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WO2009040595A1 - Composition pharmaceutique à multiples doses d'un analgésique pour administration nasale - Google Patents

Composition pharmaceutique à multiples doses d'un analgésique pour administration nasale Download PDF

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Publication number
WO2009040595A1
WO2009040595A1 PCT/IB2007/002850 IB2007002850W WO2009040595A1 WO 2009040595 A1 WO2009040595 A1 WO 2009040595A1 IB 2007002850 W IB2007002850 W IB 2007002850W WO 2009040595 A1 WO2009040595 A1 WO 2009040595A1
Authority
WO
WIPO (PCT)
Prior art keywords
nasal
pharmaceutical composition
analgesic
dose pharmaceutical
reconstitution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2007/002850
Other languages
English (en)
Inventor
Neil Wynne
Singh Sirjiwan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wockhardt Research Centre
Original Assignee
Wockhardt Research Centre
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wockhardt Research Centre filed Critical Wockhardt Research Centre
Priority to PCT/IB2007/002850 priority Critical patent/WO2009040595A1/fr
Publication of WO2009040595A1 publication Critical patent/WO2009040595A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B11/00—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use
    • B05B11/01—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use characterised by the means producing the flow
    • B05B11/10—Pump arrangements for transferring the contents from the container to a pump chamber by a sucking effect and forcing the contents out through the dispensing nozzle
    • B05B11/1042—Components or details
    • B05B11/1043—Sealing or attachment arrangements between pump and container
    • B05B11/1046—Sealing or attachment arrangements between pump and container the pump chamber being arranged substantially coaxially to the neck of the container
    • B05B11/1047—Sealing or attachment arrangements between pump and container the pump chamber being arranged substantially coaxially to the neck of the container the pump being preassembled as an independent unit before being mounted on the container
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to a multi-dose pharmaceutical composition for intranasal administration in the form of a nasal spray comprising lyophilized nasal analgesic and suitable diluent for reconsti nation.
  • the reconstitution of solution just prior to administration avoids degradation of active ingredient.
  • the present invention further relates to a kit for the preparation of multi-dose pharmaceutical composition of nasal analgesic in the form of a nasal spray bottle containing lyophilized nasal analgesic, a tube containing diluent for reconstitution, modified nasal pump, nasal tips and pack insert or a label, which provides directions for assembling the kit and the subsequent use.
  • the present invention still further relates to a device comprising nasal tip with cap, modified nasal pump and delivery tube.
  • the present invention still further relates to method of assembling the kit so as to form a device suitable for administration of multi-dose pharmaceutical composition of nasal analgesic in the form of a nasal spray.
  • Pain is experienced when the free nerve endings, which constitute the pain receptors in the skin as well as in certain internal tissues are subjected to mechanical, thermal, chemical or other noxious stimuli.
  • the pain receptors (nociceptors) can transmit signals along afferent neurons into the central nervous system and then to the brain.
  • the causes of pain can include inflammation, injury, disease, muscle spasm and the onset of a neuropathic event or syndrome.
  • Opioid analgesics exhibit morphine-like properties and can be sub-classified on the basis of their receptor specificity. They act as an agonist primarily at mu, kappa and perhaps delta receptors in the central nervous system. By acting on these receptors, they cause analgesia and anesthesia as a result of a receptor-mediated central action on pain perception, together with a receptor- medicated modulatory effect on the central transmission of noxious sensation.
  • NSAIDs have anti-inflammatory action and are effective on pain associated with the release of prostaglandins and other mediators of inflammation. They act by blocking the action of cyclooxygenase (COX).
  • COX cyclooxygenase
  • analgesics both opioids and NSAIDs depending on the mode of administration are associated with a number of undesirable side effects, including respiratory depression, nausea, vomitting, dizziness, mental clouding, constipation, urinary retention, hypotension, clotting disorders and gastric irritation.
  • respiratory depression nausea, vomitting, dizziness, mental clouding, constipation, urinary retention, hypotension, clotting disorders and gastric irritation.
  • pain relief should follow immediately upon administration of an analgesic.
  • the relief should be maintained for an extended period that is at least long enough to permit preliminary medication and avoid complicated dosage regimes.
  • the dynamics of pain relief obtained with current analgesic administration technologies does not meet these ideals. While rapid onset of pain relief can be achieved by intravenous injection, this mode of administration cannot in general be carried out by the patient himself and so is relatively expensive and inconvenient.
  • intravenous injection is generally associated with rapid offset of pain relief as the circulating analgesic is cleared from the plasma.
