(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2010/0331354 A1
`Wermeling
`(43) Pub. Date:
`Dec. 30, 2010
`
`US 2010O331354A1
`
`(54) INTRANASAL OPIOID COMPOSITIONS
`(76) Inventor:
`Daniel P. Wermeling, Lexington,
`KY (US)
`
`Correspondence Address:
`STITES & HARBSON PLLC
`401 COMMERCE STREET, SUITE 800
`NASHVILLE, TN 37219 (US)
`
`(21) Appl. No.:
`(22) Filed:
`
`12/789,608
`May 28, 2010
`Related U.S. Application Data
`(63) Continuation of application No. 10/647,789, filed on
`Aug. 25, 2003, now abandoned, which is a continua
`tion-in-part of application No. 09/790,199, filed on
`Feb. 20, 2001, now Pat. No. 6,610,271, which is a
`continuation-in-part of application No. 09/569,125,
`filed on May 10, 2000, now abandoned.
`
`Publication Classification
`(51) Ek',I/2485
`(2006.01)
`A6II 3/473
`(2006.01)
`A63L/45
`(2006.01)
`A6II 3/4468
`(2006.01)
`A63L/4535
`(2006.01)
`A63L/454
`(2006.01)
`A6IP 25/04
`(2006.01)
`(52) U.S. Cl. ......... 514/282; 514/284: 514/289; 514/330;
`514/329; 514/326
`
`ABSTRACT
`(57)
`The present invention relates to pharmaceutical compositions
`for intranasal administration to a mammal that contain an
`effective amount of an opioid, a liquid nasal carrier for the
`opioid, and optionally a Sweetener, flavoring agent or mask
`ing agent. In some embodiments of the present invention, the
`pharmaceutical compositions have improved bioavailability.
`In other embodiments of the present invention, the opioid
`compositions improve patient compliance.
`
`Adapt & Opiant Exhibit 2030
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 1
`
`

`

`Patent Application Publication
`
`Dec. 30, 2010 Sheet 1 of 5
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`US 2010/0331354 A1
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`Adapt & Opiant Exhibit 2030
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 2
`
`

`

`Patent Application Publication
`
`Dec. 30, 2010 Sheet 2 of 5
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`US 2010/0331354 A1
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`Adapt & Opiant Exhibit 2030
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 3
`
`

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`Patent Application Publication
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`Dec. 30, 2010 Sheet 3 of 5
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`Adapt & Opiant Exhibit 2030
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 4
`
`

`

`Patent Application Publication
`
`Dec. 30, 2010 Sheet 4 of 5
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`Adapt & Opiant Exhibit 2030
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 5
`
`

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`Patent Application Publication
`
`Dec. 30, 2010 Sheet 5 of 5
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`US 2010/0331354 A1
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`Adapt & Opiant Exhibit 2030
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 6
`
`

