U.S. patent application number 15/016831 was filed with the patent office on 2017-01-05 for methods for treating pruritus.
The applicant listed for this patent is TREVI THERAPEUTICS, INC.. Invention is credited to Thomas SCIASCIA.
Application Number | 20170000782 15/016831 |
Document ID | / |
Family ID | 49957912 |
Filed Date | 2017-01-05 |
United States Patent
Application |
20170000782 |
Kind Code |
A1 |
SCIASCIA; Thomas |
January 5, 2017 |
METHODS FOR TREATING PRURITUS
Abstract
The present invention relates to methods for treating uremic
pruritus with anti-pruritic compositions.
Inventors: |
SCIASCIA; Thomas; (Belmont,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TREVI THERAPEUTICS, INC. |
New Haven |
CT |
US |
|
|
Family ID: |
49957912 |
Appl. No.: |
15/016831 |
Filed: |
February 5, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14139697 |
Dec 23, 2013 |
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15016831 |
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13715625 |
Dec 14, 2012 |
8637538 |
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14139697 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 9/2077 20130101; A61K 9/2018 20130101; A61K 9/205 20130101;
A61K 9/209 20130101; A61K 31/485 20130101 |
International
Class: |
A61K 31/485 20060101
A61K031/485 |
Claims
1. A method of treating uremic pruritus comprising administering an
effective amount of an anti-pruritus agent to a human patient in
need of such treatment, wherein the anti-pruritus agent is
nalbuphine or a pharmaceutically acceptable salt or ester thereof
and wherein the anti-pruritus agent is not administered in
combination with a second anti-pruritus agent.
2-30. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is related to PCT International Application
PCT/US2013/075096, U.S. application Ser. No. 14/106,673, and U.S.
application Ser. No. 14/106,677, each of which claims priority to
U.S. Provisional Application No. 61/737,488, filed Dec. 14, 2012,
and U.S. application Ser. No. 13/715,625, filed Dec. 14, 2012. The
application is also a Continuation of U.S. application Ser. No.
13/715,625. The contents of each of the aforementioned applications
are incorporated by reference in their entireties for all
purposes.
FIELD OF THE INVENTION
[0002] The present invention relates to methods for treating uremic
pruritus with anti-pruritic compositions.
BACKGROUND
[0003] Uremic pruritus is a disorder associated with chronic kidney
disease. Pruritus, or itch, is a sensation that stimulates the
desire or reflex to scratch, which can be either generalized or
localized. The cause of uremic pruritus is not fully understood.
Overactivity of type 1 T helper cells (TH1) has been demonstrated
in uremic pruritus. Furthermore, serum levels of interleukin-2, a
cytokine produced by TH1 cells, have been demonstrated to be higher
in dialysis patients with itch compared to dialysis patients
without itch. This cytokine has a well-documented role in induction
of pruritus (Fallahzadeh et al., Nephrol. Dial. Transplant. (2011)
26 (10): 3338-3344). Other proposed contributors to the
pathogenesis of uremic pruritus may include anemia or other
manifestation of erythropoietin deficiency, inadequate dialysis,
histamine release from skin mast cells, skin dryness, secondary
hyperparathyroidism, hyperphosphatemia with increased calcium
phosphate deposition in the skin and alterations in the endogenous
opioidergic system with overexpression of opioid
.mu.-receptors.
[0004] Uremic pruritus in patients with kidney failure and/or among
patients undergoing dialysis can be quite disabling. For example,
chronic uremic pruritus leads to a statistically significant
deleterious impact on the patient that can be scientifically
measured in the realms of Quality of Life impairment, sleep
disruption problems, social functioning and affective disturbances
(Mathur et al., Clin J Am Soc Nephrol. 2010; Pisoni et al., Nephrol
Dial Transplant 2006 (21): 3495-3505, and references therein). In
addition to increased morbidity, Pisoni et al. and Narita et al.
(Kidney Int 2006 (69) 1626-1632) have also demonstrated that this
patient population has increased mortality, and that such increased
mortality can be reasonably attributed to the failure to adequately
treat the pruritus. Despite advances in the care of patients with
kidney disease and end-stage renal disease (ESRD) patients, the
treatment and management of uremic pruritus remains a challenge.
Accordingly, there is a need for effective methods to treat uremic
pruritus.
SUMMARY OF THE INVENTION
[0005] In a first aspect, the present invention provides a method
of treating uremic pruritus comprising administering an effective
amount of an anti-pruritus agent to a human patient in need of such
treatment, wherein the anti-pruritus agent is nalbuphine or a
pharmaceutically acceptable salt or ester thereof and wherein the
anti-pruritus agent is not administered in combination with a
second anti-pruritus agent.
[0006] In some embodiments, the patient is under treatment, e.g.,
pre-treatment, under treatment, or post-treatment of dialysis. In
certain embodiments, the patient has chronic kidney disease or
reduced renal function.
[0007] In some embodiments, the anti-pruritus agent is administered
at an initial oral dose of from about 15 mg to about 60 mg twice a
day and then titrated to an effective dose. In other embodiments,
the anti-pruritus agent is administered at an initial dose of from
about 15 mg to about 60 mg once a day and then titrated to an
effective dose. In some embodiments, the anti-pruritus agent is
administered at an initial dose of from about 15 mg to about 60 mg
twice a day or once a day for about 3 days and then titrated to an
effective dose at about 15 mg to about 60 mg increment.
[0008] In certain embodiments, the maximum dose is about 180 mg
when said agent is administered to a patient once a day, and 360 mg
when administered twice a day. In some embodiments, the
anti-pruritus agent is administered with an AM dosage and a PM
dosage and wherein the PM dosage is higher than the AM dosage or
the AM dosage is higher than the PM dosage.
[0009] In certain embodiments, the anti-pruritus agent is in an
extended release oral dosage form and the administration provides
in the patient a mean C.sub.max of from about 1.9 ng/mL to about
102 ng/mL. In some embodiments, the anti-pruritus agent is in an
extended release oral dosage form and the administration provides
in the patient an AUC.sub.(0-.infin.) of from about 37 nghr/mL to
about 910 nghr/mL.
[0010] In some embodiments, the anti-pruritus agent is at least 50%
dialyzable when administered to the patient under dialysis
treatment. In certain embodiments, a metabolite of the
anti-pruritus agent does not have detectable anti-pruritus
activity.
[0011] In another aspect, the present invention provides a method
of treating uremic pruritus comprising administering an effective
amount of an anti-pruritus agent to a human patient in need of such
treatment, wherein the anti-pruritus agent is nalbuphine or a
pharmaceutically acceptable salt or ester thereof. In yet another
aspect, the present invention provides a method of treating uremic
pruritus comprising administering an effective amount of an
anti-pruritus agent, wherein the anti-pruritus agent is nalbuphine,
or a pharmaceutically acceptable salt or ester thereof, and wherein
the anti-pruritus agent is in an extended release oral dosage
form.
[0012] In some embodiments, the administration provides in the
patient a pK release profile with the characteristics of a) a mean
C.sub.max from about 1.9 ng/mL to about 102 ng/mL, and b) and
AUC.sub.0-.infin. of from about 37 nghr/mL to about 910
nghr/mL.
[0013] In certain embodiments, the patient is in treatment, e.g.,
pre-treatment, under treatment, or post-treatment of dialysis. In
certain embodiments, dialysis includes hemodialysis and peritoneal
dialysis. In some embodiments, the patient has chronic kidney
disease or reduced renal function.
[0014] In certain embodiments, the anti-pruritus agent is
administered at an initial dose of about 15 mg to about 60 mg twice
a day and then titrated to an effective dose. In other embodiments,
the anti-pruritus agent is administered at an initial dose of about
15 mg to about 60 mg once a day and then titrated to a
therapeutically effective dose. In some embodiments, the
anti-pruritus agent is administered at an initial dose of about 15
mg to about 60 mg twice a day or once a day for about 3 days and
then titrated to an effective dose at about 15 mg to about 60 mg
increment.
[0015] In some embodiments, the maximum dose of the anti-pruritus
agent is about 180 mg when administered once a day or 360 mg when
administered twice a day. In certain embodiments, the anti-pruritus
agent is administered with an AM dosage and a PM dosage and wherein
the PM dosage is higher than the AM dosage or the AM dosage is
higher than the PM dosage.
[0016] In some embodiments, the anti-pruritus agent is at least 50%
dialyzable when administered to the patient under dialysis
treatment. In other embodiments, one or more metabolites of the
anti-pruritus agent do not have detectable anti-pruritus activity.
In some embodiments, one or more metabolites of the anti-pruritus
agent are at least 50% dialyzable when the anti-pruritus agent is
administered to the patient under dialysis treatment.
[0017] In certain embodiments, the anti-pruritus agent is
administered in an oral formulation comprising one or more of the
following: nalbuphine hydrochloride, mannitol, hydroxypropyl
cellulose, locust bean gum, xanthan gum, fumaric acid, calcium
sulfate dihydrate and magnesium stearate. In certain embodiments,
the anti-pruritus agent is administered in an oral extended release
formulation comprising nalbuphine hydrochloride, mannitol,
hydroxypropyl cellulose, locust bean gum, xanthan gum, calcium
sulfate dihydrate and magnesium stearate.
[0018] The present methods, and advantages thereof, are further
illustrated by the following non-limiting detailed description and
Examples.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 is a graphical representation of the log of the mean
nalbuphine plasma concentration versus time for several nalbuphine
compositions.
DETAILED DESCRIPTION
[0020] The word "about" when immediately preceding a numerical
value means a range of plus or minus 10% of that value, e.g.,
"about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500,
etc., unless the context of the disclosure indicates otherwise, or
is inconsistent with such an interpretation. For example in a list
of numerical values such as "about 49, about 50, about 55, . . . ",
"about 50" means a range extending to less than half the
interval(s) between the preceding and subsequent values, e.g., more
than 49.5 to less than 52.5. Furthermore, the phrases "less than
about" a value or "greater than about" a value should be understood
in view of the definition of the term "about" provided herein.
[0021] Throughout this disclosure, various patents, patent
applications and publications are referenced. The disclosures of
these patents, patent applications and publications in their
entireties are incorporated into this disclosure by reference in
order to more fully describe the state of the art as known to those
skilled therein as of the date of this disclosure. This disclosure
will govern in the instance that there is any inconsistency between
the patents, patent applications and publications cited and this
disclosure.
[0022] For convenience, certain terms employed in the
specification, examples and claims are collected here. Unless
defined otherwise, all technical and scientific terms used in this
disclosure have the same meanings as commonly understood by one of
ordinary skill in the art to which this disclosure belongs.
[0023] The term "salts" as used herein embraces pharmaceutically
acceptable salts commonly used to form alkali metal salts of free
acids and to form addition salts of free bases. The nature of the
salt is not critical, provided that it is pharmaceutically
acceptable. The term "salts" also includes solvates of addition
salts, such as hydrates, as well as polymorphs of addition salts.
Suitable pharmaceutically acceptable acid addition salts can be
prepared from an inorganic acid or from an organic acid. Examples
of such inorganic acids are hydrochloric, hydrobromic, hydroiodic,
nitric, carbonic, sulfuric, and phosphoric acid. Appropriate
organic acids can be selected from aliphatic, cycloaliphatic,
aromatic, arylaliphatic, and heterocyclyl containing carboxylic
acids and sulfonic acids, for example formic, acetic, propionic,
succinic, glycolic, gluconic, lactic, malic, tartaric, citric,
ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic,
benzoic, anthranilic, mesylic, stearic, salicylic,
p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,
toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,
cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric and
galacturonic acid.
[0024] The terms "administer," "administering" or "administration"
as used herein refer to either directly administering a compound or
pharmaceutically acceptable salt of the compound or a composition
to a subject.
[0025] The term "carrier" as used herein encompasses carriers,
excipients, and diluents, meaning a material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient,
solvent or encapsulating material involved in carrying or
transporting a pharmaceutical agent from one organ, or portion of
the body, to another organ or portion of the body.
[0026] The term "disorder" is used in this disclosure to mean, and
is used interchangeably with, the terms disease, condition, or
illness, unless otherwise indicated.
[0027] The terms "effective amount" and "therapeutically effective
amount" are used interchangeably in this disclosure and refer to an
amount of a compound that, when administered to a subject, is
capable of reducing a symptom of a disorder in a subject. The
actual amount which comprises the "effective amount" or
"therapeutically effective amount" will vary depending on a number
of conditions including, but not limited to, the severity of the
disorder, the size and health of the patient, and the route of
administration. A skilled medical practitioner can readily
determine the appropriate amount using methods known in the medical
arts.
[0028] The phrase "pharmaceutically acceptable" as used herein
refers to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0029] As used in this disclosure, the term "subject" includes,
without limitation, a human or an animal. Exemplary animals
include, but are not limited to, mammals such as mouse, rat, guinea
pig, dog, cat, horse, cow, pig, monkey, chimpanzee, baboon, or
rhesus monkey.
[0030] The term "treating" as used herein with regard to a subject,
refers to improving at least one symptom of the subject's disorder.
Treating can be curing, improving, or at least partially
ameliorating a disorder.
Nalbuphine
[0031] Nalbuphine HCl
(17-(cyclobutylmethyl)-4,5.alpha.-epoxymorphinian-3, 6.alpha.,
14-triol, hydrochloride) is currently available only as a generic
medication in an injectable form. An injectable form of nalbuphine
has been available as an approved drug formulation since 1978.
Nubain.RTM. was the innovator brand injectable form of nalbuphine
on which the presently sold generic bioequivalent injectable
formulations are based. The injectable formulation is currently
approved for use in the relief of moderate to severe pain, a
supplement to balanced anesthesia, for pre-operative and
post-operative analgesia and obstetrical analgesia during labor and
delivery.
Opioid Receptors
[0032] There are three classical types of opioid receptors that
have been investigated as the mediators of opiate effects. These
opioid receptors are classified as mu (.mu.), kappa (".kappa.") and
delta (".delta."). Nalbuphine is a derivative of 14-hydroxymorphine
and is structurally related to the opioid receptor agonist
oxymorphone and the opioid .mu.-receptor antagonist naloxone.
Gutstein et al. (Chapter 23: Opioid Analgesics, Goodman &
Gilman's The Pharmacologic Basis of Therapeutics, 10th Ed., McGraw
Hill 2001, pp 569-619) report that nalbuphine exerts its clinical
pharmacologic action by competitively antagonizing the opioid
.mu.-receptor and simultaneously acting as an agonist at the opioid
K-receptor, and thus is a member of the "opioid agonist-antagonist"
class of drugs that mechanistically work through this dual
pharmacologic process. Subsequent in vitro work by Gharagozlou et
al. (Neurosci. 2002 3:19) showed that nalbuphine is in addition a
.delta. opioid receptor antagonist. Gutstein et al. (supra) state
that the stimulus for the development opioid agonist-antagonist
drugs was to identify a drug with analgesic properties with less
respiratory depression and addiction potential.
Nalbuphine in the Treatment of Uremic Pruritus
[0033] In a first aspect, the present invention provides a method
of treating uremic pruritus comprising administering an effective
amount of an anti-pruritus agent to a human patient in need of such
treatment, wherein the anti-pruritus agent is nalbuphine or a
pharmaceutically acceptable salt or ester thereof, and wherein the
anti-pruritus agent is not administered in combination with a
second anti-pruritus agent.
[0034] "Nalbuphine" includes nalbuphine free base, metabolites
thereof, derivatives thereof, solvates thereof (e.g., hydrates,
alcoholates, etc.) and/or pharmaceutically acceptable salts or
esters thereof. Metabolites of nalbuphine include, for example the
glucuronide conjugate metabolite and metabolites resulting from
methylation, oxidation/dehydrogenation, hydroxylation, double
hydroxylation, triple hydroxylation, oxidative methylation,
glucoside conjugation, glucuronide conjugation, and
hydroxyl-glucuronide conjugation of nalbuphine. Exemplary
metabolites can include nornalbuphine, 6-ketonalbuphine, nalbuphine
3-glucuronide. Isomers include the C-6.beta.-epimer of nalbuphine
(Mallinckrodt, Nalbuphine hydrochloride Technical Package August
2003). Derivatives of nalbuphine can include pharmaceutically
acceptable ester prodrugs thereof (including alkoxy esters such as
methoxy and ethoxy esters) which can be hydrolyzed in vivo to
provide nalbuphine, as well as ether or other compounds prepared
by, e.g. reacting the hydroxyl groups of nalbuphine with suitable
protecting agents.
[0035] In one embodiment, nalbuphine suitable for use in the
present methods is in the form of any pharmaceutically acceptable
salt or ester known in the art. Exemplary pharmaceutically
acceptable salts include without limitation hydrochloric, sulfuric,
nitric, phosphoric, hydrobromic, maleic, malic, ascorbic, citric,
tartaric, pamoic, lauric, stearic, palmitic, oleic, myristic,
lauryl sulfuric, napthalinesulfonic, linoleic, linolenic acid, and
the like. In one embodiment the anti-pruritus agent is the
hydrochloride salt of nalbuphine.
[0036] The present invention also includes pharmaceutically
acceptable esters of the anti-pruritic agent. The term "ester"
denotes a derivative of the anti-pruritic agent containing an ester
functional group (as described herein), which is capable of
releasing the anti-pruritic agent when the ester form is
administered to a subject. Release of the active ingredient occurs
in vivo. Pharmaceutically acceptable esters can be prepared by
techniques known to one skilled in the art. These techniques
generally modify appropriate functional groups in a given compound.
These modified functional groups however regenerate original
functional groups by metabolism of the compound in vivo. Esters
include compounds wherein a hydroxy, amino, carboxylic, or a
similar group is modified.
[0037] Suitable pharmaceutically acceptable esters for a hydroxyl
group include inorganic esters such as phosphate esters and
.alpha.-acyloxyalkyl ethers and related compounds which, as a
result of in vivo hydrolysis of the ester, provide the parent
hydroxy group. In vivo hydrolyzable ester forming groups for
hydroxy include alkanoyl (e.g., C.sub.1-10 linear, branched or
cyclic alkyl), benzoyl, phenylacetyl and substituted benzoyl and
phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters),
dialkylcarbamoyl and N--(N,N-dialkylaminoethyl)-N-alkylcarbamoyl
(to give carbamates), N,N-dialkylaminoacetyl and carboxyacetyl.
[0038] Nalbuphine as employed in the present methods can form a
part of a pharmaceutical composition by combining nalbuphine, or a
pharmaceutically acceptable salt or ester thereof, with a
pharmaceutically acceptable carrier. Additionally, the compositions
can include an additive selected from the group consisting of
adjuvants, excipients, diluents, release-modifying agents and
stabilizers. The composition can be an immediate release
formulation, a delayed release formulation, a sustained release
formulation or an extended release formulation.
Formulations
[0039] The methods of the present invention can employ various
formulations for administration to humans and animals in unit
dosage forms, such as tablets, capsules, pills, powders, granules,
sterile parenteral solutions or suspensions, and oral solutions or
suspensions, and oil-water emulsions containing suitable quantities
of an anti-pruritic agent, e.g., nalbuphine, or pharmaceutically
acceptable salts or esters thereof.
[0040] Oral pharmaceutical dosage forms can be either solid or
liquid. The solid dosage forms can be tablets, capsules, granules,
and bulk powders. Types of oral tablets include compressed,
chewable lozenges and tablets which can be enteric-coated,
sugar-coated or film-coated. Capsules can be hard or soft gelatin
capsules, while granules and powders can be provided in
non-effervescent or effervescent form with the combination of other
ingredients known to those skilled in the art. In other
embodiments, the oral dosage form may be an osmotic-controlled
release oral delivery system (OROS). In other embodiments, the oral
dosage form may include matrix-embedded dosage forms or related
devices. In some embodiments, the present oral dosage forms may
include orally-disintegrating tablets.
[0041] Pharmaceutically acceptable carriers utilized in tablets
include binders, lubricants, diluents, disintegrating agents,
coloring agents, flavoring agents, and wetting agents.
[0042] Liquid oral dosage forms include aqueous solutions,
emulsions, suspensions, solutions and/or suspensions reconstituted
from non-effervescent granules and effervescent preparations
reconstituted from effervescent granules.
[0043] Aqueous solutions include, for example, elixirs and syrups.
Emulsions can be either oil-in water or water-in-oil. Elixirs are
clear, sweetened, hydroalcoholic preparations. Pharmaceutically
acceptable carriers used in elixirs include solvents. Syrups can be
concentrated aqueous solutions of a sugar, for example, sucrose,
and can contain a preservative. An emulsion is a two-phase system
in which one liquid is dispersed in the form of small globules
throughout another liquid. Pharmaceutically acceptable carriers
used in emulsions are non-aqueous liquids, emulsifying agents and
preservatives. Suspensions can use pharmaceutically acceptable
suspending agents and preservatives. Pharmaceutically acceptable
substances used in non-effervescent granules, to be reconstituted
into a liquid oral dosage form, include diluents, sweeteners and
wetting agents. Pharmaceutically acceptable substance used in
effervescent granules, to be reconstituted into a liquid oral
dosage form, can include organic acids and a source of carbon
dioxide. Coloring and flavoring agents can be used in all of the
above dosage forms.
[0044] Parenteral administration of the formulations of the present
invention includes intravenous, subcutaneous and intramuscular
administrations. of immediate, sustained (e.g., depot), extended,
and/or modified release formulations (e.g., as described herein).
Preparations for parenteral administration include sterile
solutions ready for injection, sterile dry soluble products ready
to be combined with a solvent just prior to use, including
hypodermic tablets, sterile suspensions ready for injection,
sterile dry insoluble products ready to be combined with a vehicle
just prior to use and sterile emulsions. The solutions can be
either aqueous or nonaqueous. Pharmaceutically acceptable carriers
used in parenteral preparations include aqueous vehicles,
nonaqueous vehicles, antimicrobial agents, isotonic agents,
buffers, antioxidants, local anesthetics, suspending and dispersing
agents, emulsifying agents, sequestering or chelating agents and
other pharmaceutically acceptable substances.
[0045] The concentration of the pharmaceutically active compound
can be adjusted so that an injection provides an effective amount
to produce the desired pharmacological effect. The exact dose
depends on the age, weight and condition of the patient or animal,
as is known in the art. The unit-dose parenteral preparations are
packaged in an ampoule or a syringe with a needle. All preparations
for parenteral administration must be sterile, as is known and
practiced in the art. Illustratively, intravenous or intra-arterial
infusion of a sterile aqueous solution containing an anti-pruritic
agent is an effective mode of administration.
[0046] Pharmaceutical dosage forms for rectal administration can be
rectal suppositories, capsules and tablets for systemic effect.
