U.S. patent application number 16/939660 was filed with the patent office on 2021-01-14 for pharmaceutical composition for nasal delivery.
The applicant listed for this patent is Orexo AB. Invention is credited to Andreas Fischer, Robert Ronn, Jonas Savmarker.
Application Number | 20210008059 16/939660 |
Document ID | / |
Family ID | 1000004986369 |
Filed Date | 2021-01-14 |
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United States Patent
Application |
20210008059 |
Kind Code |
A1 |
Savmarker; Jonas ; et
al. |
January 14, 2021 |
PHARMACEUTICAL COMPOSITION FOR NASAL DELIVERY
Abstract
According to the invention, there is provided a solid
pharmaceutical composition formulation for nasal delivery of an
opioid antagonist, comprising a pharmacologically-effective amount
of an opioid antagonist and a pharmaceutically-acceptable carrier.
The compositions are preferably in the form of a powder produced by
spray-drying, which are subsequently loaded into single use nasal
applicators. Preferred pharmaceutically-acceptable carriers in this
regard include disaccharides (e.g. lactose or trehalose) and
dextrins (e.g. cyclodextrins or maltodextrins), preferably
spray-dried together in combination. Compositions may further
comprise an alkyl saccharide, preferably a sucrose ester, such as
sucrose monolaurate. The compositions and applicators may be
employed in the treatment of opioid overdose in subjects.
Inventors: |
Savmarker; Jonas; (Uppsala,
SE) ; Ronn; Robert; (Uppsala, SE) ; Fischer;
Andreas; (Uppsala, SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Orexo AB |
Uppsala |
|
SE |
|
|
Family ID: |
1000004986369 |
Appl. No.: |
16/939660 |
Filed: |
July 27, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16876468 |
May 18, 2020 |
10729687 |
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16939660 |
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16506023 |
Jul 9, 2019 |
10653690 |
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16876468 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0043 20130101;
A61K 31/485 20130101; A61K 9/1652 20130101; A61K 9/1682
20130101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 9/16 20060101 A61K009/16; A61K 9/00 20060101
A61K009/00 |
Claims
1. (canceled)
2. A solid pharmaceutical composition in the form of a spray-dried
powder that is suitable for nasal delivery of naloxone or a
pharmaceutically acceptable salt thereof, to treat opioid overdose,
comprising: a pharmacologically-effective amount of naloxone or a
pharmaceutically acceptable salt thereof; and a
pharmaceutically-acceptable carrier material comprising a
combination of: (i) a disaccharide selected from the group
consisting of maltitol, trehalose, sucralose, sucrose, isomalt,
maltose, and lactose; and (ii) a dextrin; wherein the naloxone or
pharmaceutically acceptable salt thereof is less than about 15%
chemically degraded after 3 months at 75% relative humidity and
40.degree. C.
3. A composition as claimed in claim 2, wherein the powder has a
particle size distribution that includes a d10 that is above about
3 .mu.m.
4. A composition as claimed in claim 2, wherein the disaccharide
comprises lactose and/or trehalose.
5. A composition as claimed in claim 2, wherein the dextrin
comprises a cyclodextrin or a maltodextrin.
6. A composition as claimed in claim 2, wherein the carrier
material comprises .alpha.-D-lactose monohydrate as the lactose
disaccharide and one or both of 2-hydroxypropyl-.beta.-cyclodextrin
and maltodextrin 12DE as the dextrin.
7. A composition as claimed in claim 2, wherein the disaccharide is
present in an amount of between about 10% and about 30% by weight
based on the total weight of the composition.
8. A composition as claimed in claim 2, wherein the dextrin is
present in an amount of between 40% and about 80% by weight based
on the total weight of the composition.
9. A composition as claimed in claim 2, wherein the lowest
measurable glass transition temperature of the composition is at
least about 40.degree. C. when measured at a relative humidity of
up to about 35%.
10. A composition as claimed in claim 2, wherein the powder has a
particle size distribution that includes a volume-based mean
diameter within the range of about 10 .mu.m and about 100
.mu.m.
11. A process for the manufacturing of a composition as defined in
claim 2, wherein said process comprises the steps of: i) mixing
together naloxone or salt thereof, the pharmaceutically-acceptable
carrier materials in an appropriate volatile solvent; and ii)
spray-drying the mixture from step i) to form a spray-dried
plurality of particles.
12. A composition obtainable by a process as defined in claim
11.
13. A nasal applicator device suitable and/or adapted for delivery
of a composition as defined in claim 2 to the nose, which
comprises, or is adjunct and/or attached to, a reservoir, within
which reservoir said composition is contained.
14. A process for the manufacturing of an applicator device as
claimed in claim 13, the process comprising: i) mixing together
naloxone or salt thereof and the pharmaceutically-acceptable
carrier materials in an appropriate volatile solvent; ii)
spray-drying the mixture from step i) to form a spray-dried
plurality of particles; and iii) loading the composition formed in
step ii) into the reservoir within or adjunct or attached to said
applicator device.
15. A method of treating opioid overdose, which method comprises
administering a composition as defined in claim 2 to a subject in
need of such treatment.
16. A method as claimed in claim 15, wherein the composition is
administered to said subject by way of an applicator that comprises
or is adjunct and/or attached to, a reservoir, within which
reservoir said composition is contained.
Description
[0001] This application is a Continuation of U.S. patent
application Ser. No. 16/876,468, filed May 18, 2020, which is a
Continuation-in-Part of U.S. patent application Ser. No.
16/506,023, filed on Jul. 9, 2019, now U.S. Pat. No. 10,653,690,
which are hereby incorporated by reference in their entirety.
[0002] This invention relates to new pharmaceutical compositions
containing opioid antagonists that are useful in the treatment of
inter alia opioid/opiate overdose. The invention also relates to
methods of manufacturing such compositions and formulating them
into dosage forms, as well as their use in the treatment of
opioid/opiate overdose.
PRIOR ART AND BACKGROUND
[0003] The listing or discussion of an apparently prior-published
document in this specification should not necessarily be taken as
an acknowledgment that the document is part of the state of the art
or common general knowledge.
[0004] Drug addiction is a worldwide problem, of which opioid
dependence is a major component. Opioids and opiates are highly
addictive. People often start using illegal opioids, such as heroin
(diamorphine), for recreational purposes, but this commonly leads
to dependency.
[0005] That said, a new cohort of opioid-dependent individuals has
begun to emerge in the last decade or so, particularly in the US,
namely so-called `white collar` addicts, who have become dependent
upon prescription opioids, typically initiated for the treatment of
pain.
[0006] This occurs because of the increasingly extensive use of
medicinal opioids as analgesics, in the treatment of moderate to
severe, chronic cancer pain, as well as acute pain (e.g. during
recovery from surgery and breakthrough pain). Further, their use is
increasing in the management of chronic, non-malignant pain.
[0007] People who become addicted to prescription opioids sometimes
move on to illicit (`street`) drugs, such as heroin. This may be
because heroin is cheaper and (relatively speaking) easier to
obtain than a prescription opioid.
[0008] It was estimated in 2010 that there were 15.5 million
opioid-dependent people globally. Prevalence in Australasia,
Western Europe, and North America was higher than the global-pooled
prevalence. According to the European Monitoring Centre for Drugs
and Drug Addiction Report in 2017, there were an estimated 1.3
million high-risk opioid users in Europe in 2016. The opioid crisis
has affected the US especially, and this has escalated during
recent years.
[0009] Thus, opioid dependence is a major health problem and
long-term opioid use is connected to a substantially increased risk
of premature death from drug overdoses, violence and suicide, as
well as various other well publicized health issues, with an
increasingly burgeoning socio-economic impact in terms of cost of
healthcare, lost productivity, addiction treatment, and criminal
activity (see Florence et al, Med. Care., 54, 901 (2016)).
[0010] Opioid addicts typically feed their addiction by direct
purchase of opioids `on the street`, in the form of opioid-based
powders (such as heroin). Heroin is usually mixed (or `cut`) with
additives prior to sale by drug dealers, the amount and identity of
which is almost always unknown to the abuser. Furthermore, there is
an increasing number of addicts being sold, and abusing, more
potent opioids intended for the treatment of e.g. pain, such as
fentanyl and its analogues (see e.g. Prekupec et al, J. Addict.
Med., 11, 256-265 (2017)).
[0011] Even without these additional issues, opioids are extremely
dangerous drugs if not delivered under medical supervision. As
there are no quality controls on illicit drugs that are sold,
particularly in relation to the purity and strength issues
discussed above, the whole process is something of a `lottery`,
which serves to add to the danger and likelihood of overdose.
[0012] Overdose of opioids leads to depressed heart rate and
breathing, leading to hypoxia. Hypoxia not only leads to short- and
long-term effects on the central nervous system, including coma and
permanent brain damage, but often leads to fatality. Overdoses of
opioids, particularly heroin are very common. In 2015, drug
overdoses accounted for 52,404 US deaths, of which 33,091 (63.1%)
involved an opioid (see Rudd et al, MMWR, 65, 1445 (2016)). It is
not unheard of for people to overdose the very first time they use
heroin.
[0013] A subject that has overdosed on an opioid requires urgent
medical attention. The only medicines that can be employed to treat
opioid overdoses effectively are opioid receptor antagonists, which
act by binding to opioid receptors, displacing opioid agonists
(like heroin) without eliciting opioid effects of their own,
whether intended (e.g. euphoria) or unintended and/or potentially
dangerous (including respiratory depression). Emergency
administration of opioid antagonists can reduce (sometimes
completely) the degree of opioid intoxication and, in essence,
`reverse` an opioid overdose.
[0014] Opioid antagonists are administered as intravenous solutions
in Accident and Emergency departments hospitals by
medically-qualified staff. However, outside of the hospital
environment, there are relatively few treatments available for the
treatment of an opioid overdose (or a suspected overdose).
[0015] Two such treatments that are available commercially comprise
the opioid antagonist, naloxone, delivered in the form of a single
dose either as a liquid nasal spray (Narcan.RTM.; which is sprayed
directly into one nostril), or as an auto-injector (Evzio.RTM.;
which delivers drug by injection into the muscle or under the
skin). These treatments are often employed by first responders
(i.e. non-medically qualified personnel, such as ambulance crews,
paramedics, police officers, family members, friends or other
caregivers), buying time until more qualified medical assistance is
available.
[0016] These products are undoubtedly effective in helping to save
lives. Naloxone and other opioid antagonists are highly
water-soluble drugs, which enables the dissolution of an effective
dose of e.g. naloxone in a small quantity of liquid (100 .mu.L) in
a product like Narcan to treat opioid overdose. This enables it to
act quickly in an emergency situation.
[0017] However, in about one third of cases, Narcan is known to
require two or more doses in order to effect reversal of the
overdose. Furthermore, Narcan has the disadvantage that it should
not be allowed to freeze (otherwise it cannot be dispensed). This
is a problem in cold climates, for example if the product is left
inside a first responder's vehicle overnight.
[0018] Evzio, on the other hand, is a parenteral product that
requires a needle, presenting significant difficulties and/or
problems for some first responders in what is an urgent
situation.
[0019] Because of the huge increase in overdose deaths from opioid
misuse, there is considerable demand for opioid overdose prevention
medications, and also a clear clinical need for alternative and/or
improved medications, in terms of their strength, onset and
duration of action, as well as reproducibility and reliability in
an emergency situation, which treating an opioid overdose
undoubtedly is.
[0020] In addition to the commercial product, Narcan, liquid
intranasal sprays are also disclosed in international patent
application WO 2018/064672 and US patent applications US
2018/0092839A and US 2019/0070105A.
[0021] Dry powder formulations comprising opioid antagonists that
may be administered by inhalation or intranasally are known from
inter alia international patent applications WO 2010/142696 and WO
2019/038756, and US patent application US 2018/0092839A.
[0022] Russo et al (J. Pharm. Sci., 95, 2253 (2006)) discloses
spray-drying the opioid analgesic compound, morphine, with numerous
excipients. Spray-dried formulations are also disclosed in
Vengerovich et al., Bulletin of Experimental Biology and Medicine,
163, 737 (2017), where it was attempted to microencapsulate
naloxone in various substances, including
2-hydroxypropyl-.beta.-cyclodextrin, with a view to developing
sustained-release preparations based on polymeric carriers for
emergency care.
[0023] Sugar esters are a class of natural and biodegradable
non-ionic surfactants consisting of a hydrophilic sugar `head
group` esterified with fatty acids. The properties of sugar esters
depend on the nature of the sugar and fatty acids used, and the
degree of esterification of the sugar. They are made from natural
products, sugar and edible fats, are tasteless, odourless and
biodegradable, and are relatively nontoxic with a recommended
acceptable daily intake of up to 30 mg/kg (joint FAO/WHO Expert
Committee on Food Additives (JECFA)). Sugar esters, and in
particular sucrose esters, are widely used in the food and
cosmetics industries but, thus far, are relatively underutilised in
pharmaceutical formulations (see, for example, the review article
by Sz{acute over ( )}ts and Szabo-Revesz in Int. J. Pharm., 433, 1
(2012)).
[0024] Sucrose esters are known to be excellent oil-in-water-type
emulsifiers. For example, emulsion-based compositions comprising
sucrose esters are described in international patent application WO
2005/065652. See also international patent application WO
2003/061632.
[0025] Sucrose esters have also been employed to improve the
bioavailability of poorly water-soluble drugs, such as ciclosporin
in perorally administered dosage forms (see Hahn and Sucker, Pharm.
Res., 6, 958 (1989)). (It is to be noted that naloxone and other
opioid antagonists are highly water-soluble.)
[0026] Other peroral dosage forms comprising sucrose esters are
described in inter alia international patent application WO
2016/016431.