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`US 2010/0331354 A1
`
`Dec. 30, 2010
`
`INTRANASAL OPOD COMPOSITIONS
`
`0001. This application is a continuation-in-part of U.S.
`application Ser. No. 09/790,199 filed Feb. 20, 2001, which is
`a continuation-in-part of U.S. application Ser. No. 09/569,
`125 filed May 10, 2000, now abandoned. The entire disclo
`Sure of these applications is herein incorporated by reference.
`
`BACKGROUND OF THE INVENTION
`0002 Pain is a major symptom of many diseases, (e.g.,
`cancer, arthritis, neurological diseases, heart attacks, etc.).
`Inadequate treatment of pain can lead to depression, anger,
`fear of disease progression and in Some extreme cases, Sui
`cide.
`0003. Unfortunately, a patient's non-compliance or failure
`to take medication as prescribed, has been linked to inad
`equate treatment of pain. This is not surprising, since many
`pain treatment regimens involve administering pain medica
`tions by injection route (e.g., intravenous (IV), intramuscular
`(IM) or subcutaneous injection). The intravenous route is
`normally regarded as one of the most in-convenient routes to
`administerpain medication to achieve rapid pain relief. Intra
`venous administration may cause non-compliance, because
`not only do patients fear getting the injection, but unpleasant
`experiences such as pain, irritation and infection resulting at
`the injection site may also lead to non-compliance.
`0004. The intranasal route is currently receiving special
`interest, especially in the area of pain management. When
`medication is administered via the intranasal route, the medi
`cation is applied to the nasal mucosa where it is absorbed. The
`extensive network of blood capillaries under the nasal
`mucosa is particularly Suited to provide rapid and effective
`systemic absorption of drugs. The intranasal route of admin
`istration should achieve similar dose to plasma concentration
`(bioavailability) and efficacy to that of the intravenous route.
`0005 Intranasal administration of medication provides
`numerous advantages over the intravenous route. The princi
`pal advantages of intranasal route are non-invasive delivery,
`rapid drug absorption, and convenience. The intravenous
`route, unlike the intranasal route, requires sterilization of
`hypodermic syringes and, in the institutional setting, leads to
`concerns among medical personnel about the risk of contract
`ing disease if they are accidentally stuck by a contaminated
`needle. Strict requirements for the safe disposal of needles
`and Syringes have also been imposed.
`0006. In contrast, intranasal administration requires little
`time on the part of the patient and attending medical person
`nel, and is far less burdensome on the institution than inject
`able routes. There is no significant risk of infection of the
`patient or medical personnel in the institutional setting when
`dealing with the intranasal delivery of medication.
`0007. A second important advantage of intranasal admin
`istration over intravenous is patient acceptance of the intra
`nasal delivery route. In some cases, the injections cause burn
`ing edema, Swelling, turgidity, hardness and Soreness. In
`contrast, intranasal administration is perceived as non-inva
`sive, is not accompanied by pain, has no after-effects and
`produces prompt relief in the patient exhibiting pain Symp
`toms. This is of particular advantage when the patient is a
`child. Many, if not most, patients experience anxiety and
`exhibit symptoms of stress when faced with hypodermic
`injections via the IM or IV routes. Further, most people have
`some familiarity with nasal sprays in the form of over-the
`
`counter decongestants for alleviating the symptoms of colds
`and allergies that they or a family member have used rou
`tinely. Another important consideration is that the patient can
`self-administer the prescribed dosage(s) of nasal spray with
`out the need for trained medical personnel.
`0008 Among the many medications available to treat
`pain, opioids (e.g., morphine, methadone, hydromorphone,
`butorphanol, etc.) play one of the most important roles. The
`major advantage of the opioids is that they have an extensive
`history of use and are much more effective in treating severe
`pain than other classes of medications e.g. aspirin, acetami
`nophen, ibuprofen, etc. Another major advantage is that opio
`ids exhibit few adverse effects on organs such as the stomach,
`liver, or kidney, other than very minor problems such as
`nausea or constipation. This is a major benefit over other
`medications such as aspirin or anti-inflammatory drugs that
`may cause ulcers, kidney problems, high blood pressure, or
`liver inflammation. In addition to relieving pain, opioids have
`other beneficial effects. Such as, for example, peripheral arte
`rial vasodilation, when treating heart attacks, provides the
`benefit of reducing oxygen demand on the heart.
`0009. There are different intranasal opioid formulations
`known in the pharmaceutical arts. However, Some intranasal
`opioid formulations have reduced bioavailability at conven
`tional doses. These formulations require more pain medica
`tion to be administered to the patient or else the pain will be
`inadequately treated.
`0010 Given the problems associated with inadequate
`treatment of pain and patient non-compliance, there is a need
`for intranasal opioid compositions that have improved bio
`availability. There is also a need for intranasal compositions
`that improve patient compliance.
`
`SUMMARY OF THE INVENTION
`0011. In various embodiments, the present invention pro
`vides intranasal opioid compositions that have improved bio
`availability when compared to intranasal prior art opioid
`compositions. In other embodiments, the present invention
`provides intranasal opioid compositions that improve patient
`compliance.
`0012. In one embodiment, the present invention provides a
`pharmaceutical composition for intranasal administration to a
`mammal; comprising: an effective amount of an opioid; a
`liquid nasal carrier for the opioid; and one or more Sweeten
`ers, flavoring agents, or masking agents or combinations
`thereof.
`0013. In another embodiment, the present invention pro
`vides a pharmaceutical composition having improved bio
`availability for intranasal administration to a mammal; com
`prising: an effective amount ofbutorphanol; a preservative
`free liquid nasal carrier.
`0014. In still another embodiment, the present invention
`provides a pharmaceutical composition having improved bio
`availability for intranasal administration to a mammal; com
`prising: an effective amount of hydromorphone; a liquid nasal
`carrier having the essential absence of a preservative and the
`composition containing at least one Sweetener, flavoring
`agent or masking agent.
`0015. In one preferred embodiment, the present invention
`provides a pharmaceutical composition for intranasal admin
`istration to a mammal; comprising: an effective amount of
`hydromorphone; a preservative-free liquid nasal carrier com
`prising Sodium chloride, citric acid, water and at least one
`Sweetener, flavoring agent or masking agent.
`
`Adapt & Opiant Exhibit 2030
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 7
`
`