Rectal suppositories as used herein mean solid bodies for insertion
into the rectum which melt or soften at body temperature releasing
the pharmacologically and/or therapeutically active ingredients
contained in the composition of this invention. Pharmaceutically
acceptable substances utilized in rectal suppositories are bases or
vehicles and agents to raise the melting point. Examples of bases
include cocoa butter (theobroma oil), glycerin-gelatin, carbowax,
polyoxyethylene glycol and mixtures of mono-, di- and triglycerides
of fatty acids. Combinations of the various bases can be used.
Agents to raise the melting point of suppositories include
spermaceti and wax. Rectal suppositories can be prepared either by
the compressed method or by molding. The typical weight of a rectal
suppository is about 2 to 3 gm. Tablets and capsules for rectal
administration can be manufactured using the same pharmaceutically
acceptable substance and by the same methods as for formulations
for oral administration.
[0047] The compositions can be suspended in micronized or other
suitable form or can be derivatized to produce a more soluble
active product. The form of the resulting composition depends upon
a number of factors, including the intended mode of administration
and the solubility of the anti-pruritic agent in the selected
carrier or vehicle. The effective concentration is sufficient for
treating or alleviating uremic pruritus, and can be empirically
determined. The concentration is generally greater than the
concentration for systemic administration of the compound.
[0048] The resulting mixture can be a solution, suspension,
emulsion or the like, and can be formulated as a cream, gel,
ointment, emulsion, solution, elixir, lotion, suspension, tincture,
paste, foam, aerosol, irrigation, spray, suppository, bandage, or
any other formulation suitable for topical or local administration.
Modes of administration can include topical application to the
skin, scalp, eyes, and/or nasal, buccal or sublingual mucosa.
[0049] Pharmaceutical and cosmetic carriers or vehicles suitable
for administration of the compositions include any such carriers
known to those skilled in the art to be suitable for the particular
mode of administration. The anti-pruritic agent can be included in
the carriers in amounts sufficient to exert a therapeutically
useful effect without serious toxic effects on the treated
individual.
[0050] To formulate these compositions, a weight fraction of an
anti-pruritic agent is dissolved, suspended, dispersed or otherwise
mixed in a selected vehicle at an effective concentration such that
the pruritic condition is relieved or ameliorated. Generally,
emollient or lubricating vehicles that help hydrate the skin are
more preferred than volatile vehicles, such as ethanol, that dry
the skin. Examples of suitable bases or vehicles for preparing
compositions for use with human skin are petrolatum, petrolatum
plus volatile silicones, lanolin, cold cream (USP), and hydrophilic
ointment (USP).
[0051] The compositions employed in the present methods can relieve
uremic pruritus when applied to the skin. The composition can be
administered topically to the affected area up to eight times per
day, as needed, to provide reduction in and relief from itching.
Relief can be temporary or permanent, and can even be evident after
a single dose of the composition. When the composition is
administered in a form other than a topical preparation, it should
be administered in an amount sufficient to provide relief from
pruritus that is within safety guidelines established by the FDA
Determining the appropriate amount to administer to a patient is
within the skill of the person of ordinary skill in the art.
[0052] Solutions of the compositions of this invention intended for
topical administration contain an amount of the composition
effective to deliver an anti-pruritic amount, typically at a
concentration of between about 0.01% w/w to about 5% w/w. The
balance of the solution is water, a suitable organic solvent or
other suitable solvent or buffer. These compositions that are
formulated as solutions or suspensions can be applied to the skin,
or can be formulated as an aerosol or foam and applied to the skin
as a spray-on. The aerosol compositions typically contain from 25%
to 80% w/w, preferably from 30% to 50% w/w, of a suitable
propellant. Gel compositions can be formulated by simply admixing a
suitable thickening agent to the solution or suspension.
[0053] Solutions and suspensions can also be topically applied to
the eyes and mucosa. Solutions, particularly those intended for
opthalmic use, can be formulated as 0.01%-10% w/w isotonic
solutions, pH about 5-7, with appropriate salts, and preferably
containing one or more of the compositions herein at a
concentration of about 0.1% w/w, up to about 5% w/w or more.
Suitable ophthalmic solutions are known in the art.
[0054] Compositions of solid forms intended for topical application
can be formulated as stick-type compositions intended for
application to the lips or other parts of the body. Such
compositions contain an effective amount of an anti-pruritic agent,
e.g. nalbuphine or a pharmaceutically acceptable salt or ester
thereof. The amount of the anti-pruritic agent present is typically
from about 0.01% w/w to about 5% w/w. The solids also contain from
about 40% to 98% w/w, preferably from about 50% to 90% w/w, of
emollients. This composition can further contain from 1% to 20%
w/w, preferably from 5% to 15% w/w, of a suitable thickening agent,
and, if desired or needed, emulsifiers and water or buffers.
[0055] In addition, the compositions, and preparations containing
the compositions, can also be coated on bandages, mixed with
bioadhesives, or included in dressings. Thus, combinations of
bandages, bioadhesives, dressings and other such materials and the
compositions formulated as described herein are provided.
Sustained Release Formulations
[0056] Nalbuphine formulations which can be employed in the present
methods include oral sustained release nalbuphine formulations as
described in U.S. Provisional Pat. Appl. Nos. 60/772,466 and
60/710,772; and U.S. patent application Ser. Nos. 11/509,347 and
12/154,496 (published as U.S. Patent Publications 2007/0048376 and
2009/0030026, respectively), each of which is incorporated herein
by reference in their entireties.
[0057] In some embodiments, the present methods can employ oral
sustained release formulations of nalbuphine including an
anti-pruritic effective amount of nalbuphine or a pharmaceutically
acceptable salt or ester thereof. The oral sustained release
formulations can provide a controlled release of the drug over a
longer period than observed for bolus injections or immediate
release oral formulations (e.g., at least about 8-12 hours).
Reducing the frequency of dosing provides the potential for
enhanced patient convenience and compliance with the present
methods. The lower dosing frequency also has the potential to
provide reduced side effects because the patient may be exposed to
lower peak concentrations of drug over time.
[0058] The present methods can employ compositions including
nalbuphine or a pharmaceutically acceptable salt or ester thereof
and a sustained release delivery system. The sustained release
delivery system includes (i) at least one hydrophilic compound, at
least one cross-linking agent, and at least one pharmaceutical
diluent; (ii) at least one hydrophilic compound, at least one
cross-linking agent, at least one pharmaceutical diluent, and at
least one cationic cross-linking agent different from the first
cross-linking agent; or (iii) at least one hydrophilic compound, at
least one cationic cross-linking compound, and at least one
pharmaceutical diluent. Alternatively, in other embodiments, the
present methods can employ compositions including nalbuphine or a
pharmaceutically acceptable salt or ester thereof and a sustained
release delivery system, which may employ a hydrophobic compound in
a sustained release system.
[0059] The nalbuphine can be homogeneously dispersed in the
sustained release delivery system. In some embodiments, the
nalbuphine or pharmaceutically acceptable salt or ester thereof is
present in the composition in an amount of about 1 mg to about 200
mg; about 1 mg to about 150 mg; about 1 mg to about 125 mg; or
about 1 mg to about 100 mg. In some embodiments, the nalbuphine or
pharmaceutically acceptable salt or ester thereof is present in the
composition in an amount of about 5 mg to about 80 mg; about 10 mg
to about 70 mg; about 15 mg to about 60 mg; about 40 mg to about 80
mg; about 50 mg to about 70 mg; or about 45 mg to about 60 mg. In
one embodiment, the nalbuphine or pharmaceutically acceptable salt
or ester thereof is present in the composition in an amount of
about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg,
about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg,
about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,
about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130
mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about
180 mg, about 190 mg, or about 200 mg. In another embodiment, the
nalbuphine or pharmaceutically acceptable salt thereof is present
in the composition in an amount of about 30 mg, about 45 mg, about
60 mg, about 120 mg, or about 180 mg.
[0060] In some embodiments, the sustained release delivery system
is present in the composition in an amount from about 10 mg to
about 420 mg; from about 25 mg to about 225 mg; from about 21 mg to
about 198 mg; or from about 80 mg to about 200 mg; from about 80 mg
to about 220 mg; from about 90 mg to about 210 mg; from about 100
mg to about 200 mg; from about 110 mg to about 190 mg; from about
120 mg to about 180 mg; from about 130 mg to about 170 mg; from
about 140 mg to about 160 mg; from about 30 mg to about 60 mg; from
about 60 mg to about 180 mg; from about 30 mg to about 180 mg, from
about 75 mg to about 150 mg, from about 80 mg to about 160 mg, from
about 90 mg to about 150 mg, from about 100 mg to about 140 mg,
from about 110 mg to about 130 mg, from about 100 mg to about 300
mg, from about 200 mg to about 300 mg or from about 200 mg to about
250 mg. In one embodiment, the sustained release delivery system is
present in the composition in an amount from about 75 mg to about
150 mg.
[0061] In some embodiments, the sustained release delivery system
is present in the composition in an amount of about 30 mg, about 60
mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110
mg, about 112 mg, about 115 mg, about 117 mg, about 120 mg, about
125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg,
about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190
mg, about 200 mg, about 210 mg, about 220 mg, about 225 mg, about
230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg,
about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360
mg, about 380 mg, about 400 mg or about 420 mg. In another
embodiment, the sustained release delivery system is present in the
composition in an amount of about 112 mg.
[0062] The ratio of nalbuphine or pharmaceutically acceptable salt
or ester thereof in the compositions to the sustained release
delivery system is generally from about 4:1 to about 1:25. In some
embodiments, the ratio of nalbuphine or pharmaceutically acceptable
salt or ester thereof to the sustained release delivery system is
generally from about 2.5:1 to about 1:4. In some embodiments, the
ratio of nalbuphine or pharmaceutically acceptable salt or ester
thereof to the sustained release delivery system is generally from
about 5:1 to about 1:5, about 4:1 to about 1:4, about 3:1 to about
1:3, about 2:1 to about 1:2, about 1:1 to about 1:5, about 1:1 to
about 1:4, about 1:1 to about 1:3, about 1:1 to about 1.2, and
about 1:2 to about 1:3. In some embodiments, the ratio of
nalbuphine or pharmaceutically acceptable salt or ester thereof to
the sustained release delivery system is about 1:1, about 1:2,
about 1:2.5, about 1:3, about 1:4, or about 1:5.
[0063] In one embodiment, at least one hydrophilic compound is
present in the sustained release delivery system in an amount of
about 5% to about 80% by weight; the at least one cross-linking
agent is present in the sustained release delivery system in an
amount of about 0.5% to about 80% by weight; and the at least one
pharmaceutical diluent is present in the sustained release delivery
system in an amount of about 20% to about 80% by weight. In another
embodiment, the at least one hydrophilic compound is present in the
sustained release delivery system in an amount of about 8% to about
31% by weight; the at least one cross-linking agent is present in
the sustained release delivery system in an amount of about 12% to
about 47% by weight; and the at least one pharmaceutical diluent is
present in the sustained release delivery system in an amount of
about 20% to about 78% by weight. In another embodiment, the at
least one hydrophilic compound is present in the sustained release
delivery system in an amount of about 10% to about 20% by weight;
the at least one cross-linking agent is present in the sustained
release delivery system in an amount of about 15% to about 25% by
weight; and the at least one pharmaceutical diluent is present in
the sustained release delivery system in an amount of about 50% to
about 85% by weight. In some embodiments, the at least one
hydrophilic compound is present in the sustained release delivery
system in an amount of about 8%, about 9%, about 10%, about 11%,
about 12%, about 13%, about 14%, about 15%, about 16%, about 17%,
about 18%, about 19%, about 20%, about 22%, about 24%, about 26%,
about 28%, about 30%, about 32%, about 34%, or about 36% by weight;
the at least one cross-linking agent is present in the sustained
release delivery system in an amount of about 10%, about 11%, about
12%, about 13%, about 14%, about 15%, about 16%, about 17%, about
18%, about 19%, about 20%, about 22%, about 24%, about 26%, about
28%, about 30%, about 32%, about 33%, about 34%, or about 35% by
weight; and the at least one pharmaceutical diluent is present in
the sustained release delivery system in an amount of about 40%,
about 45%, about 50%, about 55%, about 60%, about 65%, about 70%,
about 80%, or about 85% by weight.
[0064] In some embodiments, the at least one hydrophilic compound
is present in the sustained release delivery system in an amount of
about 10%, about 11%, about 12%, about 13%, about 14%, about 15%,
about 16%, about 17%, about 18%, about 19%, or about 20% by weight;
the at least one cross-linking agent is present in the sustained
release delivery system in an amount of about 15%, about 16%, about
17%, about 18%, about 19%, about 20%, or about 22% by weight; and
the at least one pharmaceutical diluent is present in the sustained
release delivery system in an amount of about 55%, about 60%, about
65%, about 70%, about 80%, or about 85% by weight. In one
embodiment, the at least one hydrophilic compound is present in the
sustained release delivery system in an amount of about 8%, about
12%, or about 20% by weight; the at least one cross-linking agent
is present in the sustained release delivery system in an amount of
about 12%, about 18%, or about 30% by weight; and the at least one
pharmaceutical diluent is present in the sustained release delivery
system in an amount of about 40%, about 60%, or about 70% by
weight.
[0065] In one embodiment, nalbuphine is in the form of any
pharmaceutically acceptable salt known in the art. Exemplary
pharmaceutically acceptable salts include without limitation
hydrochloric, sulfuric, nitric, phosphoric, hydrobromic, maleric,
malic, ascorbic, citric, tartaric, pamoic, lauric, stearic,
palmitic, oleic, myristic, lauryl sulfuric, napthalinesulfonic,
linoleic, linolenic acid, and the like. One embodiment includes the
hydrochloride salt of nalbuphine.
[0066] The sustained release delivery system includes at least one
hydrophilic compound. The hydrophilic compound preferably forms a
gel matrix that releases the nalbuphine or the pharmaceutically
acceptable salt or ester thereof at a sustained rate upon exposure
to liquids. The rate of release of the nalbuphine or the
pharmaceutically acceptable salt or ester thereof from the gel
matrix depends on the drug's partition coefficient between the
components of the gel matrix and the aqueous phase within the
gastrointestinal tract. The weight ratio of nalbuphine to
hydrophilic compound is generally in the range of about 10:1 to
about 1:10, about 9:1 to about 1:9, about 8:1 to about 1:8, about
7:1 to about 1:7, about 6:1 to about 1:6, about 5:1 to about 1:5,
about 4:1 to about 1:4, about 3:1 to about 1:3, and about 2:1 to
about 1:2. In some embodiments, the weight ratio of nalbuphine to
hydrophilic compound is in the range of about 10:1 to about 1:1,
about 10:1 to about 2:1, about 9:1 to about 1:1, about 8:1 to about
1:1, about 7:1 to about 1:1, about 6:1 to about 1:1, about 5:1 to
about 1:1, about 4:1 to about 1:1, about 3:1 to about 1:1, and
about 2:1 to about 1:1. In some embodiments, the weight ratio of
nalbuphine to hydrophilic compound is in the range of about 6:1 to
about 1:1, about 5:1 to about 2:1, about 4:1 to about 3:1, about
4:1 to about 2:1, and about 5:1 to about 2:1. In some embodiments,
the weight ratio of nalbuphine to hydrophilic compound is about
1:5, about 1:4.5, about 1:4.4, about 1:4, about 1:3.5, about 1:3.3,
about 1:3, about 1:2.5, about 1:2, about 1:1, and about 1:1.5.
[0067] The sustained release delivery system generally includes the
hydrophilic compound in an amount of about 5% to about 80% by
weight. In some embodiments, the sustained release delivery system
generally includes the hydrophilic compound in an amount of about
5% to about 30%, about 8% to about 31%, about 10% to about 20%,
about 20% to about 60%, or about 40% to about 60% by weight. In one
embodiment, the sustained release delivery system includes the
hydrophilic compound in an amount of about 8% to about 31% by
weight. In one embodiment, the sustained release delivery system
includes the hydrophilic compound in an amount of about 10% to
about 20% by weight. In some embodiments, the sustained release
delivery system includes the hydrophilic compound in an amount of
about 10%, about 11%, about 12%, about 13%, about 14%, about 15%,
about 16%, about 17%, about 18%, about 19%, or about 20% by weight.
In one embodiment, the sustained release delivery system includes
the hydrophilic compound in an amount of about 12% by weight. In
one embodiment, the sustained release delivery system includes the
hydrophilic compound in an amount of about 8% by weight. In one
embodiment, the sustained release delivery system includes the
hydrophilic compound in an amount of about 20% by weight. In one
embodiment, the sustained release delivery system includes the
hydrophilic compound in an amount of about 28% by weight.
[0068] The hydrophilic compound is any compound known in the art to
be hydrophilic. Exemplary hydrophilic compounds include without
limitation gums, cellulose ethers, polyvinyl pyrrolidone,
protein-derived compounds, and mixtures thereof. Exemplary gums
include without limitation heteropolysaccharide gums and
homopolysaccharide gums, such as xanthan, tragacanth, pectins,
acacia, karaya, alginates, agar, guar, hydroxypropyl guar,
carrageenan, locust bean gums, and gellan gums. Exemplary cellulose
ethers include without limitation hydroxyalkyl celluloses and
carboxyalkyl celluloses. In some embodiments, cellulose ethers
include hydroxyethyl celluloses, hydroxypropyl celluloses,
hydroxypropylmethyl-celluloses, carboxy methylcelluloses, and
mixtures thereof. In some embodiments, the hydrophilic compound is
a gum. In other embodiments, the hydrophilic compound is a
heteropolysaccharide gum. In further embodiments, the hydrophilic
compound is a xanthan gum or derivative thereof. Derivatives of
xanthan gum include without limitation, for example, deacylated
xanthan gum, the carboxymethyl esters of xanthan gum, and the
propylene glycol esters of xanthan gum.
[0069] In another aspect, the sustained release delivery system
further includes at least one cross-linking agent. In one
embodiment, the cross-linking agent is a compound that is capable
of cross-linking the hydrophilic compound to form a gel matrix in
the presence of liquids. As used herein, "liquids" includes, for
example, gastrointestinal fluids and aqueous solutions, such as
those used for in vitro dissolution testing. The sustained release
delivery system generally includes the cross-linking agent in an
amount of about 0.5% to about 80% by weight. In one embodiment, the
sustained release delivery system generally includes the
cross-linking agent in an amount of about 12% to about 47% by
weight. In another embodiment, the sustained release delivery
system generally includes the cross-linking agent in an amount of
about 20% to about 30% by weight. In one embodiment, the sustained
release delivery system generally includes the cross-linking agent
in an amount of about 15% to about 25% by weight. In some
embodiments, the at least one cross-linking agent is present in the
sustained release delivery system in an amount of about 15%, about
16%, about 17%, about 18%, about 19%, about 20%, about 21%, about
22%, about 23%, about 24%, or about 25% by weight. In one
embodiment, the sustained release delivery system includes the
cross-linking agent in an amount of about 18% by weight. In one
embodiment, the sustained release delivery system includes the
cross-linking agent in an amount of about 12% by weight. In one
embodiment, the sustained release delivery system includes the
cross-linking agent in an amount of about 30% by weight. In one
embodiment, the sustained release delivery system includes the
cross-linking agent in an amount of about 42% by weight.
[0070] Exemplary cross-linking agents include homopolysaccharides.
Exemplary homopolysaccharides include without limitation
galactomannan gums, such as guar gum, hydroxypropyl guar gum, and
locust bean gum. In some embodiments, the cross-linking agent is a
locust bean gum or a guar gum. In other embodiments, the
cross-linking agent is an alginic acid derivative or
hydrocolloid.
[0071] In some embodiments, when the sustained release delivery
system includes at least one hydrophilic compound and at least one
cross-linking agent, the weight ratio of hydrophilic compound to
cross-linking agent is from about 1:9 to about 9:1, about 1:8 to
about 8:1, about 1:7 to about 7:1, about 1:6 to about 6:1, about
1:5 to about 5:1, about 1:4 to about 4:1, about 1:3 to about 3:1,
or about 1:2 to about 2:1. In some embodiments, the weight ratio of
hydrophilic compound to cross-linking agent is about 1:5, about
1:4.5, about 1:4, about 1:3.5, about 1:3, about 1:2.5, about 1:2,
about 1:1.5, and about 1:1.
[0072] When the sustained release delivery system includes at least
one hydrophilic compound and at least one cross-linking agent, the
weight ratio of the nalbuphine or pharmaceutically acceptable salt
or ester thereof to the sum of the at least one hydrophilic
compound and the at least one cross-linking agent is from about
10:1 to about 1:10, from about 9:1 to about 1:9, from about 8:1 to
about 1:8, from about 7:1 to about 1:7, from about 6:1 to about
1:6, from about 5:1 to about 1:5, from about 4:1 to about 1:4, from
about 3:1 to about 1:3, or from about 2:1 to about 1:2. In some
embodiments, the weight ratio of the nalbuphine or pharmaceutically
acceptable salt or ester thereof to the sum of the at least one
hydrophilic compound and the at least one cross-linking agent is
from about 4:1 to about 1:1, from about 4:1 to about 1:1.5, from
about 3:1 to about 1:1, or from about 2:1 to about 1:1. In one
embodiment, the ratio of the nalbuphine or pharmaceutically
acceptable salt or ester thereof to the sum of the at least one
hydrophilic compound and the at least one cross-linking agent is
about 5:1, about 4:1 (i.e., 1:0.25), about 3.5:1, about 3:1, about
2.5:1, about 2:1 (i.e., 1:0.5), about 1.9:1, about 1.8:1, about
1.7:1, about 1.6:1, about 1.5:1, about 1.4:1, about 1.3:1, about
1.2:1, about 1.1:1, about 1:1, about 1:1.5, about 1:2, about 1:3,
about 1:4, and about 1:5.
[0073] The sustained release delivery system further includes one
or more pharmaceutical diluents known in the art. Exemplary
pharmaceutical diluents include without limitation monosaccharides,
disaccharides, polyhydric alcohols and mixtures thereof. In some
embodiments, pharmaceutical diluents include, for example, starch,
mannitol, lactose, dextrose, sucrose, microcrystalline cellulose,
sorbitol, xylitol, fructose, and mixtures thereof. In some
embodiments, the pharmaceutical diluent is water-soluble.
