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Nasal drug products and methods of their use — Opiant Pharmaceuticals, Inc. (US20210275519A1)

Opiant Pharmaceuticals, Inc. · Google Patents

Google Patents · Patents · License: Open Access

patent, google patents, intellectual property, US20210275519A1, Opiant Pharmaceuticals, Inc., Roger Crystal, en, 2021

ABSTRACT

Abstract

Drug products adapted for nasal delivery, comprising a pre-primed device filled with a pharmaceutical composition comprising an opioid receptor antagonist, are provided. Methods of treating opioid overdose or its symptoms with the inventive drug products are also provided.

Description

This application is a continuation of U.S. application Ser. No. 16/870,406, filed May 8, 2020, which is a continuation of U.S. application Ser. No. 16/551,524, filed Aug. 26, 2019, which is a continuation of U.S. application Ser. No. 15/494,270, filed Apr. 21, 2017, which is a continuation of U.S. application Ser. No. 15/335,145, filed Oct. 26, 2016, now U.S. Pat. No. 9,629,965, issued Apr. 25, 2017, which is a continuation of U.S. application Ser. No. 14/942,344, filed Nov. 16, 2015, now U.S. Pat. No. 9,480,644, issued Nov. 1, 2016, which is a continuation-in-part of U.S. application Ser. No. 14/659,472, filed Mar. 16, 2015, now U.S. Pat. No. 9,211,253, issued Dec. 15, 2015, which claims the benefit of U.S. Provisional Application No. 61/953,379, filed Mar. 14, 2014, the disclosures of which are hereby incorporated by reference as if written herein in their entireties.

Provided are drug products adapted for nasal delivery comprising a pre-primed device and a pharmaceutical composition comprising an opioid receptor antagonist, pharmaceutical compositions comprising an opioid receptor antagonist, and methods of use thereof.

Opioid receptors are G protein-coupled receptors (GPCRs) that are activated both by endogenous opioid peptides and by clinically important alkaloid analgesic drugs such as morphine. There are three principal types of opioid receptors: the Î´-opioid receptor, the Îº-opioid receptor, and the Î¼-opioid receptor. Opioids depress respiration, which is controlled principally through medullary respiratory centers with peripheral input from chemoreceptors and other sources. Opioids produce inhibition at the chemoreceptors via Î¼-opioid receptors and in the medulla via Î¼- and Î´-opioid receptors. While there are a number of neurotransmitters mediating the control of respiration, glutamate and Î³-aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitters, respectively. This explains the potential for interaction of opioids with benzodiazepines and alcohol: both benzodiazepines and alcohol facilitate the inhibitory effect of GABA at the GABAA receptor, while alcohol also decreases the excitatory effect of glutamate at NMDA receptors. Oxycodone and other opioid painkillers, as well as heroin and methadone are all implicated in fatal overdose. Heroin has three metabolites with opioid activity. Variation in the formation of these metabolites due to genetic factors and the use of other drugs could explain differential sensitivity to overdose. Metabolites of methadone contribute little to its action. However, variation in rate of metabolism due to genetic factors and other drugs used can modify methadone concentration and hence overdose risk. The degree of tolerance also determines risk. Tolerance to respiratory depression is less than complete, and may be slower than tolerance to euphoric and other effects. One consequence of this may be a relatively high risk of overdose among experienced opioid users. While agonist administration modifies receptor function, changes (usually in the opposite direction) also result from use of antagonists, for example, supersensitivity to opioids following a period of administration of antagonists such as naltrexone.

In the United States, mortality rates closely correlate with opioid sales. In 2008, approximately 36,450 people died from drug overdoses. At least 14,800 of these deaths involved prescription opioid analgesics. Moreover, according to the Substance Abuse and Mental Health Services Administration, the number/rate of Americans 12 years of age and older who currently abuse pain relievers has increased by 20 percent between 2002 and 2009. In New York City, between 1990 and 2006, the fatality rate from prescription opioids increased seven-fold, from 0.39 per 100,000 persons to 2.7. Drugs classed as prescription opioids in this study include both typical analgesics, such as OxyContinÂ® (oxycodone HCl controlled-release) and methadone (used in the treatment of dependence on other opioids such as heroin and also prescribed for pain), but the increase in the rate of drug overdose over the 16 years of the study was driven entirely by overdoses of typical analgesics. Over the same time period, methadone overdoses remained stable, and overdoses from heroin declined. Whites were more likely than blacks and Latinos to overdose on these analgesics, and deaths mostly occurred in neighborhoods with lower rates of poverty, suggesting differential access to doctors who can write painkiller prescriptions may be a driving force behind the racial disparity. (CerdÃ¡ et al. â Prescription opioid mortality trends in New York City, 1990-2006: Examining the emergence of an epidemic,â Drug and Alcohol Dependence Volume 132, Issues 1-2, 1 Sep. 2013, 53-62.)

Naloxone is an opioid receptor antagonist that is approved for use by injection for the reversal of opioid overdose and for adjunct use in the treatment of septic shock. It is currently being used mainly in emergency departments and in ambulances by trained medical professionals. There have been efforts to expand its use by providing the drug to some patients with take-home opioid prescriptions and those who inject illicit drugs, potentially facilitating earlier administration of the drug. The UN Commission on Narcotics Drugs âencourages all Member States to include effective elements for the prevention and treatment of drug overdose, in particular opioid overdose, in national drug policies, where appropriate, and to share best practices and information on the prevention and treatment of drug overdose, in particular opioid overdose, including the use of opioid receptor antagonists such as naloxone.â

U.S. Pat. No. 4,464,378 describes a method for eliciting an analgesic or narcotic antagonist response in a warm-blooded animal, which comprises administering intranasally (IN) to said animal to elicit a narcotic antagonist response, a narcotic antagonist effective amount of naloxone. WO 82/03768 discloses a composition that contains 1 mg of naloxone hydrochloride per 0.1 ml of solution adapted for nasal administration used in the treatment of narcotic induced respiratory depression (overdose) at a dosage approximately the same as that employed for intravenous (IV), intramuscular (IM) or subcutaneous (SQ) administration. WO 00/62757 teaches pharmaceutical compositions for IN or oral (PO) administration which comprise an opioid antagonist, such as naloxone for application by spray in the reversal of opioid depression for treatment of patients suffering from opioid over-dosage, wherein the spray applicator is capable of delivering single or multiple doses and suitable dosage units are in the range of 0.2 to 5 mg.