`

`US 2010/0331354 A1
`
`Dec. 30, 2010
`
`0016. In still another preferred embodiment, the present
`invention provides a method of treating a mammal Suffering
`from pain comprising intranasally administering to the mam
`mal an effective amount ofbutorphanol or hydromorphone; a
`preservative-free liquid nasal carrier comprising sodium
`chloride, citric acid, water and at least one Sweetener, flavor
`ing agent or masking agent.
`0017 For a better understanding of the present invention
`together with other and further advantages and embodiments,
`reference is made to the following description taken in con
`junction with the examples, the scope of which is set forth in
`the appended claims.
`
`BRIEF DESCRIPTION OF THE FIGURES
`Preferred embodiments of the invention have been
`0.018
`chosen for purposes of illustration and description, but are not
`intended in any way to restrict the scope of the invention. The
`preferred embodiments of certain aspects of the invention are
`shown in the accompanying figures, wherein:
`0019 FIG. 1 is a graphic representation of the concentra
`tion of butorphanol in blood plasma versus time for two
`different butorphanol compositions.
`0020 FIG. 2 is a graphic representation of the data of FIG.
`1 over a longer time period.
`0021
`FIG. 3 is a graphic representation of the concentra
`tion of hydromorphone in blood plasma versus time for IV.
`IM and intranasal (IN) doses.
`0022 FIG. 4 is a graphic representation of the data of FIG.
`3 over a longer period of time.
`0023 FIG. 5 is a graphic representation of the concentra
`tion of hydromorphone in blood plasma versus time for a
`group of Subjects.
`
`DETAILED DESCRIPTION OF THE INVENTION
`0024. The invention will now be described in connection
`with preferred embodiments. These embodiments are pre
`sented to aid in an understanding of the present invention and
`are not intended to, and should not be construed to, limit the
`invention in any way. All alternatives, modifications and
`equivalents that may become obvious to those of ordinary
`skill on reading the disclosure are included within the spirit
`and scope of the present invention.
`0025. In accordance with one embodiment of the present
`invention, it has now been Surprisingly found that intranasal
`pharmaceutical compositions can be made having improved
`bioavailability in terms of plasma opioid levels. These intra
`nasal compositions contain an opioid; and a liquid nasal car
`rier for the opioid. For example, it has been unexpectedly
`discovered, among other things, that at least about 10 to about
`20% higher plasma levels ofbutorphanol can be achieved by
`administering an intranasal formulation that does not contain
`the preservative benzethonium. Thus, butorphanol formula
`tions without benzethonium have improved bioavailability
`due to improved nasal absorption ofbutorphanol. Improved
`bioavailability includes increases in plasma or serum opioid
`concentration when compared to prior art opioid formula
`tions. Preferred increases include, but are not limited to,
`increases of more than 5% to more than 40% in bioavailability
`of the opioid.
`0026. Opioids as herein include any substance naturally or
`synthetically derived from opium. Suitable opioids for use in
`the present invention include, but are not limited to, mor
`phine, apomorphine, hydromorphone, Oxymorphone, dihy
`
`dromorphine, levorphanol, levallorphan, levophenacylmor
`phan,
`norlevorphanol,
`nalorphine,
`nalbuphine,
`buprenorphine, butorphanol, naloxone, naltrexone, nalmex