[0027] International patent applications WO 2015/095389 and WO
2018/089709, and U.S. Pat. No. 9,895,444, also disclose that
related compounds, sugar ethers and in particular alkyl glycosides,
can increase the bioavailability of opioid compounds in liquid
nasal sprays. Sucrose esters are also mentioned in these documents.
Similar drug delivery vehicles are disclosed in US patent
application US 2016/0045474. Furthermore, Kurti et al investigated
the effect of sucrose esters on epithelial permeability in a
culture model (see Toxicology in Vitro, 26, 445 (2012)), and Li et
al investigated the effect of various surfactants, including
sucrose laurate, in in vivo absorption studies in rats, using
sumatriptan as a model drug substance (see Drug Delivery, 23, 2272
(2016)).
[0028] However, to the applicant's knowledge, there is no reported
use of sucrose esters in solid (e.g. powder) formulations intended
for intranasal delivery.
[0029] We have now unexpectedly found that it is possible to
formulate opioid antagonists in the form of dry powder
compositions, that provide for a surprising and substantial
improvement in bioavailability of opioid antagonist, as well as,
even more surprisingly, an increase in the speed of absorption of
opioid antagonist, compared to commercially-available products. In
particular, we have found that compositions that are produced by a
process of spray-drying with a specific combination of carrier
materials as disclosed hereinafter, and/or similar dry powder
compositions that comprise an alkyl saccharide, such as a sucrose
ester, are capable of giving rise to these unexpected effects.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] FIG. 1 is a diagrammatic sectional view of a first suitable
applicator based on the disclosure of U.S. Pat. No. 6,398,074,
which is incorporated herein by reference. As shown, the applicator
is configured before actuation.
[0031] FIG. 2 is a sectional view of the applicator shown in FIG.
1, but after actuation.
[0032] FIG. 3 is a diagrammatic sectional view of a second suitable
applicator based on the disclosure of U.S. Pat. No. 9,724,713,
which is incorporated herein by reference. As shown, the applicator
is configured in the rest position.
[0033] FIG. 4 is a sectional view of the applicator shown in FIG.
3, but now configured in the actuation position.
[0034] FIG. 5 is a sectional view of the applicator shown in FIG.
3, but now configured in the dispensing position.
[0035] FIG. 6 is a sectional view of the applicator shown in FIG.
3, but now configured during return of the air expeller towards its
rest position.
[0036] FIG. 7 is a diagrammatic perspective view of the air
expeller of the device in FIGS. 3 to 6 shown in its rest
position.
[0037] FIG. 8 is a graph showing permeation of naloxone through
porcine nasal tissue in an ex vivo model.
[0038] FIG. 9 is a graph showing permeation of nalmefene through
porcine nasal tissue in an ex vivo model.
[0039] FIGS. 10 and 11 show mean naloxone plasma concentrations
versus time, by treatment (linear scale), as obtained in a clinical
trial, over different time periods.
DISCLOSURE OF THE INVENTION
[0040] According to a first aspect of the invention, there is
provided a solid pharmaceutical formulation/composition that is
suitable for nasal delivery of an opioid antagonist, comprising a
pharmacologically-effective amount of an opioid antagonist, and a
pharmaceutically-acceptable carrier material.
[0041] According to a second aspect of the invention, there is
provided a solid pharmaceutical formulation/composition in the form
of a powder that is suitable for nasal delivery of an opioid
antagonist, comprising a pharmacologically-effective amount of an
opioid antagonist, optionally an alkyl saccharide, and a
pharmaceutically-acceptable carrier material.
[0042] Preferably, the powder is produced by a process of
spray-drying.
[0043] According to a third aspect of the invention, there is
provided a solid pharmaceutical formulation/composition in the form
of a spray-dried powder that is suitable for nasal delivery of an
opioid antagonist, comprising a pharmacologically-effective amount
of an opioid antagonist and a pharmaceutically-acceptable carrier
material, more preferably a carrier material that comprises a
combination of at least two pharmaceutically-acceptable carrier
materials, at least one of which carrier materials is a
disaccharide and at least one of which carrier materials is a
dextrin.
[0044] Compositions of the first, second and third aspects of the
invention are referred to hereinafter together as `the compositions
of the invention`.
[0045] The term `solid` will be well understood by those skilled in
the art to include any form of matter that retains its shape and
density when not confined, and/or in which molecules are generally
compressed as tightly as the repulsive forces among them will
allow.
[0046] Opioid antagonists that may be employed in compositions of
the invention include any compound that has little to no opioid
activity, but is capable of displacement of an opioid agonist from
an opioid receptor, so reversing or preventing the pharmacological
effects of an opioid agonist, whether such effects are intended
(euphoria, sedation and/or reduction in cravings), or unintended
(unconsciousness, depressed heart rate, depressed lung function,
hypoxia, etc.). In this respect, the term `opioid agonists` include
exogenous opioid receptor ligands (i.e. those mentioned
hereinbefore) and endogenous opioid receptor ligands (e.g.
endorphins).
[0047] Opioid antagonists thus include naloxone, nalmefene and
naltrexone, or pharmacologically-acceptable salts thereof.
Preferred salts of these compounds include hydrochloride salts.
Naloxone and nalmefene (and salts of either) are particularly
preferred.
[0048] In the context of the present invention, the term `opioid
antagonists` may also include active pharmaceutical ingredients
that are known to be partial antagonists of opioid receptors, such
as buprenorphine. Buprenorphine may be termed as a `partial
antagonist of opioid receptors` because it is a partial agonist at
the .mu.-opioid receptor. It has high binding affinity, and
competes with other agonists, such as methadone, heroin and
morphine, at the .mu.-opioid receptor. Opioid agonist effects of
buprenorphine are less than the maximal effects of other, `full`
opioid agonists, such as morphine, and are limited by a `ceiling`
effect. The drug thus produces a lower degree of physical
dependence than other opioid agonists, such as heroin, morphine or
methadone and is therefore used in substitution therapy. There is a
reduced risk of overdose and reduced recreational value in
opioid-tolerant subjects. Buprenorphine has been listed on the
WHO's List of Essential Medicines for the treatment of opioid
dependence. Displacement of full agonists may make buprenorphine
useful in the context of the invention by being capable of
reversing an opioid overdose, with a lower degree of precipitated
withdrawal compared with full antagonists.
[0049] The amount of opioid antagonist that is employed in a
composition of the invention must be sufficient so as to antagonize
the effect of the opioid receptor agonists (whether exogenous
and/or endogenous), precipitate withdrawal symptoms and/or effect
reversal of the pharmacological effects mentioned above.
Pharmacologically-appropriate amounts of opioid antagonist (or salt
thereof) may be determined by the skilled person and may vary with
the type and severity of the condition that is to be treated, and
what will be most suitable for an individual patient. This is also
likely to vary with the nature of the formulation, as well as the
route of administration, the type and severity of the condition
that is to be treated, as well as the age, weight, sex, renal
function, hepatic function and response of the particular patient
to be treated.
[0050] The total amount of opioid antagonist that may be employed
in a composition of the invention will depend on the nature of the
active compound that is included, but may be in the range of from
about 0.1%, such as about 1%, for example about 2% up to about 95%.
For example, the amount of opioid antagonist may be from about 5%,
such as about 10% (e.g. about 20%) to about 95%, such as about 75%,
for example about 50%, e.g. about 40%, by weight based upon the
total weight of the composition.
[0051] Appropriate doses of opioid antagonist (calculated as the
free acid/base) per unit dosage are in the range of about 1 mg to
about 60 mg (e.g. about 40 mg), such as between about 2 mg and
about 30 mg (e.g. about 20 mg, such as about 10 mg), depending on
the opioid antagonist that is employed.
[0052] Appropriate doses of naloxone (calculated as the free base)
are in the range of about 1 mg to about 20 mg (e.g. about 15 mg),
such as between about 1.5 mg and about 10 mg, and may thus be about
1.8 mg, about 5.4 mg, about 9.0 mg (e.g. about 10.8 mg), more
preferably about 3.6 mg and especially about 7.2 mg.
[0053] Appropriate doses of nalmefene (calculated as the free base)
per unit dosage may be about 0.5 to about 10 mg, more preferably
about 1 mg to about 6 mg, including about 1.5 mg and, especially,
about 3.0 mg.
[0054] Appropriate doses of naltrexone (calculated as the free
base) per unit dosage form may be about 1 mg to about 20 mg (e.g.
about 15 mg), more preferably about 1.5 mg to about 10 mg.
[0055] In relation to either of the aforementioned aspects of the
invention, appropriate pharmaceutically-acceptable carrier
materials that may be employed in compositions include any such
relevant material that is suitable (and/or approved) for
pharmaceutical use and/or for intranasal delivery, and is capable
of maintaining its physical and/or chemical integrity, and/or does
not affect the physical and/or chemical integrity of the opioid
antagonist and/or any other ingredients that may be present in the
composition (such as alkyl saccharide), in the solid state, under
normal storage conditions.
[0056] The phrase `maintaining physical and chemical integrity`
essentially means chemical stability and solid state stability.
[0057] By `chemical stability`, we include that any composition of
the invention may be stored in isolated solid form, or when loaded
into a nasal applicator or a reservoir therefor (with or without
appropriate pharmaceutical packaging), under normal storage
conditions, with an insignificant degree of chemical degradation or
decomposition.
[0058] By `solid state stability`, we include that any composition
of the invention may be stored in an isolated solid form, or when
loaded into a nasal applicator or a reservoir therefore (with or
without appropriate pharmaceutical packaging), under normal storage
conditions, with an insignificant degree of solid state
transformation (e.g. crystallisation, recrystallisation, loss of
crystallinity, solid state phase transition (e.g. between a glassy
or a rubbery state, or to an agglomerated form)), hydration,
dehydration, solvatisation or desolvatisation.
[0059] Examples of `normal storage conditions` for compositions of
the invention, whether loaded into applicators, devices, drug
reservoirs (such as canisters or containers) or otherwise, include
temperatures of between about -50.degree. C. and about +80.degree.
C. (preferably between about -25.degree. C. and about +75.degree.
C., such as about 50.degree. C.), and/or pressures of between about
0.1 and about 2 bars (preferably atmospheric pressure), and/or
exposure to about 460 lux of UV/visible light, and/or relative
humidities of between about 5 and about 95% (preferably about 10 to
about 40%), for prolonged periods (i.e. greater than or equal to
about twelve, such as about six months).
[0060] Under such conditions, compositions of the invention may be
found to be less than about 15%, more preferably less than about
10%, and especially less than about 5%, chemically
degraded/decomposed, and/or solid-state transformed, as
appropriate. The skilled person will appreciate that the
above-mentioned upper and lower limits for temperature and pressure
represent extremes of normal storage conditions, and that certain
combinations of these extremes will not be experienced during
normal storage (e.g. a temperature of 50.degree. C. and a pressure
of 0.1 bar).
[0061] Such chemical and, particularly, physical stability is of
critical importance in a solid state formulation, such as a powder,
that is to be employed in the treatment of e.g. an opioid
overdose.
[0062] It is well known that significant difficulties may be
experienced in attempting to obtain both chemically- and
physically-stable solid compositions, such as powders. In the
present case, if the physical form of a composition of the
invention changes under normal storage conditions (e.g. from a free
flowing powder to an agglomerated mass that is difficult to
discharge), it will likely lead to non-reproducibility of dose of
opioid antagonist when dispensing a composition (or even the
complete inability to dispense it) from, or via, a nasal
applicator, which will put the subject's life at significant
risk.
[0063] For certain compositions of the invention (e.g. powders),
exposure to atmospheric water may result in compositions that are
less solid-state stable. For example, exposure to certain (e.g.
higher) relative humidities may affect the physical form of the
composition, for example by deliquescence, and/or by lowering glass
transition temperatures of compositions, and/or individual
components of the compositions, such as carrier materials, or in
another way.
[0064] Accordingly, compositions of the invention, and nasal
applicators including them, are preferably packaged within
containers that substantially prevent the ingress of atmospheric
water under the normal storage conditions hereinbefore defined.
Such containers may include packaging materials such as heat-sealed
aluminium pouches and/or thermoformed plastics.
[0065] When the composition includes an alkyl saccharide,
appropriate pharmaceutically-acceptable solid carrier materials
thus include cellulose and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose, cellulose acetate,
hydroxypropylmethyl cellulose (hypromellose, HPMC), hydroxyethyl
cellulose (HEC), hydroxypropyl cellulose (HPC), methyl cellulose
(MC), ethyl hydroxyethyl cellulose, carboxymethyl cellulose (CMC),
modified cellulose gum, microcrystalline cellulose and sodium
carboxymethyl cellulose; starches, such as rice starch, tapioca
starch, wheat starch and, more particularly, corn starch and potato
starch; starch derivatives, such as pregelatinized starch,
carboxymethyl starch, as well as moderately cross-linked starch,
modified starch and sodium starch glycolate; polysaccharides,
including dextrins, such as dextrin, cyclodextrins and linear or
branched dextrins, such as maltodextrins; powdered tragacanth;
malt; gelatin; talc; waxy excipients, such as cocoa butter and
suppository waxes; polyols, such as solid polyethylene glycols;
sugars, sugar alcohols and saccharides, such as mannitol, maltitol,
xylitol, sorbitol, lactose, glucose, galactose, sucrose, sucralose,
trehalose, maltose, isomalt and dextrose; acrylic polymers, such as
carbomer and its derivatives; polyvinylpyrrolidone (povidone, PVP);
crosslinked polyvinylpyrrolidone; polyethylene oxide (PEO);
chitosan (poly-(D-glucosamine)); natural polymers such as gelatin,
sodium alginate, pectin; scleroglucan; xanthan gum; guar gum; poly
co-(methylvinyl ether/maleic anhydride); and croscarmellose (e.g.
croscarmellose sodium). Hypromellose acetate succinate (HPMCAS),
copovidone and polyvinyl alcohol (PVA, or PVOH) may also be
mentioned. Mixtures of any of the foregoing may be employed.