  • nasal administration by which a drug is transferred into circulating blood through the nasal mucosa, is being energetically studied as a method for non-injection type administration together with transdermal administration, transocular administration, transrectal administration, transpulmonary administration, etc.
  • nasal administration has advantages such as 1) rapid uptake of the analgesic across the nasal mucosa into the plasma can be achieved, which results in fast onset of analgesia similar to injection 2) the residence time of the analgesic in the nasal cavity can be increased, which results in prolonged analgesia. 3) an improved profile of absorption of analgesic into the systemic circulation can be achieved since the blood vessel system in the nasal mucous membrane is more developed compared with the skin, the ocular mucous membrane, the rectal mucous membrane, etc.
  • WO 2000076477, US 4,464,378, US 6,677,346, US 2006110333, WO 2006016530 disclose morphine and morphine derivatives in the form of lyophilized powder for nasal administration with the aid of nasal insufflator or jet-spray.
  • US 7,267,827 discloses an aqueous pharmaceutical formulation in the form of a nasal spray comprising an effective amount of ketorolac.
  • US 6,608,073 discloses codeine optionally in combination with opioid analgesics in the form of solution or gel for nasal administration with the aid of finger or cotton tipped applicator.
  • US 5,756,483 discloses apomorphine and morphine solution or gel for nasal administration with the aid of nasal tampon or nasal sponge.
  • US 4973596 discloses meperidine solution with a single dose dispenser.
  • US patent number 4703864 provides for a unitary molded plastic cover for a container such as medicament bottle, in which removable cap portion is attached by a severable tear strip.
  • US Patent number 5350116 provides for an actuator for a liquid spray pump provided with a skirt which cooperates with the body of the pump to compress a volume of air during pump actuation.
  • US Patent number 5509578 provides for pump which has a tubular portion which is arranged to penetrate the mouth of a container having a seal in order to dispense liquid from the container.
  • US Patent number 6948492 and US application number 2006/0021614 provide for an apparatus and method for the self administration of a plurality of doses of an intranasal liquid pharmaceutical composition including opioid analgesics, that includes a drug delivery device containing a plurality of sealed vials.
  • nasal analgesics disclosed in prior art cover solution in the fo ⁇ n of drops/spray available as pre-filled containers.
  • the mode of application is using a plastic syringe or pumps.
  • Further semisolid formulations like gels, ointments and creams are applied using nasal tampon or nasal sponges.
  • the nasal spray devices are commercially available from many manufacturers and some or all these manufacturers have their own patents which are related to a mechanical system that generates nasal spray comprising the spring, the capillary tube, the nozzle system, dose release button, dosing chamber and the dose indicator. Some of leading the manufacturers are Pfeiffer, Valois, Bespak and Becton-Dickinson.
  • the present inventors while working on the pharmaceutical compositions of analgesics for nasal administration have surprisingly found that reconstitution of lyophilized analgesic powder in the solution form just prior to administration provides a stable solution that avoids degradation of active ingredient.
  • the solution is stable for at least about two weeks and is suitable for multiple- use in the form of nasal spray for the treatment of paediatric analgesia in an emergency setting.
  • nasal pumps are not amenable to fit readily into conventional bottles. These nasal pumps are either screw threaded or can be crimped on only by a machine to external threads of bottle. Hence, it is the purpose of the invention to effect necessary changes in a fitting part of the pump for easier attachment to fit tightly externally onto the mouth of the bottle. Such a tight fit would also help in prevention of leakage.
  • Figure 1 Exploded view of the kit with the components and the method of assembling and the subsequent use.
  • Figure 3 A drawing of typical bottle of 17 mL capacity that contains lyophilized nasal analgesic.
  • a multi-dose pharmaceutical composition for intranasal administration in the form of a nasal spray comprising lyophilized nasal analgesic and suitable diluent for reconstitution.
  • a method of forming a multi-dose pharmaceutical composition for intranasal administration in the form of a nasal spray comprising reconstitution of the lyophilized nasal analgesic with suitable diluent just prior to administration, wherein the said method avoids degradation of active ingredient.
  • Embodiments of the pharmaceutical composition of the present invention may include one or more of the following features.
  • the term '"multi-dose" referred to in this invention relates to the number of doses delivered by the reconstituted solution of nasal analgesic in the form of a nasal spray.
  • diamorphine a pharmaceutically acceptable additives such as preservatives, chelating agents, pH adjusting agents and the like (Table 2), provided they do not interfere with the action of diamorphine or significantly decrease the absorption of it across the nasal mucosa.