Nonlimiting examples of water-soluble pharmaceutical diluents
include lactose, dextrose, sucrose, or mixtures thereof. The weight
ratio of pharmaceutical diluent to hydrophilic compound is
generally from about 1:9 to about 9:1, from about 1:8 to about 8:1,
from about 1:7 to about 7:1, from about 1:6 to about 6:1, from
about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3
to about 3:1, or from about 1:2 to about 2:1. In some embodiments,
the weight ratio of pharmaceutical diluent to hydrophilic compound
is generally from about 9:1 to about 1:1.5. In some embodiments,
the weight ratio of pharmaceutical diluent to hydrophilic compound
is about 9:1, about 8.75:1, about 8.5:1, about 8.25:1, about 8:1,
about 7.5:1, about 7:1, about 6.5:1, about 6:1, about 5.5:1, about
5:1, about 4.5:1, about 4:1, about 3.5:1, about 3:1, about 2.5:1,
about 2:1, about 1.5:1, or about 1:1.
[0074] The sustained release delivery system generally includes one
or more pharmaceutical diluents in an amount of about 20% to about
80%, about 30% to about 70%, about 40% to about 70%, or about 40%
to about 60%. In one embodiment, the sustained release delivery
system includes one or more pharmaceutical diluents in an amount of
about 20% to about 70% by weight. In one embodiment, the sustained
release delivery system includes one or more pharmaceutical
diluents in an amount of about 50% to about 85% by weight. In some
embodiments, the sustained release delivery system includes one or
more pharmaceutical diluents in an amount of about 55%, about 60%,
about 65%, about 70%, about 80%, or about 85% by weight. In one
embodiment, the sustained release delivery system includes one or
more pharmaceutical diluents in an amount of about 20% by weight.
In one embodiment, the sustained release delivery system includes
one or more pharmaceutical diluents in an amount of about 30% by
weight. In one embodiment, the sustained release delivery system
includes one or more pharmaceutical diluents in an amount of about
40% by weight. In one embodiment, the sustained release delivery
system includes one or more pharmaceutical diluents in an amount of
about 50% by weight. In one embodiment, the sustained release
delivery system includes one or more pharmaceutical diluents in an
amount of about 60% by weight. In one embodiment, the sustained
release delivery system includes one or more pharmaceutical
diluents in an amount of about 70% by weight.
[0075] In a further aspect, the sustained release delivery system
includes one or more cationic cross-linking compounds. In some
embodiments, the one or more cationic cross-linking compounds are
used instead of the cross-linking agent. In some embodiments, the
one or more cationic cross-linking compounds are used in addition
to the cross-linking agent. In one embodiment, the one or more
cationic cross-linking compounds are used in an amount sufficient
to cross-link the hydrophilic compound to form a gel matrix in the
presence of liquids. In some embodiments, the one or more cationic
cross-linking compounds are present in the sustained release
delivery system in an amount of about 0.5% to about 30%, about 0.5%
to about 25%, about 0.5% to about 20%, about 0.5% to about 15%,
about 0.5% to about 10%, or about 0.5% to about 5% by weight. In
some embodiments, the one or more cationic cross-linking compounds
are present in the sustained release delivery system in an amount
of about 5% to about 20%, about 5% to about 15%, about 6% to about
14%, about 7% to about 13%, about 8% to about 12%, or about 9% to
about 11% by weight. In some embodiments, the one or more cationic
cross-linking compounds are present in the sustained release
delivery system in an amount of about 5%, about 6%, about 7%, about
8%, about 9%, about 10%, about 11%, about 12%, about 13%, about
14%, or about 15% by weight. In one embodiment, the cationic
cross-linking compound is present in the sustained release delivery
system in an amount of about 10% by weight.
[0076] Exemplary cationic cross-linking compounds include without
limitation monovalent metal cations, multivalent metal cations, and
inorganic salts, including alkali metal and/or alkaline earth metal
sulfates, chlorides, borates, bromides, citrates, acetates,
lactates, and mixtures thereof. For example, the cationic
cross-linking compound include without limitation one or more of
calcium sulfate, sodium chloride, potassium sulfate, sodium
carbonate, lithium chloride, tripotassium phosphate, sodium borate,
potassium bromide, potassium fluoride, sodium bicarbonate, calcium
chloride, magnesium chloride, sodium citrate, sodium acetate,
calcium lactate, magnesium sulfate, sodium fluoride, or mixtures
thereof.
[0077] When the sustained release delivery system includes at least
one hydrophilic compound and at least one cationic cross-linking
compound, the weight ratio of hydrophilic compound to cationic
cross-linking compound ranges from about 1:9 to about 9:1, from
about 1:8 to about 8:1, from about 1:7 to about 7:1, from about 1:6
to about 6:1, from about 1:5 to about 5:1, from about 1:4 to about
4:1, from about 1:3 to about 3:1, or from about 1:2 to about 2:1.
In one embodiment, the weight ratio of hydrophilic compound to
cationic cross-linking compound ranges from about 1:3 to about 3:1.
In some embodiments, the weight ratio of hydrophilic compound to
cationic cross-linking compound is about 3:1, about 2.75:1, about
2.5:1, about 2.25:1, about 2:1, about 1.8:1, about 1.6:1, about
1.4:1, about 1.2:1, about 1:1, about 1:1.25, about 1:1.5, or about
1:2. In one embodiment, the weight ratio of hydrophilic compound to
cationic cross-linking compound is about 1:1.25. In one embodiment,
the weight ratio of hydrophilic compound to cationic cross-linking
compound is about 1.2:1. In one embodiment, the weight ratio of
hydrophilic compound to cationic cross-linking compound is about
2:1. In one embodiment, the weight ratio of hydrophilic compound to
cationic cross-linking compound is about 2.8:1.
[0078] In one embodiment, the at least one hydrophilic compound is
present in the sustained release delivery system in an amount of
about 5% to about 80% by weight; the at least one cationic
cross-linking agent is present in the sustained release delivery
system in an amount of about 0.5% to about 30% by weight; and the
at least one pharmaceutical diluent is present in the sustained
release delivery system in an amount of about 20% to about 80% by
weight. In another embodiment, the at least one hydrophilic
compound is present in the sustained release delivery system in an
amount of about 8% to about 30% by weight; the at least one
cationic cross-linking agent is present in the sustained release
delivery system in an amount of about 10% by weight; and the at
least one pharmaceutical diluent is present in the sustained
release delivery system in an amount of about 20% to about 70% by
weight. In another embodiment, the at least one hydrophilic
compound is present in the sustained release delivery system in an
amount of about 5% to about 30% by weight; the at least one
cationic cross-linking agent is present in the sustained release
delivery system in an amount of about 5% to about 20% by weight;
and the at least one pharmaceutical diluent is present in the
sustained release delivery system in an amount of about 20% to
about 85% by weight. In another embodiment, the at least one
hydrophilic compound is present in the sustained release delivery
system in an amount of about 10% to about 20% by weight; the at
least one cationic cross-linking agent is present in the sustained
release delivery system in an amount of about 5% to about 15% by
weight; and the at least one pharmaceutical diluent is present in
the sustained release delivery system in an amount of about 50% to
about 85% by weight.
[0079] In some embodiments, the at least one hydrophilic compound
is present in the sustained release delivery system in an amount of
about 8%, about 9%, about 10%, about 11%, about 12%, about 13%,
about 14%, about 15%, about 16%, about 17%, about 18%, about 19%,
about 20%, about 22%, about 24%, about 26%, about 28%, or about 30%
by weight; the at least one cationic cross-linking agent is present
in the sustained release delivery system in an amount of about 5%,
about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about
12%, about 13%, about 14%, about 15%, about 16%, about 17%, about
18%, about 19%, or about 20%, by weight; and the at least one
pharmaceutical diluent is present in the sustained release delivery
system in an amount of about 40%, about 45%, about 50%, about 55%,
about 60%, about 65%, about 70%, about 80%, or about 85% by weight.
In one embodiment, the at least one hydrophilic compound is present
in the sustained release delivery system in an amount of about 10%,
about 11%, about 12%, about 13%, about 14%, about 15%, about 16%,
about 17%, about 18%, about 19%, or about 20% by weight; the at
least one cationic cross-linking agent is present in the sustained
release delivery system in an amount of about 5%, about 6%, about
7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%,
about 14%, about 15%, by weight; and the at least one
pharmaceutical diluent is present in the sustained release delivery
system in an amount of about 55%, about 60%, about 65%, about 70%,
about 80%, or about 85% by weight. In one embodiment, the at least
one hydrophilic compound is present in the sustained release
delivery system in an amount of about 8%, about 12%, or about 20%
by weight; the at least one cationic cross-linking agent is present
in the sustained release delivery system in an amount of about 10%,
about 12%, or about 14% by weight; and the at least one
pharmaceutical diluent is present in the sustained release delivery
system in an amount of about 40%, about 60%, or about 70% by
weight.
[0080] In one embodiment, the sustained release delivery system
includes about 0.5% to about 80% locust bean gum, about 5% to about
80% xanthan gum, about 20% to about 80% mannitol and about 0.5% to
80% calcium sulfate dihydrate. In one embodiment, the sustained
release delivery system includes about 12% to about 47% locust bean
gum, about 8% to about 31% xanthan gum, about 20% to about 78%
mannitol and about 0.5% to 25% calcium sulfate dihydrate. In one
embodiment, the sustained release delivery system includes about
15% to about 25% locust bean gum, about 10% to about 20% xanthan
gum, about 50% to about 85% mannitol and about 5% to 15% calcium
sulfate dihydrate. In one embodiment, the sustained release
delivery system includes about 18% locust bean gum, about 12%
xanthan gum, about 60% mannitol and about 10% calcium sulfate
dihydrate. In one embodiment, the sustained release delivery system
includes about 12% locust bean gum, about 8% xanthan gum, about 70%
mannitol and about 10% calcium sulfate dihydrate. In one
embodiment, the sustained release delivery system includes about
20% locust bean gum, about 30% xanthan gum, about 40% mannitol and
about 10% calcium sulfate dihydrate. In one embodiment, the
sustained release delivery system includes about 30% locust bean
gum, about 20% xanthan gum, about 40% mannitol and about 10%
calcium sulfate dihydrate. In one embodiment, the sustained release
delivery system includes about 42% locust bean gum, about 28%
xanthan gum, about 20% mannitol and about 10% calcium sulfate
dihydrate.
[0081] Two properties of the components of this sustained release
system (e.g., the at least one hydrophilic compound and the at
least one cross-linking agent; or the at least one hydrophilic
compound and at least one cationic cross-linking compound) are that
it forms a gel matrix upon exposure to liquids are fast hydration
of the compounds/agents and the ability to form a gel matrix having
a high gel strength. These two properties, which are needed to
achieve a slow release gel matrix, are maximized by the particular
combination of compounds (e.g., the at least one hydrophilic
compound and the at least one cross-linking agent; or the at least
one hydrophilic compound and the at least one cationic
cross-linking compound). For example, hydrophilic compounds (e.g.,
xanthan gum) have excellent water-wicking properties that provide
fast hydration. The combination of hydrophilic compounds with
materials that are capable of cross-linking the rigid helical
ordered structure of the hydrophilic compound (e.g., cross-linking
agents and/or cationic cross-linking compounds) thereby acts
synergistically to provide a higher than expected viscosity (i.e.,
high gel strength) of the gel matrix.
[0082] In some embodiments, the sustained release compositions are
further admixed with one or more wetting agents (e.g.,
polyethoxylated castor oil, polyethoxylated hydrogenated castor
oil, polyethoxylated fatty acid from castor oil, polyethoxylated
fatty acid from hydrogenated castor oil) one or more lubricants
(e.g., magnesium stearate, sodium stearyl fumarate, and the like),
one or more buffering agents, one or more colorants, and/or other
conventional ingredients.
[0083] In some embodiments compositions employed in the present
methods can contain additional pharmaceutical excipients. For
example, in certain embodiments, fumaric acid can be added to the
formulations described herein.
[0084] In other embodiments, a non-functional coating, e.g.,
Opadry.RTM., can be added to the compositions described herein.
[0085] In some embodiments, the compositions described herein
further include a second hydrophilic compound. In some embodiments,
the second hydrophilic compound is a cellulose ether. In some
embodiments, the second hydrophilic compound is a hydroxyalkyl
cellulose or a carboxyalkyl cellulose. In some embodiments, the
second hydrophilic compound is a hydroxyethyl cellulose, a
hydroxypropyl cellulose, a hydroxypropylmethyl-cellulose, a carboxy
methylcellulose, or a mixture thereof. In some embodiments, the
second hydrophilic is an ethyl cellulose or wax (e.g., including
without limitation cetyl alcohol, stearyl alcohol, white wax, or
carnauba wax). The second hydrophilic compound is present in the
formulation in an amount ranging from about 5% to about 45%, about
5% to about 25%, about 10% to about 20%, or 12% to about 18% by
weight. In some embodiments, the second hydrophilic compound is
present in the formulation in an amount of about 5%, about 6%,
about 7%, about 8%, about 9%, about 10%, about 11%, about 12%,
about 13%, about 14%, about 15%, about 16%, about 17%, about 18%,
about 19%, about 20%, about 21%, about 22%, about 23%, about 24%,
about 25%, about 30%, about 35%, about 40%, or about 45%.
[0086] In some embodiments, the weight ratio of the second
hydrophilic compound to the nalbuphine or pharmaceutically
acceptable salt or ester ranges from about 5:1 to about 1:5, about
4:1 to about 1:4, about 3:1 to about 1:3, about 2:1 to about 1:2,
about 1:1 to about 1:3, or about 1:1 to about 1:2. In some
embodiments, the weight ratio of the second hydrophilic compound to
the nalbuphine or pharmaceutically acceptable salt or ester is
about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2,
about 1:3, about 1:4, or about 1:5.
[0087] In some embodiments, the weight ratio of the second
hydrophilic compound to the sustained release delivery system
ranges from about 10:1 to about 1:10, about 8:1 to about 1:8, about
6:1 to about 1:6, about 4:1 to about 1:4, about 2:1 to about 1:3,
about 1:1 to about 1:10, about 1:1 to about 1:6, or about 1:2 to
about 1:6. In some embodiments, the weight ratio of the second
hydrophilic compound to the sustained release delivery system is
about 10:1, about 8:1, about 6:1, about 4:1, about 2:1, about 1:1,
about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:4, about
1:5, about 1:6, about 1:7, about 1:8, about 1:9 or about 1:10.
[0088] In some embodiments, the oral sustained release solid dosage
formulations including from about 1 mg to 200 mg nalbuphine
hydrochloride and about 10 mg to about 420 mg of a sustained
release delivery system. In these embodiments, the sustained
release delivery system includes about 12% to about 42% locust bean
gum; about 8.0% to about 28% xanthan gum; about 20% to about 70%
mannitol; and about 5% to about 20% calcium sulfate dihydrate. In
some embodiments, the present methods can employ oral sustained
release solid dosage formulations including from about 5 mg to
about 80 mg nalbuphine hydrochloride and about 80 mg to about 360
mg of a sustained release delivery system. In some embodiments, the
present methods can employ oral sustained release solid dosage
formulations including from about 50 mg to about 150 mg nalbuphine
hydrochloride and about 100 mg to about 300 mg of a sustained
release delivery system.
[0089] In some embodiments, the present methods employ oral
sustained release solid dosage formulations including about 15 mg
nalbuphine hydrochloride, and from about 25 mg to about 225 mg, for
example about 195 mg, of a sustained release delivery system. In
these embodiments, the sustained release delivery system includes
about 14% locust bean gum; about 9% xanthan gum; about 47%
mannitol; and about 8% calcium sulfate dihydrate.
[0090] In some embodiments, the present methods employ oral
sustained release solid dosage formulations including about 30 mg
nalbuphine hydrochloride, and from about 25 mg to about 225 mg, for
example about 180 mg, of a sustained release delivery system. In
these embodiments, the sustained release delivery system includes
about 18% locust bean gum; about 12% xanthan gum; about 60%
mannitol; and about 10% calcium sulfate dihydrate.
[0091] In some embodiments, the present methods employ oral
sustained release solid dosage formulations including about 60 mg
nalbuphine hydrochloride, and from about 25 mg to about 225 mg, for
example about 120 mg, of a sustained release delivery system. In
these embodiments, the sustained release delivery system includes
about 10% locust bean gum; about 12% xanthan gum; about 60%
mannitol; and about 10% calcium sulfate dihydrate. In some
embodiments, the present methods employ oral sustained release
solid dosage formulations including from about 5 mg to about 80 mg
nalbuphine hydrochloride and about 80 mg to about 360 mg of a
sustained release delivery system.
[0092] In some embodiments, the present methods employ oral
sustained release solid dosage formulations including about 120 mg
nalbuphine hydrochloride, and from about 25 mg to about 250 mg, for
example about 240 mg, of a sustained release delivery system. In
these embodiments, the sustained release delivery system includes
about 18% locust bean gum; about 12% xanthan gum; about 60%
mannitol; and about 10% calcium sulfate dihydrate.
[0093] In some embodiments, the present methods employ oral
sustained release solid dosage formulations including about 30 mg
nalbuphine hydrochloride, and from about 25 mg to about 350 mg, for
example about 270 mg or about 360 mg, of a sustained release
delivery system. In these embodiments, the sustained release
delivery system includes about 18% locust bean gum; about 12%
xanthan gum; about 60% mannitol; and about 10% calcium sulfate
dihydrate.
[0094] In some embodiments, the present methods employ oral
sustained release solid dosage formulations including about 45 to
about 60 mg nalbuphine hydrochloride and from about 100 mg to about
200 mg of a sustained release delivery system. In these
embodiments, the sustained release delivery system includes about
15% to about 25% locust bean gum; about 10% to about 20% xanthan
gum; about 50% to about 85% mannitol; and about 5% to about 15%
calcium sulfate dihydrate.
[0095] In some embodiments, the present methods employ oral
sustained release solid dosage formulations including about 30 mg
nalbuphine hydrochloride, about 32.4 mg locust bean gum; about 21.6
mg xanthan gum; about 108 mg mannitol; about 18 mg calcium sulfate
dihydrate, about 35 mg hydroxypropylcellulose, and about 1.9 mg
magnesium stearate.
[0096] In some embodiments, the present methods employ oral
sustained release solid dosage formulations including about 60 mg
nalbuphine hydrochloride, about 21.6 mg locust bean gum; about 14.4
mg xanthan gum; about 72 mg mannitol; about 12 mg calcium sulfate
dihydrate, about 30 mg hydroxypropylcellulose, and about 1.6 mg
magnesium stearate.
[0097] In some embodiments, the present methods employ oral
sustained release solid dosage formulations including about 120 mg
nalbuphine hydrochloride, about 43.2 mg locust bean gum; about 28.8
mg xanthan gum; about 144 mg mannitol; about 24 mg calcium sulfate
dihydrate, about 60 mg hydroxypropylcellulose, and about 3.2 mg
magnesium stearate.
[0098] In some embodiments, the present methods employ oral
sustained release solid dosage formulations including about 180 mg
nalbuphine hydrochloride, about 64.8 mg locust bean gum; about 43.2
mg xanthan gum; about 216 mg mannitol; about 36 mg calcium sulfate
dihydrate, about 90 mg hydroxypropylcellulose, about 5 mg magnesium
stearate, and about 25 mg fumaric acid.
[0099] In some embodiments, the present methods employ oral
sustained release solid dosage formulations including about 180 mg
nalbuphine hydrochloride, about 48.6 mg locust bean gum; about 32.4
mg xanthan gum; about 162 mg mannitol; about 27 mg calcium sulfate
dihydrate, about 60 mg hydroxypropylcellulose, about 4 mg magnesium
stearate, and about 25 mg fumaric acid.
[0100] The sustained release formulations of nalbuphine are orally
administrable solid dosage formulations. Nonlimiting examples of
oral solid dosage formulations include tablets, capsules including
a plurality of granules, sublingual tablets, powders, granules,
syrups, and buccal dosage forms or devices (e.g., buccal patches,
tablets, etc.). In some embodiments, tablets have an enteric
coating or a hydrophilic coating.
[0101] The sustained release delivery system is prepared by dry
granulation or wet granulation, before the nalbuphine or
pharmaceutically acceptable salt or ester thereof is added,
although the components can be held together by an agglomeration
technique to produce an acceptable product. In the wet granulation
technique, the components (e.g., hydrophilic compounds,
cross-linking agents, pharmaceutical diluents, cationic
cross-linking compounds, hydrophobic polymers, etc.) are mixed
together and then moistened with one or more liquids (e.g., water,
propylene glycol, glycerol, alcohol) to produce a moistened mass
that is subsequently dried. The dried mass is then milled with
conventional equipment into granules of the sustained release
delivery system. Thereafter, the sustained release delivery system
is mixed in the desired amounts with the nalbuphine or the
pharmaceutically acceptable salt or ester thereof and, optionally,
one or more wetting agents, one or more lubricants, one or more
buffering agents, one or more coloring agents, one or more second
hydrophilic compounds, or other conventional ingredients, to
produce a granulated composition. The sustained release delivery
system and the nalbuphine can be blended with, for example, a high
shear mixer. The nalbuphine is preferably finely and homogeneously
dispersed in the sustained release delivery system. The granulated
composition, in an amount sufficient to make a uniform batch of
tablets, is subjected to tableting in a conventional production
scale tableting machine at typical compression pressures, i.e.,
about 2,000-16,000 psi. In some embodiments, the mixture should not
be compressed to a point where there is subsequent difficulty with
hydration upon exposure to liquids.
[0102] In some embodiments, the nalbuphine formulation is prepared
by dry granulation or wet granulation. The components of the
sustained release delivery system are added, along with the
nalbuphine or a pharmaceutically acceptable salt or ester thereof.
Alternatively, all of the components can be held together by an
agglomeration technique to produce an acceptable product. In the
wet granulation technique, nalbuphine or pharmaceutically salt or
ester thereof and the components (e.g., hydrophilic compounds,
cross-linking agents, pharmaceutical diluents, cationic
cross-linking compounds, hydrophobic polymers, etc.) are mixed
together and then moistened with one or more liquids (e.g., water,
propylene glycol, glycerol, alcohol) to produce a moistened mass
that is subsequently dried. The dried mass is then milled with
conventional equipment into granules. Optionally, one or more
wetting agents, one or more lubricants, one or more buffering
agents, one or more coloring agents, one or more second hydrophilic
compounds, or other conventional ingredients, are also added to the
granulation. The granulated composition, in an amount sufficient to
make a uniform batch of tablets, is subjected to tableting in a
conventional production scale tableting machine at typical
compression pressures, i.e., about 2,000-16,000 psi. In some
embodiments, the mixture should not be compressed to a point where
there is subsequent difficulty with hydration upon exposure to
liquids.
[0103] The average particle size of the granulated composition is
from about 50 .mu.m to about 400 gm by weight. In some embodiments,
the average particle size by weight is from about 185 .mu.m to
about 265 .mu.m. The average density of the granulated composition
is from about 0.3 g/mL to about 0.8 g/mL. In some embodiments, the
average density is from about 0.5 g/mL to about 0.7 g/mL. The
tablets formed from the granulations are generally from about 4 Kp
to about 22 Kp hardness. The average flow of the granulations is
from about 25 to about 40 g/sec.