The use of nasal naloxone is not without controversy. For instance, Loimer et al. (International Journal of Addictions, 29(6), 819-827, 1994) reported that the nasal administration of naloxone is as effective as the intravenous route in opiate addicts, however, Dowling et al. (Ther Drug Monit, Vol 30, No 4, August 2008) reported that naloxone administered intranasally displays a relative bioavailability of 4% only and concluded that the IN absorption is rapid but does not maintain measurable concentrations for more than an hour.

One early study of 196 consecutive patients with suspected opioid overdose conducted in an urban out-of-hospital setting, had shown the mean interval from emergency medical services (EMS) arrival to a respiratory rate of â¥10 breaths/min was 9.3Â±4.2 min with administration of naloxone 0.4 mg IV, versus 9.6Â±4.58 min with administration of naloxone 0.8 mg SQ. The authors concluded that the slower rate of absorption via the SQ route was offset by the delay in establishing an IV line. (Wanger et al., Intravenous vs subcutaneous naloxone for out - of - hospital management of presumed opioid overdose . Acad Emerg Med. 1998 April; 5(4):293-9).

The Denver Health Paramedic system subsequently investigated the efficacy and safety of atomized intranasal naloxone for the treatment of suspected opiate overdose (Barton, et al., Efficacy of intranasal naloxone as a needleless alternative for treatment of opioid overdose in the prehospital setting . J Emerg Med, 2005. 29(3): p. 265-71). All adult patients encountered in the prehospital setting as suspected opiate overdose, found down, or with altered mental status who met the criteria for naloxone administration were included in the study. IN naloxone (2 mg) was administered immediately upon patient contact and before IV insertion and administration of IV naloxone (2 mg). Patients were then treated by EMS protocol. The main outcome measures were: time of IN naloxone administration, time of IV naloxone administration, time of appropriate patient response as reported by paramedics. Ninety-five patients received IN naloxone and were included in the study. A total of 52 patients responded to naloxone by either IN or IV, with 43 (83%) responding to IN naloxone alone. Seven patients (16%) in this group required further doses of IV naloxone. The median times from arrival at patient side to awakening and from administration of the IN naloxone to patient awakening were 8.0 minutes and 3.0 minutes respectively.

The Drug Overdose Prevention and Education (DOPE) Project was the first naloxone prescription program (NPP) established in partnership with a county health department (San Francisco Department of Public Health), and is one of the longest running NPPs in the USA. From September 2003 to December 2009, 1,942 individuals were trained and prescribed naloxone through the DOPE Project, of whom 24% returned to receive a naloxone refill, and 11% reported using naloxone during an overdose event. Of 399 overdose events where naloxone was used, participants reported that 89% were reversed. In addition, 83% of participants who reported overdose reversal attributed the reversal to their administration of naloxone, and fewer than 1% reported serious adverse effects. Findings from the DOPE Project add to a growing body of research that suggests that intravenous drug users (IDUs) at high risk of witnessing overdose events are willing to be trained on overdose response strategies and use take-home naloxone during overdose events to prevent deaths (Enteen, et al., Overdose prevention and naloxone prescription for opioid users in San Francisco . J Urban Health. 2010 December; 87(6):931-41).

Another reported study reviewed EMS and hospital records before and after implementation of a protocol for administration of intranasal naloxone by the Central California EMS Agency in order to compare the prehospital time intervals from patient contact and medication administration to clinical response for IN versus intravenous IV naloxone in patients with suspected narcotic overdose. The protocol for the treatment of opioid overdose with intranasal naloxone was as follows: âIntranasal (IN)âAdminister 2 mg intranasally (1 mg per nostril) using mucosal atomizer device (MADâ¢) if suspected narcotic intoxication and respiratory depression ( rate 8 or less). This dose may be repeated in 5 minutes if respiratory depression persists. Respirations should be supported with a bag valve mask until respiratory rate is greater than 8. Intramuscular (IM)âAdminister 1 mg if unable to administer intranasally (see special considerations). May repeat once in 5 minutes. Intravenous (IV)âAdminister 1 mg slow IV push if no response to intranasal or IM administration after 10 minutes. Pediatric doseâ0.1 mg/kg intranasally, if less than 10 kg and less than 1 year oldâ. Patients with suspected narcotic overdose treated in the prehospital setting over 17 months, between March 2003 and July 2004 were included. Paramedics documented dose, route of administration, and positive response times using an electronic record. Clinical response was defined as an increase in respiratory rate (breaths/min) or Glasgow Coma Scale score of at least 6. Main outcome variables included time from medication to clinical response and time from patient contact to clinical response. Secondary variables included numbers of doses administered and rescue doses given by an alternate route. Between-group comparisons were accomplished using t-tests and chi-square tests as appropriate. One hundred fifty-four patients met the inclusion criteria, including 104 treated with IV and 50 treated with IN naloxone. Clinical response was noted in 33 (66%) and 58 (56%) of the IN and IV groups, respectively (p=0.3). The mean time between naloxone administration and clinical response was longer for the IN group (12.9 vs. 8.1 min, p=0.02). However, the mean times from patient contact to clinical response were not significantly different between the IN and IV groups (20.3 vs. 20.7 min, p=0.9). More patients in the IN group received two doses of naloxone (34% vs. 18%, p=0.05), and three patients in the IN group received a subsequent dose of IV or IM naloxone. (Robertson et al., Intranasal naloxone is a viable alternative to intravenous naloxone for prehospital narcotic overdose . Prehosp Emerg Care. 2009 October-December; 13(4):512-5).