  • nasal analgesic includes opioids and NSAIDS that can be used for nasal administration in the form of nasal spray.
  • Opioid analgesics can be selected from the group comprising of alfentanil, butorphanol, diamorphine, dihydrocodeine, fentanyl, meperidine, metazocine, methadone, morphine, naloxone, naltrexone, oxycodone, pentazocine, tramadol and the like.
  • NSAIDs include ibuprofen, flurbiprofen, diclofenac, indomethacin, piroxicam, ketoprofen, etodolac, diflusinal, meloxicam, aceclofenac, fenoprofen, naproxen, celecoxib rofecoxib and the like.
  • a method of forming a multi-dose pharmaceutical composition of diamorphine for intranasal administration in the form of a nasal spray wherein the method comprises reconstitution of the lyophilized diamorphine with suitable diluent just prior to administration.
  • Diamorphine is an opioid synthesized directly from the extracts of the opium poppy, Papaver somniferum. It is the 3,6-diacetyl derivative of morphine. It is a narcotic analgesic, which acts primarily on the central nervous system and smooth muscle. It may be used in the treatment of severe pain associated with surgical procedures, myocardial infarction or pain in the terminally ill and for the relief of dyspnoea in acute pulmonary oedema. Diamorphine in solution form rapidly hydrolyses to 6 acetyl morphine.
  • injection strengths of 5mg, lOmg, 30mg, lOOmg, 250mg and 500mg
  • lOmg a white to off-white, sterile, freeze dried powder for reconstitution for injection.
  • lyophilized diamoiphine is reconstituted with preserved saline solution just prior to administration.
  • the reconstituted solution is stable for at least about two weeks.
  • the solution is then administered intranasally in the form of a nasal spray with the aid of assembled nasal spray device.
  • Suitable preservatives that can be added to the diluent for reconstitution to extend shelf life include, for example, benzyl alcohol, parabens, thimerosal, chlorobutanol, benzalkonium and combinations thereof, with benzalkonium chloride being preferred.
  • the preservative will be present in the formulations in a concentration of from about 0.001% up to about 5% by weight of the total formulation.
  • chelating agents that can be added to the diluent for reconstitution include one or more of edetic acid and its salts, disodium edetate and the like. Chelating agents help to stabilize the product during storage.
  • pH adjusting agents examples include one or more of hydrochloric acid and sodium hydroxide solutions.
  • kits for the preparation of multi-dose pharmaceutical composition of nasal analgesic in the form of a nasal spray comprising a bottle containing lyophilized nasal analgesic, a tube containing diluent for reconstitution, modified nasal pump, nasal tips and pack insert or a label, which provides directions for assembling the kit and the subsequent use.
  • the kit of the present invention is in the form of a rectangular box, comprising 5 closed ends, four of which are on the sides and one in the bottom.
  • the upper part of the rectangular box comprises three fold flaps, two of which arises from shorter edges of equal shape and size as to meet at the center. Folding these two fold flaps ensures safe custody of the package contents.
  • the flap arising from the longer edge of the upper portion of the rectangular box has a small protrusion that fits well into the groove when closed as to form a tight fit. ( Figure 1 )
  • the pump capacity chosen is such that it would deliver a certain predetermined quantity of the reconstituted liquid nasal analgesic.
  • Some of the analgesics need to be administered in certain predetermined strengths and doses.
  • diamorphine dosage strength would be different for children in the range 12-30 kg and the other 30 - 50 kg.
  • Typical dosage strengths would be 0.1 mg/kg ( ⁇ 20%) over the weight range 12-50 kg.
  • a device of figure 2 comprising a) Nasal tip with cap b) Modified nasal pump c) Delivery tube 007/002850
  • a typical modified nasal pump (0.05 mL capacity) employed for attachment to 17 mL bottle is exhibited in Figure 2.
  • the various components of the pump are numbered in Figure 2 such as nasal tip with cap (10), delivery tube (300) and the like. Suitable changes have been effected in the main attachment component (200) of the pump as to make a tight fit into the bottle exhibited in Figure 3. To achieve this, allowable tolerances in variation in diameter of the fitting circular components requires to be as less as possible. It may be noticed that the outer diameter isl9.9 mm ( ⁇ 0.25 mm) at the entry of the bottle.
  • the inner diameter of the component of the modified nasal pump that fits tightly onto the mouth of the bottle by hand is 20.05 mm ( ⁇ 0.1 mm).