[0066] Compositions according to the first aspect of the invention
may thus be compressed into a single unit dosage form, granulated
into a pellet or a pill, but are preferably provided in the form of
a dry, free-flowing powder. Compositions of the second and third
aspects of the invention are provided in the form of a dry,
free-flowing powder. In the context of any aspect of the invention,
by `dry` we include essentially free of water and other liquid
solvents, which includes that there is less than about 10%, such as
less than about 5%, more preferably about 3%, such as less than
about 2%, e.g. less than about 1% of the formulation is a liquid,
such as water.
[0067] Compositions of the invention may thus be administered in
the form of a plurality of particles, which particles may
individually and/or collectively consist of, and/or comprise,
compositions of the invention. Compositions of the invention may be
prepared in a form of a simple powder mixtures, powder
microspheres, coated powder microspheres, a lyophilised liposomal
dispersion, or a combination thereof.
[0068] Whether in the form of a powder or otherwise, amounts of
carrier material(s) that may be employed in compositions of the
invention are typically in the range of about 5% to about 99.9%,
including up to about 99% (e.g. up to about 95% or about 90%), such
as about 10% (e.g. about 25%, including about 35%) to about 85%,
including about 50% to about 75%, by weight, based upon the total
weight of the composition.
[0069] Furthermore, whether in the form of a powder or otherwise,
compositions of the invention may be prepared by standard
techniques, and using standard equipment, known to the skilled
person. In this respect, the compositions of the invention may be
combined with conventional pharmaceutical additives and/or
excipients used in the art for relevant preparations, and
incorporated into various kinds of pharmaceutical preparations
using standard techniques (see, for example, Lachman et al, "The
Theory and Practice of Industrial Pharmacy", Lea & Febiger,
3.sup.rd edition (1986); "Remington: The Science and Practice of
Pharmacy", Troy (ed.), University of the Sciences in Philadelphia,
21.sup.st edition (2006); and/or "Aulton's Pharmaceutics: The
Design and Manufacture of Medicines", Aulton and Taylor (eds.),
Elsevier, 4.sup.th edition, 2013).
[0070] Dry powders may be prepared by mixing the opioid antagonist
along with the pharmaceutically-acceptable carrier material and, if
present, the alkyl saccharide, and any other ingredients that may
be included. Appropriate techniques that may be employed include
simple dry mixing, granulation (including dry granulation, wet
granulation, melt granulation, thermoplastic pelletising, spray
granulation), extrusion/spheronisation or freeze-drying.
[0071] Dry granulation techniques are also well known to those
skilled in the art and include any technique in which primary
powder particles are aggregated under high pressure, including
slugging and roller compaction, for example as described
hereinafter.
[0072] Wet granulation techniques are well known to those skilled
in the art and include any technique involving the massing of a mix
of dry primary powder particles using a granulating fluid, which
fluid comprises a volatile, inert solvent, such as water, ethanol
or isopropanol, either alone or in combination, and optionally in
the presence of a binder or binding agent. The technique may
involve forcing a wet mass through a sieve to produce wet granules
which are then dried, preferably to a loss on drying of less than
about 3% by weight.
[0073] Melt granulation will be known by those skilled in the art
to include any technique in which granules are obtained through the
addition of a molten binder, or a solid binder which melts during
the process (which binder materials may comprise the
pharmaceutically acceptable carrier material). After granulation,
the binder solidifies at room temperature. Thermoplastic
pelletising will be known to be similar to melt granulation, but in
which plastic properties of the binder are employed. In both
processes, the agglomerates (granules) obtained comprise a matrix
structure.
[0074] Extrusion/spheronisation will be well known to those skilled
in the art to include any process involving the dry mixing of
ingredients, wet massing along with a binder, extruding,
spheronising the extrudate into spheroids of uniform size, and
drying.
[0075] Spray granulation will be known by those skilled in the art
to include any technique involving the drying of liquids
(solutions, suspensions, melts) while simultaneously building up
granulates in a fluid bed. The term thus includes processes in
which foreign seeds (germs) are provided upon which granules are
built up, as well as those in which inherent seeds (germs) form in
the fluid bed due to abrasion and/or fracture, in addition to any
spray coating granulation technique generally. The sprayed liquid
coats the germs and assists further agglomeration of particles. It
is then dried to form granules in the form of a matrix.
[0076] The term `freeze drying` includes lyophilisation or
cryodesiccation, and any low temperature desolvatization (e.g.
dehydration) process, in which product is frozen, pressure is
lowered, and the frozen solvent (e.g. water) is removed by
sublimation.
[0077] However, we prefer that compositions of the invention are
prepared by a process of spray-drying.
[0078] Spray-drying will be understood by the skilled person to
include any method of producing a dry powder from a liquid,
including a solution or a suspension (including a slurry) that
involves rapid drying using hot gas to convert a stream of liquid
into vaporized solvent and particles of solid, which solid
particles comprise the solute that was previously dissolved in a
solution, and/or particles that were previously suspended in the
evaporated liquid.
[0079] Appropriate spray-drying equipment includes some form of
atomization means, such as a spray nozzle, which disperses the
liquid into a spray with a relatively uniform droplet size. Such
means may include any means that is capable of producing a dry,
free-flowing powder, and may include high pressure swirl nozzles,
rotary disks and/or atomizer wheels, high pressure single fluid
nozzles, two-fluid nozzles and/or ultrasonic nozzles.
[0080] The spray-dryer may be a single effect or a multiple effect
spray-dryer, and may comprise an integrated and/or an external
vibrating fluidized bed, a particle separator, and/or a collection
means which may be a drum or a cyclone.
[0081] Spray-drying may be employed to produce compositions of the
invention in the form of powders and, in doing so, encapsulate
substances in a carrier material, or produce an amorphous composite
of active ingredient, carrier materials and other ingredients.
[0082] In this respect, compositions of the invention in the form
of powders, particularly if produced by spray-drying, may be
considered to comprise a plurality of particles, which particles
are themselves `mono-particulate` in their nature. By
`mono-particulate`, we include that the particles comprise a
homogeneous or a heterogeneous mixture, in which active ingredients
are encapsulated in an amorphous state within carrier materials in
the presence of other ingredients (e.g. an amorphous composite of
those things). In this respect, such compositions of the invention
do not comprise mixtures of two or more discrete, separate
particles of different ingredients in the form of a mixture, such
as an ordered, or interactive, mixture of smaller particles of
active ingredients associated with larger, but separate and
chemically distinct, particles of carrier substances, as is often
the case for inhaled drug delivery compositions (see, for example
Mehta, J. Drug Delivery, Art. ID 5635010, 1-19 (2018)).
[0083] Spray-dried compositions of the invention are thus
preferably amorphous in their nature, which includes wholly
amorphous and/or predominantly amorphous (for example more than
about 50% by weight, such as more than about 75% by weight,
including more than about 80% by weight, such as more than about
90% by weight, or 95% by weight, including more than about 99% by
weight amorphous), and may give rise to pharmaceutical products
that show excellent shelf-life, in terms of both physical and
chemical stability, when stored under normal storage conditions, as
hereinbefore defined.
[0084] According to a further aspect of the invention, there is
provided a process for the manufacturing of a composition of the
invention (in the form of a dry powder), wherein said process
comprises the steps of: [0085] i) mixing together the opioid
antagonist, the alkyl saccharide (if present) and the
pharmaceutically-acceptable carrier material, in an appropriate
volatile solvent, [0086] ii) spray-drying the mixture from step i)
to form a spray-dried plurality of particles.
[0087] Preferred volatile solvents include water, or organic
solvents, such as lower alkyl alcohols (e.g. ethanol), haloalkanes.
Other solvents that may be mentioned include hydrocarbons (e.g.
C.sub.5-10 alkanes), dimethylformamide, dimethylsulfoxide, ethyl
acetate, acetone, etc. Mixtures of any of the foregoing solvents
may be employed.
[0088] We prefer that mixing together the opioid antagonist, the
alkyl saccharide (if present) and the pharmaceutically-acceptable
carrier material with the solvent results in a solution that can be
spray-dried.
[0089] Particularly preferred pharmaceutically-acceptable carrier
materials that may be employed to produce spray-dried compositions
of the invention (whether according to the first, the second or the
third aspect of the invention), and which possess the desirable
characteristics mentioned herein, include saccharides, more
preferably disaccharides, such as maltitol, trehalose, sucralose,
sucrose, isomalt, maltose and, particularly, lactose (including
.beta.-D-lactose and .alpha.-D-lactose, especially
.alpha.-D-lactose monohydrate); and/or polymers, including any
polymeric materials mentioned hereinbefore as appropriate carrier
materials (such as sodium carboxymethyl cellulose, sodium starch
glycolate, polyvinylpyrrolidone and, particularly,
hydroxypropylmethyl cellulose, and the like) and, particularly,
polysaccharides, such as dextrins, including cyclodextrins (e.g.
.alpha.-, .beta.- and .gamma.-cyclodextrins and derivatives
thereof, such as, 2-hydroxypropyl-.gamma.-cyclodextrin,
sulfobutylether .beta.-cyclodextrin sodium salt, randomly
methylated .beta.-cyclodextrin, branched .beta.-cyclodextrin and
the like and, particularly, 2-hydroxypropyl-.beta.-cyclodextrin);
and linear or branched dextrins, such as maltodextrins, which are
classified by DE (dextrose equivalent), which can be between 3 and
20 (the higher the DE value, the shorter the glucose chains),
especially maltodextrin with a DE of between 6 and 15, such as 8
and 12.
[0090] Also included within the scope of the invention are
combinations of two or more of the above-mentioned preferred
materials.
[0091] It is preferred that a carrier material, whether a single
carrier material or a combination of two or more carrier materials,
is capable of giving rise to a spray-dried composition of the
invention in the form of a powder, wherein the composition
possesses a glass transition temperature (Tg) that: [0092] (a)
enables its production as a hard and/or brittle, `glassy`,
amorphous, powdered physical form, that can be easily loaded into a
nasal applicator, or a drug reservoir and/or container within, or
adjunct to, such an applicator, as described herein; and [0093] (b)
is high enough that, after such an applicator or reservoir is
packaged as described herein, and thereafter subjected to a high
external temperature (e.g. up to about 50.degree. C. to about
80.degree. C.), it remains in that glassy state, rather than being
transformed into a more viscous or rubbery state, and/or a
crystalline state.
[0094] Such extreme external temperatures are often experienced
inside vehicles (e.g. of first responders) in warm and/or sunny
climates, which vehicles will frequently be parked for extended
periods of time in full sun, where the resultant heat gain can be
enormous. If the Tg of a composition of the invention is low, the
composition may transform after exposure to such high temperatures
to such a viscous/rubbery state, this will give rise to inefficient
discharging of the composition from the applicator or reservoir
(and so too the dose of opioid antagonist) once the applicator is
actuated.
[0095] In this respect, we prefer that the lowest measurable Tg of
a composition of the invention is at least about 40.degree. C.,
such as at least about 50.degree. C., such as at least about
55.degree. C., including at least about 60.degree. C., when
measured at a relative humidity of up to about 35%, such as up to
about 30%, including up to about 25% (e.g. up to about 20%, such as
less than about 15%, e.g. less than about 10%). By `lowest
measurable Tg`, we include that the composition of the invention
may comprise particles that are heterogenous in their nature. In
particular, if more than one carrier material is employed,
particles may comprise discrete regions of carrier materials, or
composite mixtures thereof, that may possess individual and
separate Tg values. It will be clear to the skilled person that the
value of the lowest measurable Tg has a strong impact on the
physical stability of the composition.
[0096] When the carrier material comprises a combination of one or
more disaccharide (as hereinbefore defined) and one or more
polymeric ingredients (as hereinbefore defined, but particularly so
when the polymer is a dextrin) relative amounts of those
ingredients in the combination can be tailored to ensure the
required level of physical and/or chemical stability of active
ingredient whilst, at the same time, not lowering the Tg of the
composition of the invention in such a manner that it affects its
physical stability. We have found that a ratio of between about
50:1 to about 1:50 of disaccharide:polymer (e.g. dextrin) by
weight, based on the total weight of the composition, may work
depending on the active ingredient that is employed. Preferred
ratios are in the range of about 10:1 to about 1:40 (including up
to about 1:30 or up to about 1:20), for example between about 2:1
and about 1:10, more preferably about 1:1 to about 1:8 of
disaccharide:polymer (e.g. dextrin) by weight, based on the total
weight of the composition.
[0097] In particular, and as described hereinafter, we have found
that compositions of the invention, when fabricated by spray-drying
and: [0098] (i) employing a disaccharide as a carrier material give
rise to vastly improved chemical stability of the opioid antagonist
when compared to monosaccharides, such as mannitol. This is
surprising, because mannitol has been used previously in physical
mixtures together with opioid antagonists, such as naloxone, with
no stability issues whatsoever; [0099] (ii) employing a dextrin,
such as cyclodextrin or maltodextrin, as a carrier material provide
for significantly improved physical stability when compared to
other carrier materials. [0100] (iii) However, employing such a
dextrin gave rise to an unexpected chemical instability of the
opioid antagonist; [0101] (iv) which chemical instability could be
solved by spray-drying the dextrin along with a disaccharide.
[0102] A particularly preferred combination of carrier materials
thus includes a disaccharide, and especially trehalose and, more
preferably, a lactose, such as .alpha.-D-lactose monohydrate, and a
dextrin, and especially a cyclodextrin, such as
2-hydroxypropyl-.beta.-cyclodextrin, or a maltodextrin, such as
maltodextrin 12DE. We have found that such a combination of carrier
materials can be spray-dried together along with an opioid
antagonist and an alkyl saccharide in appropriate proportions to
produce a composition of the invention that possesses both the
desired physical and chemical stability under normal storage
conditions, as hereinbefore defined.