`one, oxilorphan, cyclorphan, ketobemidone, fentanyl, Sufen
`tanil, alfentanyl, or combinations thereof. The most preferred
`opioids for use in the present invention include butorphanol
`and/or hydromorphone.
`0027. The opioid may be in free form or in pharmaceuti
`cally acceptable salt or complex form. Some examples of
`pharmaceutically acceptable salts of opioids include those
`salt-forming acids and bases that do not substantially increase
`the toxicity of the compound. Some examples of suitable salts
`include salts of alkali metals such as magnesium, potassium
`and ammonium. Salts of mineral acids such as hydrochloric,
`hydriodic, hydrobromic, phosphoric, metaphosphoric, nitric
`and Sulfuric acids, as well as Salts of organic acids such as
`tartaric, acetic, citric, malic, benzoic, glycollic, gluconic,
`gulonic, succinic, arylsulfonic, e.g. p-toluenesulfonic acids,
`and the like.
`0028 Intranasal opioid compositions of the present inven
`tion include a liquid nasal carrier. As used herein, “liquid
`nasal carrier includes a solution, emulsion, or Suspension
`designed for delivery of the opioid to the nasal mucosa. The
`liquid nasal carrier includes a diluent Suitable for application
`to the nasal mucosa. Suitable diluents include aqueous or
`non-aqueous diluents or combination thereof. Examples of
`aqueous diluents include, but are not limited to, Saline, water,
`dextrose or combinations thereof. Non-aqueous diluents
`include, but are not limited to, alcohols, particularly polyhy
`droxy alcohols such as propylene glycol, polyethylene gly
`col, glycerol, and vegetable and mineral oils. These aqueous
`and/or non-aqueous diluents can be added in various concen
`trations and combinations to form Solutions, Suspensions,
`oil-in-water emulsions or water-in-oil emulsions. In the pre
`ferred butorphanol or hydromorphone compositions, the
`diluent is saline or water.
`0029. The nasal carrier of the present invention may also
`contain excipients such as antioxidants, chemical preserva
`tives, buffering agents, Surfactants and/or agents that increase
`Viscosity. Antioxidants are substances that prevent oxidation
`of the formulations. Suitable antioxidants for use in the
`present invention include, but are not limited to, butylated
`hydroxytoluene, butylated hydroxyanisole, potassium met
`abisulfite, and the like.
`0030. In some embodiments of the present invention, the
`composition contains a preservative that is chosen in quanti
`ties that preserve the composition, but do not cause irritation
`of the nasal mucosa. Suitable preservatives for use in some
`embodiments of the present invention include, but are not
`limited to, benzalkonium chloride, methyl, ethyl, propyl or
`butylparaben, benzyl alcohol, phenylethyl alcohol, benzetho
`nium, or combination thereof. Typically, the preservative is
`added to the compositions of the present invention in quanti
`ties of from about 0.01% to about 0.5% by weight. However,
`in some embodiments of the present invention, the inclusion
`of benzethonium has been found to reduce bioavailability. For
`example, it has been unexpectedly discovered that at least
`about 10 to about 20% higher plasma levels of butorphanol
`can be achieved by administering an intranasal composition
`that does not contain the preservative benzethonium. Thus,
`butorphanol formulations without benzethonium have
`improved bioavailability due to improved nasal absorption of
`butorphanol.
`
`Adapt & Opiant Exhibit 2030
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 8
`
`