  • the changes effected in the attachment component (200) are such that it is devoid of screw threading or crimping on by machine.
  • the changes effected in the component of the pump are essential as normally threads would be present in a bottle. Further, the changes effected on the pump attachment calls for modification of the existing mould.
  • a method of assembling the kit (figure 1 ) so as to form a device suitable for administration of multi-dose pharmaceutical composition of nasal analgesic in the form of a nasal spray comprising a) attaching the modified nasal pump to the bottle by hand so that it fits tightly into a bottle to prevent leakage, b) shaking the assembly of step 1 for reconstitution of the lyophilized nasal analgesic, c) priming the assembly of step 3 to release the intended quantity of the reconstituted nasal analgesic. d) inserting the nasal tip into the patient's nostril and directing the spray to the sidewall of the nose.
  • priming Before the usage of the reconstituted liquid, priming needs to be carried out for adequate number of times. Replacement of nasal tip before use on a new patient is an additional requirement for its effective administration.
  • a typical analgesic such as reconstituted diamorphine in 0.05 mL capacity modified nasal pump and 17 mL bottle, the components assemblage, require priming eight times to ensure that the pump is fully primed and releases 50 ⁇ L each time it is used. Normal use by a patient is about 2-4 sprays. Twice priming after new nasal tip replacement is an additional feature. Almost 10 treatments per device can be repeated by employing 0.05 mL modified nasal pump and 17 mL bottle.
  • Table 1 Composition of batches of the present invention.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Otolaryngology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur une composition pharmaceutique à multiples doses d'un analgésique sous la forme d'un pulvérisateur nasal. Le produit est disponible sous forme d'un coffret qui comprend une pompe nasale modifiée et une bouteille contenant un analgésique nasal lyophilisé à reconstituer avec un diluant approprié juste avant l'administration. La reconstitution de la solution évite la dégradation de l'ingrédient actif.
PCT/IB2007/002850 2007-09-28 2007-09-28 Composition pharmaceutique à multiples doses d'un analgésique pour administration nasale Ceased WO2009040595A1 (fr)

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PCT/IB2007/002850 WO2009040595A1 (fr) 2007-09-28 2007-09-28 Composition pharmaceutique à multiples doses d'un analgésique pour administration nasale

Applications Claiming Priority (1)

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PCT/IB2007/002850 WO2009040595A1 (fr) 2007-09-28 2007-09-28 Composition pharmaceutique à multiples doses d'un analgésique pour administration nasale

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010094792A1 (fr) * 2009-02-20 2010-08-26 Schmerz & Palliativ Zentrum Fulda Ensemble de secours pour la production d'un médicament pour l'application nasale d'opioïdes en cas de dyspnée
ITFI20100113A1 (it) * 2010-05-21 2011-11-22 Molteni & C Spray nasale liquido contenente naltrexone a bassi dosaggi.
GB2498865A (en) * 2012-10-08 2013-07-31 Wockhardt Ltd Diamorphine formulations for intranasal administration
WO2014016653A1 (fr) 2012-07-26 2014-01-30 Wockhardt Limited Composition pharmaceutique comprenant de la diamorphine destinée à une administration intranasale
US20150258019A1 (en) * 2014-03-14 2015-09-17 Lightlake Therapeutics, Inc. Nasal drug products and methods of their use
WO2015155544A1 (fr) * 2014-04-10 2015-10-15 Patrick Crowley Administration d'agents anti-inflammatoires non stéroïdiens par l'intermédiaire du tractus nasal pour traiter des troubles neurologiques
US9192570B2 (en) 2013-12-20 2015-11-24 AntiOP, Inc. Intranasal naloxone compositions and methods of making and using same
US9468747B2 (en) 2014-03-14 2016-10-18 Opiant Pharmaceuticals, Inc. Nasal drug products and methods of their use
US9474869B2 (en) 2011-02-28 2016-10-25 Kaleo, Inc. Medicament delivery device for administration of opioid antagonists including formulations for naloxone
US9517307B2 (en) 2014-07-18 2016-12-13 Kaleo, Inc. Devices and methods for delivering opioid antagonists including formulations for naloxone