[0103] We have found that an amount of between about 5%
(particularly about 10%) and about 30%, such as between about 15%
and about 25%, e.g. between about 17% and about 24%, by weight
based on the total weight of the composition, of disaccharide
provides for the required level of chemical stability of opioid
antagonist, such as naloxone, whilst at the same time not lowering
the Tg of the composition of the invention in such a manner that it
affects physical stability. Appropriate amounts of dextrin are
accordingly in the range of about 30% up to about 90%, such as up
to about 85%, including up to about 80%, and especially up to about
75%, such as between about 40% and about 70%, e.g. between about
43% and 67%, by weight based on the total weight of the
composition.
[0104] As described hereinafter, compositions of the invention have
been found to exhibit surprisingly good bioavailability, and highly
surprisingly more rapid absorption, which likely will result in a
more rapid onset of action, compared to relevant reference products
(e.g., in the case of naloxone, Narcan nasal spray).
[0105] This is highly unexpected for several reasons, including
that: [0106] (a) unlike compositions of the invention, which are
solids, in existing products, such as Narcan, opioid antagonist (in
that case naloxone) is presented in a pre-dissolved state, ready
for absorption; and [0107] (b) in any event, naloxone, and other
opioid antagonists mentioned herein are known to be highly
bioavailable drugs, with a rapid onset of action, when administered
via the nasal mucosa. Accordingly, the compositions represent a
therapeutic improvement on something that is already highly
bioavailable and rapidly acting.
[0108] As is further described hereinafter, compositions of the
invention that include alkyl saccharides have also been found to
exhibit surprisingly good bioavailability and speed of absorption
compared to corresponding compositions that do not include alkyl
saccharides, and/or include different excipients that are known to
act as surfactants. This is very surprising given that, when tested
ex vivo, such alkyl saccharides showed a tendency to decrease
permeation of opioid antagonist, such as naloxone, through mucosal
membranes, whereas different surfactants, including some of those
listed hereinafter, showed a tendency to increase permeation.
[0109] Alkyl saccharides that may be employed in the compositions
of the invention include alkyl glycosides, which may be defined as
any sugar joined by a linkage to an alkyl group, such as a
C.sub.7-18 alkyl glycoside. Alkyl glycosides thus may include alkyl
maltosides (such as dodecyl maltoside), alkyl glucosides, alkyl
sucrosides, alkyl thiomaltosides, alkyl thioglucosides, alkyl
thiosucroses and alkyl maltotriosides. However, we prefer that the
alkyl saccharide is a sugar ester.
[0110] Sugar esters that may be used in the compositions of the
invention include trisaccharide esters, such as raffinose esters,
monosaccharide esters, such as glucose esters, galactose esters and
fructose esters, and/or, preferably, disaccharide esters, such as
maltose esters, lactose esters, trehalose esters and, in
particular, one or more sucrose esters.
[0111] Sucrose esters that are employed in compositions of the
invention have a hydrophilic-lipophilic balance value of between 6
and 20. The term `hydrophilic-lipophilic balance` (HLB) is a term
of art that will be well understood by those skilled in the art
(see, for example, "The HLB System: A Time-Saving Guide to
Emulsifier Selection", published by ICI Americas Inc, 1976 (revised
1980), in which document, Chapter 7 (pages 20-21) provides a method
of how to determine HLB values). The longer the fatty acid chains
in the sucrose esters and the higher the degree of esterification,
the lower the HLB value. Preferred HLB values are between 10 and
20, more preferably between 12 and 20.
[0112] Sucrose esters thus include C.sub.8-22 saturated or
unsaturated fatty acid esters, preferably saturated fatty acid
esters and preferably C.sub.10-18 fatty acid esters and most
preferably C.sub.12 fatty acid esters. Particularly suitable fatty
acids from which such sucrose esters may be formed include erucic
acid, behenic acid, oleic acid, stearic acid, palmitic acid,
myristic acid and lauric acid. A particularly preferred such fatty
acid is lauric acid. Commercially-available sucrose esters include
those sold under the trademark Surfhope.RTM. and Ryoto.RTM.
(Mitsubishi-Kagaku Foods Corporation, Japan).
[0113] Sucrose esters may be diesters or monoesters of fatty acids,
preferably monoesters, such as sucrose monolaurate. The skilled
person will appreciate that the term `monolaurate` refers to a
mono-ester of lauric acid, and that the terms `lauric acid ester`
and `laurate` have the same meaning and can therefore be used
interchangeably. Commercially available sucrose monolaurate
products are also sometimes referred to as `sucrose laurate`.
Commercially-available sucrose monolaurate (or sucrose laurate)
products, such as Surfhope.RTM. D-1216 (Mitsubishi-Kagaku Foods
Corporation, Japan), which may contain small amounts of diesters
and/or higher sucrose esters, and minor amounts of other sucrose
esters and free sucrose, are suitable for use in the invention. The
skilled person will understand that any reference to a specific
sucrose ester herein includes commercially available products
comprising that sucrose ester as a principle component.
[0114] Preferred sucrose esters contain only one sucrose ester,
which means that a single sucrose ester (e.g. a
commercially-available sucrose ester product) contains a single
sucrose ester as the/a principle component (commercially available
products may contain impurities, for example a monoester product
may contain small amounts of diesters and/or higher esters, such
products may be considered to `contain only one sucrose ester` in
the context of the present invention). As used herein, the term
`principle component` will be understood to refer to the major
component (e.g. greater than about 50%, such as about 70%
weight/weight or volume/volume) in a mixture of sucrose esters,
such as common commercially available surfactant products, which
are typically sold with a certain range of ester compositions.
[0115] A particularly preferred sucrose ester is sucrose
monolaurate.
[0116] Amounts of alkyl saccharide in compositions of the invention
are in the range of about 0.1% up to about 50%, more particularly
up to about 10%, such as about 0.5% to about 5%, preferably about
0.75% to about 3% (e.g. to about 2%, such as about 1%), by weight,
based upon the total weight of the composition.
[0117] In addition to any alkyl saccharide component that is
included within a composition of the invention, further, optional,
additional excipients may be employed.
[0118] Such additional excipients may include one or more (further)
surfactants. Surfactants that may be mentioned include
polyoxyethylene esters (e.g. Myrj.TM.), including polyoxyl 8
stearate (Myrj.TM. S8), polyoxyl 32 stearate (Gelucire.RTM. 48/16),
polyoxyl 40 stearate (Myrj.TM. S40), polyoxyl 100 stearate
(Myrj.TM. S100), and polyoxyl 15 hydroxystearate (Kolliphor.RTM. HS
15), polyoxyethylene alkyl ethers (e.g. Brij.TM.), including
polyoxyl cetostearyl ether (e.g. Brij.TM. CS12, CS20 and CS25),
polyoxyl lauryl ether (e.g. Brij.TM. L9 and L23), and polyoxyl
stearyl ether (e.g. Brij.TM. S10 and S20), and polyoxylglycerides
(e.g. Gelucire.RTM.), including lauroyl polyoxylglycerides
(Gelucire.RTM. 44/14) and stearoyl polyoxylglycerides
(Gelucire.RTM. 50/13), sorbitan esters (e.g. Span.TM.), including
sorbitan monopalmitate (Span.TM. 40) and sorbitan monostearate
(Span.TM. 60), polysorbates (Tweens.TM.), including polysorbate 40
(polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60
(polyoxyethylene (20) sorbitan monostearate) and polysorbate 20
(polyoxyethylene (20) sorbitan monolaurate), and sodium lauryl
sulfate; and monoacyl glycerols (monoglycerides), such as
2-oleoylglycerol, 2-arachidonoylglycerol, monolaurin, glycerol
monomyristate, glycerol monopalmitate, glyceryl hydroxystearate
and, preferably, glycerol monostearate, glycerol monooleate (e.g.
Cithrol.RTM.) and glycerol monocaprylate (e.g. Capmul.RTM.).
[0119] Other additional ingredients (excipients) that may be
included in compositions of the invention include isotonicity
and/or osmotic agents (e.g. sodium chloride), sterols (or steroid
alcohols), such as cholesterol and phytosterols (e.g. campesterol,
sitosterol, and stigmasterol); antioxidants (e.g.
.alpha.-tocopherol, ascorbic acid, potassium ascorbate, sodium
ascorbate, ascorbyl palmitate, butylated hydroxytoluene, butylated
hydroxyanisole, dodecyl gallate, octyl gallate, propyl gallate,
ethyl oleate, monothioglycerol, vitamin E polyethylene glycol
succinate, or thymol); chelating (complexing) agents (e.g. edetic
acid (EDTA), citric acid, tartaric acid, malic acid, maltol and
galactose); preservatives (e.g. benzyl alcohol, boric acid,
parabens, propionic acid, phenol, cresol, or xylitol); viscosity
modifying agents or gelling agents (such as cellulose derivatives,
including hydroxypropylcellulose, methylcellulose, hydroxypropyl
methylcellulose, carboxymethylcellulose, etc., starches and
modified starches, colloidal silicon dioxide, aluminium
metasilicate, polycarbophils (e.g. Noveon.RTM.), carbomers (e.g.
Carbopol.RTM.) and polyvinylpyrrolidone); mucoadhesive polymers,
such as carboxymethyl cellulose, modified cellulose gum and sodium
carboxymethyl cellulose (NaCMC); starch derivatives, such as
moderately cross-linked starch, modified starch and sodium starch
glycolate; crosslinked polyvinyl pyrollidone, acrylic polymers,
such as carbomer and its derivatives (Polycarbophyl, Carbopol.RTM.,
etc.); polyethylene oxide (PEO); chitosan (poly-(D-glucosamine));
natural polymers such as gelatin, sodium alginate, pectin;
scleroglucan; xanthan gum; guar gum; poly co-(methylvinyl
ether/maleic anhydride); and croscarmellose (e.g. croscarmellose
sodium); pH buffering agents (e.g. citric acid, maleic acid, malic
acid, or glycine); colouring agents; penetration enhancers (e.g.
isopropyl myristate, isopropyl palmitate, pyrrolidone, or
tricaprylin); other lipids (neutral and polar); and aromatic
carboxylic acid, such as benzoic acid optionally substituted with
one or more groups selected from methyl, hydroxyl, amino, and/or
nitro, for instance, toluic acid or salicylic acid.
[0120] Total amounts of such `additional` excipients (including
surfactants that are not the one or more alkyl saccharide(s) that
is/are (or may be) present in compositions of the invention) may be
up to about 15% (e.g. about 10%), such as up to about 5%, by
weight, based on the total weight of the composition.
[0121] The skilled person will appreciate that, if any additional
optional ingredients are included within compositions of the
invention, the nature of those ingredients, and/or the amounts of
those ingredients that are included, should not have a detrimental
effect on the Tg of the composition for the reasons described
hereinbefore. In this respect, when compositions of the invention
are made by spray-drying, such optional ingredients may be
incorporated in the spray-drying process (i.e. mixed together along
with the opioid antagonist, the optional alkyl saccharide and the
pharmaceutically-acceptable carrier material in the appropriate
volatile solvent and then spray-dried), or may be included
separately to the spray-dried plurality of particles.
[0122] According to a further aspect of the invention, there is
provided the compositions of the invention for use in medicine
(human and veterinary), and in particular in the treatment of
substance (such as opioid, including opiate) overdose.
[0123] Overdose will be understood in the art to include what
occurs when larger quantities of abusable substance, such as
opioid, than may be physically tolerated by an individual are
taken, resulting in (in the case of opioids) central nervous system
and respiratory depression, hypoxia, miosis, and apnoea, one or
more of which lead to death if not treated rapidly (vide
supra).
[0124] According to a further aspect of the invention there is
provided a method of treatment of substance (e.g. opioid) overdose,
which method of treatment comprises administration of a composition
of the invention to a patient suffering from such a condition.
[0125] By `treatment` of substance (e.g. opioid) overdose, we
include the prophylaxis or the diagnosis of such overdose (i.e. if
an overdose is suspected), in addition to therapeutic, symptomatic
and palliative treatment. This is because, by employing
compositions of the invention in the treatment of drug overdose,
they may abrogate or prevent the development of the symptoms of
opioid overdose mentioned hereinbefore.
[0126] Care should be taken when administering compositions of the
invention comprising partial opioid antagonists, such as
buprenorphine, with a view to ensuring that the patient has
definitely overdosed on an opioid (and not, for example, on a
benzodiazepine), and/or that the patient is physically addicted to
opioids.
[0127] Opioid antagonists may also be administered for use in the
treatment of conditions mediated by endogenous opioid agonists
(e.g. endorphins), which conditions may be collectively classified
together as `endorphin-mediated hedonia`, as manifest by addictive
behaviours (e.g. excessive eating (bulimia), drinking (alcoholism),
exercise, sex, gambling, etc.).
[0128] Thus, according to a further aspect of the invention there
is provided a method of treatment of addiction and/or an addictive
behaviour mediated by activation of endogenous opioid agonists,
such as endorphins (including bulimia, alcohol dependence, and
addictions to exercise, sex, gambling, etc.), which method of
treatment comprises administration of a composition of the
invention to patient suffering from, or susceptible to, the
relevant condition.
[0129] In the case of such addictions and addictive behaviours, by
`treatment`, we include in particular the prophylaxis (prevention)
and diagnosis of such conditions, in addition to the palliative
and, particularly, the symptomatic treatment of such
conditions.
[0130] Compositions of the invention may be administered
intranasally by way of any suitable intranasal dosing means that is
known to the skilled person, such as by way of a nasal applicator,
or dispenser, means that is capable of administering a suitable
dose of opioid antagonist in the form of a composition of the
invention to the nasal cavity.