In August 2006, the Boston Public Health Commission passed a public health regulation that authorized an opioid overdose prevention program that included intranasal naloxone education and distribution of the spray to potential bystanders. Participants were instructed by trained staff to deliver 1 mL (1 mg) to each nostril of the overdose victim. After 15 months, the program had provided training and intranasal naloxone to 385 participants who reported 74 successful overdose reversals (Doe-Simkins et al. Overdose prevention education with distribution of intranasal naloxone is a feasible public health intervention to address opioid overdose . Am J Public Health. 2009; 99:788-791).

Overdose education and nasal naloxone distribution (OEND) programs are community-based interventions that educate people at risk for overdose and potential bystanders on how to prevent, recognize and respond to an overdose. They also equip these individuals with a naloxone rescue kit. To evaluate the impact of OEND programs on rates of opioid related death from overdose and acute care utilization in Massachusetts, an interrupted time series analysis of opioid related overdose death and acute care utilization rates from 2002 to 2009 was performed comparing community-year strata with high and low rates of OEND implementation to those with no implementation. The setting was nineteen Massachusetts communities (geographically distinct cities and towns) with at least five fatal opioid overdoses in each of the years 2004 to 2006. OEND was implemented among opioid users at risk for overdose, social service agency staff, family, and friends of opioid users. OEND programs equipped people at risk for overdose and bystanders with nasal naloxone rescue kits and trained them how to prevent, recognize, and respond to an overdose by engaging emergency medical services, providing rescue breathing, and delivering naloxone. Among these communities, OEND programs trained 2,912 potential bystanders who reported 327 rescues. Both community-year strata with 1-100 enrollments per 100,000 population (adjusted rate ratio 0.73, 95% confidence interval 0.57 to 0.91) and community-year strata with greater than 100 enrollments per 100,000 population (0.54, 0.39 to 0.76) had significantly reduced adjusted rate ratios compared with communities with no implementation. Differences in rates of acute care hospital utilization were not significant. Opioid overdose death rates were reduced in communities where OEND was implemented. This study provides observational evidence that by training potential bystanders to prevent, recognize, and respond to opioid overdoses, OEND is an effective intervention (Walley et al., Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis . BMJ 2013; 346:f174).

Naloxone prescription programs are also offered by community-based organizations in Los Angeles and Philadelphia. Programs in both cities target IDUs. Studies which recruited 150 IDUs across both sites for in-depth qualitative interviews compared two groups of IDUs, those who had received naloxone prescriptions and those who had never received naloxone prescriptions. In both L.A. and Philadelphia, IDUs reported successfully administering naloxone to reverse recently witnessed overdoses. Reversals often occurred in public places by both housed and homeless IDUs. Despite these successes, IDUs frequently did not have naloxone with them when they witnessed an overdose. Two typical reasons reported were naloxone was confiscated by police, and IDUs did not feel comfortable carrying naloxone in the event of being stopped by police. Similarly, some untrained IDUs reported discomfort with the idea of carrying naloxone on them as their reason for not gaining a prescription.

A randomized trial comparing 2 mg naloxone delivered intranasally with a mucosal atomizer to 2 mg intramuscular naloxone was reported by Kelly et al., in 2005 (Med J Aust. 2005 Jan. 3; 182(1):24-7). The study involved 155 patients (71 IM and 84 IN) requiring treatment for suspected opiate overdose and attended by paramedics of the Metropolitan Ambulance Service (MAS) and Rural Ambulance Victoria in Victoria, Australia. The IM group had more rapid response than the IN group, and were more likely to have more than 10 spontaneous respirations per minute within 8 minutes (82% v. 63%; P=0.0173). There was no statistically significant difference between the IM and IN groups for needing rescue naloxone (13% [IM group] v. 26% [IN group]; P=0.0558). The authors concluded that IN naloxone is effective in treating opiate-induced respiratory depression, but is not as effective as IM naloxone.

Kerr et al. (Addiction. 2009 December; 104(12):2067-74) disclosed treatment of heroin overdose by intranasal administration of naloxone constituted in a vial as a preparation of 2 mg in 1 mL. Participants received 1 mg (0.5 ml) in each nostril. The rate of response within 10 minutes was 60/83 (72.3%) for 2 mg IN naloxone versus 69/89 (77.5%) for 2 mg IM naloxone. The mean response times were 8.0 minutes and 7.9 minutes for IN and IV naloxone respectively. Supplementary naloxone was administered to fewer patients who received IM naloxone (4.5%) than IN (18.1%).

WO2012156317 describes a study in which naloxone, 8 mg and 16 mg, was administered as 400 Î¼L IN (200 Î¼L per nostril). The administration was performed as follows: The pump of the nasal spray was primed by removing the cap and pressing downward. This is repeated at least 6 times or until a fine spray appears; priming is done just prior to dosing. The subject is in a standing or upright position and should gently blow the nose to clear the nostrils. The subject should tilt the head forward slightly and gently close one nostril by pressing the outside of the nose with a finger on the nostril to be closed. The device is inserted into the open nostril and it is sprayed 2 times into the nostril. The subject should gently breath inward through the nostril, the device is removed, and the steps are repeated for the other nostril. The mean T max values were reported to be 0.34 h (20.4 min) and 0.39 h (23.4 min) for the 8 and 16 mg doses respectively.