[0104] In some embodiments, the present methods can employ a
multilayer solid dosage form, in which the layers are formulated to
release the nalbuphine hydrochloride at different rates. For
example, in one embodiment, the second layer is an extended release
layer that includes nalbuphine or a pharmaceutically acceptable
salt or ester thereof and a sustained release delivery system
designed to release the nalbuphine or the pharmaceutically
acceptable salt or ester thereof at a controlled rate so that
therapeutically beneficial blood levels are maintained over an
extended period of time (e.g., from about 8 to about 12 hours). The
first layer is an immediate release layer that includes a
formulation of nalbuphine or a pharmaceutically acceptable salt or
ester thereof designed to release the nalbuphine or the
pharmaceutically acceptable salt or ester thereof at a rate that is
faster than the rate of the second layer to achieve a
therapeutically beneficial blood level in an immediate period of
time (e.g., from about 1 to about 2 hours). In some embodiments,
the first layer includes a sustained release delivery system. In
some embodiments, the first layer does not include a sustained
release delivery system.
[0105] In some embodiments, the weight ratio of the second layer to
the first layer is about 10:1 to about 1:10, about 9:1 to about
1:9, about 8:1 to about 1:8, about 7:1 to about 1:7, about 6:1 to
about 1:6, about 5:1 to about 1:5, about 4:1 to about 1:4, about
3:1 to about 1:3, about 2:1 to about 1:2. In one embodiment, the
weight ratio of the second layer to the first layer is about 5:1 to
about 1:5. In a further embodiment, the weight ratio of the second
layer to the first layer is about 1:1 to about 1:2. In some
embodiments, the weight ratio of the second layer to the first
layer is about 1:1, about 1:1.2, about 1:1.4, about 1:1.6, about
1:1.8, or about 1:2. In one embodiment, the weight ratio of the
second layer to the first layer is about 1:2. In one embodiment,
the weight ratio of the second layer to the first layer is about
1:1.4. In some embodiments, the weight ratio of the second layer to
the first layer is about 3:1, about 2.5:1, about 2:1, about 1.5:1.
In one embodiment, the weight ratio of the second layer to the
first layer is about 2.5:1.
[0106] The sustained release delivery system of the multilayer
dosage form includes (i) at least one hydrophilic compound, at
least one cross-linking agent, and at least one pharmaceutical
diluent; (ii) at least one hydrophilic compound, at least one
cross-linking agent, at least one pharmaceutical diluent, and at
least one cationic cross-linking agent different from the first
cross-linking agent; or (iii) at least one hydrophilic compound, at
least one cationic cross-linking compound, and at least one
pharmaceutical diluent. In some embodiments, when the first layer
includes a sustained release delivery system, the sustained release
delivery system of the first layer includes the same components as
the sustained release delivery system of the second layer (e.g.,
both the first and second layers are one of embodiments (i)-(iii),
listed above). In other embodiments, the sustained release delivery
system of the first layer includes different components as the
sustained release delivery system of the second layer (e.g., the
first layer is embodiment (i), listed above, while the second layer
is embodiment (iii), listed above). It is recognized that the
sustained release delivery system of either layer can be one of
embodiments (i)-(iii) listed above. Moreover, it is recognized that
in some embodiments, the first layer does not include a sustained
release delivery system.
[0107] The sustained release delivery system is generally present
in the second layer (e.g., extended release layer) in an amount
ranging from about 10 mg to about 420 mg. In some embodiments, the
sustained release delivery system is present in the second layer in
an amount ranging from about 110 mg to about 200 mg. In some
embodiments, the sustained release delivery system is present in
the second layer in an amount ranging from about 110 mg to about
150 mg. In some embodiments, the sustained release delivery system
is present in the second layer in an amount ranging from about 90
mg to about 150 mg. In some embodiments, the sustained release
delivery system is present in the second layer in an amount of
about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg,
about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140
mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about
190 mg, or about 200 mg. In one embodiment, the sustained release
delivery system is present in the second layer in an amount of
about 123 mg. In one embodiment, the sustained release delivery
system is present in the second layer in an amount of about 101 mg.
In one embodiment, the sustained release delivery system is present
in the second layer in an amount of about 92 mg. In another
embodiment, the sustained release delivery system is present in the
second layer in an amount of about 112.5 mg. In one embodiment, the
sustained release delivery system is present in the second layer in
an amount of about 135 mg. In one embodiment, the sustained release
delivery system is present in the second layer in an amount of
about 150 mg.
[0108] Nalbuphine or a pharmaceutically acceptable salt or ester
thereof is generally present in the second layer in an amount
ranging from about 15 mg to about 60 mg. In some embodiments,
nalbuphine or a pharmaceutically acceptable salt or ester thereof
is present in the second layer in an amount ranging from about 30
mg to about 60 mg. In some embodiments, nalbuphine or a
pharmaceutically acceptable salt or ester thereof is present in the
second layer in an amount ranging from about 45 mg to about 60 mg.
In one embodiment, nalbuphine or a pharmaceutically acceptable salt
or ester thereof is present in the second layer in an amount of
about 15 mg. In one embodiment, nalbuphine or a pharmaceutically
acceptable salt or ester thereof is present in the second layer in
an amount of about 30 mg. In one embodiment, nalbuphine or a
pharmaceutically acceptable salt or ester thereof is present in the
second layer in an amount of about 45 mg. In one embodiment,
nalbuphine or a pharmaceutically acceptable salt or ester thereof
is present in the second layer in an amount of about 60 mg.
[0109] In some embodiments, the weight ratio of nalbuphine or a
pharmaceutically acceptable salt or ester thereof to the sustained
release delivery system in the second layer is about 10:1 to about
1:10, about 9:1 to about 1:9, about 8:1 to about 1:8, about 7:1 to
about 1:7, about 6:1 to about 1:6, about 5:1 to about 1:5, about
4:1 to about 1:4, about 3:1 to about 1:3, or about 2:1 to about
1:2. In one embodiment, the weight ratio of nalbuphine or a
pharmaceutically acceptable salt or ester thereof to the sustained
release delivery system in the second layer is about 1:2 to about
1:4. In one embodiment, the weight ratio of nalbuphine or a
pharmaceutically acceptable salt or ester thereof to the sustained
release delivery system in the second layer is about 1:1 to about
1:5. In some embodiments, the weight ratio of nalbuphine or a
pharmaceutically acceptable salt or ester thereof to the sustained
release delivery system in the second layer is about 1:1, about
1:1.2, about 1:1.4, about 1:1.6, about 1:1.8, about 1:2, about
1:2.5, about 1:3, or about 1:3.5. In one embodiment, the weight
ratio of nalbuphine or a pharmaceutically acceptable salt or ester
thereof to the sustained release delivery system in the second
layer is about 1:2.5. In another embodiment, the weight ratio of
nalbuphine or a pharmaceutically acceptable salt or ester thereof
to the sustained release delivery system in the second layer is
about 1:3.3. In a further embodiment, the weight ratio of
nalbuphine or a pharmaceutically acceptable salt or ester thereof
to the sustained release delivery system in the second layer is
about 1:3. In yet another embodiment, the ratio of nalbuphine or a
pharmaceutically acceptable salt or ester thereof to the sustained
release delivery system in the second layer is about 1:2.
[0110] When the sustained release delivery system is present in the
first layer (e.g., immediate release layer), it is generally
present in an amount ranging from about 0 mg to about 50 mg. In
some embodiments, the sustained release delivery system is present
in the first layer in an amount ranging from about 5 mg to about 25
mg or from about 5 mg to about 15 mg. In one embodiment, the
sustained release delivery system is present in the first layer in
an amount of about 3 mg to about 9 mg. In one embodiment, the
sustained release delivery system is present in the first layer in
an amount of about 4 mg to about 6 mg. In some embodiments, the
sustained release delivery system is present in the first layer in
an amount of about 2 mg, about 4 mg, about 6 mg, about 8 mg, about
10 mg, about 12 mg, about 14 mg, about 15 mg, about 16 mg, about 18
mg, about 20 mg about 25 mg, about 30 mg, about 35 mg, about 40 mg,
about 45 mg or about 50 mg. In one embodiment, the sustained
release delivery system is present in the first layer in an amount
of about 6 mg.
[0111] Nalbuphine or a pharmaceutically acceptable salt or ester
thereof is generally present in the first layer (e.g., immediate
release layer) in an amount ranging from about 5 mg to about 50 mg.
In some embodiments, nalbuphine or a pharmaceutically acceptable
salt or ester thereof is present in the first layer in an amount
ranging from about 5 mg to about 25 mg or from about 10 mg to about
20 mg. In some embodiments, the nalbuphine or a pharmaceutically
acceptable salt or ester thereof is present in the first layer in
an amount of about 5 mg, about 10 mg, about 11 mg, about 12 mg,
about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg,
about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg,
about 35 mg, about 40 mg, about 45 mg or about 50 mg. In one
embodiment, nalbuphine or a pharmaceutically acceptable salt or
ester thereof is present in the first layer in an amount of about
15 mg.
[0112] In some embodiments, when the first layer includes a
sustained release delivery system, the ratio of nalbuphine or
pharmaceutically acceptable salt or ester thereof to the sustained
release delivery system in the first layer is about 10:1 to about
1:10, about 9:1 to about 1:9, about 8:1 to about 1:8, about 7:1 to
about 1:7, about 6:1 to about 1:6, about 5:1 to about 1:5, about
4:1 to about 1:4, about 3:1 to about 1:3, about 2:1 to about 1:2.
In one embodiment, the ratio of nalbuphine or pharmaceutically
acceptable salt or ester thereof to the sustained release delivery
system in the first layer is about 2:1 to about 4:1. In some
embodiments, the ratio of nalbuphine or pharmaceutically acceptable
salt or ester thereof to the sustained release delivery system in
the first layer is about 5:1, about 4.5:1, about 4:1, about 3.5:1,
about 3:1, about 2.5:1, about 2:1, about 1.5:1, or about 1:1. In
one embodiment, the ratio of nalbuphine or pharmaceutically
acceptable salt or ester thereof to the sustained release delivery
system in the first layer is about 2.5:1. In another embodiment,
the ratio of nalbuphine or pharmaceutically acceptable salt or
ester thereof to the sustained release delivery system in the first
layer is about 3:1.
[0113] In some embodiments, the multilayer dosage form further
includes a pharmaceutical disintegrant. The disintegrant promotes
the dissolution and absorption of nalbuphine or pharmaceutically
acceptable salt or ester thereof from the immediate release layer.
Nonlimiting examples of pharmaceutical disintegrants include
croscarmellose sodium, starch glycolate, crospovidone, and
unmodified starch. In one embodiment, the disintegrant is in the
first layer (i.e., the immediate release layer), of the dosage
form. The disintegrant is generally present in the layer in an
amount of about 1.5 mg to about 4.5 mg. In one embodiment, the
disintegrant is present in an amount of about 3 mg. In one
embodiment, the disintegrant is present in the layer in an amount
of about 2-10% by weight. In one embodiment, the disintegrant is
present in the layer in an amount of about 5% by weight. When the
layer contains a sustained release delivery system, the weight
ratio of the sustained release delivery system to the disintegrant
is in a range of about 5:1 to about 1:5. In some embodiments, the
ratio of the sustained release delivery system to the disintegrant
is in a range of about 1:1 to about 3:1. In other embodiments, the
ratio of the sustained release delivery system to the disintegrant
is in a range of about 2:1.
[0114] In some embodiments, the multilayer tablets are prepared by
first preparing the immediate release layer and extended release
layer blends separately. The extended release layer is prepared as
described above. The wet granulation of the extended release layer
is then dried and milled to an appropriate size. Magnesium stearate
is added and mixed with the milled granulation. The immediate
release layer is prepared by first mixing the nalbuphine or the
pharmaceutically acceptable salt or ester thereof with one or more
diluents (e.g., microcrystalline cellulose). This mix is then
optionally mixed with one or more disintegrants. The blend is mixed
with magnesium stearate. Finally, the immediate release layer blend
and the extended release layer blend are compressed into
multi-layer (e.g., bi-layer) tablets.
[0115] The invention provides methods for treating uremic pruritus
by administering an effective amount of a sustained release
formulation of nalbuphine or a pharmaceutically acceptable salt or
ester thereof to a patient in need thereof. An effective amount is
an amount sufficient to eliminate or significantly reduce uremic
pruritus symptoms or to alleviate those symptoms (e.g., reduce the
symptoms, such as itching, compared to the symptoms present prior
to administration of the nalbuphine sustained release formulation).
"Sustained release" or "extended release" means that the nalbuphine
or pharmaceutically acceptable salt or ester thereof is released
from the formulation at a controlled rate so that therapeutically
beneficial blood levels (but below toxic levels) of the nalbuphine
or pharmaceutically acceptable salt or ester thereof are maintained
over an extended period of time. Alternatively, "sustained release"
or "extended release" means that the desired pharmacologic effect
is maintained over an extended period of time. Clinical trials of
the formulations described herein find that the duration of relief
of uremic pruritus symptoms is longer than expected. The half-life
of experimental orally administered nalbuphine formulations (i.e.,
immediate release formulations) has been reported to be relatively
short, only about 5-7 hours. Moreover, the published literature
suggests that the duration of effect for experimental formulations
of immediate release nalbuphine was only about 4 hours. Based on
these data, it was expected that a sustained release formulation
would provide a duration of anti-pruritic effect for approximately
6-8 hours, i.e., allowing for 2-3 times daily dosing. In the
clinical trials described herein, however, nalbuphine sustained
release formulations have an anti-pruritic effect of longer than 8
hours. In some cases, the duration of anti-pruritic effect is at
least about 12 hours, thus providing the possibility of fewer
dosing administrations.
[0116] Without wishing to be bound by a particular theory, the
longer than expected duration of anti-pruritic effect is attributed
to the enterohepatic recirculation of nalbuphine. Nalbuphine forms
a glucuronic acid or other type of conjugated metabolite in vivo
through enzymatic reaction with an enzyme system such as
UDP-glucuronyl transferase. It is also possible that enterohepatic
recirculation also occurs when parent drug in the bile is released
from the gallbladder into the intestine and reabsorbed. Once
formed, the conjugated nalbuphine product is thought to be
transported into the gastrointestinal tract via biliary secretion
whereby the drug conjugate is cleaved liberating nalbuphine which
can be reabsorbed from the intestine. The sustained release
formulation can improve the duration of anti-pruritic effect, by
more slowly releasing nalbuphine into the in vivo system and
allowing more drug to be conjugated and therefore available for
recirculation and later reabsorption from the intestine.
[0117] In certain embodiments, the chemistry of certain of the
components of the formulation, such as the hydrophilic compound
(e.g., xanthan gum), is such that the components are considered to
be self-buffering agents which are substantially insensitive to the
solubility of the nalbuphine and the pH changes along the length of
the gastrointestinal tract. Moreover, the chemistry of the
components is believed to be similar to certain known muco-adhesive
substances, such as polycarbophil. Muco-adhesive properties are
desirable for buccal delivery systems. Thus, the sustained release
formulation can loosely interact with the mucin in the
gastrointestinal tract and thereby provide another mode by which a
constant rate of delivery of the nalbuphine is achieved.
[0118] The two phenomenon discussed above (buoyancy and
muco-adhesive properties) are mechanisms by which the sustained
release formulations can interact with the mucin and fluids of the
gastrointestinal tract and provide a constant rate of delivery of
the nalbuphine.
[0119] When measured by USP Procedure Drug Release General Chapter
<711> Dissolution, (incorporated by reference herein in its
entirety), the sustained release formulations employed in the
present methods generally exhibit an in vitro dissolution of about
15% to about 50% by weight nalbuphine after 1 hour, about 45% to
about 80% by weight nalbuphine after 4 hours, or at least about 80%
by weight nalbuphine after 10 hours. In some embodiments, the in
vitro and in vivo release characteristics of the sustained release
formulations are modified using mixtures of one or more different
water insoluble and/or water soluble compounds, using different
plasticizers, varying the thickness of the sustained release film,
including providing release-modifying compounds in the coating,
and/or by providing passageways through the coating. In some
embodiments, the dissolution rate is determined using apparatus USP
Type 111/250 mL at pH 6.8, 37.degree. C. and 15 dpm. In some
embodiments, the dissolution rate is determined using apparatus USP
Type 111/250 mL performed in pH change (0-1 hours pH 1.2, after
hour 1 pH 4.5, after hour 2 pH 6.8) at 37.degree. C. and 15
dpm.
[0120] In some embodiments, the sustained release formulation has
an in vitro dissolution of about 50% to about 100% by weight
nalbuphine after about 6 hours. In some embodiments, the sustained
release formulation has an in vitro dissolution of about 75% to
about 100% by weight nalbuphine after about 6 hours. In other
embodiments, the sustained release formulation has an in vitro
dissolution of about 75% to about 100% by weight nalbuphine from
about 6 hours to about 8 hours. In further embodiments, the
sustained release formulation has an in vitro dissolution of about
80% to about 100% by weight nalbuphine after about 12 hours. In
still other embodiments, the sustained release formulation has an
in vitro dissolution of about 80% to about 100% by weight
nalbuphine from about 12 hours to about 24 hours. In some
embodiments, the sustained release formulation has an in vitro
dissolution of about 80% to about 100% after about 8 hours to about
12 hours. In yet other embodiments, the sustained release
formulation has an in vitro dissolution of about 15% to about 75%
by weight nalbuphine after about 1 hour. In still further
embodiments, the sustained release formulation has an in vitro
dissolution of about 50% by weight nalbuphine after about 1 hour.
In some embodiments, the sustained release formulation has an in
vitro dissolution of about 50% by weight nalbuphine after about 1
hour and about 75% to about 100% by weight nalbuphine from about 6
hours to about 8 hours. In some embodiments, the sustained release
formulation has an in vitro dissolution of about 50% by weight
nalbuphine after about 1 hour and about 75% to about 100% by weight
nalbuphine from about 8 hours to about 12 hours. In some
embodiments, the sustained release formulation has an in vitro
dissolution of about 50% by weight nalbuphine after about 1 hour
and about 75% to about 100% by weight nalbuphine from about 12
hours to about 24 hours. In some embodiments, the sustained release
formulation has an in vitro dissolution of about 50% by weight
nalbuphine after about 1 hour and about 80% to about 100% by weight
nalbuphine after about 12 hours.
[0121] Where the tablet is a multilayer dosage form having a first
extended release layer and a second, immediate release, layer, the
sustained release formulation has an in vitro dissolution of about
25% to about 75% by weight nalbuphine after about 1 hour. In some
embodiments, the multilayer dosage form has an in vitro dissolution
of about 25% by weight nalbuphine after about 1 hour. In some
embodiments, the multilayer dosage form has an in vitro dissolution
of about 50% by weight nalbuphine after about 1 hour. In some
embodiments, the multilayer dosage form has an in vitro dissolution
of about 75% to about 100% nalbuphine after about 6-8 hours. In
some embodiments, the multilayer dosage form has an in vitro
dissolution of about 75% to about 100% nalbuphine after about 8-12
hours. In some embodiments, the multilayer dosage form has an in
vitro dissolution of about 75% to about 100% nalbuphine after about
12-24 hours. In some embodiments, the multilayer dosage form has an
in vitro dissolution of about 75% to about 100% nalbuphine after
about 12 hours.
[0122] When administered orally to patients having either normal or
impaired (e.g., reduced) kidney function, the sustained release
formulations described herein exhibit the following in vivo
characteristics: (a) a peak plasma level of nalbuphine occurs
within about 2 to about 6 hours after administration; (b) onset of
nalbuphine anti-pruritic effect from about 30 minutes of dosing to
within about 6 hours of dosing; (c) duration of the nalbuphine
anti-pruritic effect is about 2 to about 24 hours; and (d) the
relative nalbuphine bioavailability is about 0.5 to about 1.5
compared to an orally administered aqueous solution of nalbuphine.
The time of onset for an anti-pruritic effect can depend on at
least on dosing and the severity of pruritic symptoms. In some
embodiments, the duration of the nalbuphine anti-pruritic effect is
at least about 8 hours. In some embodiments, the duration of the
nalbuphine anti-pruritic effect is at least about 9 hours. In some
embodiments, the duration of the nalbuphine anti-pruritic effect is
at least about 10 hours. In some embodiments, the duration of the
nalbuphine anti-pruritic effect is at least about 11 hours. In some
embodiments, the duration of the nalbuphine anti-pruritic effect is
at least about 12 hours. In some embodiments, the duration of
nalbuphine anti-pruritic effect is about 6, hours, 8 hours, 10
hours, 12 hours, 15 hours, or 18 hours. In some embodiments, the
relative nalbuphine bioavailability is about 0.94 compared to an
orally administered aqueous solution of nalbuphine. In some
embodiments, the relative nalbuphine bioavailability is about 1.35
compared to an orally administered aqueous solution of
nalbuphine.
[0123] In some embodiments, the sustained release nalbuphine
formulations provide an oral unit dosage form including nalbuphine
or a pharmaceutically acceptable salt or ester thereof. The oral
dosage form provides an anti-pruritic effect over a period of at
least about 6 hours, about 7 hours, about 8 hours, about 9 hours,
about 10 hours, about 11 hours, about 12 hours, about 13 hours,
about 14 hours, about 15 hours, about 16 hours, about 17 hours,
about 18 hours, about 19 hours, about 20 hours, about 21 hours,
about 22 hours, about 23 hours or about 24 hours. In some
embodiments, the oral dosage form provides an anti-pruritic effect
over a period of about 6-18 hours, about 8-16 hours, about 8-12
hours, about 8 to about 24 hours, about 12 to about 24 hours, about
18 to about 24 hours, or about 8-10 hours. The oral dosage form
provides an anti-pruritic effect over a period of about 6 hours,
about 7 hours, about 8 hours, about 9 hours, about 10 hours, about
11 hours, about 12 hours, about 13 hours, about 14 hours, about 15
hours, about 16 hours, about 17 hours, about 18 hours, about 19
hours, about 20 hours, about 21 hours, about 22 hours, about 23
hours or about 24 hours.
