectively stimulate the cardiac
`muscle, the central nervous system, or the gas-
`trointestinal tract, whereas other drugs have the
`opposite effect. Mydriatic drugs dilate the pupil
`of the eye, and miotics constrict or diminish
`pupillary size. Drugs can render blood more
`coagulable or less coagulable; they can increase
`the hemoglobin content of the erythrocytes,
`reduce serum cholesterol, or expand blood
` volume.
`induce vomiting,
`Drugs termed emetics
`whereas antiemetic drugs prevent vomiting.
`
`Diuretic drugs increase the fl ow of urine;
` expectorant drugs increase respiratory tract fl uid;
`and cathartics or laxatives evacuate the bowel.
`Other drugs decrease the fl ow of urine, diminish
`body secretions, or induce constipation.
`Drugs may be used to reduce pain, fever,
`thyroid activity, rhinitis, insomnia, gastric acid-
`ity, motion sickness, blood pressure, and men-
`tal depression. Other drugs can elevate mood,
`blood pressure, or activity of the endocrine
`glands. Drugs can combat infectious disease,
`destroy intestinal worms, or act as antidotes
`against the poisoning effects of other drugs.
`Drugs can assist in smoking cessation or alco-
`hol withdrawal or can modify obsessive–
`compulsive disorders.
`Drugs are used to treat common infections,
`AIDS, benign prostatic hyperplasia, cancer, car-
`diovascular disease, asthma, glaucoma, Alzheimer
`disease, and male impotence. They can protect
`against the rejection of transplanted tissues and
`organs and reduce the incidence of measles and
`1
`
`Chap01.indd 1
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`10/22/2009 8:48:55 PM
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`Opiant Exhibit 2041
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 4
`
`

`

`2
`
`SECTION I • DRUGS, DRUG DOSAGE FORMS, AND DRUG DELIVERY SYSTEMS
`
`mumps. Antineoplastic drugs provide one means
`of attacking the cancerous process; radioactive
`pharmaceuticals provide another. Drugs may be
`used to diagnose diabetes, liver malfunction,
`tuberculosis, or pregnancy. They can replenish a
`body defi cient in antibodies, vitamins, hormones,
`electrolytes, protein, enzymes, or blood. Drugs
`can prevent pregnancy, assist fertility, and sus-
`tain life itself.
`Certainly, the vast array of effective medicinal
`agents available today is one of our greatest
`scientifi c accomplishments. It is diffi cult to con-
`ceive our civilization devoid of these remarkable
`and benefi cial agents. Through their use, many of
`the diseases that have plagued humans through-
`out history, such as smallpox and poliomyelitis,
`are now virtually extinct. Illnesses such as diabe-
`tes, hypertension, and mental depression are
`effectively controlled with modern drugs. Today’s
`surgical procedures would be virtually impossible
`without the benefi t of anesthetics, analgesics,
`antibiotics, blood transfusions, and intravenous
`fl uids.
`New drugs may be derived from plant or
` animal sources, as by-products of microbial
`growth, or through chemical synthesis, molecu-
`lar modifi cation, or biotechnology. Computer
`libraries and data banks of chemical compounds
`and sophisticated methods of screening for
`potential biologic activity assist drug discovery.
`The process of drug discovery and develop-
`ment is complex. It entails the collective contri-
`butions of many scientifi c specialists, including
`organic, physical, and analytical chemists; bio-
`chemists; molecular biologists; bacteriologists;
`physiologists; pharmacologists; toxicologists;
`hematologists; immunologists; endocrinologists;
`pathologists; biostatisticians; pharmaceutical
` scientists; clinical pharmacists; physicians; and
`many others.
`After a potential new drug substance is dis-
`covered and undergoes defi nitive chemical and
`physical characterization, a great deal of biologic
`information must be gathered. The basic phar-
`macology, or the nature and mechanism of action
`of the drug on the biologic system, must be
`determined including toxicologic features. The
`drug’s site and rate of absorption, its pattern
`of distribution and concentration within the
`body, its duration of action, and the method and
`rate of its elimination or excretion must be stud-
`ied. Information on the drug’s metabolic degra-
`dation and the activity of any of its metabolites
`
`must be obtained. A comprehensive study of the
` short-term and long-term effects of the drug on
`various body cells, tissues, and organs must be
`made. Highly specifi c information, such as the
`effect of the drug on the fetus of a pregnant
` animal or its ability to pass to a nursing baby
`through the breast milk of its mother, may be
`obtained. Many a promising new drug has been
`abandoned because of its potential to cause
`excessive or hazardous adverse effects.