Wermeling (Drug Deliv Transl Res. 2013 Feb. 1; 3(1): 63-74) teaches that the initial adult dose of naloxone in known or suspected narcotic overdose is 0.4 to 2 mg, which may be repeated to a total dose of 10 mg and that the current formulations of naloxone are approved for intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration, with IV being the recommended route. Wermeling also predicts that a 2 mg nasal solution dose of naloxone will likely have a C max of 3-5 ng/mL and a t max of approximately 20 minutes.

Since the onset of action of naloxone used in opioid overdose cases should be as fast as possible, naloxone is thus far mainly administered intravenously or intramuscularly by emergency health care personnel. Due to a high first pass metabolism, oral dosage forms comprising naloxone display a low bioavailability and thus seem to be not suitable for such purposes. The administration of naloxone via injection into the blood stream or into the muscle requires first of all trained medical personnel (for intravenous injection) or a trained carer (for intramuscular injection). Secondly, depending on the constitution of the addict and the period of intravenous drug abuse, it can be particularly difficult to find access into a vein of the addict's body for administering naloxone intravenously. Clearly, there is a risk of exposure to blood borne pathogens for the medical personnel or the trained carer since a large population of drug addicts suffers from blood borne pathogen induced diseases such as HIV, hepatitis B and C, and the like since accidental needlestick is a serious safety concern. 385,000 needle-stick injuries have been estimated to have occurred in the year 2000 in the US alone (Wilburn, Needlestick and sharps injury prevention , Online J Issues Nurs 2004, Sep. 30; 9(3):5).

Naloxone has a relatively short half-life of compared to some longer-acting opioid formulations and so after a typical therapeutic dose of naloxone is administered to an opioid overdose patient there is often the need to re-administer naloxone, in some cases even several times, and it is important to seek immediate medical attention.

Furthermore, it has been suggested that in view of the growing opioid overdose crisis in the US, naloxone should be made available over-the-counter (OTC), which would require a device, such as a nasal spray device, that untrained consumers are able to use safely. A nasal spray device that was pre-filled with a naloxone formulation would also be less likely to be confiscated by police than the system developed by some EMS programs that combines an FDA-approved naloxone injection product with a marketed, medical device called the Mucosal Atomization Device.

Thus, there remains a need for durable, easy-to-use, needleless devices with storage-stable formulations, that can enable untrained individuals to quickly deliver a therapeutically effective dose of a rapid-acting opioid antagonist to an opioid overdose patient. The therapeutically effective dose should be sufficient to obviate the need for the untrained individual to administer either a second dose of opioid antagonist or an alternative medical intervention to the patient, and to stabilize the patient until professional medical care becomes available. The devices described herein meet this and other needs.

Provided are devices adapted for nasal delivery of a pharmaceutical composition to a patient, comprising a therapeutically effective amount of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof, wherein the device is pre-primed, and wherein the therapeutically effective amount, is equivalent to about 2 mg to about 12 mg of naloxone hydrochloride.

Also provided are methods of treating opioid overdose or a symptom thereof, comprising nasally administering to a patient in need thereof a therapeutically effective amount of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof, wherein the therapeutically effective amount is equivalent to about 2 mg to about 12 mg of naloxone hydrochloride.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mean (Â±SD) naloxone plasma concentration following administration of 0.4 mg intramuscular (IM), 2 mg intranasal (IN), and 4 mg IN in 14 human subjects.

FIG. 2 shows the mean (Â±SD) naloxone plasma concentration with logarithmic transformation following administration of 0.4 mg intramuscular (IM), 2 mg intranasal (IN), and 4 mg IN in 14 human subjects.

FIG. 3A shows the mean naloxone plasma concentration following single intranasal administrations of naloxone to healthy subjects (N=28) over a twelve-hour period and FIG. 3B shows the mean naloxone plasma concentration following intramuscular injections of naloxone to healthy subjects (N=28) over a twelve-hour period.

FIG. 4A shows the mean naloxone plasma concentration following single intranasal administrations of naloxone to healthy subjects (N=28) over a four-hour period and FIG. 4B shows the mean naloxone plasma concentration following intramuscular injections of naloxone to healthy subjects (N=28) over a four-hour period.

FIG. 5A shows the mean naloxone plasma concentration following intramuscular injection of 0.4 mg naloxone to healthy male (N=16) and female (N=12) subjects over a twelve-hour period (top) and FIG. 5B shows the mean naloxone plasma concentration following one spray of 20 mg/mL naloxone (bottom) to healthy male (N=16) and female (N=12) subjects over a twelve-hour period.

FIG. 6A shows the mean naloxone plasma concentration following two sprays of 20 mg/mL to healthy male (N=16) and female (N=12) subjects over a twelve-hour period (top) and FIG. 6B shows the mean naloxone plasma concentration following one spray of 40 mg/mL (bottom) to healthy male (N=16) and female (N=12) subjects over a twelve-hour period.

FIG. 7 shows the mean naloxone plasma concentration following two sprays of 40 mg/mL to healthy male (N=16) and female (N=12) subjects over a twelve-hour period.

DETAILED DESCRIPTION OF THE INVENTION

For clarity and consistency, the following definitions will be used throughout this patent document.

The term âactive ingredientâ or âpharmaceutically active compoundâ is defined in the context of a âpharmaceutical compositionâ and is intended to mean a component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to an âinactive ingredientâ which would generally be recognized as providing no pharmaceutical benefit.