[0124] In some embodiments, the oral dosage form provides a blood
plasma level of nalbuphine characterized by one or more peaks
followed by a plateau region. The plateau region is characterized
as having a relatively consistent blood plasma level of nalbuphine
(e.g., the blood plasma level of nalbuphine does not consistently
increase or decrease from time point to time point). In some
embodiments, the plateau region is characterized as having a
consistent average blood plasma level of nalbuphine. The plateau
region is contrasted with the region following the plateau region,
in which the blood plasma level of nalbuphine generally decreases
from one time point to the next. In some embodiments, the plateau
region has a duration of at least about 1 hour, about 2 hours,
about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7
hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours
or about 12 hours. In some embodiments, the plateau region has a
duration from about 1 hour to about 12 hours, from about 2 hours to
about 10 hours, from about 2 hours to about 8 hours, from about 2
hours to about 7 hours or from about 4 hours to about 10 hours,
from about 4 hours to about 8 hours, or from about 4 hours to about
6 hours. In some embodiments, the blood plasma level of nalbuphine
at each time point in the plateau region ranges from about 75% to
about 125% of the mean blood plasma level in the plateau region. In
some embodiments, the blood plasma level of nalbuphine at each time
point in the plateau region ranges from about 80% to about 120% of
the mean blood plasma level in the plateau region. In some
embodiments, the blood plasma level of nalbuphine at each time
point in the plateau region ranges from about 85% to about 115% of
the mean blood plasma level in the plateau region. In some
embodiments, the blood plasma level of nalbuphine at each time
point in the plateau region ranges from about 90% to about 110% of
the mean blood plasma level in the plateau region.
[0125] In some embodiments, the minimum blood plasma level of
nalbuphine observed during the plateau region is not more than
about 25% below the mean blood plasma level for all time points in
the plateau region. In some embodiments, the minimum blood plasma
level of nalbuphine observed during the plateau region is not more
than about 20% below the mean blood plasma level in the plateau
region. In some embodiments, the minimum blood plasma level of
nalbuphine observed during the plateau region is not more than
about 15% below the mean blood plasma level in the plateau region.
In some embodiments, the minimum blood plasma level of nalbuphine
observed during the plateau region ranges from about 75% to about
100% of the mean blood plasma level in the plateau region. In some
embodiments, the minimum blood plasma level of nalbuphine observed
during the plateau region ranges from about 80% to about 100% of
the mean blood plasma level in the plateau region. In some
embodiments, the minimum blood plasma level of nalbuphine observed
during the plateau region ranges from about 85% to about 100% of
the mean blood plasma level in the plateau region. In some
embodiments, the minimum blood plasma level of nalbuphine observed
during the plateau region ranges from about 80% to about 95% of the
mean blood plasma level in the plateau region.
Co-Therapy
[0126] While the compositions can be administered as the sole
active pharmaceutical ingredient or sole active anti-pruritus
ingredient in the methods described herein, in other embodiments
they can also be used in combination with one or more ingredients
which are known to be therapeutically effective against pruritus
and/or compliment the effect of anti-pruritus ingredient.
[0127] For example, in some embodiments, the present methods can
employ nalbuphine or a pharmaceutically acceptable salt or ester
thereof in conjunction with one or more anti-pruritic agents. In
some embodiments, additional compounds combined with the
anti-pruritic agent, e.g., nalbuphine, or a pharmaceutically
acceptable salt or ester thereof, include antihistamines,
anti-inflammatory corticosteroids, topical anti-infectives and
antifungals, antibacterials, and antivirals, cytotoxic agents, and
counter-irritants/analgesics. Other antipruritic agents include
anti-depressants, vitamin D, kappa agonists, irritants such as coal
tar derivatives and psoralens, 5-HT3 antagonists such as
ondansetron, H2 receptor antagonist such as cimetidine, H1 receptor
antagonist such as cetirizine, immunomodulators such as tacrolimus,
immunosupressants such as cyclosporine A, .mu.-antagonists,
capsaicin, cannabinoids, latex extracts from various Croton species
found in the Amazon jungle (e.g., Zangrado.RTM.).
Dosing
[0128] Formulations employed in the present methods can incorporate
nalbuphine in a controlled release formulation such that the
formulation provides therapeutically effective blood plasma levels
of nalbuphine for the treatment of uremic pruritus. A dosing
regimen can be selected for administration of the formulation on a
once a day basis, a twice a day basis, thrice a day basis, or four
times a day basis. The frequency of dosing can be selected to
provide a target plasma concentration of nalbuphine to provide
effective relief of the symptoms of uremic pruritus.
[0129] In some embodiments, the total daily dose of nalbuphine,
either as a single dose or as the sum of two, three or four doses,
can range from about 15 mg a day to about 360 mg a day (e.g., about
15 mg a day, about 20 mg a day, about 25 mg a day, about 30 mg a
day, about 35 mg a day, about 40 mg a day, about 45 mg a day, about
50 mg a day, about 55 mg a day, about 60 mg a day, about 65 mg a
day, about 70 mg a day, about 75 mg a day, about 80 mg a day, about
85 mg a day, about 90 mg a day, about 95 mg a day, about 100 mg a
day, about 105 mg a day, about 110 mg a day, about 115 mg a day,
about 120 mg a day, about 125 mg a day, about 130 mg a day, about
135 mg a day, about 140 mg a day, about 145 mg a day, about 150 mg
a day, about 155 mg a day, about 160 mg a day, about 165 mg a day,
about 170 mg a day, about 175 mg a day, about 180 mg a day, about
185 mg a day, about 190 mg a day, about 195 mg a day, about 200 mg
a day, about 205 mg a day, about 210 mg a day, about 215 mg a day,
about 220 mg a day, about 225 mg a day, about 230 mg a day, about
235 mg a day, about 240 mg a day, about 245 mg a day, about 250 mg
a day, about 255 mg a day, about 260 mg a day, about 265 mg a day,
about 270 mg a day, about 275 mg a day, about 280 mg a day, about
285 mg a day, about 290 mg a day, about 295 mg a day, about 300 mg
a day, about 305 mg a day, about 310 mg a day, about 315 mg a day,
about 320 mg a day, about 325 mg a day, about 330 mg a day, about
335 mg a day, about 340 mg a day, about 345 mg a day, about 350 mg
a day, about 355 mg a day, about 360 mg a day, or any other value
or range of values therein).
[0130] In some embodiments, the maximum total daily dose of
nalbuphine or a pharmaceutically acceptable salt or ester thereof
is about 75 mg to about 180 mg, administered once a day, for
example about 75 mg, about 80 mg, about 85 mg, about 90 mg, about
95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg,
about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140
mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about
165 mg, about 170 mg, about 175 mg, or about 180 mg, administered
once a day, including all values or ranges therebetween.
[0131] In some embodiments, the maximum total daily dose of
nalbuphine or a pharmaceutically acceptable salt or ester thereof
is about 90 mg to about 360 mg, administered once a day, for
example about 90 mg, about 100 mg, about 110 mg, about 120 mg,
about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170
mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about
220 mg, about 230 mg, about 240 mg, about 250 mg, about to 60 mg,
about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310
mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, in
about 360 mg, including all values or ranges therebetween.
[0132] In some embodiments, the dosing regimen is a twice-daily
dose of a controlled release formulation, and the amount of
nalbuphine in the controlled release formulation is from about 15
mg to about 180 mg (e.g., about 15 mg, about 20 mg, about 25 mg,
about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,
about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,
about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg,
about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125
mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about
150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg,
about 175 mg, about 180 mg, or any other value or range of values
therein). A twice-daily dosage regimen may include a total daily
dosage over the two administrations of from about 15 mg a day to
about 360 mg a day (e.g., about 15 mg a day, about 20 mg a day,
about 25 mg a day, about 30 mg a day, about 35 mg a day, about 40
mg a day, about 45 mg a day, about 50 mg a day, about 55 mg a day,
about 60 mg a day, about 65 mg a day, about 70 mg a day, about 75
mg a day, about 80 mg a day, about 85 mg a day, about 90 mg a day,
about 95 mg a day, about 100 mg a day, about 105 mg a day, about
110 mg a day, about 115 mg a day, about 120 mg a day, about 125 mg
a day, about 130 mg a day, about 135 mg a day, about 140 mg a day,
about 145 mg a day, about 150 mg a day, about 155 mg a day, about
160 mg a day, about 165 mg a day, about 170 mg a day, about 175 mg
a day, about 180 mg a day, about 185 mg a day, about 190 mg a day,
about 195 mg a day, about 200 mg a day, about 205 mg a day, about
210 mg a day, about 215 mg a day, about 220 mg a day, about 225 mg
a day, about 230 mg a day, about 235 mg a day, about 240 mg a day,
about 245 mg a day, about 250 mg a day, about 255 mg a day, about
260 mg a day, about 265 mg a day, about 270 mg a day, about 275 mg
a day, about 280 mg a day, about 285 mg a day, about 290 mg a day,
about 295 mg a day, about 300 mg a day, about 305 mg a day, about
310 mg a day, about 315 mg a day, about 320 mg a day, about 325 mg
a day, about 330 mg a day, about 335 mg a day, about 340 mg a day,
about 345 mg a day, about 350 mg a day, about 355 mg a day, about
360 mg a day, or any other value or range of values therein).
[0133] In some embodiments, the dosing regimen is a thrice-daily
dose of a controlled release formulation, and the amount of
nalbuphine in the controlled release formulation is from about 15
mg to about 180 mg (e.g., about 15 mg, about 20 mg, about 25 mg,
about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,
about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,
about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg,
about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125
mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about
150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg,
about 175 mg, about 180 mg, or any other value or range of values
therein). A thrice-daily dosage regimen may include a total daily
dosage over the three administrations of from about 15 mg a day to
about 360 mg a day (e.g., about 15 mg a day, about 20 mg a day,
about 25 mg a day, about 30 mg a day, about 35 mg a day, about 40
mg a day, about 45 mg a day, about 50 mg a day, about 55 mg a day,
about 60 mg a day, about 65 mg a day, about 70 mg a day, about 75
mg a day, about 80 mg a day, about 85 mg a day, about 90 mg a day,
about 95 mg a day, about 100 mg a day, about 105 mg a day, about
110 mg a day, about 115 mg a day, about 120 mg a day, about 125 mg
a day, about 130 mg a day, about 135 mg a day, about 140 mg a day,
about 145 mg a day, about 150 mg a day, about 155 mg a day, about
160 mg a day, about 165 mg a day, about 170 mg a day, about 175 mg
a day, about 180 mg a day, about 185 mg a day, about 190 mg a day,
about 195 mg a day, about 200 mg a day, about 205 mg a day, about
210 mg a day, about 215 mg a day, about 220 mg a day, about 225 mg
a day, about 230 mg a day, about 235 mg a day, about 240 mg a day,
about 245 mg a day, about 250 mg a day, about 255 mg a day, about
260 mg a day, about 265 mg a day, about 270 mg a day, about 275 mg
a day, about 280 mg a day, about 285 mg a day, about 290 mg a day,
about 295 mg a day, about 300 mg a day, about 305 mg a day, about
310 mg a day, about 315 mg a day, about 320 mg a day, about 325 mg
a day, about 330 mg a day, about 335 mg a day, about 340 mg a day,
about 345 mg a day, about 350 mg a day, about 355 mg a day, about
360 mg a day, or any other value or range of values therein).
[0134] In some embodiments, the dosing regimen is a once-daily
dose, and the amount of nalbuphine in the formulation is from about
15 mg to about 180 mg (e.g., about 15 mg, about 20 mg, about 25 mg,
about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,
about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,
about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg,
about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125
mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about
150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg,
about 175 mg, about 180 mg, or any other value or range of values
therein).
[0135] In some embodiments, irrespective of the dosing regimen, the
controlled release formulation comprises about 15 mg nalbuphine,
about 30 mg nalbuphine, about 60 mg nalbuphine, about 120 mg
nalbuphine, about 180 mg nalbuphine.
[0136] In some embodiments, the daily dose of nalbuphine can be
selected as described above, in either a once-daily dose, a twice
daily dose, or a thrice-daily dose, and then titrated upward until
the patient experiences satisfactory relief from the pruritic
condition. Titrating the dose can include administering a baseline
daily dose, in either a once-daily dose, a twice daily dose, or a
thrice daily dose, then after a period of observation at the
baseline daily dose value to determine the efficacy of the baseline
first daily dose, renal clearance, and/or side effect severity,
increasing the first daily dose if the subject does not experience
adequate symptom relief. The period of period of observation at the
baseline daily dose before increasing the daily dose can be from
about 1 day to about 21 days (e.g., about 1 day, about 2 days,
about 3 days, about 4 days, about 5 days, about 6 days, about 7
days, about 8 days, about 9 days, about 10 days, about 11 days,
about 12 days, about 13 days, about 14 days, about 15 days, about
16 days, about 17 days, about 18 days, about 19 days, about 20
days, about 21 days). The daily dose can be titrated in increments
ranging from about 5 mg to about 180 mg (e.g., about 5 mg, about 10
mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35
mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60
mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85
mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110
mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about
135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg,
about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180
mg, or any other value or range of values therein). The daily dose
can be titrated in one or more steps. The daily dosage can be
titrated by increasing a single daily dosage, or each dose of a
twice-daily dosing regimen. The amount a dosage is stepped, where
there are multiple titration steps, can be the same, or can be
different. In some embodiments, a dosage in, e.g., a twice-daily or
thrice-daily dosing regimen can be titrated downward, while the
corresponding second dose (e.g., in a twice-daily regimen) or the
corresponding second and third doses (e.g., in a twice-daily
regimen) can independently be held constant or increased, to reduce
the total number of doses per day while retaining therapeutic
efficacy.
[0137] When nalbuphine HCl solution is administered with food, AUC
is relatively unchanged whereas Cmax values are about 1.5 fold
higher in the fed than the fasted state. Exposure (AUC) following
tablets was comparable to that from the solution with a relative
bioavailability of 94% under fasted state. On the other hand, with
sustained release nalbuphine formulations, Cmax was blunted
(.about.50%) and Tmax prolonged both in the fed and fasted state
relative to the nalbuphine HCl solution. Following oral
administration of an aqueous solution, nalbuphine was readily
absorbed with a median Tmax of 0.5-1 hr and a mean plasma half-life
(T.sub.1/2) ranging between 6.87 and 6.99 hr across studies under
fasted conditions.
[0138] In some embodiments, the dosing frequency and dose amount
per administration are selected to provide therapeutically
effective blood plasma levels of nalbuphine for the treatment of
uremic pruritus when administered on a once-a-day basis. For
example, in certain embodiments, the controlled release
formulation, provides a mean C.sub.max of from about 1.0 to about
120 ng/mL for example a mean C.sub.max of about 1.0, about 1.1,
about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7,
about 1.8, about 1.9, about 2.0, about 2.2, about 2.4, about 2.6,
about 2.8, about 3.0, about 3.2, about 3.4, about 3.6, about 3.8,
about 4.0, about 4.2, about 4.4, about 4.6, about 4.8, about 5.0,
about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2,
about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4,
about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6,
about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8,
about 10, about 11, about 12, about 13, about 14, about 15, about
16, about 17, about 18, about 19, about 20, about 21, about 22,
about 23, about 24, about 25, about 26, about 27, about 28, about
29, about 30, 31, about 32, about 33, about 34, about 35, about 36,
about 37, about 38, about 39, about 40, about 41, about 42, about
43, about 44, about 45, about 46, about 47, about 48, about 49,
about 50, about 51, about 52, about 53, about 54, about 55, about
56, about 57, about 58, about 59, about 60, about 61, about 62,
about 63, about 64, about 65, about 66, about 67, about 68, about
69, about 70, about 71, about 72, about 73, about 74, about 75,
about 76, about 77, about 78, about 79, about 80, 81, about 82,
about 83, about 84, about 85, about 86, about 87, about 88, about
89, about 90, about 91, about 92, about 93, about 94, about 95,
about 96, about 97, about 98, about 99, about 100, about 101, about
102, about 1 to 3, about 104, about 105, about 16, about 107, about
108, about 109, about 110, about 111, about 112, about 113, about
114, about 115, about 116, about 117, about 118, about 119, about
120 ng/mL, or any other value or range of values therein. In one
embodiment, the controlled release formulation provides a mean
C.sub.max of from about 1.9 ng/mL to about 102 ng/mL. In another
embodiment, the controlled release formulation provides a mean
C.sub.max of from about 30 ng/mL to about 60 ng/mL. In yet another
embodiment, the controlled release formulation provides a mean
C.sub.max of from about 2 ng/mL to about 15 ng/mL. In yet another
embodiment, the controlled release formulation provides a mean
C.sub.max of from about 5 ng/mL to about 10 ng/mL.
[0139] In other embodiments, the present formulations provide a
mean Cmax from about 0.088 (ng/mL)/mg to about 0.245 (ng/mL)/mg
(e.g., about 0.08 (ng/mL)/mg, about 0.09 (ng/mL)/mg, about 0.1
(ng/mL)/mg, about 0.11 (ng/mL)/mg, about 0.12 (ng/mL)/mg, about
0.13 (ng/mL)/mg, about 0.14 (ng/mL)/mg, about 0.15 (ng/mL)/mg,
about 0.16 (ng/mL)/mg, about 0.17 (ng/mL)/mg, about 0.18
(ng/mL)/mg, about 0.19 (ng/mL)/mg, about 0.20 (ng/mL)/mg, about
0.21 (ng/mL)/mg, about 0.22 (ng/mL)/mg, about 0.23 (ng/mL)/mg,
about 0.24 (ng/mL)/mg, or any other value or range of values
therein).
[0140] In some embodiments, the dosing frequency and dose amount
per administration are selected to provide a mean C.sub.min of from
about 1 ng/mL to about 20 ng/mL (e.g., about 1 ng/mL, about 2
ng/mL, about 3 ng/mL, about 4 ng/mL, about 5 ng/mL, about 6 ng/mL,
about 7 ng/mL, about 8 ng/mL, about 9 ng/mL, about 10 ng/mL, about
11 ng/mL, about 12 ng/mL, about 13 ng/mL, about 14 ng/mL, about 15
ng/mL, about 16 ng/mL, about 17 ng/mL, about 18 ng/mL, about 19
ng/mL, about 20 ng/mL, or any other value or range of values
therein). In certain embodiments, the dosing frequency and dose
amount per administration are selected to provide a mean C.sub.min
of from about 2 ng/mL to about 15 ng/mL. In other embodiments, the
dosing frequency and dose amount per administration are selected to
provide a mean C.sub.min of from about 5 ng/mL to about 10
ng/mL.
[0141] In certain embodiments, the dosing frequency and dose amount
of the controlled release formulation provides a nalbuphine
AUC.sub.(0-.infin.) of from about 30 nghr/mL to about 950 nghr/mL,
for example about 30, about 31, about 32, about 33, about 34, about
35, about 36, about 37, about 38, about 39, about 40, about 45,
about 50, about 55, about 60, about 65, 70, 75 about 80, 85, about
90, about 95, about 100, about 105, about 110, about 115, about
120, about 125, about 130, about 135, about 140, about 145, about
150, about 155, about 160, 165, about 170, about 175, about 180,
about 185, about 190, about 195, about 200, about 205, about 210,
about 215, about 220, about 225, about to 30, about 235, about 240,
about 245, about 250 about 255, about 260, about 265, about 270,
about 275, about 280, about 285, about 290, about 295, about 300,
about 305, about 310, about 315, about 320, about 325, about 330,
about 335, about 340, about 345, about 350, about 355, about 360,
about 365, about 370, about 375, about 380, about 35, about 390,
about 395, about 400, about 405, about 410, about 415, about 420,
about 425, about 430, about 435, about 440, about 445, about 450,
about 455, about 460, about 465, about 470, about 475, about 480,
about 485, about 490, about 495, about 500, about 505, about 510,
about 515, about 520, about 525, about 530, about 535, about 540,
about 545, about 550, about 555, about 560, about 565, about 570,
575, about 580, 585, about 590, about 595, about 600, about 605,
about 610, about 615, about 620, about 625, about 630, about 635,
about 640 about 645, about 650, about 655, about 670, about 675,
about 680, about 685, about 690, about 695, about 700, about 705,
about 710, about 715, about 720, about 725, about 730, about 735,
about 740, about 745, about 750, about 755, about 760, about 765,
about 770, about 775, about 780, about 785, about 790, about 795,
about 800, about 805, about 810, about 815, about 820, about 825,
about 830, about 835, about 840, about 845, about 850, about 855,
about 860, but 865, about 870, about 875, about 880, about 885,
about 890, about 895, about 900, about 905, about 910, about 915,
about 920, about 925, about 930, about 935, about 940, about 945,
about 950 nghr/mL, or any other value or range of values therein.
In one embodiment, the dosing frequency and dose amount of the
controlled release formulation provides a nalbuphine
AUC.sub.(0-.infin.) of from about 37 nghr/mL to about 910 nghr/mL.
In another embodiment, the controlled release formulation provides
a nalbuphine AUC.sub.(0-.infin.) of from about 200 nghr/mL to about
500 nghr/mL. In another embodiment, the controlled release
formulation provides a nalbuphine AUC.sub.(0-.infin.) of from about
70 nghr/mL to about 210 nghr/mL.
[0142] In other embodiments, the present formulations provide a
nalbuphine AUC.sub.(0-inf) from about 1.392 (ng*hr/ml)/mg to about
3.43 (ng*hr/ml)/mg (e.g., about 1.4 (ng*hr/ml), about 1.5
(ng*hr/ml), about 1.6 (ng*hr/ml), about 1.7 (ng*hr/ml), about 1.8
(ng*hr/ml), about 1.9 (ng*hr/ml), about 2.0 (ng*hr/ml), about 2.1
(ng*hr/ml), about 2.2 (ng*hr/ml), about 2.3 (ng*hr/ml), about 2.4
(ng*hr/ml), about 2.5 (ng*hr/ml), about 2.6 (ng*hr/ml), about 2.7
(ng*hr/ml), about 2.8 (ng*hr/ml), about 2.9 (ng*hr/ml), about 3.0
(ng*hr/ml), about 3.1 (ng*hr/ml), about 3.2 (ng*hr/ml), about 3.3
(ng*hr/ml), about 3.4 (ng*hr/ml), or any other value or range of
values therein).
[0143] In certain embodiments, the present methods can further
comprise administering a rescue dose comprising nalbuphine to
provide breakthrough relief of uremic pruritus. The rescue dose can
comprise nalbuphine in an amount of from about 1 mg to about 60 mg
(e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg,
about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg,
about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg,
about 60 mg, or any other value or range of values therein). In
some embodiments, the rescue dose comprises from about 3 mg to
about 30 mg of nalbuphine. In other embodiments, the rescue dose
comprises from about 3 mg to about 45 mg of nalbuphine. The rescue
dose can be administered parenterally, orally in an immediate
release formulation, or as a buccal, sublingual, intranasal, or
rectal dosage form. In some embodiments, the rescue dose is a
tablet, capsule, a solution, a lozenge, or a suppository. In other
embodiments, the rescue dose can be administered via a bilayer
tablet which includes a recue nalbuphine dose in an immediate
release layer, and the tablet further comprises a nalbuphine dose
in an extended release layer.