`

`US 2010/0331354 A1
`
`Dec. 30, 2010
`
`0031. In some embodiments of the present invention, the
`formulation is preservative-free. As used herein, preserva
`tive-free includes compositions that do not contain any pre
`servative. Thus, the composition does not contain, for
`example, benzalkonium chloride, methyl, ethyl, propyl or
`butylparaben, benzyl alcohol, phenylethyl alcohol, or benze
`thonium.
`0032. If a buffering agent is employed in the composition,
`it is chosen in quantities that preferably do not irritate the
`nasal mucosa. Buffering agents include agents that reduce pH
`changes. Preferred buffering agents for use in the present
`invention include, but are not limited to, salts of citrate,
`acetate, or phosphate. The most preferred buffers include
`Sodium citrate, Sodium acetate, Sodium phosphate, and/or
`combinations thereof. Typically, the buffer is added to the
`compositions of the present invention in quantities of from
`about 0.01% to about 3% by weight.
`0033. When one or more surfactants is employed, the
`amount present in the compositions of the invention will vary
`depending on the particular Surfactant chosen, the particular
`mode of administration (e.g. drop or spray) and the effect
`desired. In general, however, the amount present will be of the
`order of from about 0.1 mg/ml to about 10 mg/ml, preferably
`about 0.5 mg/ml to 5 mg/ml and most preferably about 1
`mg/ml.
`0034. The pharmaceutical compositions of the present
`invention may include one or more agents that increase vis
`cosity chosen in quantities that preferably do not irritate the
`nasal mucosa and increase nasal retention time. Preferred
`agents that increase viscosity include, but are not limited to,
`methylcellulose, carboxymethylcellulose sodium, ethylcel
`lulose, carrageenan, carbopol, and/or combinations thereof.
`The most preferred agents used to increase viscosity and
`increase nasal retention time is methylcellulose or carbopol.
`Typically, the agent that increases viscosity is added to the
`compositions of the present invention in quantities of from
`about 0.1% to about 10% by weight.
`0035. In some embodiments of the present invention, one
`or more Sweetener or flavoring agents are employed. The
`Sweetener or flavoring agent includes any agent that Sweetens
`or provides flavor to the pharmaceutical composition: The
`Sweetener or flavoring agent will mask any bitter or bad taste
`that may occur if the pharmaceutical composition drips back
`into the mouth after intranasal administration. By addition of
`a Sweetener or flavoring agent to the intranasal composition,
`any barrier that a patient may have to taking the intranasal
`composition because of unpleasant taste is reduced. By add
`ing a Sweetener, flavoring agent or masking agent to the
`intranasal pharmaceutical composition of the present inven
`tion, patient compliance is enhanced or improved.
`0036 Preferred sweeteners or flavoring agents or masking
`agents to use in Some embodiments of the present invention
`include, but are not limited to, acacia syrup, anethole, anise
`oil, aromatic elixir, benzaldehyde, benzaldehyde elixir,
`cyclodextrins, compound, caraway, caraway oil, cardamom
`oil, cardamom seed, cardamom spirit, compound, cardamom
`tincture, compound, cherry juice, cherry syrup, cinnamon,
`cinnamon oil, cinnamon water, citric acid, citric acid syrup,
`clove oil, cocoa, cocoa syrup, coriander oil, dextrose, eriod
`ictyon, eriodictyon fluidextract, eriodictyon syrup, aromatic,
`ethylacetate, ethyl Vanillin, fennel oil, ginger, ginger fluidex
`tract, ginger oleoresin, dextrose, glucose, Sugar, maltodex
`trin, glycerin, glycyrrhiza, glycyrrhiza elixir, glycyrrhiza
`extract, glycyrrhiza extract pure, glycyrrhiza fluidextract,
`
`glycyrrhiza syrup, honey, iso-alcoholic elixir, lavender oil,
`lemon oil, lemon tincture, mannitol, methyl salicylate, nut
`meg oil, orange bitter, elixir, orange bitter, oil, orange flower
`oil, orange flower water, orange oil, orange peel, bitter,
`orange peel Sweet, tincture, orange spirit, compound, orange
`syrup, peppermint, peppermint oil, peppermint spirit, pepper
`mint water, phenylethyl alcohol, raspberry juice, raspberry
`syrup, rosemary oil, rose oil, rose water, rose water, stronger,
`saccharin, saccharin calcium, saccharin Sodium, Sarsaparilla
`syrup, Sarsaparilla compound, Sorbitol Solution, spearmint,
`spearmint oil. Sucrose. Sucralose, syrup, thyme oil, tolu bal
`sam, tolu balsam syrup, Vanilla, Vanillatincture, Vanillin, wild
`cherry syrup, or combinations thereof.
`0037 Most preferred sweeteners to use in some embodi
`ments of the present invention include, but are not limited to,
`saccharin, Sodium saccharin, Xylitol, mannitol, Sorbitol,
`Sucralose, maltodextrin, Sucrose, aspartame, acesulfame
`potassium, dextrose, glycosides, maltose, Sweet orange oil,
`dextrose, glucose, honey or combinations thereof. Most pre
`ferred flavoring agents to use in Some embodiments of the
`present invention include, but are not limited to, glycerin,
`wintergreen oil, peppermint oil, peppermint water, pepper