The term âactuation,â as used herein, refers to operation of the device such that the pharmaceutical composition is delivered therefrom.

The term âagonist,â as used herein, refers to as used herein refers to a moiety that interacts with and activates a receptor, and thereby initiates a physiological or pharmacological response characteristic of that receptor. The term âantagonist,â as used herein, refers to a moiety that competitively binds to a receptor at the same site as an agonist (for example, the endogenous ligand), but which does not activate the intracellular response initiated by the active form of the receptor and can thereby inhibit the intracellular responses by an agonist or partial agonist. An antagonist does not diminish the baseline intracellular response in the absence of an agonist or partial agonist. The term âinverse agonistâ refers to a moiety that binds to the endogenous form of the receptor or to the constitutively activated form of the receptor and which inhibits the baseline intracellular response initiated by the active form of the receptor below the normal base level of activity which is observed in the absence of an agonist or partial agonist.

The term âantimicrobial preservative,â as used herein, refers to a pharmaceutically acceptable excipient with antimicrobial properties which is added to a pharmaceutical composition to maintain microbiological stability.

The term âAUC,â as used herein, refers to the area under the drug plasma concentration-time curve. The term âAUC 0-t ,â as used herein, refers to the area under the drug plasma concentration-time curve from t=0 to the last measurable concentration. The term âAUC 0-â ,â as used herein, refers to the area under the drug plasma concentration-time curve extrapolated to â. The term âAUC 0-t/D ,â as used herein, refers to the AUC 0-t normalized to 0.4 mg IM naloxone. The term âAUC 0-â/D ,â as used herein, refers to the AUC 0â normalized to 0.4 mg IM naloxone

The term âbioavailability (F),â as used herein, refers to the fraction of a dose of drug that is absorbed from its site of administration and reaches, in an unchanged form, the systemic circulation. The term âabsolute bioavailabilityâ is used when the fraction of absorbed drug is related to its IV bioavailability. It may be calculated using the following formula:

â¢

extravascular

â¢

intravenous

â¢

intravenous

â¢

extravascular

The term relative bioavailability (Frei) is used to compare two different extravascular routes of drug administration and it may be calculated using the following formula:

rel

â¢

extravascular

â¢

extravascular

â¢

extravascular

â¢

extravascular

â¢

The term âclearance (CL),â as used herein, refers to the rate at which a drug is eliminated divided by its plasma concentration, giving a volume of plasma from which drug is completely removed per unit of time. CL is equal to the elimination rate constant (Î») multiplied by the volume of distribution (V d ), wherein âV d â is the fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma. The term âapparent clearance (CL/F),â as used herein, refers to clearance that does not take into account the bioavailability of the drug. It is the ratio of the dose over the AUC.

The term âC max â as used herein, refers to the maximum observed plasma concentration. The term âC max/D ,â as used herein, refers to C max normalized to 0.4 mg IM naloxone.

The term âcoefficient of variation (CV),â as used herein, refers to the ratio of the sample standard deviation to the sample mean. It is often expressed as a percentage.

The term âconfidence interval,â as used herein, refers to a range of values which will include the true average value of a parameter a specified percentage of the time.

The term âdevice,â as used herein, refers to an apparatus capable of delivering a drug to patient in need thereof.

The term âdelivery time,â as used herein, refers to the amount of time that elapses between a determination made by a healthcare professional, or an untrained individual that an individual is in need of nasal delivery of an opioid antagonist and completion of the delivery.

The term âelimination rate constant (Î»),â as used herein, refers to the fractional rate of drug removal from the body. This rate is constant in first-order kinetics and is independent of drug concentration in the body. Î» is the slope of the plasma concentration-time line (on a logarithmic y scale). The term âÎ» z ,â as used herein, refers to the terminal phase elimination rate constant, wherein the âterminal phaseâ of the drug plasma concentration-time curve is a straight line when plotted on a semilogarithmic graph. The terminal phase is often called the âelimination phaseâ because the primary mechanism for decreasing drug concentration during the terminal phase is drug elimination from the body. The distinguishing characteristic of the terminal elimination phase is that the relative proportion of drug in the plasma and peripheral volumes of distribution remains constant. During this âterminal phaseâ drug returns from the rapid and slow distribution volumes to the plasma, and is permanently removed from the plasma by metabolism or renal excretion.

The term âequivalent,â as used herein refers to a weight of an opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof that is equimolar to a specified weight of naloxone hydrochloride. For example, 8 mg of anhydrous naloxone hydrochloride (molecular weight, 363.84) is equivalent to about 7.2 mg of naloxone freebase (molecular weight, 327.37), and to about 8.8 mg of naloxone hydrochloride dihydrate (molecular weight 399.87).

The term âfilled,â as used herein, refers to an association between a device and a pharmaceutical composition, for example, when a pharmaceutical composition described herein comprising a therapeutically effective amount of an opioid antagonist is present within a reservoir that forms a part of a device described herein.

The term âhydrate,â as used herein, refers to an opioid antagonist described herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

The term âin need of treatmentâ and the term âin need thereofâ when referring to treatment are used interchangeably and refer to a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, that a patient will benefit from treatment.

As used herein, two embodiments are âmutually exclusiveâ when one is defined to be something which is different than the other. For example, an embodiment wherein the amount of naloxone hydrochloride is specified to be 4 mg is mutually exclusive with an embodiment wherein the amount of naloxone hydrochloride is specified to be 2 mg. However, an embodiment wherein the amount of naloxone hydrochloride is specified to be 4 mg is not mutually exclusive with an embodiment in which less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.