[0131] Such an applicator means should thus be capable of housing,
and storing, the composition of the invention itself, or capable of
being attached to a reservoir/container that houses and stores the
composition of the invention, for example in the form of a powder,
and do so without the consequence of a significant loss of physical
and chemical integrity of the composition, including by way of
ingress of water. In this way, the composition will be usable as
soon as the applicator device is actuated by an end user, whereupon
the applicator will deliver composition (e.g. powder) with an
appropriate dose of opioid antagonist as defined herein to the
nasal mucosa of a subject.
[0132] Appropriate applicator means have been described in the
prior art. When used with compositions of the invention
(particularly those in the form of a powder), such compositions may
be loaded into a reservoir that is attached to, or forms part of,
such an applicator means, where it is contained until the
applicator means, or dispenser, is actuated. Hereinafter the terms
`applicator`, `dispenser`, `device` `applicator means`, `dispensing
means`, `applicator device` and `dispensing device` may be used
interchangeably and mean the same thing.
[0133] Such applicator means may thus also include a mechanism for
expelling the powder formulation from the reservoir through an exit
means, which exit means includes anything sized for placement
within a human nostril, such as an appropriately-shaped nozzle.
[0134] Thus, the applicator should be capable of providing a
reproducible and sufficient amount of powder formulation in a
single administration step (and in a manner in which the device
does not require `priming`), that will provide a therapeutic dose
of opioid antagonist.
[0135] Nasal applicators/inhalation devices that may be employed to
administer compositions of the invention in the form of powders may
include multiple-dose applications, such as metered dose inhalation
devices (MDIs), dry powder inhalation devices (DPIs; including low,
medium and high resistant DPIs) and soft mist inhalation devices
(SMIs) that may be adapted based on technology that is known in the
field of delivery of active ingredients to the lung.
[0136] In MDIs, compositions of the invention should be capable of
forming a stable suspension when suspended in solvents that are
typically employed therein, such as a propellant, which propellant
has a sufficient vapour pressure to form aerosols upon activation
of the delivery device (e.g. a hydrocarbon, a fluorocarbon, a
hydrogen-containing fluorocarbon, or a mixture thereof).
[0137] However, we prefer that the nasal applicator is a single
dose applicator from which a composition is dispensed following
actuation, and is then disposed of after use.
[0138] In this respect, suitable applicator means or devices
include those described in U.S. Pat. Nos. 6,398,074, 6,938,798 or
9,724,713, the relevant disclosures in all of which documents are
incorporated herein by reference. FIGS. 1 and 2 of the present
application are based on FIG. 1 and FIG. 2, respectively, of U.S.
Pat. No. 6,398,074, and FIGS. 3 to 7 are based on FIG. 19 to FIG.
23, respectively, of U.S. Pat. No. 9,724,713. Both are
illustrations of applicators that be may be employed to administer
a composition of the invention intranasally.
[0139] In FIG. 1, the device comprises an upper body/dispenser head
1 incorporating an outlet channel 40 (i.e. part of the `exit means`
as hereinbefore described) and a gripping means 60 allowing the
user to actuate the device. Inside the upper body/dispenser head 1
an element is mounted, designated in its assembly by reference
number 2, that incorporates a reservoir 10 and an air chamber 22
for the air blast 20. It is possible for this element 2 to be
produced in one piece with the body 1. A lower body 3 is also
provided in order to be able to slide relative to the upper body 1
and relative to the element 2, the user exerting a push force on
the lower body to actuate the device.
[0140] The reservoir 10 contains a single dose of a composition of
the present invention. The reservoir 10 has an air inlet 11 and a
product outlet 15. A product retention device 12, comprising a grid
that is permeable to air, is disposed in the air inlet 11 to keep
the product in the reservoir 10 until the composition is dispensed.
The product outlet 15 is blocked, preferably in a sealed fashion,
by a closing ball 16, which is removed from its blocking position
by the flow of air when the applicator is actuated and the product
is being dispensed.
[0141] When a user actuates the device, a pressure is exerted on
the plunger 25 in such a way that the piston 21 compresses the air
20 contained in the chamber 22. Since the grid 12 is permeable to
air, the compression of the air in chamber 22 creates a blast of
air that is transmitted to the reservoir 10 and consequently is
applied to the closing ball 16 which is blocking the product outlet
15.
[0142] The dimensions of the closing ball 16 and its fixing at the
reservoir product outlet 15 are such that the ball 16 is removed
from its blocking position, when a minimum predetermined pressure
is created through the reservoir 10 by way of a blast of the air
20.
[0143] The pre-compression created by the closing ball 16 ensures
that when it is removed from its blocking position, the energy
accumulated in the hand of the user is such that the piston 21
integral with the plunger 25 is propelled within the chamber 22
thereby creating a powerful blast of air 20, that is to say an air
flow suitable to finely spray the dose of composition of the
invention.
[0144] When this minimum pressure is reached, the ball is quickly
moved towards the outlet channel 40 of the device and the flow of
air 20 created by the blast expels substantially all of the dose of
composition of the invention that is contained within the reservoir
10.
[0145] Preferably, the outlet channel 40 has a diameter greater
than the diameter of the closing ball 16 in order to allow the dose
of product to be expelled through the outlet channel 40 by flowing
around the ball 16. As shown in FIG. 2, which represents the same
device after actuation, the channel 40 comprises a means 41 of
arresting or fixing the ball 16 in order to prevent its expulsion
out of the device when the product is being expelled.
[0146] A further embodiment that may be employed to administer
compositions of the invention intranasally is provided in U.S. Pat.
No. 9,724,713 at column 7, line 50 to column 8, line 61 and FIGS.
19 to 23, which are reproduced as FIGS. 3 to 7 of the present
application.
[0147] In this embodiment, the reservoir 10 is secured in the upper
body/dispenser head 1 which includes the dispenser outlet channel
40 (i.e. part of the `exit means` as hereinbefore described), which
has gripping means or finger rest 60, which allows the user to
actuate the device. A radial shoulder 37 (see FIG. 5) of the upper
body/dispenser head 1 advantageously defines the assembled position
of the reservoir 10 in said of the upper body/dispenser head 1.
[0148] The mechanical opening system includes a set of rods 61, 62,
wherein a second rod portion 62 is pushed by said first rod portion
61 when the device is actuated. At the end of their actuation
stroke, i.e. in the dispensing position, the set of rods 61, 62
co-operate with the closure element 16, which is spherical, in
particular a ball as in the first embodiment discussed above, so as
to expel it mechanically from its closed position.
[0149] In this embodiment, the piston 21 is separate from the first
rod portion 61, and slides both relative to the air chamber 22 and
to a cylindrical surface 614 that is secured to the first rod
portion 61. FIG. 7 is a diagrammatic perspective view of the air
expeller of the device in FIGS. 3 to 6, in its rest position.
[0150] The air chamber 22 may thus be cylindrical, and in its rest
position is put into communication with the surrounding air at
fluting or grooves 615 that are formed in said cylindrical surface
614 and that co-operate with the piston 21, in particular in its
rest position. The piston 21 thus includes an inner lip 215 that
slides in airtight manner over the cylindrical wall 614 during
actuation, and that co-operates with said fluting 615 in its rest
position. The piston 21 also includes an axial extension 216 that
co-operates with a top edge 251 of the pusher element 25 (termed a
`plunger` in the first embodiment) that moves said piston 21 in the
air chamber 22 during actuation.
[0151] A retainer member 42 is extended downwards by an axial
extension 43 that comes into contact with the top axial end 610 of
the first rod portion 61 during actuation.
[0152] In addition, in this embodiment, there is no outer body, but
merely a cover 27 that is assembled on the bottom axial edge of the
air chamber 22.
[0153] A spring 80 is provided between the radial flange 225 of the
air chamber 22 and the part that forms the first rod portion 61 and
the cylindrical surface 614, so as to return the air expeller
automatically into its rest position after actuation.
[0154] The operating principle is as follows. In the rest position
in FIG. 3, the reservoir 10 is closed in sealed manner by the
retainer member 42 and by the closure element/ball 16. The air
expeller is open to the atmosphere by co-operation between the
inner lip 215 of the piston 21 and the fluting 615 of the
cylindrical surface 614.
[0155] When it is desired to actuate the device, the user presses
on the pusher element 25. During this initial stroke, the inner lip
215 of the piston leaves the fluting 615 so as to come to
co-operate in airtight manner with the cylindrical surface 614,
thereby closing the air chamber 22. At the same moment, the top
edge 251 of the pusher element 25 comes into contact with the axial
extension 216 of the piston 21, and the top axial end 610 of the
first rod portion 61 comes into contact with the axial extension 43
of the retainer member 42.
[0156] However, the top axial end 621 of the second rod portion 62
is still not in contact with the rounded surface 55 of the closure
element/ball 16, as can be seen in FIG. 4.
[0157] Continued actuation thus simultaneously moves the piston 21
in the air chamber, thereby compressing the air contained therein,
and moves the retainer member 42 away from its position of closing
the reservoir 10. When the second rod portion 62 contacts the
rounded surface 55 of the closure element/ball 16, said closure
element/ball is expelled mechanically from its closed position, so
as to enable the composition to be expelled under the effect of the
air compressed by the air expeller.
[0158] The dispensing position is shown in FIG. 5. As can be seen
in FIG. 5, the retainer member 42 may become detached from the
first rod portion 61 while the composition is being expelled under
the effect of the compressed air provided by the air expeller. In
this position, said closure element/ball is expelled out from the
reservoir 10 so as to enable the fluid or powder to be dispensed
under the effect of the compressed air. The closure element/ball 16
thus becomes jammed in splines 3 of the upper body/dispenser head
1, which splines prevent in particular any risk of said closure
element/ball 16 being expelled out from said upper body dispenser
head 1.
[0159] When the user relaxes the device, as shown in FIG. 6, the
spring 80 that was compressed during actuation, returns the first
rod portion 61 towards its rest position. This creates suction that
sucks the closure element 16 and the retainer member 42 back
towards, or close to, their closure positions. This thus blocks the
path for new suction so as to avoid soiling the air expeller while
it returns automatically into its rest position, with the empty
reservoir still assembled on the air expeller. However, the piston
21 remains in its dispensing position as a result of friction with
the air chamber 22 and of the suction created in the reservoir 30,
such that the cylindrical surface 614 slides over the inner lip 215
of the piston until said inner lip co-operates once again with the
fluting 615. At this moment, the air chamber 22 is once again in
communication with the surrounding air, and suction is no longer
created by the return into the rest position. The piston 21 is thus
also entrained towards its rest position. This makes it possible to
close the reservoir after use.
[0160] Optionally, the unit formed by the upper body/dispenser head
1 and the empty reservoir 10 could be removed from the air expeller
and replaced by a new unit that includes a full reservoir.
[0161] Appropriate applicator devices that may be used include
those available from Aptar Pharma, France (UDS Monopowder). Other
examples of applicator devices that may be used in conjunction with
compositions of the invention (especially those in the form of
powders) include those described in US patent application US
2011/0045088A, U.S. Pat. No. 7,722,566 (see e.g. FIGS. 1 and 7) and
U.S. Pat. No. 5,702,362 and international patent application WO
2014/004400, the relevant disclosures of which documents are hereby
incorporated by reference.
[0162] According to a further aspect of the invention, there is
provided a process for the manufacturing of an applicator device
comprising a composition of the invention, wherein said process
comprises the step of loading said composition into a reservoir
within or adjunct to said applicator device.
[0163] According to another aspect of the invention, there is
provided an applicator and/or dispenser device comprising a
composition of the invention in the form of a powder, suitable for
dispensing that powder, which applicator/dispenser device
comprises:
[0164] an outlet through which composition of the invention is
dispensed;
[0165] a means of externally generating a force (e.g. an air-flow)
upon actuation of the device by a user;
[0166] at least one (optionally replaceable) reservoir that
contains a composition of the invention, which reservoir is, or is
capable of being placed, in direct or indirect communication with
the dispenser outlet;
[0167] a displaceable sealing means in the device and/or the
reservoir for retaining the composition within the reservoir until
the composition is dispensed; and
[0168] a mechanical opening system that co-operates with said
sealing means such that the composition of the invention is
expelled mechanically by the forcing means when the device is
actuated.
[0169] According to a still further aspect of the invention there
is provided an applicator and/or dispenser device comprising a
composition of the invention in the form of a powder, suitable for
dispensing that powder, which applicator/dispenser device
comprises:
[0170] a dispenser outlet;
[0171] an air expeller for generating a flow of air while the
device is being actuated, said air expeller including a piston that
slides in an air chamber between a rest position and a dispensing
position;
[0172] said piston slides in airtight manner within said air
chamber;
[0173] at least one reservoir that contains a dose of a composition
of the invention, said reservoir including an air inlet that is
connected to said air expeller;
[0174] a composition outlet that is connected to said dispenser
outlet;
[0175] said air inlet including a displaceable sealing means (e.g.
a retainer member) for retaining the composition in the reservoir
until the composition is dispensed;
[0176] said composition outlet being closed by a closure element
that is fitted in the composition outlet of the reservoir;
[0177] said device further including a mechanical opening system
that co-operates with said closure element so as to expel it
mechanically from its closed position while the device is being
actuated; and
[0178] said piston of said air expeller, when in its rest position,
co-operating in non-airtight manner with said air chamber.
[0179] In the latter aspect of the invention, it is preferred that:
[0180] (i) the air chamber within which said piston slides in
airtight manner is substantially cylindrical; [0181] (ii) the
closure element is force fitted in the composition outlet of the
reservoir; [0182] (iii) said air chamber is in communication with
the atmosphere in the rest position; and/or [0183] (iv) said piston
includes an inner lip that is suitable for co-operating with a
cylindrical surface, said cylindrical surface includes fluting that
co-operates in non-airtight manner with said inner lip of the
piston in its rest position.
[0184] Such an applicator or dispensing device is capable of
providing for an appropriate and reproducible powder spray pattern
and/or plume geometry that enables efficient delivery of said
powder to the nasal cavity (e.g. a nostril).