`mint spirit, menthol, syrup, or combinations thereof. Most
`preferred masking agents do not make contact with the taste
`buds. The preferred masking agent for use in the present
`invention includes, but is not limited to, cyclodextrins, cyclo
`dextrins emulsions, cyclodextrins particles, cyclodextrins
`complexes, or combinations thereof.
`0038. The pharmaceutical compositions of different
`embodiments of the present invention may of course also
`include additional ingredients, such as pharmaceutically
`acceptable Surfactants, co-solvents, adhesives, agents to
`adjust the pH and osmolarity.
`0039. The pharmaceutical compositions of the present
`invention are not limited to any particular pH. However, gen
`erally for nasal administration a mildly acid pH will be pre
`ferred. The pH ranges from about 3 to 6 are preferred, more
`preferred pH ranges are from about 3 to about 5, and most
`preferred pH ranges are from about 4 to about 5. If the adjust
`ment of the pH is needed, it can beachieved by the addition of
`an appropriate acid, Such as hydrochloric acid, or base. Such
`as for example, sodium hydroxide. In the preferred embodi
`ments of the present invention, butorphanol or hydromor
`phone formulations, have a pH of about 5.0 and a pH of about
`4, respectively.
`0040. The pharmaceutical composition in some embodi
`ments of the present invention can be made, for example, by
`mixing the opioid with a liquid nasal carrier and/or a Sweet
`ener, flavoring agent, or masking agent or combinations
`thereof at room temperature under aseptic conditions to form
`a mixture. In other embodiments of the present invention, the
`mixture is filtered. It will be understood by those of ordinary
`skill in the art that the order of mixing is not critical, and the
`present invention includes without limitation mixing of the
`formulation in any order.
`0041) Pharmaceutical compositions of the present inven
`tion can be administered intranasally by nasal spray, drop,
`Solution, Suspension, gel, and the like. In one preferred
`embodiment, the pharmaceutical composition of the present
`invention is a sterile solution or Suspension.
`0042. When the pharmaceutical composition is a liquid,
`preferred volumes of the liquid are absorbed through the nasal
`mucosa. The preferred volume of the liquid includes volumes
`of from about 0.025 ml to about 2 ml, more preferably, from
`
`Adapt & Opiant Exhibit 2030
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 9
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`US 2010/0331354 A1
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`Dec. 30, 2010
`
`about 0.25 ml to 1 ml, and most preferably from about 0.05 ml
`to about 15 ml in an adult and smaller for children. However,
`the pharmaceutical compositions of the present invention are
`not limited to one particular Volume.
`0043 Preferred devices for intranasal delivery of pharma
`ceutical compositions of the present invention are available
`from, for example, Pfeiffer of America of Princeton, N.J. and
`Valois of America, Inc. of Greenwich, Conn. These devices
`are preferred because they have the capability of consistently
`delivering the pharmaceutical composition. These devices are
`easily operable by the patient, leave virtually no opioid
`remaining in the device after use and can thereafter be dis
`carded without concern that others may abuse the opioid or
`other controlled substance.
`0044) The device can be filled with single or multidose
`amounts of opioids. Preferably, the device is filled with one
`single dose of opioid. In a preferred embodiment, the con
`tainer holding the pharmaceutical composition and its sealing
`means are sterilizable, most preferably, at least parts of the
`device that are in contact with the pharmaceutical composi
`tion is constructed and assembled in a configuration that can
`be sterilized. Devices with one or more unit-dose(s) can be
`sterilized either before or after packaging, employing meth
`ods and technology that are well known in the art. Individual
`devices can be packaged, sterilized and shipped; alterna
`tively, entire shipping and storage packages can be sterilized
`at once, and the devices removed individually for dispensing,
`without affecting the sterility of the remaining units,
`004.5 The amount of opioid that can be intranasally
`administered in accordance with the composition and meth
`ods of the present invention will depend on the particular
`opioid chosen, the condition to be treated, the desired fre
`quency of administration and the effect desired. As used
`herein, an effective amount of opioid includes that amount
`effective to achieve the relief or palliation of symptoms, con
`dition and/or diseases associated with pain. Some diseases
`and/or conditions that cause pain include, but are not limited
`to, cancer, arthritis, neurological diseases, heart attacks,
`trauma, childbirth, migraines, or Surgery.
`0046 Maximal dosage of the pharmaceutical composition
`of the present invention for a mammal is the highest dosage
`that elicits analgesia or anesthesia, which does not cause