The term ânaloxone,â as used herein, refers to a compound of the following structure:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof. The CAS registry number for naloxone is 465-65-6. Other names for naloxone include: 17-allyl-4,5Î±-epoxy-3,14-dihydroxymorphinan-6-one; (â)-17-allyl-4,5Î±-epoxy-3,14-dihydroxymorphinan-6-one; 4,5Î±-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one; and (â)-12-allyl-7,7a,8,9-tetrahydro-3,7a-dihydroxy-4aH-8,9c-iminoethanophenanthro[4,5-bcd]furan-5(6H)-one. Naloxone hydrochloride may be anhydrous (CAS Reg. No. 357-08-4) and also forms a dihydrate (CAS No. 51481-60-8). It has been sold under various brand names including NarcanÂ®, NaloneÂ®, NalossoneÂ®, NaloxonaÂ®, NaloxonumÂ®, NarcantiÂ®, and NarconÂ®.

The term ânaltrexone,â as used herein, refers to a compound of the following structure:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof. The CAS registry number for naltrexone is 16590-41-3. Other names for naltrexone include: 17-(cyclopropylmethyl)-4,5Î±-epoxy-3,14-dihydroxymorphinan-6-one; (5a)-17-(cyclopropylmethyl)-3,14-dihydroxy-4,5-epoxymorphinan-6-one; and (1S,5R,13R,17S)-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.01,13.05,17.07,18]octadeca-7(18),8,10-trien-14-one. Naltrexone hydrochloride (CAS Reg. No. 16676-29-2) has been marketed under the trade names AntaxoneÂ®, DepadeÂ®, NalorexÂ®, ReviaÂ®, TrexanÂ®, VivitrexÂ®, and VivitrolÂ®.

The term âmethylnaltrexone,â as used herein, refers to a pharmaceutically acceptable salt comprising the cation (5a)-17-(cyclopropylmethyl)-3,14-dihydroxy-17-methyl-4,5-epoxymorphinanium-17-ium-6-one a compound of the following structure:

wherein X â is a pharmaceutically acceptable anion. Methylnaltrexone bromide (CAS Reg. No. 75232-52-7) has been marketed under the trade name RelistorÂ®.

The term ânalmefene,â as used herein, refers to 17-cyclopropylmethyl-4,5Î±-epoxy-6-methylenemorphinan-3,14-diol, a compound of the following structure:

Nalmefene hydrochloride (CAS Reg. No. 58895-64-0) has been marketed under the trade names NalmetreneÂ®, CerveneÂ®, RevexÂ®, ArthreneÂ®, and IncysteneÂ®.

The term ânostril,â as used herein, is synonymous with ânaris.â

The term âopioid antagonistâ includes, in addition to naloxone and pharmaceutically acceptable salts thereof: naltrexone, methylnaltrexone, and nalmefene, and pharmaceutically acceptable salts thereof. In some embodiments, the opioid antagonist is naloxone hydrochloride. In some embodiments, the opioid antagonist is naloxone hydrochloride dihydrate. In some embodiments, the opioid antagonist is naltrexone hydrochloride. In some embodiments, the opioid antagonist is methylnaltrexone bromide. In some embodiments, the opioid antagonist is nalmefene hydrochloride. In some embodiments, the nasally administering is accomplished using a device described herein.

The term âopioid overdose,â as used herein, refers to an acute medical condition induced by excessive use of one or more opioids. Symptoms of opioid overdose include including respiratory depression (including postoperative opioid respiratory depression, acute lung injury, and aspiration pneumonia), central nervous system depression (which may include sedation, altered level consciousness, miotic (constricted) pupils), and cardiovascular depression (which may include hypoxemia and hypotension). Visible signs of opioid overdose or suspected opioid overdose include: unresponsiveness and/or loss of consciousness (won't respond to stimuli such as shouting, shaking, or rubbing knuckles on sternum); slow, erratic, or stopped breathing; slow, erratic, or stopped pulse; deep snoring or choking/gurgling sounds; blue or purple fingernails or lips; pale and/or clammy face; slack or limp muscle tone; contracted pupils; and vomiting. Because opioid overdose may be difficult to diagnose and/or quantify, particularly by a lay person, as used herein, treatment of opioid overdose is meant to include treatment of suspected opioid overdose in opioid-intoxicated patients. Opioids that may induce overdose include, codeine, morphine, methadone, fentanyl, oxycodone HCl, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, tapentadol, and certain narcotic-antagonist analgesics, such as, nalbuphine, pentazocine and butorphanol. In some embodiments, the opioid agonist is in a tamper-proof formulation. In some embodiments, the opioid agonist is in a tamper-resistant formulation. In some embodiments, the opioid agonist is selected from AcuroxÂ® Oxycodone DETERxÂ®, Egalet hydrocodone, Egalet morphine, Egalet oxycodone, ExalgoÂ®, OpanaÂ®, and RemoxyÂ®.

The term âpatient,â as used herein, refers to any subject (preferably human) afflicted with a condition likely to benefit from a treatment with a therapeutically effective amount of an opioid antagonist.

The terms âpermeation enhancerâ and âpenetration enhancer,â as disclosed herein, are intended to be equivalent, both referring to an agent which aids in absorption of a compound, such as through the nasal mucosa.

The term âpharmaceutical composition,â as used herein, refers to a composition comprising at least one active ingredient; including but not limited to, salts, solvates and hydrates of the opioid antagonists described herein, whereby the composition is amenable to use for a specified, efficacious outcome in a mammal (for example, without limitation, a human).