[0144] In some embodiments, the present methods employ a twice
daily dosage regimen, and the first daily dose is less than the
second daily dose. For example, in some embodiments, the second
daily dose is from about 5 mg to about 180 mg greater than the
first daily dose (e.g., about 5 mg greater, about 10 mg greater,
about 15 mg greater, about 20 mg greater, about 25 mg greater,
about 30 mg greater, about 35 mg greater, about 40 mg greater,
about 45 mg greater, about 50 mg greater, about 55 mg greater,
about 60 mg greater, about 65 mg greater, about 70 mg greater,
about 75 mg greater, about 80 mg greater, about 85 mg greater,
about 90 mg greater, about 95 mg greater, about 100 mg greater,
about 105 mg greater, about 110 mg greater, about 115 mg greater,
about 120 mg greater, about 125 mg greater, about 130 mg greater,
about 135 mg greater, about 140 mg greater, about 145 mg greater,
about 150 mg greater, about 155 mg greater, about 160 mg greater,
about 165 mg greater, about 170 mg greater, about 175 mg greater,
about 180 mg greater, or any other value or range of values
therein).
[0145] In some embodiments, the second daily dose of nalbuphine can
be selected as described above, and then titrated upward until the
patient experiences satisfactory relief from the pruritic
condition. Titrating the dose can include administering a baseline
second daily dose, then after a period of observation at the
baseline second daily dose value to determine the efficacy, renal
clearance, and/or side effect severity, of the baseline second
daily dose, increasing the second daily dose if the subject does
not experience adequate symptom relief. The period of period of
observation at the baseline second daily dose before increasing the
second daily dose can be from about 1 day to about 21 days (e.g.,
about 1 day, about 2 days, about 3 days, about 4 days, about 5
days, about 6 days, about 7 days, about 8 days, about 9 days, about
10 days, about 11 days, about 12 days, about 13 days, about 14
days, about 15 days, about 16 days, about 17 days, about 18 days,
about 19 days, about 20 days, about 21 days). The second daily dose
can be titrated in increments ranging from about 5 mg to about 180
mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about
25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50
mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75
mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100
mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about
125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg,
about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170
mg, about 175 mg, about 180 mg, or any other value or range of
values therein). The second daily dose can be titrated in one or
more steps. The amount a dosage is stepped, where there are
multiple titration steps, can be the same, or can be different.
[0146] In some embodiments, the present methods employ a twice
daily dosage regimen, and the first daily dose is greater than the
second daily dose. For example, in some embodiments, the first
daily dose is from about 5 mg to about 180 mg greater than the
second daily dose (e.g., about 5 mg greater, about 10 mg greater,
about 15 mg greater, about 20 mg greater, about 25 mg greater,
about 30 mg greater, about 35 mg greater, about 40 mg greater,
about 45 mg greater, about 50 mg greater, about 55 mg greater,
about 60 mg greater, about 65 mg greater, about 70 mg greater,
about 75 mg greater, about 80 mg greater, about 85 mg greater,
about 90 mg greater, about 95 mg greater, about 100 mg greater,
about 105 mg greater, about 110 mg greater, about 115 mg greater,
about 120 mg greater, about 125 mg greater, about 130 mg greater,
about 135 mg greater, about 140 mg greater, about 145 mg greater,
about 150 mg greater, about 155 mg greater, about 160 mg greater,
about 165 mg greater, about 170 mg greater, about 175 mg greater,
about 180 mg greater, or any other value or range of values
therein).
[0147] In some embodiments, the first daily dose of nalbuphine can
be selected as described above, and then titrated upward until the
patient experiences satisfactory relief from the pruritic
condition. Titrating the dose can include administering a baseline
first daily dose, then after a period of observation at the
baseline first daily dose value to determine the efficacy of the
baseline first daily dose, renal clearance, and/or side effect
severity, increasing the first daily dose if the subject does not
experience adequate symptom relief. The period of period of
observation at the baseline first daily dose before increasing the
first daily dose can be from about 1 day to about 21 days (e.g.,
about 1 day, about 2 days, about 3 days, about 4 days, about 5
days, about 6 days, about 7 days, about 8 days, about 9 days, about
10 days, about 11 days, about 12 days, about 13 days, about 14
days, about 15 days, about 16 days, about 17 days, about 18 days,
about 19 days, about 20 days, about 21 days). The first daily dose
may be from about 5 mg to about 180 mg (e.g., about 5 mg, about 10
mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35
mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60
mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85
mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110
mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about
135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg,
about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180
mg, or any other value or range of values therein).
[0148] The titration dose can be in increments ranging from about 5
mg to about 180 mg (e.g., about 5 mg, about 10 mg, about 15 mg,
about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,
about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg,
about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,
about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115
mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about
140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg,
about 165 mg, about 170 mg, about 175 mg, about 180 mg, or any
other value or range of values therein). The first daily dose can
be titrated in one or more steps. The amount a dosage is stepped,
where there are multiple titration steps, can be the same, or can
be different.
[0149] Accordingly, the total daily dose in a once daily dosing
regimen with a titration dose, including baseline dose and one or
more titration doses, may be from about 5 mg to about 180 mg (e.g.,
about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg,
about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,
about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,
about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg,
about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125
mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about
150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg,
about 175 mg, about 180 mg, or any other value or range of values
therein).
[0150] In one embodiment, the present methods include treating
uremic pruritus in a human patient, comprising (a) orally
administering to a human patient suffering from uremic pruritis an
initial dosing regimen of nalbuphine in a controlled release
formulation containing about 15 mg, 30 mg or 60 mg nalbuphine on a
once a day or twice-a-day basis; (b) determining the effectiveness
of the dosing regimen of nalbuphine in treating the patient's
pruritus after at least about 1, 2 or 3 days of treatment; and (c)
adjusting the dose and/or dosing interval of the oral controlled
release nalbuphine formulation based on the information obtained in
step (b) in order to provide improved efficacy of treatment of said
patient's uremic pruritus. In other embodiments, the initial dosing
is about 15 mg, 30 mg, or 60 mg once a day or twice a day and an
effective dosing is obtained via titration, e.g., based on a
pre-determined schedule, e.g., about 15 mg, 30 mg or 60 mg
increment after about 2 or 3 days or based on a schedule designed
by the physician treating the patient. In some other embodiments,
the maximum daily dose is about 75 mg, 150 mg, 180 mg once a day,
or 360 mg, 240 mg, or 90 mg twice a day.
[0151] In some embodiments, the effectiveness of a dosage regimen
can be determined by evaluation via a Pruritis Visual Analog Scale
(VAS) test. In other embodiments, determining the effectiveness of
the dose of nalbuphine can include evaluation of the patient's
uremic pruritus symptoms using an instrument selected from the
group consisting of Pruritis Visual Analog Scale (VAS) test, Brief
Itching Inventory, Skindex-10, Itch MOS of sleep, Beck Depression
Index, and Patient Categorization of Pruritus Disease Severity.
[0152] In some embodiments, a patient can be treated initially with
a twice-daily dosing regimen, and then after titrating either the
first daily dose, the second daily dose, or both to arrive at a
total daily dose effective to treat the patient's uremic pruritus
symptoms, the dosage regimen can be changed to a once-daily dosage.
Each dose of the twice daily dosage can then be further titrated as
described hereinabove to provide a therapeutically effective once
daily dosage of nalbuphine. Thus, in some embodiments, the dosage
regimen is a twice-daily dose, and each of the first and second
doses can be titrated to achieve maximum therapeutic effect and/or
minimal side effect severity. Accordingly, in some embodiments each
of the first and second doses in a twice-daily dosage regimen may
be from about 5 mg to about 180 mg (e.g., about 5 mg, about 10 mg,
about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,
about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg,
about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg,
about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg,
about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135
mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about
160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, or
any other value or range of values therein).
[0153] In some embodiments, each of the first and second daily
doses in a twice daily dosage regimen may be independently titrated
in an amount of from about 5 mg to about 180 mg (e.g., about 5 mg,
about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg,
about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg,
about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg,
about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg,
about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130
mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about
155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg,
about 180 mg, or any other value or range of values therein). The
first and second doses in a twice-daily dosage regimen may be
independently titrated in one or more steps. The amount a dosage is
stepped, where there are multiple titration steps, can be the same,
or can be different.
[0154] Accordingly, the total daily dose in a twice daily dosing
regimen, including baseline dose for each administration and one or
more titration doses for each administration independently, may be
from about 5 mg a day to about 360 mg a day (e.g., about 15 mg a
day, about 20 mg a day, about 25 mg a day, about 30 mg a day, about
35 mg a day, about 40 mg a day, about 45 mg a day, about 50 mg a
day, about 55 mg a day, about 60 mg a day, about 65 mg a day, about
70 mg a day, about 75 mg a day, about 80 mg a day, about 85 mg a
day, about 90 mg a day, about 95 mg a day, about 100 mg a day,
about 105 mg a day, about 110 mg a day, about 115 mg a day, about
120 mg a day, about 125 mg a day, about 130 mg a day, about 135 mg
a day, about 140 mg a day, about 145 mg a day, about 150 mg a day,
about 155 mg a day, about 160 mg a day, about 165 mg a day, about
170 mg a day, about 175 mg a day, about 180 mg a day, about 185 mg
a day, about 190 mg a day, about 195 mg a day, about 200 mg a day,
about 205 mg a day, about 210 mg a day, about 215 mg a day, about
220 mg a day, about 225 mg a day, about 230 mg a day, about 235 mg
a day, about 240 mg a day, about 245 mg a day, about 250 mg a day,
about 255 mg a day, about 260 mg a day, about 265 mg a day, about
270 mg a day, about 275 mg a day, about 280 mg a day, about 285 mg
a day, about 290 mg a day, about 295 mg a day, about 300 mg a day,
about 305 mg a day, about 310 mg a day, about 315 mg a day, about
320 mg a day, about 325 mg a day, about 330 mg a day, about 335 mg
a day, about 340 mg a day, about 345 mg a day, about 350 mg a day,
about 355 mg a day, about 360 mg a day, or any other value or range
of values therein).
[0155] In some embodiments, the present methods employ a thrice
daily dosage regimen, and the first daily dose is less than the
second and third daily doses. For example, in some embodiments, the
second and third daily doses may each independently be from about 5
mg to about 180 mg greater than the first daily dose (e.g., about 5
mg greater, about 10 mg greater, about 15 mg greater, about 20 mg
greater, about 25 mg greater, about 30 mg greater, about 35 mg
greater, about 40 mg greater, about 45 mg greater, about 50 mg
greater, about 55 mg greater, about 60 mg greater, about 65 mg
greater, about 70 mg greater, about 75 mg greater, about 80 mg
greater, about 85 mg greater, about 90 mg greater, about 95 mg
greater, about 100 mg greater, about 105 mg greater, about 110 mg
greater, about 115 mg greater, about 120 mg greater, about 125 mg
greater, about 130 mg greater, about 135 mg greater, about 140 mg
greater, about 145 mg greater, about 150 mg greater, about 155 mg
greater, about 160 mg greater, about 165 mg greater, about 170 mg
greater, about 175 mg greater, about 180 mg greater, or any other
value or range of values therein).
[0156] In some embodiments, each of the first, second and third
doses in a thrice-daily dosing regimen of nalbuphine can be
selected as described above, and then titrated upward until the
patient experiences satisfactory relief from the pruritic
condition. Titrating the dose can include administering a baseline
dose, then after a period of observation at the baseline dose value
to determine the efficacy, renal clearance, and/or side effect
severity, of the baseline dose, increasing the dose if the subject
does not experience adequate symptom relief. The period of period
of observation at the baseline for any of the first, second and
third doses independently can be from about 1 day to about 21 days
(e.g., about 1 day, about 2 days, about 3 days, about 4 days, about
5 days, about 6 days, about 7 days, about 8 days, about 9 days,
about 10 days, about 11 days, about 12 days, about 13 days, about
14 days, about 15 days, about 16 days, about 17 days, about 18
days, about 19 days, about 20 days, about 21 days). The dose (e.g.,
any one of three doses in a thrice daily dosing regimen) can be
titrated in increments ranging from about 5 mg to about 180 mg
(e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25
mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50
mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75
mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100
mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about
125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg,
about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170
mg, about 175 mg, about 180 mg, or any other value or range of
values therein). The second daily dose can be titrated in one or
more steps. The amount a dosage is stepped, where there are
multiple titration steps, can be the same, or can be different.
[0157] In other embodiments, the present methods employ a thrice
daily dosage regimen, and the first daily dose is greater than the
second and third daily doses. For example, in some embodiments, the
first daily dose is from about 5 mg to about 180 mg greater than
the second and third daily doses (e.g., about 5 mg greater, about
10 mg greater, about 15 mg greater, about 20 mg greater, about 25
mg greater, about 30 mg greater, about 35 mg greater, about 40 mg
greater, about 45 mg greater, about 50 mg greater, about 55 mg
greater, about 60 mg greater, about 65 mg greater, about 70 mg
greater, about 75 mg greater, about 80 mg greater, about 85 mg
greater, about 90 mg greater, about 95 mg greater, about 100 mg
greater, about 105 mg greater, about 110 mg greater, about 115 mg
greater, about 120 mg greater, about 125 mg greater, about 130 mg
greater, about 135 mg greater, about 140 mg greater, about 145 mg
greater, about 150 mg greater, about 155 mg greater, about 160 mg
greater, about 165 mg greater, about 170 mg greater, about 175 mg
greater, about 180 mg greater, or any other value or range of
values therein).
[0158] In some embodiments, the each of the first, second and third
doses in a thrice-daily dosing regimen can be selected as described
above, and then titrated upward until the patient experiences
satisfactory relief from the pruritic condition. Titrating the dose
can include administering a baseline dose, then after a period of
observation at the baseline dose value to determine the efficacy of
the baseline dose, renal clearance, and/or side effect severity,
increasing the dose if the subject does not experience adequate
symptom relief. The baseline dose may be from about 5 mg to about
180 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg,
about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg,
about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg,
about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg,
about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120
mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about
145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg,
about 170 mg, about 175 mg, about 180 mg, or any other value or
range of values therein).
[0159] The titration dose can be in increments ranging from about 5
mg to about 180 mg (e.g., about 5 mg, about 10 mg, about 15 mg,
about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,
about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg,
about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,
about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115
mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about
140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg,
about 165 mg, about 170 mg, about 175 mg, about 180 mg, or any
other value or range of values therein). Each of the first, second
and third doses can be titrated in one or more steps. The amount a
dosage is stepped, where there are multiple titration steps, can be
the same, or can be different. Accordingly, the total daily dose in
a thrice daily dosing regimen with a titration dose, including
baseline doses and one or more titration doses, may be from about 5
mg to about 180 mg (e.g., about 5 mg, about 10 mg, about 15 mg,
about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,
about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg,
about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,
about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115
mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about
140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg,
about 165 mg, about 170 mg, about 175 mg, about 180 mg, or any
other value or range of values therein).
[0160] Accordingly, the total daily dose in a thrice daily dosing
regimen, including baseline dose for each administration and one or
more titration doses for each administration independently, may be
from about 5 mg a day to about 360 mg a day (e.g., about 15 mg a
day, about 20 mg a day, about 25 mg a day, about 30 mg a day, about
35 mg a day, about 40 mg a day, about 45 mg a day, about 50 mg a
day, about 55 mg a day, about 60 mg a day, about 65 mg a day, about
70 mg a day, about 75 mg a day, about 80 mg a day, about 85 mg a
day, about 90 mg a day, about 95 mg a day, about 100 mg a day,
about 105 mg a day, about 110 mg a day, about 115 mg a day, about
120 mg a day, about 125 mg a day, about 130 mg a day, about 135 mg
a day, about 140 mg a day, about 145 mg a day, about 150 mg a day,
about 155 mg a day, about 160 mg a day, about 165 mg a day, about
170 mg a day, about 175 mg a day, about 180 mg a day, about 185 mg
a day, about 190 mg a day, about 195 mg a day, about 200 mg a day,
about 205 mg a day, about 210 mg a day, about 215 mg a day, about
220 mg a day, about 225 mg a day, about 230 mg a day, about 235 mg
a day, about 240 mg a day, about 245 mg a day, about 250 mg a day,
about 255 mg a day, about 260 mg a day, about 265 mg a day, about
270 mg a day, about 275 mg a day, about 280 mg a day, about 285 mg
a day, about 290 mg a day, about 295 mg a day, about 300 mg a day,
about 305 mg a day, about 310 mg a day, about 315 mg a day, about
320 mg a day, about 325 mg a day, about 330 mg a day, about 335 mg
a day, about 340 mg a day, about 345 mg a day, about 350 mg a day,
about 355 mg a day, about 360 mg a day, or any other value or range
of values therein).
[0161] In some embodiments, a patient can be treated initially with
a thrice-daily dosing regimen, and then after titrating either the
first daily dose, the second daily dose, and/or the third daily to
arrive at a total daily dose effective to treat the patient's
uremic pruritus symptoms, the dosage regimen can be changed to
either a twice-daily dosage or a once-daily dosage. Each dose of
the thrice-daily dosage can be further titrated as described
hereinabove to arrive at a therapeutically effective once daily
dosage of nalbuphine.
[0162] In still other embodiment, the second dose in a thrice-daily
dosing regimen may be greater than the first and third doses. In
still other embodiments, the third daily dose may be greater than
each of the first and second doses. Furthermore, as described
above, each of the first, second and third doses in a thrice-daily
regimen may be titrated independently of the other two doses, to
arrive at a therapeutically efficacious dosing regimen.
[0163] In some embodiments, the single daily dosage can be
administered in the evening or before bedtime. In other
embodiments, the single daily dosage can be administered in the
morning. In some embodiments, the single daily dose can be
administered around midday (e.g., from about 11 am to about 1 pm).
In twice-daily dosing regimens, the two doses may be administered
in the morning and evening. In a thrice daily dosing regimen, the
three doses may be administered with one dose given in the morning,
one dose given at midday and one dose given in the evening.
[0164] In some embodiments, the present methods include treating
uremic pruritus in human patients, comprising administering to a
human patient suffering from uremic pruritus an effective amount of
a medication consisting of a pharmaceutical compound which is a
.mu.-opioid receptor antagonist and a pharmaceutical compound which
is a .kappa.-opioid receptor agonist, or pharmaceutically
acceptable salts or esters thereof. In certain embodiments, the
pharmaceutical compound which is a .mu.-opioid receptor antagonist
and the pharmaceutical compound which is a .kappa.-opioid receptor
agonist are the same. In some embodiments, the compound is
nalbuphine.
Nalbuphine Use in Patients with Reduced Renal Function
[0165] The safe use of opioids presents challenges in patients with
chronic renal failure as the renal clearance of the opioids and
their metabolites is an important elimination pathway for this
class of drugs. One of the most commonly used opioids, morphine, is
not recommended for use in patients with chronic renal failure, and
if used, needs to be carefully monitored. While the T 1/2 (2-3 hr)
of morphine is not changed in patients with renal failure (likely
because morphine is largely converted by the liver into its
respective glucuronide conjugates M3G and M6G), the T 1/2 of its
glucuronide conjugates is substantially prolonged in these patients
(Niscola et al., Curr Drug Targets 2010 11(6) 752-8). The T 1/2 of
M3G is reported to increase from roughly 4-6 hours to .about.50
hours and the T 1/2 for M6G is reported to increase from roughly 2
hours to 27 hours in patients with renal failure. As M6G has a
similar spectrum of pharmacologic activity as morphine, its
accumulation in patients with renal failure can lead to CNS and
respiratory depression. M6G slowly penetrates the CNS (Mercadante
et al., Journal of Pain 2004 (5) 2-19; Dean, J Pain Symptom Manage
2004 28(5) 497-504) therefore CNS and respiratory depression can
occur at times lagging behind the Cmax of morphine, and it is only
slowly removed from the CNS by dialysis. As M3G has purported
neurostimulant activity, its accumulation is not as problematic as
accumulation of M6G.
[0166] In contrast, hydromorphone has a better safety profile in
patients with chronic renal failure and its use in this patient
population is recommended. This is likely because the analogous
6-glucuronide of hydromorphone is not formed in measurable
quantities in humans (Dean, supra; see also Smith, Mayo Clin Proc.
2009 (84) 613-624) and only the 3-glucuronide (H3G) is formed but
does not cause CNS or respiratory depression (Niscola, supra).
Similar to findings with morphine, hydromorphone does not
accumulate in patients with chronic renal failure, but substantial
accumulation of the H3G moiety does occur (the T 1/2 of H3G
increases from .about.3 hours while on dialysis to 33 hours between
dialysis sessions) (Davison and Mayo, Journal of Opioid Management
2008 (4) 335-344). Dialysis does not appear to remove
hydromorphone, but it does not accumulate because it is rapidly
metabolized to H3G, and H3G is removed during dialysis (Davison,
2008).
[0167] As discussed above, patients suffering from renal
dysfunction or renal failure may not be able to clear fluids and or
waste products normally removed by the kidneys. When healthy, the
kidneys maintain the body's internal equilibrium of water and
minerals (e.g., sodium, potassium, chloride, calcium, phosphorus,
magnesium, sulfate, etc.). Dialysis is a process for removing waste
and excess water from the blood, and is used primarily to partially
replace kidney function in patients with renal failure. Dialysis
treatments replace some of these functions through diffusion (e.g.,
for waste removal) and ultrafiltration (e.g., for fluid removal).
Dialysis can be used for those with an acute disturbance in kidney
function (acute kidney injury, previously acute renal failure), or
progressive but chronically worsening kidney function (e.g.,
chronic renal failure or end-stage renal disease).
[0168] In some embodiments, methods of the present invention are
used to treat patients with reduced renal function, e.g., less than
normal renal function as measured by any suitable means known to
one skilled in the art. In certain embodiments, the patient can
have less than 100% of normal renal function, less than 95% renal
function, less than 90% renal function, less than 85% renal
function, less than 80% renal function, less than 75% renal
function, less than 70% renal function, less than 65% renal
function, less than 60% renal function, less than 55% renal
function, less than 50% renal function, less than 45% renal
function, less than 40% renal function, less than 35% renal
function, less than 30% renal function, less than 25% renal
function, less than 20% renal function, less than 15% renal
function, less than 10% renal function, less than 5% renal
function, or any other value or range of values therein.