[0185] In compositions of the invention, mean particle sizes may be
presented as weight-, number-, or volume-, based mean diameters. As
used herein, the term `weight based mean diameter` will be
understood by the skilled person to include that the average
particle size is characterised and defined from a particle size
distribution by weight, i.e. a distribution where the existing
fraction (relative amount) in each size class is defined as the
weight fraction, as obtained by e.g. sieving (e.g. wet sieving).
The term `volume based mean diameter` is similar in its meaning to
weight based mean diameter, but will be understood by the skilled
person to include that the average particle size is characterised
and defined from a particle size distribution by volume, i.e. a
distribution where the existing fraction (relative amount) in each
size class is defined as the volume fraction, as measured by e.g.
laser diffraction. As used herein, the term `number based mean
diameter` will be understood by the skilled person to include that
the average particle size is characterised and defined from a
particle size distribution by number, i.e. a distribution where the
existing fraction (relative amount) in each size class is defined
as the number fraction, as measured by e.g. microscopy. Other
instruments that are well known in the field may be employed to
measure particle size, such as equipment sold by e.g. Malvern
Instruments, Ltd (Worcestershire, UK), Sympatec GmbH
(Clausthal-Zellerfeld, Germany) and Shimadzu (Kyoto, Japan).
[0186] In the context of the present invention, the skilled person
will understand that, to allow for intranasal administration,
powders will typically have a volume-based mean diameter (VMD)
within the range of about 5 .mu.m (e.g. about 10 .mu.m) up to about
1,000 .mu.m (e.g. up to about 500 .mu.m). Depending on the
applicator device that is employed, the VMD may be in the range of
about 10 .mu.m to about 100 .mu.m, such as about 20 .mu.m to about
60 .mu.m.
[0187] Preferred particle size distributions may also include those
in which the d10 is above about 3 .mu.m and below about 75 .mu.m
(e.g. up to about 50 .mu.m), such as greater than about 10 .mu.m,
and the d90 is between about 80 .mu.m and about 1,000 .mu.m (e.g.
about 500 .mu.m), such as less than about 100 .mu.m. The skilled
person will understand that the parameter `d10` (or `Dv(10)`) means
the size (or diameter) in a particle size distribution below which
10% of the total volume of material in the sample is contained.
Similarly, the `d90` (or `Dv(90)`) means the size below which 90%
of the material is contained.
[0188] By powders having particle size diameters and/or VMDs within
the above ranges, we include the bulk VMD and/or the emitted VMD,
that is the particle size distribution when initially loaded into
the device and/or when it is expelled therefrom, respectively.
[0189] Particle sizes may be measured by standard equipment, such
as a dry (or a wet) particle size measurement technique, including
dry dispersion technologies available from manufacturers, such as
Sympatec and Malvern.
[0190] Preferred particle shapes include spherical or substantially
spherical, by which we mean that the particles possess an aspect
ratio smaller than about 20, more preferably less than about 10,
such as less than about 4, and especially less than about 2, and/or
may possess a variation in radii (measured from the centre of
gravity to the particle surface) in at least about 90% of the
particles that is no more than about 50% of the average value, such
as no more than about 30% of that value, for example no more than
about 20% of that value.
[0191] Nevertheless, particles may be any shape, including
irregular shaped (e.g. `raisin`-shaped), needle-shaped, disc-shaped
or cuboid-shaped, particles. For a non-spherical particle, the size
may be indicated as the size of a corresponding spherical particle
of e.g. the same weight, volume or surface area.
[0192] The spray angle of emitted (dispensed) powder composition of
the invention from an applicator and/or a dispenser device should
preferably be less than about 90.degree..
[0193] Compositions of the invention may be formulated with
additional active ingredients, such as those known to treat opioid
withdrawal symptoms, such as lofexidine, and/or partial opioid
antagonists that are employed in the treatment of opioid
dependence, for example, buprenorphine (vide supra).
[0194] Accordingly, co-administering at least one (preferably full)
opioid antagonist as described hereinbefore alongside such an
opioid withdrawal symptom treatment (such as lofexidine or
buprenorphine) may serve to abrogate the strong withdrawal symptoms
that may be observed when administering a composition of the
invention in the absence of such a compound.
[0195] Compositions of the invention may thus be provided along
with a compound that is suitable for use in the treatment of opioid
withdrawal symptoms (such as lofexidine or buprenorphine, or a
pharmaceutically acceptable (e.g. HCl) salt of either compound,
wherein the latter compound/treatment is included within the
composition (i.e. presented as a single pharmaceutical composition
including both active ingredients). Alternatively, compositions of
the invention may be co-administered along with a separate
composition comprising a compound that is suitable for use in the
treatment of opioid withdrawal symptoms (such as lofexidine or
buprenorphine) or a salt thereof.
[0196] Thus, there is further provided a pharmaceutical preparation
comprising a composition of the invention as hereinbefore defined,
which composition further includes a compound that is suitable for
use in the treatment of opioid withdrawal symptoms (such as
lofexidine or buprenorphine) or a pharmaceutically acceptable salt
thereof, such a preparation is hereinafter referred to as a
`combined preparation`.
[0197] There is further provided a process for the preparation of a
combined preparation as hereinbefore defined, which process
comprises bringing into association an opioid antagonist as
hereinbefore defined and a compound that is suitable for use in the
treatment of opioid withdrawal symptoms (e.g. lofexidine,
buprenorphine or salt thereof) along with the other ingredients of
a composition of the invention, and optionally loading into a
container that is for use within, or along with (e.g. attached to),
an applicator device as hereinbefore described.
[0198] In such an instance, the combined preparation may have the
same or similar physical attributes as those described hereinbefore
for compositions of the invention that do not include a compound
suitable for treatment of opioid withdrawal symptoms, in respect of
which the relevant disclosures herein are incorporated by
reference.
[0199] In a further aspect of the invention, there is also provided
a kit of parts comprising components (A) and (B) as follows: [0200]
(A) a composition of the invention; and [0201] (B) a pharmaceutical
composition including a compound that is suitable for use in the
treatment of opioid withdrawal symptoms (e.g. lofexidine or
buprenorphine) or a pharmaceutically acceptable salt thereof in
admixture with a pharmaceutically-acceptable diluent or carrier,
[0202] wherein compositions (A) and (B) are optionally loaded, or
are presented for loading, into separate containers, which
containers are for use within, or along with (e.g. attached to),
the same, or separate, applicator devices that is/are suitable for
administration of compositions to the nasal cavity, e.g. as
hereinbefore described.
[0203] In such an instance, the pharmaceutical composition
comprising opioid withdrawal symptom treatment described under (B)
above may have the same or similar physical attributes as those
described hereinbefore for a composition of the invention,
including that under (A) above. For example, the pharmaceutical
composition comprising opioid withdrawal symptom treatment may be
presented in the form of a powder containing particles with a
similar particle size to those mentioned hereinbefore for
compositions of the invention.
[0204] According to a further aspect of the invention, there is
provided a method of making a kit of parts as defined above, which
method comprises bringing component (A), as defined above, into
association with a component (B), as defined above, thus rendering
the two components suitable for administration in conjunction with
each other.
[0205] As alluded to above, by bringing the two components `into
association with` each other, we include that components (A) and
(B) of the kit of parts may be: [0206] (i) provided as separate
formulations (i.e. independently of one another), which are
subsequently brought together for use in conjunction with each
other in combination therapy; or [0207] (ii) packaged and presented
together as separate components of a `combination pack` for use in
conjunction with each other in combination therapy.
[0208] Thus, there is further provided a kit of parts comprising:
[0209] (I) one of components (A) and (B) as defined herein;
together with [0210] (II) instructions to use that component in
conjunction with the other of the two components.
[0211] The kits of parts described herein may comprise more than
one formulation including an appropriate quantity/dose of opioid
antagonist/salt, and/or more than one formulation including an
appropriate quantity/dose of compound suitable for treatment of
opioid withdrawal symptoms, in order to provide for repeat dosing.
If more than one formulation (comprising either active compound) is
present, such formulations may be the same, or may be different in
terms of the dose of either compound, chemical composition(s)
and/or physical form(s).
[0212] With respect to the kits of parts as described herein, by
`administration in conjunction with`, we include that respective
formulations comprising opioid antagonist (or salt thereof) and
compound suitable for treatment of opioid withdrawal symptoms (or
salt thereof) are administered, sequentially, separately and/or
simultaneously, to treat the relevant condition.
[0213] Thus, in respect of the combination product according to the
invention, the term `administration in conjunction with` includes
that the two components of the combination product are administered
(optionally repeatedly), either together, or sufficiently closely
in time, to enable a beneficial effect for the patient, that is
greater than if either formulation is administered (optionally
repeatedly) alone, in the absence of the other component.
Determination of whether a combination provides a greater
beneficial effect during treatment of a relevant condition will
depend upon the condition to be treated or prevented, but may be
achieved routinely by the skilled person.
[0214] After the emergency situation of treating acute opioid
overdose has been dealt with, further compositions comprising
compound suitable for treatment of opioid withdrawal symptoms (e.g.
lofexidine or, more preferably, buprenorphine or salt thereof) may
be administered as necessary or desired. Such compositions may be
similar in form to compositions of the invention (and in respect of
which the relevant disclosures herein are incorporated by
reference) or otherwise (e.g. sublingual formulations).
[0215] When the compound suitable for treatment of opioid
withdrawal symptoms is buprenorphine, suitable doses may be in the
range of between about 1 mg to about 32 mg, more preferably about 5
mg to about 20 mg, calculated as the free base.
[0216] When the compound suitable for treatment of opioid
withdrawal symptoms is lofexidine, suitable doses (e.g. daily
doses) may be in the range of between about 0.1 mg to about 3 mg,
such as about 0.5 mg to about 2 mg, calculated as the free
base.
[0217] Wherever the word `about` is employed herein in the context
of amounts, for example absolute amounts, such as doses, weights,
volumes, sizes, diameters, etc., or relative amounts of individual
constituents in a composition or a component of a composition
(including concentrations and ratios), timeframes, and parameters,
such as temperatures, pressure, relative humidities, etc., it will
be appreciated that such variables are approximate and as such may
vary by .+-.10%, for example .+-.5% and preferably .+-.2% (e.g.
.+-.1%) from the actual numbers specified herein. This is the case
even if such numbers are presented as percentages in the first
place (for example `about 10%` may mean .+-.10% about the number
10, which is anything between 9% and 11%).
[0218] Compositions of the invention have the advantage that they
are capable of being stored over a wider range of temperatures than
prior art compositions, including those that are
commercially-available (e.g., in the case of naloxone, Narcan).
Thus, compositions of the invention may be subject to low
temperatures (e.g. below freezing) without impacting the amount of
opioid antagonist that is administered to a subject. Further,
compositions of the invention may have the advantage that they are
more physically and chemically stable at higher temperature than
such prior art compositions.
[0219] Compositions of the invention further have the significant
advantage that they provide for higher bioavailability of opioid
antagonist compared to prior art compositions, including those that
are commercially-available (e.g., in the case of naloxone, Narcan).
The compositions of the invention provide for this higher
bioavailability alongside a more rapid absorption, which will
likely lead to a more rapid onset of action than such prior art
and/or commercially-available compositions, and thus meets a
significant and serious medical need.
[0220] The compositions, pharmaceutical formulations, uses and
methods described herein may also have the advantage that, in the
treatment of the conditions mentioned hereinbefore, they may be
more convenient for the first responder, physician and/or patient
than, be more efficacious than, be less toxic than, have a broader
range of activity than, be more potent than, produce fewer side
effects than, have a lower inter-patient variability, or that
it/they may have other useful pharmacological properties over,
similar formulations or methods (treatments) known in the prior
art, whether for use in the treatment of opioid overdose (or of
bulimia or alcohol dependence), or otherwise.
[0221] The invention is illustrated but in no way limited by way of
the following examples, with reference to the attached figures, in
which: FIGS. 1 to 7 represent drawings of actuator devices that may
be used to dispense compositions of the invention, FIGS. 8 and 9
show permeation of naloxone, and nalmefene, respectively, through
porcine nasal tissue in an ex vivo model; and FIGS. 10 and 11 show
mean naloxone plasma concentrations versus time, by treatment
(linear scale), as obtained in a clinical trial, over different
time periods.
EXAMPLE 1
[0222] Spray-Drying Opioid Antagonists with Various Saccharides
[0223] Naloxone HCl dihydrate (1.199 g; Johnson Matthey, UK) or
nalmefene HCl (0.600 g; Santa Cruz Biotechnology Inc., USA) and
naltrexone HCl (0.600 g; Mallinckrodt Inc., USA) were separately
mixed, along with different saccharides (5.088 g for naloxone and
2.554 g for nalmefene and naltrexone), which were employed as
carrier materials in the composition and purified water for
irrigation (56.58 g for naloxone and 28.29 g for nalmefene and
naltrexone), and the mixtures fed into a spray-dryer according to a
general procedure as follows.
[0224] Solid ingredients were weighed into a beaker equipped with a
magnetic stirring bar, dissolved in water and fed into a
spray-dryer (ProCepT, Belgium) equipped with an ultrasonic nozzle
operating at 25 kHz. The feed rate of the spray-dryer was set at
3.0 g/minute, the inlet temperature was set at 180.degree. C., the
gas flow was set at 300 L/min, and the cyclone gas was set at 1.5
bar.
[0225] The resultant spray-dried powder was collected and packed
into devices suitable for nasal powder administration (single shot
nasal unidose device for disposable use; UDS Monopowder, Aptar
Pharma, France), with a fill weight of 23 mg. (For naloxone, this
constituted a single dose of 4 mg of naloxone (calculated as the
HCl salt).)
[0226] The devices were placed in heat-sealed aluminum pouches
before storage for 6 months at 40.degree. C. and 75% relative
humidity (RH).