`The most effective routes of administration
`(e.g., oral, rectal, parenteral, topical) must be
`determined, and guidelines for the dosages rec-
`ommended for persons of varying ages (e.g., neo-
`nates, children, adults, geriatrics), weights, and
`states of illness have to be established. It has
`been said that the only difference between a
`drug and a poison is the dose. To facilitate
` administration of the drug by the selected routes,
`appropriate dosage forms, such as tablets, cap-
`sules, injections, suppositories, ointments, aero-
`sols, and others, are formulated and prepared.
`Each of these dosage units is designed to contain
`a specifi ed quantity of medication for ease and
`accuracy of dosage administration. These dosage
`forms are highly sophisticated delivery systems.
`Their design, development, production, and use
`are the product of application of the pharma-
`ceutical sciences—the blending of the basic,
`applied, and clinical sciences with pharmaceuti-
`cal technology.
`Each particular pharmaceutical product is a
`formulation unique unto itself. In addition to the
`active therapeutic ingredients, a pharmaceutical
`formulation contains a number of nontherapeu-
`tic or pharmaceutical ingredients. It is through
`their use that a formulation achieves its unique
`composition and characteristic physical appear-
`ance. Pharmaceutical ingredients include such
`materials as fi llers, thickeners, solvents, suspen-
`ding agents, tablet coatings and disintegrants,
`penetration enhancers, stabilizing agents, anti-
`microbial preservatives, fl avors, colorants, and
`sweeteners.
`To ensure the stability of a drug in a formula-
`tion and the continued effectiveness of the drug
`product throughout its usual shelf life, the prin-
`ciples of chemistry, physical pharmacy, microbi-
`ology, and pharmaceutical technology must be
`applied. The formulation must be such that
`all components are physically and chemically
` compatible, including the active therapeutic
`agents, the pharmaceutical ingredients, and the
`
`Chap01.indd 2
`
`10/22/2009 8:48:56 PM
`
`Opiant Exhibit 2041
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 5
`
`

`

`
`
`CHAPTER 1 • INTRODUCTION TO DRUGS AND PHARMACY
`
`3
`
` packaging materials. The formulation must be
` preserved against decomposition due to chemi-
`cal degradation and protected from microbial
`contamination and the destructive infl uences of
`excessive heat, light, and moisture. The thera-
`peutic ingredients must be released from the
`dosage form in the proper quantity and in such a
`manner that the onset and duration of the drug’s
`action are that which are desired. The pharma-
`ceutical product must lend itself to effi cient
`administration and must possess attractive
` features of fl avor, odor, color, and texture that
`enhance acceptance by the patient. Finally,
`the product must be effectively packaged and
`clearly and completely labeled according to legal
` regulations.
`Once prepared, the pharmaceutical product
`must be properly administered if the patient is to
`receive maximum benefi t. The medication must
`be taken in suffi cient quantity, at specifi ed inter-
`vals, and for an indicated duration to achieve the
`desired therapeutic outcomes. The effectiveness
`of the medication in achieving the prescriber’s
`objectives should be reevaluated at regular inter-
`vals and necessary adjustments made in the dos-
`age, regimen, schedule, or form, or indeed, in
`the choice of the drug administered. Patients’
`expressions of disappointment in the rate of
`progress or complaints of side effects to the pre-
`scribed drug should be evaluated and decisions
`made as to the continuance, adjustment, or
`major change in drug therapy. Before initially
`taking a medication, a patient should be advised
`of any expected side effects and of foods, bever-
`ages, and/or other drugs that may interfere with
`the effectiveness of the medication.
`Through professional interaction and com-
`munication with other health professionals, the
`pharmacist can contribute greatly to patient care.
`An intimate knowledge of drug actions, pharma-
`cotherapeutics, formulation and dosage form
`design, available pharmaceutical products, and
`drug information sources makes the pharmacist
`a vital member of the health care team. The
`pharmacist is entrusted with the legal responsi-
`bility for the procurement, storage, control, and
`distribution of effective pharmaceutical products
`and for the compounding and fi lling of prescrip-
`tion orders. Drawing on extensive training and
`knowledge, the pharmacist serves the patient as
`an advisor on drugs and encourages their safe
`and proper use through patient counseling. The
`pharmacist delivers pharmaceutical services in a
`
`variety of community and institutional health
`care environments and effectively uses medica-
`tion records, patient monitoring, and assessment
`techniques in safeguarding the public health.
`To appreciate the progress that has been
`made in drug discovery and development and to
`provide background for the study of modern
`drugs and pharmaceutical dosage forms, it is
`important to examine pharmacy’s heritage.
`
`THE HERITAGE OF PHARMACY
`
`Drugs, in the form of vegetation and minerals,
`have existed as long as humans. Human disease
`and the instinct to survive have led to their dis-
`covery through the ages. The use of drugs,
`crude though they may have been, undoubt-
`edly began long before recorded history, for
`the instinct of primitive man to relieve the pain
`of a wound by bathing it in cool water or by
`soothing it with a fresh leaf or protecting it with
`mud is within the realm of belief. From experi-
`ence, early humans would learn that certain
`therapy was more effective than others, and
`from these beginnings came the practice of
`drug therapy.