[0169] Since uremic pruritus is associated with renal disease
and/or renal failure, patients treated in accord with the present
methods are usually concurrently treated with dialysis (e.g.,
hemodialysis, peritoneal dialysis). In certain embodiments, the
anti-pruritus agent employed in the present methods is at least
about 50% dialyzable when administered to the patient under the
treatment of dialysis. The term "at least 50% dialyzable" means the
amount of anti-pruritus agent, or metabolite(s) thereof (depending
upon context) which is removed during dialysis. In other
embodiments, the anti-pruritus agent is at least about 5%
dialyzable, at least about 10% dialyzable, at least about 15%
dialyzable, at least about 20% dialyzable, at least about 25%
dialyzable, at least about 30% dialyzable, at least about 35%
dialyzable, at least about 40% dialyzable, at least about 45%
dialyzable, at least about 50% dialyzable, at least about 55%
dialyzable, at least about 60% dialyzable, at least about 65%
dialyzable, at least about 70% dialyzable, or at least about 75%
dialyzable, at least about 80% dialyzable, at least about 85%
dialyzable, at least about 90% dialyzable, at least about 95%
dialyzable, or any other value or range of values therein. In some
embodiments, the anti-pruritus agent is not dialyzable.
[0170] In other embodiments, one or more metabolites of the
anti-pruritus agent is/are at least 50% dialyzable. In other
embodiments, one or more metabolites of the anti-pruritus agent
is/are at least about 5% dialyzable, at least about 10% dialyzable,
at least about 15% dialyzable, at least about 20% dialyzable, at
least about 25% dialyzable, at least about 30% dialyzable, at least
about 35% dialyzable, at least about 40% dialyzable, at least about
45% dialyzable, at least about 50% dialyzable, at least about 55%
dialyzable, at least about 60% dialyzable, at least about 65%
dialyzable, at least about 70% dialyzable, or at least about 75%
dialyzable, at least about 80% dialyzable, at least about 85%
dialyzable, at least about 90% dialyzable, at least about 95%
dialyzable, or any other value or range of values therein. In some
embodiments, one or more metabolites of the anti-pruritus agent
is/are not dialyzable. In certain embodiments, the anti-pruritic
agent is nalbuphine, and the metabolites include glucuronides (most
likely on the phenol and cyclohexane rings), two hydroxylated
nalbuphine metabolites (on the cyclobutane ring) and three ketones
(hydroxylation of the cyclobutane ring, followed by oxidation to a
carbonyl). In some embodiments, the nalbuphine metabolites include
nornalbuphine, 6-ketonalbuphine and nalbuphine 3-glucuronide. In
certain embodiments, the one or more metabolites of the
anti-pruritus agent do not have detectable anti-pruritus activity.
In other embodiments, one or more of the metabolites of the
anti-pruritus agent exhibit anti-pruritus activity. In embodiments
wherein one or more metabolites of the anti-pruritus agent exhibit
anti-pruritus activity, the dosing regimen of the anti-pruritus
agent may be adjusted and/or titrated as described hereinabove
depending on the clearance rate of the one or more metabolites
exhibiting anti-pruritic activity. Such dosage adjustment and/or
titration of the dosage of the anti-pruritic agent can be performed
to prevent accumulation of either the anti-pruritic agent and/or
one or more metabolites, which can also exhibit anti-pruritic
activity, to avoid toxicity effects in a patient treated with the
present anti-pruritic agent.
[0171] In some embodiments, the anti-pruritus agent is completely
metabolized (e.g., about 100% metabolized). In other embodiments,
the anti-pruritus agent is not completely metabolized (e.g., less
than about 100% metabolized). For example, in some embodiments, the
anti-pruritus agent is about 100% metabolized, about 95%
metabolized, about 90% metabolized, about 85% metabolized, about
80% metabolized, about 75% metabolized, about 70% metabolized,
about 65% metabolized, about 60% metabolized, about 55%
metabolized, about 50% metabolized, about 45% metabolized, about
40% metabolized, about 35% metabolized, about 25% metabolized,
about 20% metabolized, about 15% metabolized, about 10%
metabolized, about 5% metabolized, about 1% metabolized, or about
0% metabolized.
[0172] In certain embodiments, the amount of dialyzable
anti-pruritus agent can be measured or monitored by the level of
accumulation, e.g., blood plasma level of the anti-pruritus agent
or one or more of its metabolites.
[0173] In some embodiments, the present methods can further
comprise monitoring the plasma concentration of either an
anti-pruritic agent, or one or more metabolites thereof. Such
monitoring can be performed via measurement of the concentration of
the anti-pruritic agent, or one or more metabolites thereof, in the
blood of a patient via routine blood testing. Such testing can be
conducted at suitable intervals to determine the peak blood plasma
concentration of the anti-pruritic agent, or one or more
metabolites thereof. As described above, patients undergoing
dialysis, or with reduced renal function, can be prone to buildup
of the anti-pruritic agent, or one or more metabolites thereof.
Accordingly, titration of dosage as described hereinabove can also
be conducted via blood testing (in addition to qualitative measures
described hereinabove for determining therapeutic levels of
pruritus relief) to maintain safe levels of the anti-pruritic
agent, or one or more metabolites thereof, in the present methods.
Once a clearance rate of the anti-pruritic agent, or one or more
metabolites thereof, in a patient with reduced renal function,
either with or without dialysis, is established, an appropriate
dosing regimen can be selected to provide target C.sub.max and
AUC.sub.(0-.infin.) ranges as described herein above.
[0174] Thus, in certain embodiments, the present methods can be
employed with patients in treatment including pre-treatment, under
treatment, or post-treatment of dialysis. In certain embodiments,
the patient treated with the present methods can have chronic
kidney disease or reduced renal function, e.g., regardless of
etiology.
[0175] The following non-limiting examples illustrate various
aspects of the present invention.
EXAMPLES
Examples 1 to 3
[0176] Three sustained release delivery systems were prepared by
dry blending xanthan gum, locust bean gum, calcium sulfate
dihydrate, and mannitol in a high speed mixed/granulator for 3
minutes. While running choppers/impellers, water was sprayed to the
dry blended mixture, and granulated for another 6 minutes. Then the
granulation process was stopped and the mixer/granulation bowl was
scraped. While running choppers/impellers, the granulation was
mixed for one more minute. After the granulation was checked for
consistency, while running choppers/impellers additional water was
added to the granulation and granulated for additional 3.5 minutes.
The granulation was then dried to LOD (loss on drying) of less than
about 4% by weight. The granulation was then milled using screen
#1521-0033. The relative quantities of the ingredients are listed
in Table 1.
TABLE-US-00001 TABLE 1 Sustained Release Delivery Example 1 Example
2 Example 3 System Excipient % % % Xanthan Gum, NF 8.0 12.0 20.0
Locust Bean Gum, FCC 12.0 18.0 30.0 Mannitol, USP 70.0 60.0 40.0
Calcium Sulfate Dihydrate, NF 10.0 10.0 10.0 Sterile Water for
Injection, USP.sup.1 -- -- -- Total 100.0 100.0 100.0 .sup.1Sterile
Water for Injection, USP is removed during processing
Examples 4 to 7
[0177] A series of tablets containing different amounts of gum were
prepared using the sustained release delivery system of Example 3.
The quantities of ingredients per tablet are listed in Table 2.
TABLE-US-00002 TABLE 2 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Component mg mg mg
mg Nalbuphine 60 60 60 60 HCI, USP Sustained 60.sup.1 120.sup.1
180.sup.1 90.sup.1 release delivery system Magnesium 0.5 1.8 1.2
0.75 stearate, NF Total Weight 120.5 181.8 241.2 150.75 Active:Gum
1:0.5 1:1 1:1.5 1:0.75 Tooling Size 0.2812'' 0.2812'' 0.3125''
0.2812'' Hardness (Kp) 1.2 8.8 8.9 7.2 .sup.1Sustained release
system of Example 3
[0178] The tablets were prepared by mixing nalbuphine with the
sustained release delivery system in a mixer. The magnesium
stearate was passed through a #30 mesh screen sieve and then mixed
with the dry blend containing nalbuphine and the sustained release
delivery system. This lubricated blend was compressed using the
tooling as specified in Table 2 to make tablets of the total weight
indicated.
[0179] The tablets of Examples 4-7 were tested for in vitro %
release rate according to USP Procedure Drug Release General
Chapter <711> Dissolution, using apparatus USP Type 111/250
mL. The test was performed at pH 6.8, 37.degree. C./15 dpm (dips
per minute) in 100 mM ammonium phosphate buffer. The results are
shown in Table 3.
TABLE-US-00003 TABLE 3 Dissolution Time Example 4 Example 5 Example
6 Example 7 (hours) pH 6.8 pH 6.8 pH 6.8 pH 6.8 0 0 0 0 0 1 29.3
23.8 19.5 25.0 2 41.8 35.1 29.4 35.9 4 59.2 51.7 45.0 53.0 6 72.9
65.6 56.4 67.1 8 84.2 77.8 65.3 79.6 12 98.1 92.9 81.0 93.9 Remnant
4.3 6.9 16.3 6.0 % Recovery 102.4 98.8 97.3 99.9
Examples 8 to 10
[0180] A series of tablets containing different amounts of gum and
different sustained release delivery systems were prepared using
the sustained release delivery systems of Examples 1 and 2. The
quantities of ingredients per tablet are listed in Table 4.
TABLE-US-00004 TABLE 4 Ext. 8 Ex. 9 Ex. 10 Component mg Mg mg
Nalbuphine 60 60 60 HCI, USP Sustained 225.sup.2 150.sup.3
100.sup.3 release delivery system Magnesium 1.43 1.1 0.8 stearate
Total weight 286.4 211.1 160.8 Active:Gum 1:0.75 1:0.75 1:0.5
Tooling Size 0.3125'' 0.3125'' 0.2812'' Hardness (Kp) 20 17 20
.sup.2Sustained release delivery system of Example 1
.sup.3Sustained release delivery system of Example 2
[0181] The tablets were prepared by first mixing nalbuphine with
the sustained release delivery system in a mixer for Example 8 and
in a high shear granulator for Example 9 and 10. For Examples 9 and
10, the blend was then granulated with water until consistent
granulation was achieved, followed by drying in a fluidized bed
dryer for 30 minutes at 70.degree. C. The dried granules were then
passed through a Fitzmill at 2500 rpm using 1521-0050 screen. The
magnesium stearate was passed through a #30 mesh screen sieve, and
then mixed with the milled granules for Examples 9 and 10 and with
the dry blend for Example 8 for 5 minutes. The lubricated blend was
compressed using the tooling as specified in Table 4 to make
tablets of the total weight indicated.
[0182] The tablets of Examples 8-10 were tested for in vitro %
release rate according to USP Procedure Drug Release General
Chapter <711> Dissolution, using apparatus USP Type III/250
mL. The test was performed in pH change, at 37.degree. C./15 dpm.
The pH change was as follows: pH 1.2 for the first hour, pH 4.5 for
the second hour, and pH 6.8 after the second hour and through the
duration of the test. The results are shown in Table 5.
TABLE-US-00005 TABLE 5 Dissolution Example 8 Example 9 Example 10
Time (hours) pH change pH change pH change 0 0.0 0 0 1 19.4 18.8
22.5 2 36.4 39.7 45.3 4 59.0 66.3 73.2 6 72.5 82.6 89 8 79.4 89.8
95.9 12 82.1 92.3 100.1 Remnant 0.1 0.1 0.8 % Recovery 82.2 92.4
100.9
Examples 11 to 16
[0183] To determine the effect of the amount of gum in combination
with microcrystalline cellulose (Emococel 90M), six batches of
tablets were prepared using the sustained release delivery system
of Example 3. The range of Active: Gum ratios used in Examples
11-16 varied between 1:0.25 and 1:0.5. Compositions of the tablets
are shown in Table 6.
TABLE-US-00006 TABLE 6 Ex. 11 Ex. 12 Ex. 13 Ex. 14 Ex. 15 Ex. 16
Ingredient mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab Sustained
release .sup. 30.sup.4 .sup. 60.sup.4 .sup. 60.sup.4 .sup. 30.sup.4
.sup. 60.sup.4 .sup. 60.sup.4 delivery system Nalbuphine HCl 60 60
60 60 60 60 Microcrystalline 30 30 60 60 120 -- Cellulose Magnesium
stearate 0.6 0.8 0.9 0.8 1.2 0.6 Total Weight (mg) 120.6 150.8
180.9 150.8 241.2 120.6 Active:Gum 1:0.25 1:0.5 1:0.5 1:0.25 1:0.5
1:0.5 Tooling Size 0.2500'' 0.2812'' 0.2812'' 0.2812'' 0.3125''
0.2500'' Hardness (Kp) 10.2 10 12 13 22 13.2 .sup.4Sustained
release delivery system of Example 3
[0184] The tablets of Examples 11-15 were prepared by first sifting
magnesium stearate through #30 mesh screen sieve. Then blend
nalbuphine with the sustained release delivery system, and
magnesium stearate in a blender for 5 minutes. The lubricated blend
was compressed using the tooling as specified in Table 6 to make
tablets of the total weight indicated.
[0185] The tablets of Example 16 were prepared by mixing nalbuphine
in a high shear granulator with the sustained release delivery
system. The blend was then granulated with water until consistent
granulation was achieved. The granulation is then dried in a
fluidized bed dryer for 40 minutes at 70.degree. C. The dried
granules were then passed through a Fitzmill at 2500 rpm using
1521-0050 screen. The magnesium stearate was passed through a 430
mesh screen sieve and then mixed with the milled granules for 5
minutes. The lubricated blend was compressed using the tooling as
specified in Table 6 to make tablets of the total weight
indicated.
[0186] The tablets of Examples 11-16 were tested for in vitro %
release rate according to USP Procedure Drug Release General
Chapter <711> Dissolution, using apparatus USP Type III/250
mL. The test was performed in pH change, at 37.degree. C./15 dpm,
as described above for Examples 8-10. The results are shown in
Table 7.
TABLE-US-00007 TABLE 7 Dissolution time Ex. 11 Ex. 12 Ex. 13 Ex. 14
Ex. 15 Ex. 16 (hours) pH change pH change pH change pH change pH
change pH change 0 0.0 0.0 0.0 0.0 0.0 0.0 1 93.2 59.4 94.5 93.4
92.1 17.1 2 94.4 73.0 96.0 94.8 93.4 39.7 4 94.5 84.5 96.0 94.8
93.5 64.4 6 94.5 87.4 96.0 94.8 93.5 74.6 8 94.5 88.7 96.0 94.8
93.5 81.5 12 94.5 90.2 96.0 94.8 93.5 93.1 Remnant 0.0 1.2 0.0 0.0
0.0 7.0 % Recovery 94.5 91.5 96.0 94.8 93.5 100.1
Examples 17 and 18
[0187] Two batches of bi-layer tablets were prepared using the
sustained release delivery system of Example 2 (Examples 17 and
18). In the bi-layer tablets, the first layer of the tablets was
formulated to provide relatively a slow sustained release; the
second layer was formulated to provide relatively fast (immediate)
release. The in vitro dissolution profiles of the bi-layer tablets
were compared to the dissolution profile of single layer tablets
that were formulated to provide a sustained release (Example 9).
Compositions of the tablets are shown in Table 8.
TABLE-US-00008 TABLE 8 Example 17 Example 18 Example 9 Ingredient
mg/tab mg/tab mg/tab Extended release layer (ER) Sustained release
delivery 112.5.sup.5 112.9.sup.5 150 system Nalbuphine HCI 45 45 60
Magnesium stearate 0.8 0.8 1.1 ER weight 158.3 158.3 211.1
Immediate release layer (IR) Sustained release delivery 6.0.sup.5
N/A system Nalbuphine HCI 15.0 N/A Microcrystalline Cellulose, 35.7
N/A NF (Emcocel 90 M) Croscarmellose Sodium, NF 3.0 N/A (Primellose
.RTM.) Magnesium stearate, NF 0.3 N/A IR Weight 60.0 N/A Total
Weight 218.3 218.3 211.1 Active:Gum 1:0.6 1:0.6 1:0.75 Tooling Size
0.2812'' 0.2812'' 0.3125'' Hardness N/A N/A 17 .sup.5Sustained
release delivery system of Example 2
[0188] For the extended release layer, the nalbuphine was mixed
with the sustained release delivery system in a high shear
granulator for 3 minutes. The mixture was granulated with water
until consistent granulation was achieved, then the wet mass was
dried in a fluidized bed dryer for 20 minutes at 70.degree. C. The
dried granules were then passed through a Fitzmill at 2500 rpm
using 1521-0050 screen. For the immediate release layer, the
nalbuphine was blended with the sustained release delivery system,
microcrystalline cellulose (Emcocel.RTM. 90M), and croscarmellose
sodium, NF (Primellose.RTM.) in a V-Blender for 10 minutes. The
magnesium stearate was passed through a #30 mesh screen sieve. The
milled granules of the slow release layer was mixed with the sieved
magnesium stearate in a V-blender for 5 minutes and the dry blend
of the immediate release layer was mixed with the sieved magnesium
stearate in a V-blender for 5 minutes, separately. This lubricated
blend of the extended release layer and the immediate release layer
were then compressed into bi-layer tablets using the tooling
specified in Table 8, to make the tablets of the total weight
indicated.
[0189] The tablets of Examples 17-18 were tested for in vitro %
release rate according to USP Procedure Drug Release USP General
Chapter <711> Dissolution, using apparatus USP Type III/250
mL. The test was performed in pH change as described above for
Examples 8-10, at 37.degree. C./15 dpm, as described above for
Examples 8-10. The results are shown in Table 9. For purposes of
comparing the dissolution profiles of the bi-layer tablets with a
single-layer tablet, the dissolution data for Example 9 is also
shown in Table 9.
TABLE-US-00009 TABLE 9 Dissolution Ex. 17 Ex. 18 Ex. 9 time (hours)
pH change pH change pH change 0 0 0.0 0 1 44.5 42.6 18.0 2 62.8
62.7 39.7 4 83.1 84.3 66.3 6 92.3 92.3 82.6 8 94.0 93.7 89.8 12
94.0 93.9 92.3 Remnant 0.0 0 0.1 % Recovery 94.1 93.9 92.4
Examples 19 and 20
[0190] For a clinical study, one batch of bi-layer tablets and one
batch of single layer tablets were prepared using the sustained
release delivery system of Example 2. The first layer of the
tablets was formulated to provide relatively a slow sustained
release; the second layer was formulated to provide relatively fast
(immediate release). Compositions of the tablets are shown in Table
10.
TABLE-US-00010 TABLE 10 Component Amount mg/tablet (%) Ingredient
Example 19(F-2) Example 20(F-1) Extended release player (ER)
Sustained Release Excipient (30%) 112.5.sup.6 150.0.sup.6
Nalbuphine HCI 45.0 60.0 Magnesium stearate, NF 0.8 1.10 Sterile
Water for Injection, USP.cndot. .cndot. .cndot. Mg/tablet weight
(ER portion) 158.3 211.1 Immediate release layer (IR) Nalbuphine
HCI 15.0 Microcrystalline Cellulose, NF 41.7 Croscarmellose Sodium,
NF 3.0 Magnesium stearate, NF 0.3 Mg/tablet weight (IR portion)
60.0 Total Weight (mg/tablet) 218.3 211.1 Type of tablet
Bi-layer(ER/IR) Single layer (ER) Active to Gum Ratio 1:0.75 1:0.75
Tooling Size 0.3125 0.3125 Hardness ~11 Kp ~11 Kp .cndot. Sterile
Water for Injection, USP is removed during process .sup.6Sustained
release delivery system of Example 2
[0191] For the extended release layer of Example 19 and 20, the
nalbuphine was mixed with the sustained release delivery system in
a high shear granulator (6-liter Diosna-Pharma Mixer 1/6) for 5
minutes with the impeller speed at 300 rpm and the chopper off.
After the mixer stopped, the bowl was scraped and sample was taken
for LOD. While the impeller and the chopper are running at 300 rpm,
the mixture was granulated with water for 2 minutes. After the
mixer stopped, the bowl was scraped. While impeller speed is
running at 500 rpm and the chopper speed at 300 rpm, the
granulation was continued by mixing for an additional 1 minute. At
the end of mixing the bowel was scraped. While the impeller and
chopper were running at 300 rpm, additional of water (about 50.0 g)
was added and granulated for 2 minutes in Example 19 and for 1
minute in Example 20. To achieve consistent granules, the
granulation was mixed for additional 3 minutes in Example 19 and 1
minute in Example 20, while the impeller and chopper were running
at 500 and 300 rpm, respectively. Then the wet mass was dried in a
Uni-Glatt fluid bed dryer for 30 minutes at 70.degree. C. The dried
granules were then passed through a Fitzmill, knives forward, with
the speed of 2200-2700 rpm using 1521-0033 screen. The magnesium
stearate was passed through a #30 mesh screen sieve. The milled
granules of the extended release layer for Example 19 and 20 were
mixed separately with the sieved magnesium stearate in a V-blender
with a 4-quart stainless steel shell for 5 minutes.
[0192] For Example 20, the lubricated blend of the extended release
layer was compressed into single layer tablets with the Piccola
tablet press using the tooling specified in Table 11, to make the
tablets of the total weight indicated.
[0193] In the immediate release layer portion of Example 19, the
nalbuphine was blended with the microcrystalline cellulose (Emcocel
90M) in a P-K Blend Master V-Blender for 5 minutes. To the mixture,
croscarmellose sodium, NF (Primellose.RTM.) was added and mixed for
5 minutes. The magnesium stearate was passed through a #30 mesh
screen sieve. The milled granules of the extended release layer
portion of Example 19 was mixed with the sieved magnesium stearate
in a V-blender with a 4-quart stainless steel shell for 5 minutes
and the dry blend of the immediate release layer portion was mixed
with the sieved magnesium stearate in a V-blender with a 4-quart
stainless steel shell for 5 minutes, separately. This lubricated
blend of the extended release layer portion and the immediate
release layer portion were then compressed into bi-layer tablets
with the Piccola tablet press using the tooling specified in Table
10, to make the tablets of the total weight indicated.
[0194] The tablets of Examples 19-20 were tested for in vitro %
release rate according to USP Procedure Drug Release USP General
Chapter <711> Dissolution, using apparatus USP Type III/250
mL. The test was performed in pH 6.8, at 37.degree. C./15 dpm. The
results are shown in Table 11.
TABLE-US-00011 TABLE 11 Dissolution Time (h) Example 19(F-2)
Example 20(F-1) 0 0 0 1 47 26 3 69 51 4 77 61 6 88 76 8 95 86 12 99
96 Remnant 0 2 Recovery 99 98
[0195] These data demonstrate that the dissolution rate from the
bi-layer (ER/IR) formulation (Example 19(F-2)) was about 21% and
16% faster than the rate from the single layer (ER) formulation
(Example 20(F-1)) at 1 and 4 hours time point, respectively.