[0227] The chemical composition of the spray-dried mixtures after
storage, and the amount of powder emitted from the devices after
actuation, were determined.
[0228] The stability of naloxone after 6 months (6 M), with amounts
of impurities expressed as a percentage of the related substance (%
RS) is summarized for the different saccharides in Table 1 below.
Initial values of % RS were less than 0.1% for all samples.
TABLE-US-00001 TABLE 1 Galactose Trehalose Maltitol (Acros (Acros
Sucralose Sucrose (Roquette, Organics, Organics, (Merck, (Merck,
Saccharide France) Belgium Belgium Germany) Germany) Stability 6M
2.44 0.20 0.09 5.40 1.04 (% RS) Emitted dose 2.2 mg 5.3 mg 22.4 mg
4.5 mg 3.8 mg Isomalt Lactose (BENEO- Mannitol Maltose (Acros
Palatinit, (Roquette, (Merck, Organics, Saccharide Germany) France)
Germany) Belgium Stability 1.27 0.99 4.18 0.07 (% RS) Emitted dose
6.1 mg 21.2 mg 3.9 mg 21.4 mg
Unexpectedly, certain monosaccharides, like mannitol, which has
been previously used in physical mixtures together with naloxone,
proved incompatible when employed in this spray-drying process (in
terms of the chemical stability of naloxone). This was to be
contrasted with disaccharides, like lactose, which were generally
compatible.
[0229] Further, polysaccharides known to have a higher Tg tended to
give rise to a higher emitted powder dose. Physical changes as a
result of a low Tg gave caking and aggregation of the powder in the
devices.
[0230] For nalmefene and naltrexone, a similar trend was observed
(see Table 2 below, where initial % RS values are presented in
parentheses).
TABLE-US-00002 TABLE 2 API Nalmefene Nalmefene Naltrexone
Naltrexone Saccharide Lactose Mannitol Lactose Mannitol Stability
(% RS) 0.83 (0.77) 1.82 (0.75) 0.33 (0.11) 1.12 (0.08) 6M 40/75
Emitted dose 21.7 mg 21.6 mg 20.4 mg 19.3 mg
EXAMPLE 2
Physical Stability of Spray-Dried Powders
[0231] In order to assess the physical stability and mitigate the
risk for crystallization during storage, glass transition
temperatures (Tg) were determined using differential scanning
calorimetry (DSC) and are presented in Table 3 below.
[0232] Compositions were prepared generally in accordance with the
procedure described in Example 1 above, using mannitol, trehalose
and lactose as carrier materials.
[0233] For lactose, the true Tg, as well as that of the formulation
subjected to equilibration at four different RH conditions at
25.degree. C. (10%, 20%, 30% and 40% RH), were measured (although
30% was not logged). For mannitol and trehalose, Tg was measured as
received (`Ambient`) and after drying (`Dried`).
[0234] For the dried samples, the DSC ampoule lid was punched
automatically immediately before start of the DSC run, introducing
a hole of about 0.3 mm diameter. The purpose of this was to allow
any remaining moisture to evaporate before the glass transition
temperature for a dry formulation was reached. Hence, this Tg value
corresponds to the true Tg without interference from available
plasticizers like water.
[0235] For the samples equilibrated at different RH values, the DSC
lid was gas-tight throughout the DSC run. Samples were prepared as
described above.
TABLE-US-00003 TABLE 3 Composition RH (%) Tg (.degree. C.) Mannitol
Dried -- Ambient -- Trehalose Dried 119 Ambient 51 Lactose Dried
115 10 60 20 57 30 52 40 36
Using trehalose or lactose as carrier materials gave completely
amorphous compositions, in contrast to mannitol which seemed to
crystalize in the spray-dryer as no Tg could be found and the water
content was below 1%.
EXAMPLE 3
Ex-Vivo Evaluation of Nasal Mucosal Absorption of Naloxone and
Nalmefene
[0236] A standard static diffusion (Franz) cell set up was employed
to set up an ex vivo model for nasal mucosa absorption, using an
excised porcine nasal tissue.
[0237] Solutions containing naloxone HCl dihydrate, nalmefene HCl,
benzalkonium chloride (Sigma-Aldrich Sweden AB), sucrose
monolaurate (IMCD Nordic AB) and/or polysorbate 80 (Croda Nordica
AB) were prepared by standard techniques, to provide formulations
according to Table 4 below. Potassium phosphate buffer
(Sigma-Aldrich Sweden AB) was added to give the pH stated in Table
4 below.
TABLE-US-00004 TABLE 4 Formulation 1 2 3 4 5 6 7 8 naloxone (mg/mL)
5 5 5 5 5 5 5 nalmefene (mg/mL) 5 5 5 5 5 5 5 benzalkonium chloride
(mg/mL) 0.1 0.1 0.1 sucrose monolaurate (mg/mL) 0.4 2 polysorbate
80 (mg/mL) 2 pH 4.5 4.5 4.5 4.5 4.5 4.5 4.5 6.5
Diffusion through the tissue was measured after 7 hours and
permeation is shown as mean (three repeats) cumulative transport
(.mu.g/cm.sup.2; with SD) in FIGS. 8 and 9 for naloxone and
nalmefene, respectively.
[0238] For both naloxone and nalmefene, slightly higher apparent
permeation coefficients (Papp) were observed in Formulations 7 and
8, which contained polysorbate 80 and a higher amount of pH buffer,
respectively. No corresponding absorption enhancement was observed
in the case of benzalkonium chloride or sucrose monolaurate.
EXAMPLE 4
Naloxone-Containing Composition B
[0239] The general procedure described in Example 1 was employed to
make a spray-dried composition from naloxone HCl dihydrate (1.199
g), along with .alpha.-D-lactose monohydrate (5.026 g; DFE Pharma
Germany), sucrose monolaurate D-1216 (0.062 g; Mitsubishi-Kagaku
Foods Corporation, Japan).
[0240] Composition B comprised a single dose of naloxone of 4 mg
(calculated as the HCl salt).
[0241] Devices were placed in heat-sealed aluminum pouches
(Protective Packaging, UK) before use.
[0242] The geometric particle size distribution (PSD) was measured
using a Malvern Mastersizer 2000 (Malvern Panalytical Ltd, UK) and
aerodynamic particle size distribution (aPSD) using a fast
screening impactor (FSI, Copley Scientific, UK). PSD: d10=15 .mu.m
and d90=55 .mu.m; aPSD<5 .mu.m=0%.
[0243] General method for PSD measurements: 80 to 100 mg of sample
was dispersed in 5 mL of silicone oil and mixed well before
sonication for 20 to 30 seconds. Three measurements were made on
the solution using a Malvern Mastersizer 2000 (Malvern Panalytical
Ltd., UK).
[0244] General method for aPSD measurements: A loaded device was
actuated in a fast screening impactor (FSI, Copley Scientific, UK)
fitted with a suitable adaptor, an expansion bulb and a 10 micron
insert. Flow was adjusted to 30.+-.0.5 L/min. Results were reported
as fine particle mass (FPM) as % recovered in the filter stage
(<5 .mu.m).
EXAMPLE 5
Naloxone-Containing Compositions A, C and D
[0245] The same general procedure as that described in Example 4
above was followed to prepare three further spray-dried powders,
with compositions according to Table 5 below.
TABLE-US-00005 TABLE 5 Component Quantity per batch (g)
Naloxone-Containing Composition A Naloxone HCl dihydrate 1.199
.alpha.-D-Lactose Monohydrate 5.088 Water for irrigation 56.580
Total 62.867 Naloxone-Containing Composition C Naloxone HCl
dihydrate 1.199 .alpha.-D-Lactose Monohydrate 4.469 Kollidon 30
(BASF, Germany) 0.619 Water for irrigation 56.580 Total 62.867
Naloxone-Containing Composition D Naloxone HCl dihydrate 2.398
.alpha.-D-Lactose Monohydrate 3.889 Water for irrigation 56.580
Total 62.867
Compositions A and C comprised single doses of naloxone of 4 mg,
and Composition D comprised a single dose of naloxone of 8 mg (each
calculated as the HCl salt). PSD and aPSD were analyzed using the
general method in Example 4 above (see Table 6 below for
results).
TABLE-US-00006 TABLE 6 Composition A C D d10 (.mu.m) 15 17 17 d90
(.mu.m) 44 57 58 % <5 .mu.m 0 0 0
EXAMPLE 6
Intranasally-Administered Naloxone--Pharmacokinetic Study (Healthy
Volunteers)
[0246] A Phase I clinical study was performed to determine the
bioavailability of the four investigational naloxone nasal powder
formulations (obtained as described in Examples 4 and 5 above)
relative to the reference commercial product NARCAN.RTM. nasal
spray (`Ref`; naloxone hydrochloride liquid nasal spray, 4 mg;
Adapt Pharma, Inc., Radnor, Pa., USA).
[0247] The study was a single-centre, open label, randomised,
single dose 5-treatment crossover, relative bioavailability study
in healthy subjects. Each subject received each of the four
naloxone-containing powders (Compositions A to D), as well as Ref
in a sequence according to a pre-set randomisation schedule,
separated by a minimum 24 hours washout.
[0248] Subjects were randomised immediately before administration
of the first dose of investigational medicinal product (IMP) or Ref
(if used). A computer-generated randomisation schedule was used to
allocate subject numbers to 1 of 10 treatment sequences (according
to a balanced Williams design) with 2 subjects receiving each
treatment sequence.
[0249] 48 subjects were screened for inclusion in the study up to
28 days before dosing. 21 eligible subjects (healthy male and
non-pregnant, non-lactating, female subjects between 18 and 55
years of age with a body mass index between 18.0 and 32.0
kg/m.sup.2) were admitted to the clinical unit on the evening prior
to IMP administration (Day -1) and remained on site until being
discharge at 24 hours post-final dose (after receiving all 5
treatments).
[0250] Subjects received IMP or Ref in the morning of Days 1, 2, 3,
4 and 5, with an appropriate interval between subjects based on
logistical requirements (approximately 10 minutes). IMP was
administered to alternate nostrils on each day of dosing, starting
with the left nostril on Day 1. A follow-up phone call took place 3
to 5 days after the final dose to ensure the ongoing wellbeing of
the subjects.
[0251] Of the 21 subjects that were enrolled, all received IMP. For
analysis purposes, all 21 subjects were included in the safety
population, safety analysis dataset and the PK population. 1
profile was excluded from the PK analysis dataset owing to a dosing
failure, such that 20 subjects completed the study and were
included in the PK analysis dataset.
[0252] Plasma concentrations of naloxone were analysed using
non-compartmental analysis methods to obtain estimates of standard
PK parameters as set out below:
TABLE-US-00007 Parameter Definition AUC(0-t) area under the curve
from 0 time to the last measurable concentration AUC(0-inf) area
under the curve from 0 time extrapolated to infinity AUCextrap
percentage of AUC(0-inf) extrapolated beyond the last measurable
concentration Cmax maximum observed concentration Tlag Time to the
first measurable concentration Tmax Time of maximum observed
concentration Lambda-z slope of the apparent elimination phase T1/2
apparent elimination half-life AUC(0-4 min) area under the curve
from 0 time to 4 min (0.067 h) post-dose AUC(0-10 min) area under
the curve from 0 time to 10 min (0.17 h) post-dose AUC(0-30 min)
area under the curve from 0 time to 30 min (0.5 h) post-dose
The evaluation of safety parameters comprised analysis of adverse
events (AEs), intranasal tolerability, laboratory evaluations,
vital signs, electrocardiogram (ECG) and physical examination
findings.
[0253] Log-transformed exposure parameters (AUCs and C max) were
compared with standard methods to assess relative bioavailability
using SAS Software procedure PROC MIXED. A single mixed effects
model was fitted for each parameter to obtain estimates of
geometric mean ratios (GMRs) and corresponding confidence intervals
(CIs) for all treatment comparisons of interest. Models included
terms for actual treatment received, study day (i.e. period) and
planned sequence fitted as fixed effects and subject within
sequence fitted as a random effect. Results were presented
back-transformed to the linear scale. The following comparisons
were of interest: [0254] Relative bioavailability compared to Ref:
IMP:Ref GMRs for AUC(0-t), AUC(0-inf) and C max were determined
[0255] Early exposure compared to Ref: IMP:Ref GMRs for AUC(0 0-4
min), AUC(0-10 min) and AUC(0-30 min) were determined [0256] Dose
proportionality of IMD formulations: 8 mg:4 mg GMRs for AUC(0-t),
AUC(0-inf) and C max were determined and dose normalized.
Results
[0257] Arithmetic mean naloxone plasma concentrations vs time, by
treatment (linear scale) are shown in FIGS. 10 and 11 (first five
hours and first hour after administration, respectively) and are
described in Table 7 below. Geometric mean naloxone plasma
concentrations vs time, by treatment (semi log scale) are described
in Table 7 below.