`Among many early races, disease was believed
`to be caused by the entrance of demons or evil
`spirits into the body. The treatment naturally
`involved ridding the body of the supernatural
`intruders. From the earliest records, the primary
`methods of removing spirits were through the
`use of spiritual incantations, the application of
`noisome materials, and the administration of
`specifi c herbs or plant materials.
`
`THE FIRST APOTHECARY
`Before the days of the priestcraft, the wise man
`or woman of the tribe, whose knowledge of the
`healing qualities of plants had been gathered
`through experience or handed down by word of
`mouth, was called upon to attend to the sick or
`wounded and prepare the remedy. It was in the
`preparation of the medicinal materials that the
`art of the apothecary originated.
`The art of the apothecary has always been
`associated with the mysterious, and its practitio-
`ners were believed to have connection with the
`world of spirits and thus performed as interme-
`diaries between the seen and the unseen. The
`belief that a drug had magical associations meant
`that its action, for good or for evil, did not
`
`Chap01.indd 3
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`Opiant Exhibit 2041
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 6
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`140
`
`SECTION II • DRUG DOSAGE FORM AND DRUG DELIVERY SYSTEM DESIGN
`
`them unavailable for their preservative function.
`It is essential for the research pharmacist to
`examine all formulative ingredients as one affects
`the other to ensure that each agent is free to do
`its job. In addition, the preservative must not
`interact with a container, such as a metal oint-
`ment tube or a plastic medication bottle, or with
`an enclosure, such as a rubber or plastic cap or
`liner. Such an interaction could result in decom-
`position of the preservative or the container clo-
`sure or both, causing decomposition and
` contamination. Appropriate tests should be
`devised and conducted to prevent this type of
`preservative interaction.
`
` •
` •
`
` •
`
`Mode of Action
`Preservatives interfere with microbial growth,
`multiplication, and metabolism through one or
`more of the following mechanisms:
`Modifi cation of cell membrane permeability
` •
`and leakage of cell constituents (partial lysis)
`Lysis and cytoplasmic leakage
`Irreversible coagulation of cytoplasmic con-
`stituents (e.g., protein precipitation)
`Inhibition of cellular metabolism, such as by
`interfering with enzyme systems or inhibition
`of cell wall synthesis
` •
`Oxidation of cellular constituents
`
`Hydrolysis
` few of the commonly used pharmaceutical
`preservatives and their probable modes of action
`are presented in Table 4.6.
`
`• A
`
`Preservative Utilization
`Suitable substances may be added to a pharma-
`ceutical preparation to enhance its permanency or
`usefulness. Such additives are suitable only if they
`are nontoxic and harmless in the amounts admin-
`istered and do not interfere with the therapeutic
`effi cacy or tests or assays of the preparation. Cer-
`tain intravenous preparations given in large vol-
`umes as blood replenishers or as nutrients are not
`permitted to contain bacteriostatic additives,
`because the amounts required to preserve such
`large volumes would constitute a health hazard
`when administered to the patient. Thus prepara-
`tions like dextrose injection, USP, and others com-
`monly given as fl uid and nutrient replenishers by
`intravenous injections in amounts of 500 to
`1,000 mL may not contain antibacterial preserva-
`tives. On the other hand, injectable preparations
`
` •
`
` •
`
`The preservative is completely compatible
`with all other formulative ingredients and
`does not interfere with them, nor do they
`interfere with the effectiveness of the preser-
`vative agent.
`The preservative does not adversely affect the
`preparation’s container or closure.
`
`General Preservative Considerations
`Microorganisms include molds, yeasts, and bac-
`teria, with bacteria generally favoring a slightly
`alkaline medium and the others an acid medium.
`Although few microorganisms can grow below
`pH 3 or above pH 9, most aqueous pharmaceuti-
`cal preparations are within the favorable pH
`range and therefore must be protected against
`microbial growth. To be effective, a preservative
`agent must be dissolved in suffi cient concentra-
`tion in the aqueous phase of a preparation. Fur-
`thermore, only the undissociated fraction or
`molecular form of a preservative possesses pre-
`servative capability, because the ionized portion
`is incapable of penetrating the microorganism.
`Thus, the preservative selected must be largely
`undissociated at the pH of the formulation being
`prepared. Acidic preservatives like benzoic, boric,
`and sorbic acids are more undissociated and thus
`more effective as the medium is made more acid.