The term âpre-primed,â as used herein, refers to a device, such as a nasal spray which is capable of delivering a pharmaceutical composition to a patient in need thereof with the first actuation of the spray pump, i.e., without the need to prime the pump prior to dosing, such as by actuating the pump one or more times until a spray appears.

The term âprone,â as used herein, refers to a patient who is lying face down.

The term âreceptor binding or occupancyâ refers to a characterization of the kinetics between a radioactive drug and receptors or other binding sites throughout the body, and characterization of the radioactive drug binding affinity to these receptors.

The term ârecovery position,â as used herein, means a position of the human body in which a patient lies on his/her side, with a leg or knee out in front (e.g., to prevent rolling onto his/her stomach) and at least one hand supporting the head (e.g., to elevate the face to facilitate breathing and prevent inhalation of vomit).

The term âsolvate,â as used herein, refers to an opioid antagonist described herein or a salt, thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.

The term âsterile filling,â as used herein, refers methods of manufacturing the devices and pharmaceutical compositions described herein, such that the use of preservatives is not required. Sterile drug products may be produced using aseptic processing or terminal sterilization. Terminal sterilization usually involves filling and sealing product containers under high-quality environmental conditions. In an aseptic process, the drug product, container, and closure are first subjected to sterilization methods separately, as appropriate, and then brought together.

The term âstorage-stable,â as used herein, refers to a pharmaceutical composition in which at least about 95% to 99.5% of the active ingredient remains in an undegraded state after storage of the pharmaceutical composition at specified temperature and humidity for a specified time, for example, for 12 months at 25Â° C. and 60% relative humidity.

The term âsupine,â as used herein, refers to a patient who is lying face up.

The term ât 1/2 â or âhalf-life,â as used herein, refers to the amount of time required for half of a drug to be eliminated from the body or the time required for a drug concentration to decline by half.

The term âtonicity agent,â as used herein, refers to a compound which modifies the osmolality of a formulation, for example, to render it isotonic. Tonicity agents include, dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine and the like.

The term âtomography,â as used herein, refers to a process of imaging by sections. The images may be looked at individually, as a series of two-dimensional slices or together, as a computer-generated three-dimensional representation.

The term âpharmaceutically acceptable,â as used herein, refers to a c

CLAIMS

Claims ( 33 )

1 . A pharmaceutical formulation for intranasal administration comprising, in an aqueous solution of not more than about 140 Î¼L:

about 2 mg naloxone hydrochloride;

about 0.74 mg NaCl;

about 0.01 mg benzalkonium chloride;

about 0.2 mg disodium edetate; and

an amount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5.

2 . The pharmaceutical formulation of claim 1 , wherein the aqueous solution has a volume of 100 Î¼L.

3 . The pharmaceutical formulation of claim 1 , which yields, when intranasally administered to a patient, a mean naloxone plasma concentration of >0.2 ng/mL within 2.5 minutes, a mean naloxone plasma concentration of >1 ng/mL within 5 minutes, or a mean naloxone plasma concentration of >3 ng/mL within 10 minutes in said patient.

4 - 5 . (canceled)

6 . The pharmaceutical formulation of claim 1 , which yields, when intranasally administered to a patient, a naloxone T max selected from the group consisting of less than 30 minutes, less than 25 minutes and less than 20 minutes.

7 - 8 . (canceled)

9 . A single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient by one actuation of said device into one nostril of said patient, having a single reservoir comprising a pharmaceutical composition which comprises per 100 Î¼L of aqueous solution:

about 2 mg naloxone hydrochloride;

between about 0.2 mg and about 1.2 mg of an isotonicity agent;

between about 0.005 mg and about 0.015 mg of a preservative;

between about 0.1 mg and about 0.5 mg of a stabilizing agent; and

an amount of an acid sufficient to achieve a pH of 3.5-5.5.

10 . The device as recited in claim 9 , wherein the device has at least one of the following features:

a. the isotonicity agent is NaCl, the preservative is benzalkonium chloride the stabilizing agent is disodium edetate, and the acid is hydrochloric acid; b. the aqueous solution comprises per 100 Î¼L: about 2 mg naloxone hydrochloride, about 0.74 mg NaCl, about 0.01 mg benzalkonium chloride, about 0.2 mg disodium edetate, and an amount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5; c. the device is actuatable with one hand; d. the volume of said reservoir is not more than about 140 Î¼L; e. about 100 Î¼L of said aqueous solution in said reservoir is delivered to said patient in one actuation; f. the pharmaceutical composition which is an aqueous solution comprises about 2 mg naloxone hydrochloride; g. the device is configured such that 90% confidence interval for dose delivered per actuation is about Â±2%; h. the device is configured such that 95% confidence interval for dose delivered per actuation is about Â±2.5%; i. the device is configured such that delivery time is less than about 25 seconds; j. the device is configured such that delivery time is less than about 20 seconds.

11 - 19 . (canceled)

20 . A method of treatment of opioid overdose or a symptom thereof, comprising nasally administering to a patient in need thereof a dose of naloxone hydrochloride from the device of claim 9 .

21 . The method of claim 20 , wherein the method has at least one of the following features:

a. (i) the isotonicity agent is NaCl, (ii) the compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer is benzalkonium chloride, (iii) the stabilizing agent is disodium edetate, and (iv) the acid is hydrochloric acid; b. the aqueous solution comprises about 2 mg naloxone hydrochloride, about 0.74 mg NaCl, about 0.01 mg benzalkonium chloride, about 0.2 mg disodium edetate, and an amount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5; c. the device is actuatable with one hand; d. the volume of said reservoir is not more than about 140 Î¼L; e. wherein the plasma concentration versus time curve of said naloxone hydrochloride in said patient has a T max of between about 20 and about 30 minutes.