TABLE-US-00008 TABLE 7 Composition A B C D Ref N 19 20 20 20 20
AUC(0-t) 10.7 14.7 10.9 16.9 7.99 (ng h/mL).sup.a (24.8) (18.5)
(27.6) (35.9) (44.1) AUC(0-inf) 10.8 14.8 11.1 17.1 8.06 (ng
h/mL).sup.a (25.3) [n = 18] (18.6) (28.7) [n = 18] (35.9) [n = 18]
(44.6) [n = 19] AUCextrap 0.955 0.688 1.254 0.865 1.240 (%).sup.a
(50.5) [n = 18] (43.9) (79.7) [n = 18] (106.0) (58.0) [n = 19] [n =
18] Cmax 8.43 15.6 8.94 12.1 5.67 (ng/mL).sup.a (44.2) (46.5)
(35.4) (45.4) (55.8) Tlag 0.000 0.000 0.000 0.000 0.000 (h).sup.b
(0.00-0.033) (0.00-0.00) (0.00-0.034) (0.00-0.034) (0.00-0.035)
Tmax 0.3333 0.2500 0.2500 0.3333 0.3333 (h ).sup.b (0.108- (0.117-
(0.118- (0.167- (0.117- 0.667) 0.500) 0.500) 0.667) 0.502) Lambda-z
0.59019 0.57066 0.53326 0.50483 0.52148 (1/h).sup.c (20.9) [n = 18]
(20.6) (31.7) [n = 18] (20.0) [n = 18] (24.7) [n = 19] T1/2 1.243
1.269 1.471 1.425 1.404 (h).sup.c (30.0) [n = 18] (22.8) (43.6) [n
= 18] (20.0) [n = 18] (23.2) [n = 19] N: number of subjects in the
dataset; n: number of subjects with an observation. .sup.aGeometric
mean (geometric CV %); .sup.bMedian (range); .sup.cArithmetic mean
(arithmetic CV %)
[0258] The analysis of relative bioavailability (GMR, 90% CI) is
shown in Table 8 below.
TABLE-US-00009 TABLE 8 Comparison AUC(0-t) (%) AUC(0-inf) (%) Cmax
(%) A:Ref 136.23 135.47 149.56 (122.64, 151.33) (121.33, 151.26)
(125.75, 177.87) B:Ref 184.47 183.89 274.68 (166.36, 204.55)
(165.28, 204.60) (231.63, 325.74) C:Ref 136.37 136.91 157.57
(122.99, 151.22) (122.58, 152.92) (132.88, 186.86) D:Ref 211.37
213.61 213.07 (190.62, 234.38) (191.25, 238.58) (179.68,
252.67)
All IMPs displayed significantly higher overall and peak plasma
exposure of naloxone than Ref. Composition B displayed the highest
relative bioavailability of the 4 mg formulations, with
approximately 84% higher AUC and 175% higher C max than Ref on
average (noting that formulation D included 8 mg naloxone
hydrochloride, double the amount in the other formulations). The
IMPs, A, B, C and D, also displayed lower interpatient variability
(CV) in overall and peak exposure parameters than Ref (see Table
7).
[0259] Tables 9 and 10 below shows descriptive statistics of
naloxone partial AUCs (as geometric means; geometric CV %) by
treatment, on an absolute (Table 9) and relative (Table 10)
basis.
TABLE-US-00010 TABLE 9 Composition A B C D Ref AUC(0-4 min) 0.0412
0.0895 0.0469 0.0543 0.0238 (ng h/mL).sup.a (149.1) (175.4) (159.6)
(262.7) (186.5) AUC(0-10 min) 0.450 0.991 0.479 0.550 0.267 (ng
h/mL).sup.a (90.7) (87.8) (90.2) (104.9) (103.7) AUC(0-30 min) 2.70
4.82 2.89 3.86 1.88 (ng h/mL).sup.a (46.1) (42.9) (43.6) (52.3)
(60.8)
TABLE-US-00011 TABLE 10 AUC(0-4 min) AUC(0-10 min) AUC(0-30 min)
AUC(0-t) Comparison (%) (%) (%) (%) A:Ref 174.56 167.04 144.29
136.23 (109.45, 278.41) (122.05, 228.59) (120.63, 172.59) (122.64,
151.33) B:Ref 376.43 370.69 256.89 184.47 (237.87, 595.70) (272.29,
504.64) (215.41, 306.36) (166.36, 204.55) C:Ref 197.03 179.25
153.80 136.37 (124.51, 311.80) (131.67, 244.03) (128.96, 183.41)
(122.99, 151.22) D:Ref 228.33 205.89 205.54 211.37 (144.28, 361.33)
(151.24, 280.30) (172.35, 245.12) (190.62, 234.38)
All IMPs displayed significantly higher plasma exposure of naloxone
than Ref over the first 4, 10 and 30 minutes after dosing. For
Composition B, early partial AUC GMRs were much higher than the
corresponding AUC(0-t) GMR for this IMP, which is indicative of a
higher initial rate of absorption from this formulation than with
Ref.
[0260] Analysis of dose proportionality of IMPs as dose normalised
GMRs (90% CI; 8 mg:4 mg; D:A) are shown in Table 11 below.
TABLE-US-00012 TABLE 11 Comparison AUC(0-t) (%) AUC(0-inf) (%) Cmax
(%) D:A 77.58 78.84 71.23 (69.84, 86.17) (70.46, 88.21) (59.90,
84.72)
For the scaled point estimates of D:A GMRs for AUC(0-t), AUC(0-inf)
and C max, the 90% CIs lie entirely below 100%.
[0261] All IMPs demonstrated significantly higher naloxone exposure
than Ref. Compositions A, B, C and D displayed approximately 36%,
84%, 37% and 112% higher overall exposure, respectively, relative
to Ref, with peak exposure (C max) being 50%, 175%, 58% and 113%
higher on average, respectively (again noting that Composition D
contained 8 mg naloxone hydrochloride, which is double the amount
of the other compositions.)
[0262] Inter-subject variability in the overall exposure parameters
AUC(0-t), AUC(0-inf) and C max was lower following administration
of Compositions A, B, C and D compared to Ref.
[0263] As can be seen clearly from FIG. 10 and, more clearly from
FIG. 11, rapid absorption of all formulations, with median T max
values between 0.250 h and 0.333 h, was observed. Early exposure
(in terms of AUC(0-4 min), AUC(0-10 min) and AUC(0-30 min)) was
higher from all IMPs than that from Ref. Absorption was most rapid
from Composition B, with point estimates indicative of >270%
higher exposure than Ref during the first 10 min after dosing. This
is a remarkable and completely unexpected result, for all of the
reasons described hereinbefore.
[0264] Elimination of naloxone was similar between all
formulations, with arithmetic mean terminal T1/2 values between
1.243 and 1.471 hours.
[0265] Nasal administration of naloxone nasal powder at all doses
was considered to be safe and well tolerated under the conditions
of the trial.
[0266] There were no SAEs, severe AEs or AEs leading to subject
withdrawal reported in this study, and the AE profiles were similar
to previous studies of the reference nasal spray in healthy
subjects. The most commonly reported AEs were nasal inflammation,
headache and dizziness. All AEs were mild in severity and, overall,
the safety profile of the IMPs corresponded well with previous
experience of naloxone HCl in healthy subjects and there were no
findings that raised any safety concerns.
EXAMPLE 7
Physical Stability of Spray-Dried Powders Containing Dextrins
[0267] The general procedure as described in Example 1 above was
employed to make two formulations with the following compositions
(percentages are by weight of the total composition):
Composition X
[0268] Naloxone HCl (35%), 2-hydroxypropyl-.beta.-cyclodextrin
(Cavasol W7, HP Pharma, Wacker, Germany; 53%), lactose (Merck,
Germany; 10%) and Tween 20 (Croda Nordica AB, Sweden; 1%)
Composition Y
[0268] [0269] Naloxone HCl (17%), maltodextrin (Glucidex IT 12 DE,
Roquette, France; 72%), lactose (10%), sucrose monolaurate
(1%).
[0270] A similar experiment to that described in Example 2 above
was set up measuring physical stabilities of Compositions X and Y
at different RH values, as Tg values. The results are show in Table
12 below.
TABLE-US-00013 TABLE 12 Composition RH (%) Tg (.degree. C.) X Dried
152 11 128/97 22 108/78 33 96/-- 43 81/52 Y Dried 158/-- 11 156/97
22 142/85 33 128/70 43 107/51
Both dextrins increased Tg compared to compositions comprising only
lactose as carrier material, facilitating acceptable emitted dose
even after 24-72 hours of storage at 80.degree. C. The multiple Tg
values presented in Table 10 indicates that the relevant
compositions were not fully homogenous, but rather regions with an
increased concentration of higher molecular weight polysaccharide
that are separate from regions of lower molecular weight
compounds.
[0271] Subsequently-conducted dissolution tests also showed that
high concentrations of maltodextrin did not affect the dissolution
of naloxone.
EXAMPLE 8
Chemical Stability of Spray-Dried Powders Containing Dextrins
[0272] In order to explore the chemical stability of naloxone as an
effect of dextrins and lactose/dextrin mixtures, samples were
prepared using the general procedure as described in Example 1
above. Compositions (percentages are by weight of the total
composition) are provided in Table 13.
[0273] The chemical stability of naloxone after 3 and 6 months at
40.degree. C./75% RH, with amounts of impurities expressed as a
percentage of the related substance (% RS) is summarized for the
different compositions in Table 13 below. All initial % RS values
were less than 0.1%.
TABLE-US-00014 TABLE 13 Composition 3M 6M Naloxone HCl (17%) 0.38
(0.10) 0.07 (0.04) Lactose (83%) Naloxone HCl (17%) 0.34 (0.09)
0.19 (0.06) Lactose (82%) Sucrose monolaurate (1%) Naloxone HCl
(17%) 0.75 (0.62) 3.40 (3.40) 2-hydroxypropyl-.beta.-cyclodextrin
(82%) Sucrose monolaurate (1%) Naloxone HCl (17%) 0.09 (0.06) 0.24
(0.21) 2-hydroxypropyl-.beta.-cyclodextrin (58%) Lactose (24%)
Sucrose monolaurate (1%) Naloxone HCl (35%) 0.45 (0.42) 3.05 (3.05)
2-hydroxypropyl-.beta.-cyclodextrin (64%) Sucrose monolaurate (1%)
Naloxone HCl (35%) 0.12 (0.09) 0.71 (0.68)
2-hydroxypropyl-.beta.-cyclodextrin (45%) Lactose (19%) Sucrose
monolaurate (1%) Naloxone HCl (17%) 0.39 (0.24) 0.29 (0.29)
Maltodextrin 12DE (82%) Sucrose monolaurate (1%) Naloxone HCl (17%)
0.12 (0.05) 0.05 (0.05) Maltodextrin 12DE (63%) Lactose (19%)
Sucrose monolaurate (1%) Naloxone HCl (35%) 0.29 (0.29) 0.28 (0.28)
Maltodextrin 12DE (64%) Sucrose monolaurate (1%) Naloxone HCl (35%)
0.13 (0.10) 0.11 (0.08) Maltodextrin 12DE (45%) Lactose (19%)
Sucrose monolaurate (1%)
The numbers in brackets in Table 13 are the % RS taking away that
value measured for Impurity E (Imp E), which is a documented
impurity related to naloxone (dimer). In this study, Imp E seems to
be formed during sample preparation prior to analysis, which
affects the total % RS value in an uncontrolled way and prevents
the detection of minor degradation trends.
[0274] It is clear from Table 13 that dextrins unexpectedly induce
decomposition of naloxone, but that the addition of lactose
mitigates this effect.
EXAMPLE 9
Nalmefene-Containing Compositions E, F and G
[0275] The same general procedure essentially as described in
Examples 1 and/or 4 above was followed to prepare three
nalmefene-containing spray-dried powders, with compositions
according to Table 14 below. In this and the next example,
nalmefene was sourced from Mallinckrodt Inc., USA.
TABLE-US-00015 TABLE 14 Component Quantity per batch (g)
Nalmefene-Containing Composition E Nalmefene HCl 3.106
.alpha.-D-Lactose Monohydrate 18.162 Sucrose monolaurate 0.206
Water for irrigation 193.257 Total 214.731 Nalmefene-Containing
Composition F Nalmefene HCl 3.004 .alpha.-D-Lactose Monohydrate
4.188 Maltodextrin 12DE 12.713 Sucrose monolaurate 0.199 Water for
irrigation 178.852 Total 198.956 Nalmefene-Containing Composition G
Nalmefene HCl 3.284 .alpha.-D-Lactose Monohydrate 9.158
Maltodextrin 12DE 31.298 Sucrose monolaurate 0.218 Water for
irrigation 395.620 Total 439.578
Compositions E and F comprised single doses of nalmefene of 3 mg,
and Composition G comprised a single dose of nalmefene of 3 mg, but
at half concentration and double fill weight (each calculated as
the free base). PSD and aPSD were analyzed using the general method
in Example 4 above (see Table 15 below for results).
TABLE-US-00016 TABLE 15 Composition E F G d10 (.mu.m) 18 20 19 d90
(.mu.m) 51 66 65 % <5 .mu.m 0 0 0
Using the method described in Example 2 above, all of the
compositions exhibited a glass transition at around 60.degree. C.,
in ambient conditions. However, Composition E produced a large
crystallisation event at just above 100.degree. C., which was not
seen in the maltodextrin-containing Compositions F and G. In
addition, Composition E underwent crystallization at room
temperature in 60% RH, something that was not seen in Compositions
F and G.
EXAMPLE 10
Chemical Stability of Spray-Dried Powders Containing Nalmefene
[0276] Samples were prepared using the general procedure
essentially as described in Examples 1 and/or 4 above. Compositions
(percentages are by weight of the total composition) are provided
in Table 16 below.
[0277] The chemical stability of nalmefene 3 and 6 months at
40.degree. C./75% RH, with amounts of impurities expressed as a
percentage of the related substance (% RS) is summarized for the
different compositions in Table 16 below. All initial % RS values
were less than 0.1%.
TABLE-US-00017 TABLE 16 Composition 3M 6M Nalmefene HCl (15%, 0.45
g) 0.14 0.05 Lactose (84%) Sucrose monolaurate (1%) Nalmefene HCl
(15%, 0.45 g) 0.10 0.00 Maltodextrin 12DE (64%) Lactose (20%)
Sucrose monolaurate (1%) Nalmefene HCl (15%, 0.45 g) 0.11 0.07
Maltodextrin 12DE (74%) Lactose (10%) Sucrose monolaurate (1%)
Nalmefene HCl (7.5%, 0.225 g) 0.16 0.00 Maltodextrin 12DE (71.5%)
Lactose (20%) Sucrose monolaurate (1%)
* * * * *