`Conversely, alkaline preservatives are less effec-
`tive in acid or neutral media and more effective in
`alkaline media. Thus, it is meaningless to suggest
`preservative effectiveness at specifi c concentra-
`tions unless the pH of the system is mentioned
`and the undissociated concentration of the agent
`is calculated or otherwise determined. Also, if
`formulative materials interfere with the solubility
`or availability of the preservative agent, its chem-
`ical concentration may be misleading, because it
`may not be a true measure of the effective con-
`centration. Many incompatible combinations of
`preservative agents and other pharmaceutical
`adjuncts have been discovered in recent years,
`and undoubtedly many more will be uncovered
`in the future as new preservatives, pharmaceuti-
`cal adjuncts, and therapeutic agents are combined
`for the fi rst time. Many of the recognized incom-
`patible combinations that inactivate the preserva-
`tive contain macromolecules, including various
`cellulose derivatives, polyethylene glycols, and
`natural gums. These include tragacanth, which
`can attract and hold preservative agents, such as
`the parabens and phenolic compounds, rendering
`
`Chap04.indd 140
`
`10/22/2009 8:41:55 PM
`
`Opiant Exhibit 2041
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 7
`
`

`

`
`
`CHAPTER 4 • PHARMACEUTICAL AND FORMULATION CONSIDERATIONS
`
`141
`
`TABLE 4.6 PROBABLE MODES OF ACTION OF SOME PRESERVATIVES
`
`PRESERVATIVE
`
`PROBABLE MODES OF ACTION
`
`Benzoic acid, boric acid, p-hydroxybenzoates
`
`Denaturation of proteins
`
`Phenols and chlorinated phenolic compounds
`
`Alcohols
`
`Quaternary compounds
`
`Mercurials
`
`Lytic and denaturation action on cytoplasmic membranes and
`for chlorinated preservatives, also by oxidation of enzymes
`
`Lytic and denaturation action on membranes
`
`Lytic action on membranes
`
`Denaturation of enzymes by combining with thiol (-SH) groups)
`
`given in small volumes—for example, morphine
`sulfate injection, USP, which provides a therapeutic
`amount of morphine sulfate in approximately a
`1-mL volume—can be preserved with a suitable
`preservative without the danger of the patient
`receiving an excessive amount of the preservative.
`Examples of the preservatives and their con-
`centrations commonly employed in pharmaceu-
`tical preparations are benzoic acid (0.1% to
`0.2%), sodium benzoate (0.1% to 0.2%), alcohol
`(15% to 20%), phenylmercuric nitrate and ace-
`tate (0.002% to 0.01%), phenol (0.1% to 0.5%),
`cresol (0.1% to 0.5%), chlorobutanol (0.5%),
`benzalkonium chloride (0.002% to 0.01%), and
`combinations of methylparaben and propylpara-
`ben (0.1% to 0.2%), the latter being especially
`good against fungus. The required proportion
`
`varies with the pH, dissociation, and other
` factors already
`indicated as well with the
` presence of other formulative ingredients with
`inherent preservative capabilities.
`For each type of preparation to be preserved,
`the research pharmacist must consider the infl u-
`ence of the preservative on the comfort of the
`patient. For instance, a preservative in an oph-
`thalmic preparation must have an extremely low
`degree of irritant qualities, which is characteris-
`tic of chlorobutanol, benzalkonium chloride, and
`phenylmercuric nitrate, frequently used in oph-
`thalmic preparations. In all instances, the pre-
`served preparation must be biologically tested to
`determine its safety and effi cacy and shelf-tested
`to determine its stability for the intended shelf
`life of the product.
`
`APPLYING THE PRINCIPLES AND CONCEPTS
`
`GROUP ACTIVITIES
`1. Develop a listing of examples where patients
`misunderstand the intent of the administra-
`tion of a pharmaceutical dosage form.
`2. Develop a listing of examples where patients
`misuse/abuse a pharmaceutical dosage form.
`3. Explain the appropriate use of specifi c dosage
`forms for different patient types, e.g., geriatric,
`pediatric, visually impaired, hearing impaired.
`4. Identify four ophthalmic products with differ-
`ing preservative agents and provide a rationale
`for the selection of the specifi c preservative in
`the product.
`5. Identify elixir dosage form products that con-
`tain minimal or no alcohol content. Explain
`the reasons for this misnomer.
`
`INDIVIDUAL ACTIVITIES
`1. Given a specifi c dosage form, list the signs of
`degradation a pharmacist might observe indi-
`cating product instability.
`2. Given a concentration of drug in a liquid dos-
`age form, determine its type of degradation
`rate and calculate its half life and when its
`concentration will be 90% of the labeled
`amount.
`3. Compare and contrast a zero-order rate of
`degradation and a fi rst-order rate of degrada-
`tion.
`4. Make a listing of drugs that follow a zero-order
`rate of degradation in a liquid dosage form.
`5. Make a listing of drugs that follow fi rst-order
`rates of degradation in a liquid dosage form
`
`Chap04.indd 141
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`10/22/2009 8:41:55 PM
`
`Opiant Exhibit 2041
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 8
`
`