22 - 24 . (canceled)

25 . The method of claim 21 , wherein when the volume of said reservoir is not more than about 140 Î¼L, about 100 Î¼L of said aqueous solution in said reservoir is delivered to said patient in one actuation.

26 . The method of claim 25 , wherein the pharmaceutical composition which is an aqueous solution comprises 2 mg naloxone hydrochloride.

27 . The method of claim 26 , wherein the method has at least one of the following features:

a. 90% confidence interval for dose delivered per actuation is about Â±2%; b. 95% confidence interval for dose delivered per actuation is about Â±2.5%; c. delivery time is less than about 25 seconds; d. delivery time is less than about 20 seconds.

28 - 30 . (canceled)

31 . The method of claim 21 , wherein when the method has feature b, upon nasal delivery of said pharmaceutical composition to said patient, less than about 20% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally, less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally, or less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.

32 - 34 . (canceled)

35 . The method of claim 20 , wherein said patient is an opioid overdose patient or a suspected opioid overdose patient.

36 . The method of claim 35 , wherein the patient exhibits one or more symptoms chosen from: respiratory depression, central nervous system depression, cardiovascular depression, altered level consciousness, miotic pupils, hypoxemia, acute lung injury, aspiration pneumonia, sedation, hypotension, unresponsiveness to stimulus, unconsciousness, stopped breathing; erratic or stopped pulse, choking or gurgling sounds, blue or purple fingernails or lips, slack or limp muscle tone, contracted pupils, and vomiting.

37 . The method of claim 36 , wherein the patient exhibits respiratory depression and wherein the method has at least one of the following features:

a. said respiratory depression is caused by the illicit use of opioids, or by an accidental misuse of opioids during medical opioid therapy; b. said patient is free from respiratory depression for at least about 1 hour following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist; c. patient is free from respiratory depression for at least about 2 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist; d. said patient is free from respiratory depression for at least about 4 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist; e. said patient is free from respiratory depression for at least about 6 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist; f. said patient is in a lying, supine, or recovery position.

38 - 43 . (canceled)

44 . A method of complete or partial reversal of narcotic depression or respiratory depression induced by opioids in a patient, comprising nasally administering to a patient in need thereof a dose of naloxone hydrochloride from the device of claim 9 .

45 . The method of claim 44 , wherein the method has at least one of the following features:

a. the isotonicity agent is NaCl, the compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer is benzalkonium chloride, the stabilizing agent is disodium edetate, and the acid is hydrochloric acid; b. the aqueous solution comprises about 2 mg naloxone hydrochloride, about 0.74 mg NaCl, about 0.01 mg benzalkonium chloride, about 0.2 mg disodium edetate, and an amount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5; c. the method is actuatable with one hand; d. volume of said reservoir is not more than about 140 Î¼L; e. plasma concentration versus time curve of said naloxone hydrochloride in said patient has a T max of between about 20 and about 30 minutes; f. said patient is an opioid overdose patient or a suspected opioid overdose patient.

46 - 48 . (canceled)

49 . The method of claim 45 , wherein when the volume of said reservoir is not more than about 140 Î¼L, about 100 Î¼L of said aqueous solution in said reservoir is delivered to said patient in one actuation.

50 . The method of claim 49 , wherein the method has at least one of the following features:

a. the pharmaceutical composition which is an aqueous solution comprises 2 mg naloxone hydrochloride; b. 90% confidence interval for dose delivered per actuation is about Â±2%; c. 95% confidence interval for dose delivered per actuation is about Â±2.5%; d. delivery time is less than about 25 seconds; e. delivery time is less than about 20 seconds; f. the pharmaceutical composition which is an aqueous solution comprises 2 mg naloxone hydrochloride and wherein the delivery time is less than about 25 seconds; g. the pharmaceutical composition which is an aqueous solution comprises 2 mg naloxone hydrochloride and wherein the delivery time is less than about 20 seconds.

51 - 54 . (canceled)

55 . The method of claim 45 , wherein when the method has feature b, upon nasal delivery of said pharmaceutical composition to said patient, less than about 20% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally, less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally, or less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.

56 - 59 . (canceled)

60 . The method of claim 45 , wherein when said patient is an opioid overdose patient or a suspected opioid overdose patient, the patient exhibits one or more symptoms chosen from: respiratory depression, central nervous system depression, cardiovascular depression, altered level consciousness, miotic pupils, hypoxemia, acute lung injury, aspiration pneumonia, sedation, hypotension, unresponsiveness to stimulus, unconsciousness, stopped breathing; erratic or stopped pulse, choking or gurgling sounds, blue or purple fingernails or lips, slack or limp muscle tone, contracted pupils, and vomiting.

61 . The method of claim 60 , wherein the patient exhibits respiratory depression and wherein the method has at least one of the following features:

a. said respiratory depression is caused by the illicit use of opioids, or by an accidental misuse of opioids during medical opioid therapy; b. said patient is free from respiratory depression for at least about 1 hour following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist; c. said patient is free from respiratory depression for at least about 2 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist; d. said patient is free from respiratory depression for at least about 4 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist; e. said patient is free from respiratory depression for at least about 6 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist; f. said patient is in a lying, supine, or recovery position.

62 - 67 . (canceled)

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US9468747B2

( en )

2016-10-18

US20160184294A1

( en )

2016-06-30

US20160166503A1

( en )

2016-06-16

US20170304295A1

( en )

2017-10-26

US9480644B2

( en )

2016-11-01

US9629965B2

( en )

2017-04-25

US20170043107A1

( en )

2017-02-16

Nasal drug products and methods of their use — Opiant Pharmaceuticals, Inc. (US20210275519A1)

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