`undesirable or intolerable side effects such as respiratory
`depression. The minimal dose of the opioid is the lowest dose
`that achieves the desired result. In any event, the practitioner
`is guided by skill and knowledge in the field, and the present
`invention includes without limitation dosages that are effec
`tive to achieve the pain relieving effect in the mammal. Pre
`ferred doses of opioids for intranasal administration include,
`but are not limited to, hydromorphone HCL from about 0.1
`mg to about 30 mg; butorphanol tartrate from about 0.1 to
`about 10.0 mg; fentanyl citrate from about 5 mcg to about 500
`mcg; methadone HCl from about 0.5 to about 50 mg. oxy
`morphone HCL from about 0.1 mg to about 30 mg; and
`morphine HCL from about 1 mg to about 40 mg.
`0047. The intranasal opioids of the present invention can
`be used, for example, to elicit analgesia or an analgesic
`response to relieve or alleviate pain. The opioids of the
`present invention may also be used to produce anesthesia or
`an anesthetic response where the mammal experiences loss of
`feeling or sensation, especially loss in pain sensation, to per
`mit the performance of Surgery or other painful procedures.
`The opioid is administered to a mammal Suffering from a
`condition and/or disease that require opioid treatment. Mam
`
`mals include, for example, humans, as well as pet animals
`Such as dogs and cats, laboratory animals, such as rats and
`mice, and farm animals. Such as horses and cows.
`
`Examples
`
`0048. The examples below demonstrate improved bio
`availability of the preferred compositions of the present
`invention compared to the prior art pharmaceutical composi
`tions. The examples also show pharmaceutical compositions
`that include Sweeteners, flavoring agents, or masking agents
`or combinations thereof, which improve patient compliance.
`
`Example 1
`
`0049. This example compares the butorphanol formula
`tion of the present invention to prior art butorphanol for
`intranasal administration sold commercially by Bristol-My
`ers Squibb under the trademark STADOL(R) NS. The 1 ml of
`STADOL(R) NS (reference formulation) contains 10 mg
`butorphanol tartrate, 6.5 mg sodium chloride, 1.0 mg citric
`acid, 0.20 mg benzethonium chloride in purified water with
`1.2 mg Sodium hydroxide and hydrochloric acid added to
`adjust the pH to 5.0. The prior art formulation is a multi-dose
`sprayer that purports by its label to administer 0.1 ml of liquid
`composition by metering upon activation by the user.
`0050. The butorphanol composition (test formulation), in
`one embodiment of the present invention, contains 10 mg
`butorphanol tartrate, 6.5 mg sodium chloride, 1.0 mg anhy
`drous citric acid in purified water with 1N sodium hydroxide
`and/or 1N hydrochloric acid added to adjust the pH to 5.0.
`The butorphanol test formulation did not contain benzetho
`nium chloride. The delivery system employed to administer
`one of the butorphanol compositions of the present invention
`was a unit-dose disposable intranasal applicator that is com
`mercially available from Pfeiffer of America under the des
`ignation “Unitdose Second Generation. Each of the Pfeiffer
`spray applicators was charged with Sufficient liquid to deliver
`a 0.1. mL dose of the butorphanol test formulation without the
`benzethonium chloride. The glass containers were filled
`using a pipette under clean conditions, sealed and assembled
`to the applicator. Each of the applicators was weighed prior to
`use and after use. Qualified medical personnel took the
`respective applicators to patients in a clinical setting for
`whom the drug had been prescribed and attended each of the
`patient's self-administration, one dose up each nostril, after
`which the applicator was recovered for weighing. In the case
`of the unit-dose applicators (test formulation), each patient
`used two devices, both of which were discarded following the
`post-use weighing. The results of these studies of the method
`and system of the invention and the comparative prior art
`method follow.
`
`TABLE I
`
`Sample Characteristics of Dose Weight Delivery.
`
`Delivery
`System
`
`mean Wt.
`gns
`
`N
`
`stol. dev.
`
`stol.
`error
`
`minimum maximum
`
`Unit-
`Dose
`Multi-
`Dose
`
`23
`
`O.2O6
`
`O.OO66O O.OO138
`
`0.193
`
`O.223
`
`24
`
`O.18O
`
`O.O28S
`
`O.OOS82
`
`0.114
`
`O.220
`
`Adapt & Opiant Exhibit 2030
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 10
`
`

`

`US 2010/0331354 A1
`
`Dec. 30, 2010
`
`Unit-Dose:
`0051. The statistical comparison of dose 1 and dose 2 for
`the test formulation unit dose delivery system was done using
`a paired t-test. Analysis of the data indicated that the differ
`ence between the mean, sprays of the two applications using
`the Pfeiffer device was not statistically significant (t=1.0:
`p=0.3). The sample of 23 sprayers (actually 23 sets of 2
`sprayers, since they were single-dose) had a mean total dose
`for two sprays of 0.206 grams with a standard deviation of
`0.00660 grams.
`Multiple-Dose:
`0052. The total dose dispensed by two