US9561177B2 (en) 2014-03-14 2017-02-07 Adapt Pharma Limited Nasal drug products and methods of their use
US9814838B2 (en) 2011-01-26 2017-11-14 Kaleo, Inc. Medicament delivery device for administration of opioid antagonists including formulations for naloxone
US10085937B2 (en) 2014-03-14 2018-10-02 Adapt Pharma Limited Nasal drug products and methods of their use
US10653690B1 (en) 2019-07-09 2020-05-19 Orexo Ab Pharmaceutical composition for nasal delivery
US10729687B1 (en) 2019-07-09 2020-08-04 Orexo Ab Pharmaceutical composition for nasal delivery
US11020343B2 (en) 2011-05-13 2021-06-01 Harm Reduction Therapeutics, Inc. Intranasal pharmaceutical dosage forms comprising naloxone
US11737980B2 (en) 2020-05-18 2023-08-29 Orexo Ab Pharmaceutical composition for drug delivery
US11957647B2 (en) 2021-11-25 2024-04-16 Orexo Ab Pharmaceutical composition comprising adrenaline
US12017026B2 (en) 2021-03-12 2024-06-25 Pocket Naloxone Corp. Drug delivery device and methods for using same
US12194263B2 (en) 2019-03-26 2025-01-14 Pocket Naloxone Corp. Devices and methods for delivery of pharmaceutical compositions
US12303472B2 (en) 2021-11-25 2025-05-20 Orexo Ab Pharmaceutical device for use in intranasal administration

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US20060157491A1 (en) * 2003-07-07 2006-07-20 Whittle Brian A Dispenser with reservoir containing a drug of abuse
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Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010094792A1 (fr) * 2009-02-20 2010-08-26 Schmerz & Palliativ Zentrum Fulda Ensemble de secours pour la production d'un médicament pour l'application nasale d'opioïdes en cas de dyspnée
ITFI20100113A1 (it) * 2010-05-21 2011-11-22 Molteni & C Spray nasale liquido contenente naltrexone a bassi dosaggi.
WO2011144746A3 (fr) * 2010-05-21 2012-02-02 L. Molteni & C. Dei Fratelli Alitti Societa' Di Esercizio S.P.A. Spray nasal liquide contenant du naltrexone à faible dose
US9814838B2 (en) 2011-01-26 2017-11-14 Kaleo, Inc. Medicament delivery device for administration of opioid antagonists including formulations for naloxone
US10322239B2 (en) 2011-01-26 2019-06-18 Kaleo, Inc. Medicament delivery device for administration of opioid antagonists including formulations for naloxone
US9474869B2 (en) 2011-02-28 2016-10-25 Kaleo, Inc. Medicament delivery device for administration of opioid antagonists including formulations for naloxone
US10143792B2 (en) 2011-02-28 2018-12-04 Kaleo, Inc. Medicament delivery device for administration of opioid antagonists including formulations for naloxone
US12458591B2 (en) 2011-05-13 2025-11-04 Harm Reduction Therapeutics, Inc. Intranasal pharmaceutical dosage forms comprising naloxone
US11806428B2 (en) 2011-05-13 2023-11-07 Harm Reduction Therapeutics, Inc. Intranasal pharmaceutical dosage forms comprising naloxone
US11020343B2 (en) 2011-05-13 2021-06-01 Harm Reduction Therapeutics, Inc. Intranasal pharmaceutical dosage forms comprising naloxone
WO2014016653A1 (fr) 2012-07-26 2014-01-30 Wockhardt Limited Composition pharmaceutique comprenant de la diamorphine destinée à une administration intranasale
GB2498865A (en) * 2012-10-08 2013-07-31 Wockhardt Ltd Diamorphine formulations for intranasal administration
US9289425B2 (en) 2013-12-20 2016-03-22 AntiOP, Inc. Intranasal naloxone compositions and methods of making and using same
US9192570B2 (en) 2013-12-20 2015-11-24 AntiOP, Inc. Intranasal naloxone compositions and methods of making and using same
ES2631504R1 (es) * 2014-03-14 2017-12-11 Opiant Pharmaceuticals, Inc. Medicamentos de administración nasal y métodos para su uso
GB2538682B (en) * 2014-03-14 2017-12-13 Opiant Pharmaceuticals Inc Nasal drug products and methods of their use
US9629965B2 (en) 2014-03-14 2017-04-25 Opiant Pharmaceuticals, Inc. Nasal drug products and methods of their use
US9707226B2 (en) 2014-03-14 2017-07-18 Adapt Pharma Limited Nasal drug products and methods of their use
US9775838B2 (en) 2014-03-14 2017-10-03 Adapt Pharma Limited Nasal drug products and methods of their use
US9211253B2 (en) * 2014-03-14 2015-12-15 Lightlake Therapeutics Inc. Nasal drug products and methods of their use
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