Clinical Study
[0196] A Phase I, open label, five treatment arm, single dose
escalation study under fasting conditions was conducted and
pharmacokinetic data were obtained with the following formulations:
a) the sustained delivery system-nalbuphine 60 mg bi-layer tablet
(IR/ER) (Example 19 (F-2)), b) the sustained delivery
system-nalbuphine 60 mg single layer tablet (ER) (Example 20
(F-1)), c) two tablets of the 60 mg single layer tablet (ER, 120 mg
total dose), d) three tablets of the 60 mg single layer tablet (ER,
180 mg total dose) and e) a dose of nalbuphine immediate release 60
mg oral solution (control). Eleven healthy volunteers were
initially enrolled with six subjects completing all five
treatments. The pharmacokinetic data are summarized below both as
arithmetic and geometric mean results. The mean blood level
("plasma") concentration of nalbuphine for each time point is shown
in Table 16. A logarithmic graph of the mean nalbuphine plasma
concentration versus time for each formulation is shown in FIG.
1.
TABLE-US-00012 TABLE 12 Pharmacokinetic Parameters Arithmetic Mean
Values Cmax .cndot.Tmax AUC(0-t) AUC(0-.infin.) Formulation ng/mL
(h) (ng h/mL) (ng h/mL) 60 mg (F-2) 8.58 1.5 75.95 83.87 60 mg
(F-1) 7.17 3.5 78.73 90.70 120 mg (F-1) 12.87 6.0 154.63 170.75 180
mg (F-1) 15.59 8.0 200.63 213.22 60 mg oral 13.75 1.0 61.85 68.50
solution (IR) .cndot.Median Tmax values reported
TABLE-US-00013 TABLE 13 Relative Bioavailability (based on dose
normalized arithmetic mean values) Cmax AUC (0-t) AUC (0-.infin.)
ratio ratio ratio 60 mg (F-2)/ER 0.62 1.23 1.22 60 mg (F-1)/ER 0.52
1.27 1.32 120 mg (F-1)/ER 0.47 1.25 1.25 180 mg (F-1)/ER 0.38 1.08
1.04
TABLE-US-00014 TABLE 14 Pharmacokinetic Parameters Geometric Mean
Values Cmax AUC(0-t) AUC(0-.infin.) Formulation ng/mL (ng * h/mL)
(ng * h/mL) 60 mg (F-2) 7.58 68.72 77.85 60 mg (F-1) 6.28 69.95
85.65 120 mg (F-1) 12.24 140.61 158.62 180 mg (F-1) 13.67 175.73
189.32 60 mg oral 12.48 56.29 63.14 solution (IR)
TABLE-US-00015 TABLE 15 Relative Bioavailability (based on dose
normalized arithmetic mean values) Cmax AUC (0-t) AUC (0-.infin.)
ratio ratio ratio 60 mg (F-2)/ER 0.62 1.22 1.23 60 mg (F-1)/ER 0.50
1.24 1.36 120 mg (F-1)/ER 0.49 1.25 1.26 180 mg (F-1)/ER 0.37 1.04
1.00
TABLE-US-00016 TABLE 16 Nalbuphine Blood Concentration
Concentration (ng/mL) Time Point 60 mg 60 mg 120 mg 180 mg (hrs) 60
mg IR (F-1) (F-2) (F-1) (F1) 0 0 0 0 0 0 0.25 10.57 1.83 0.79 1.01
1.00 0.5 14.81 4.69 1.71 2.94 3.55 1 13.53 7.57 3.33 6.51 7.87 1.5
11.20 7.42 3.63 8.81 10.59 2 9.77 6.89 5.88 9.41 11.40 3 6.58 6.18
4.96 9.04 11.90 4 4.65 5.36 4.77 8.20 10.71 6 3.29 5.31 6.18 10.45
14.01 8 1.76 4.00 4.76 8.55 10.59 12 1.67 2.83 3.32 6.77 9.20 16
1.01 1.87 2.24 4.27 5.14 20 0.76 1.13 1.51 2.96 3.27 24 0.68 0.84
1.11 2.02 2.46 36 NT.cndot. 0.57 0.54 0.94 0.98 48 NT NT NT NT 0.75
.cndot.Not tested
[0197] In general, the F-1 (Example 20) and F-2 (Example 19)
formulations had higher AUCs (0-t and 0-.infin.) and lower Cmax
values (for both arithmetic and geometric mean values) compared to
the immediate release oral solution. These differences were
moderate for AUCs (0-t and 0-.infin.) and moderate to significant
for Cmax and were based on dose-normalized comparisons of the F-1
and F-2 formulations with the immediate release oral solution.
Minimal differences in AUCs (0-t and 0-.infin.) were seen between
the F-1 and F-2 formulations at a comparative dose of 60 mg.
[0198] These data demonstrate that the oral bioavailability for the
sustained release nalbuphine formulations was greater than that of
the immediate release control formulation. Specifically, the oral
availability of formulation F-2 was 23% greater than that of the
immediate release oral solution, based on the geometric mean values
for the area under the plasma concentration time curve. Similarly,
the oral bioavailability of Formulation F-1 was 36% greater than
that of the immediate release oral solution, based on the geometric
mean values for the area under the plasma concentration time
curve.
[0199] The C.sub.max values for the sustained release formulations
were approximately 60% of the C.sub.max observed with the immediate
release oral solution. These data suggest that the potential for
adverse events (i.e., side effects) could be decreased with the
sustained release formulation compared to immediate release
formulations.
[0200] Median T.sub.max values reported were 1.0, 1.5 and 3.5 hours
for the oral solution, F-2 and F-1 formulations, respectively.
Longer T.sub.max values were observed for the 2 higher doses of the
F-1 formulation (6.0 and 8.0 hours for the 120 and 180 mg doses,
respectively).
[0201] Dose linearity was observed for all three doses of the F-1
formulation (60, 120 and 180 mg.
[0202] As shown in FIG. 1, the blood plasma concentration of
nalbuphine for the extended release formulations increases quickly
to one or more peaks shortly following administration, followed by
a plateau region. The duration of the plateau period varies based
on the dose strength and type of formulation, but is generally in
the range from about 1.5 hours to about 10 hours. In contrast, the
blood plasma level for the immediate release formulation quickly
maximizes, followed by an immediate decrease in nalbuphine
concentration from time point to time point. Following the plateau
period, there is a decrease in the nalbuphine blood plasma
concentration from one time point to the next.
Example 21
[0203] A Phase 1 study in uremic pruritus patients is conducted to
investigate the safety and pharmacokinetic profile of nalbuphine in
renally impaired patients undergoing dialysis. The trial
investigates the frequency of dosing, the effect of dialysis on
plasma levels of the drug, identifies any unique metabolites
generated in this patient population, and explores on a preliminary
basis any reduction in pruritus.
[0204] The nalbuphine ER formulation used in the study is
represented by that described in Table 19, Example 24.
[0205] This study is conducted as open label, non-randomized,
enrolling end-stage renal disease (ESRD) hemodialysis (HD) subjects
first then the healthy subject matches to determine the
pharmacokinetics (PK), safety, and tolerability as a function of
escalating doses in individual hemodialysis subjects compared to
matched healthy subjects (body mass index (BMI), age and gender).
The dose escalating scheme mimics the intended dosing schedule for
subsequent clinical studies. The dosing frequency and dose levels
(BID, 30 to 180 mg) have been evaluated in single and multiple dose
studies in previous clinical studies in subjects with normal renal
function in which the safety profile was considered adequate with
no dose-limited toxicity being noted.
[0206] The study determines the PK properties on a non-dialysis day
during a 2-day break and assesses the effect of hemodialysis on
nalbuphine PK in the hemodialysis population in support of
establishing a safe dosing regimen (frequency and dose range) for
the clinical efficacy studies in UP patients. In addition, the PK
of nalbuphine metabolite(s) relative to healthy subjects is
explored.
[0207] The PK of plasma circulating metabolite(s) is explored in
this study by comparing the peak intensity of metabolite(s) by
LC/MS/MS in hemodialysis relative to healthy subjects. This
approach provides information regarding the formation/elimination
of metabolites though the identity of nalbuphine metabolites in
plasma following oral administration is not fully elucidated in the
published literature. No metabolites of nalbuphine have been
reported to have a pharmacological activity.
[0208] Both ESRD subjects with and without uremic pruritus (UP) are
enrolled in this study. From a pharmacokinetic perspective, the
ESRD patients on hemodialysis without UP are representative of the
target UP patient population except for the presence of
pruritis.
[0209] The study comprises two cohorts: Cohort 1 consists of 12 HD
subjects while Cohort 2 consists of 8 healthy subjects.
Cohort 1
[0210] Cohort 1 consists of 12 HD subjects divided into 3 groups of
2, 2, and 8 HD subjects in Group 1, 2, and 3, respectively.
[0211] Hemodialysis subjects are dialyzed on Day -1, then Day 2, 5,
7, 9, 12, and 14 (termination day). Hemodialysis is conducted at
approximately the same time (between 11 and 2 pm) while on study.
Drug is administered within 4 hr prior to dialysis, (morning
dose).
[0212] Group 1: Two HD subjects receive their first dose, a 30 mg
single dose on a non-dialysis day, that is escalated to 30 mg BID,
60 mg BID, 120 mg BID and finally to 180 mg BID. Subjects remain at
each dose level for 2-3 days or a minimum of 5 consecutive doses.
Subjects are allowed to use an antiemetic such as Zofran as needed
to alleviate nausea and emesis, the most common side effects
associated with opioids particularly at high doses. Escalation of
the dose in each subject is predicated on the safety and
tolerability of the preceding dose.
[0213] For subjects who can tolerate up to 120 mg BID but cannot
tolerate the first or second 180 mg morning dose with the use of an
antiemetic, the dose is titrated back to 120 mg BID and subjects
continue on that dose until the end of the dosing period.
[0214] Dosing of the 2 HD subjects in Group 1 is staggered by
approximately one week such that dosing of the second subject is
initiated following interim review of the safety parameters and/or
at discretion of the principal investigator (PI).
[0215] In addition to safety and tolerability evaluation, PK
parameters are obtained for Group 1, at least for the 30 & 60
mg doses prior to dosing Group 2.
[0216] Upon completion of the Day 14 safety assessments of both HD
subjects in Group 1, safety variables and nalbuphine PK parameters
are reviewed by the Investigator, the Study Manager, and Sponsor
(or designee) in order to determine the progression of dose
escalation and dosing regimen in Group 2. These approaches are
described below:
[0217] i) Adjusting the dose range depending on safety review. When
the 180 mg dose is not well tolerated, the dose escalation is
changed to 30 mg, 60 mg, 90 mg and 120 mg for Group 2. The dosing
frequency is also reduced in view of the certain adverse events
(AEs) observed.
[0218] ii) When the nalbuphine half-life (T1/2) is more than 16
hours and the accumulation is greater or equal to 5 (after
dialysis), then daily dosing frequency is reduced to once a day
(QD) for the subsequent group, regardless of the safety
profile.
[0219] Group 2: consists of 2 HD subjects who are dosed
concurrently or as enrolled. Dosing is based on the preceding Group
1 PK and safety evaluation. Upon completion of the Day 14 safety
assessments of both HD subjects in Group 2, safety variables are
reviewed by the Investigator, the Study Manager, and Sponsor (or
designee) in order to determine the progression of dose escalation
and dosing frequency, as applicable in Group 3.
[0220] Group 3: consists of 10 HD subjects who are dosed either
concurrently or as enrolled. Dosing is based on the preceding Group
2 safety evaluation.
Cohort 2
[0221] Subjects in Cohort 2 include eight (8) healthy subjects
matched to the HD subjects with BMI, age, and gender either in
Group 3 or bracket Groups 2&3, when the dosing frequency of
Group 2 and 3 is unchanged. The frequency of daily dosing is
identical to Group 3 except dose escalation will be over the 30 to
180 mg dose level.
[0222] Results demonstrate that nalbuphine can be safely dosed in
renally impaired patients, once or twice daily, in a dose ranging
from 30 mg to 180 mg. Dialysis appears to have a minor impact on
the plasma levels of the drug and it is recommended that the drug
be dosed following dialysis on the days patients are required to be
dialyzed. Also, it does not appear there are any active metabolites
in this patient population. It does appear that patients with more
severe pruritus experience some relief from itching when dosed with
nalbuphine. Side effects were noted in the study and were dose
dependent. The side effect profile is that expected from the opioid
class of drugs and no unusual side effects are found.
Example 22
Nalbuphine 60 mg Extended Release Tablets
[0223] The 60 mg extended release nalbuphine tablets of Example 22
were prepared as follows: Nalbuphine HCl and TIMERx M30A were added
to a high shear mixer and dry mixed at low speed. A granulating
solution (water for injection or purified water) was then
introduced to the mixer at low speed. The subsequent mixture was
granulated at high speed and dried in a fluid bed processor. The
dried granules were milled and sized via a conventional mill. The
milled granulation was then transferred into a diffusion (tumble)
mixer. Magnesium stearate was added to the diffusion mixer and
blended. The final blend was compressed using a rotary tablet
press. The resulting tablets were then coated with the
non-functional coating using a conventional coating pan.
TABLE-US-00017 TABLE 17 60 mg Extended Release Nalbuphine Tablet
with Non-Functional Coating Ingredient mg/tablet Nalbuphine HCI
60.0 TIMERx M30A.sup.1 150.0 (Mannitol) (90.0) (Locust bean gum)
(27.0) (Xanthan Gum) (18.0) (Calcium sulfate dihydrate) (15.0)
Magnesium stearate 1.1 Opadry II Purple 6.3 Water for injection or
Purified water QS Total: 217.4 .sup.1Sustained release excipient of
Example 2
[0224] The formulation of Example 22 is identical to the tablet
formulation of Examples 9 and 20, except with the addition of a
non-functional coating.
Example 23
Nalbuphine 60 mg Extended Release Tablets
[0225] The 60 mg extended release nalbuphine tablets of Example 23
were prepared as follows: Nalbuphine HCl and TIMERx M30A were added
to a high shear mixer and dry mixed at low speed. A granulating
solution (water for injection or purified water) was then
introduced to the mixer at low speed. The subsequent mixture was
granulated at high speed and dried in a fluid bed processor. The
dried granules were milled and sized via a conventional mill. The
milled granulation was then transferred into a diffusion (tumble)
mixer. Hydroxypropyl cellulose was added to the diffusion mixer and
blended. Thereafter, magnesium stearate was added to the diffusion
mixer and blended. The final blend was compressed using a rotary
tablet press. The resulting tablets were then coated with the
non-functional coating using a conventional coating pan.
TABLE-US-00018 TABLE 18 60 mg Extended Release Nalbuphine Tablet
with Addition of Hydroxypropyl Cellulose and Reduction of TimeRx
Excipient Ingredient mg/tablet Nalbuphine HCI 60.0 TIMERx
M30A.sup.1 120.0 (Mannitol) (72.0) (Locust bean gum) (21.6)
(Xanthan Gum) (14.4) (Calcium sulfate dihydrate) (12.0)
Hydroxypropylcellulose 30.0 Magnesium stearate 1.6 Water for
injection or QS Purified water Total: 211.6 .sup.1Sustained release
excipient of Example 2
Examples 24-29
[0226] The nalbuphine tablets of Examples 24-29 were prepared as
follows: Nalbuphine HCl, mannitol, xanthan gum, locust bean gum and
calcium sulfate dihydrate were added to a high shear mixer and
dried mix at low speed. A granulating solution (water for injection
or purified water) was introduced into the mixer at low speed. The
wet granulation was granulated at high speed and dried in a fluid
bed processor. The dried granules were milled and sized using a
conventional mill. The milled granulation was transferred into a
diffusion (tumble) mixer. Hydroxypropylcellulose and, when
applicable, fumaric acid (180 mg formulations only) were added to
the diffusion mixer and blended. Thereafter, magnesium stearate was
added to the diffusion mixer and blended. The final blend was
compressed using a rotary tablet press.
TABLE-US-00019 TABLE 19 (Example 24) 30 mg Extended Release
Nalbuphine Tablet Ingredient mg/tablet Nalbuphine HCI 30.0 Mannitol
108.0 Hydroxypropylcellulose 35.0 Locust bean gum 32.4 Xanthan gum
21.6 Calcium sulfate dehydrate 18.0 Magnesium stearate 1.9 Water
for injection or QS Purified water Total: 246.9
TABLE-US-00020 TABLE 20 (Example 25) 60 mg Extended Release
Nalbuphine Tablet Ingredient mg/tablet Nalbuphine HCI 60.0 Mannitol
72.0 Hydroxypropylcellulose 30.0 Locust bean gum 21.6 Xanthan gum
14.4 Calcium sulfate dehydrate 12.0 Magnesium stearate 1.6 Water
for injection or QS Purified water Total: 211.6
TABLE-US-00021 TABLE 21 (Example 26) 120 mg Extended Release
Nalbuphine Tablet Ingredient mg/tablet Nalbuphine HCI 120.0
Mannitol 144.0 Hydroxypropylcellulose 60.0 Locust bean gum 43.2
Xanthan gum 28.8 Calcium sulfate dehydrate 24.0 Magnesium stearate
3.2 Water for injection or QS Purified water Total: 423.2
TABLE-US-00022 TABLE 22 (Example 27) 180 mg Extended Release
Nalbuphine Tablet (release 1 Ingredient mg/tablet Nalbuphine HCI
180.0 Mannitol 216.0 Hydroxypropylcellulose 90.0 Locust bean gum
64.8 Xanthan gum 43.2 Fumaric acid 25.0 Calcium sulfate dehydrate
36.0 Magnesium stearate 5.0 Water for injection or QS Purified
water Total: 660.0
TABLE-US-00023 TABLE 23 (Example 28) 180 mg Extended Release
Nalbuphine Tablet (release 2 Ingredient mg/tablet Nalbuphine HCI
180.0 Mannitol 162.0 Hydroxypropylcellulose 60.0 Locust bean gum
48.6 Xanthan gum 32.4 Fumaric acid 25.0 Calcium sulfate dehydrate
27.0 Magnesium stearate 4.0 Water for injection or QS Purified
water Total: 539.0
TABLE-US-00024 TABLE 24 (Example 24) 15 mg Extended Release
Nalbuphine Tablet Ingredient mg/tablet Nalbuphine HCI 15.0 Mannitol
117.0 Hydroxypropylcellulose 35.0 Locust bean gum 35.1 Xanthan gum
23.4 Calcium sulfate dehydrate 19.5 Magnesium stearate 1.9 Water
for injection or QS Purified water Total: 246.9
Example 30
[0227] A Phase II, randomized, double-blind, single-dose,
placebo-controlled, multi-center, parallel group study of the
safety and efficacy of the nalbuphine bi-layer tablet formulation
of Example 19 was conducted. Study subjects were randomized to
active agent received either a single 60 mg extended release dose
of nalbuphine or a single 120 mg (2.times.60 mg tablets) dose of
nalbuphine. Table 25A-B provides a summary of the observed
pharmacokinetic parameters.
TABLE-US-00025 TABLE 25A (60 mg single dose) Statistic Cmax (ng/mL)
Tmax (hr) AUC (ng hr/m1) N 65 65 65 Mean 8.1 4.5 75.2 SD 4.9 2.2
45.2 Minimum 3.0 0.5 23.6 Median 6.6 6 65.3 maximum 22.3 12 256.6 %
CV 60.4% 48.5% 60.1% Geometric mean 6.9 3.9 64.8
TABLE-US-00026 TABLE 25B (120 mg single dose) Statistic Cmax
(ng/mL) Tmax (hr) AUC (ng hr/m1) N 66 66 66 Mean 16.4 4.3 149.2 SD
10.6 2.7 77.0 Minimum 4.6 0.5 33.2 Median 13.2 3 128.3 maximum 77.4
12 450.2 % CV 64.9% 63.8% 51.6% Geometric mean 14.1 3.4 133.1
Example 31
[0228] A Phase I, randomized single dose, four period cross-over
study to evaluate the effect of food on two nalbuphine extended
release tablet formulations (bi-layer formulation of Example 19 and
extended release formulation of Example 20) administered orally to
healthy subjects under fed and fasted conditions was conducted. The
total single dose administered to each study subject was 120 mg
(2.times.60 mg tablets). Table 25 provides a summary of the
observed pharmacokinetic parameters.
TABLE-US-00027 TABLE 26 C.sub.max T.sub.max AUC.sub.(0-last)
AUC.sub.(0-.infin.) Treatment Statistics (ng/mL) (hr) (ng hr/mL)
(ng hr/mL) Formula of N 9 9 9 9 Example 20 Mean 14.1 -- 170 183 120
mg Fast SD 6.23 -- 59.7 62.9 Min 4.57 1.50 56.7 61.6 Median 15.1
6.00 179 195 Max 23.6 12.00 245 256 Formula of N 9 9 9 9 Example 20
Mean 22.4 -- 201 211 120 mg Fed SD 12.7 -- 67.2 68.3 Min 8.77 3.00
70.2 73.9 Median 21.0 6.00 219 227 Max 48.6 10.00 295 307 Formula
of N 9 9 9 9 Example 19 Mean 18.5 -- 160 170 120 mg Fast SD 7.40 --
55.6 54.7 Min 6.33 1.00 81.5 87.7 Median 18.6 2.00 178 186 Max 28.7
6.00 239 250 Formula of N 9 9 9 9 Example 19 Mean 28.0 -- 204 214
120 mg Fed SD 16.6 -- 68.6 71.0 Min 11.0 2.00 98.2 111 Median 24.0
6.00 227 237 Max 63.7 6.00 279 295
Example 32
[0229] A Phase I, randomized, single dose, four period, cross-over
study to evaluate the intra-subject variability of two nalbuphine
extended release formulations (bi-layer formulation of Example 19
[ERF-2] and extended release formulation of Example 20 [ERF-1])
administered orally to healthy subjects under fasted conditions was
conducted. The total single dose administered to each study subject
was 120 mg (2.times.60 mg tablets). Table 27 provides a summary of
the observed pharmacokinetic parameters.
TABLE-US-00028 TABLE 27 C.sub.max T.sub.max AUC.sub.(0-last)
AUC.sub.(0-.infin.) Treatment Statistics (ng/mL) (hr) (ng hr/mL)
(ng hr/mL) ERF-1 (A1) N 7 7 7 7 Mean 11.3 -- 139 162 SD 7.17 --
75.0 78.8 Minimum 3.08 2.00 39.0 47.0 Median 12.1 6.00 157 173
Maximum 20.5 12.00 257 279 ERF-1 (A2) N 7 7 7 6 Mean 13.4 -- 152
167 SD 8.81 -- 73.5 80.9 Minimum 3.70 1.50 44.7 57.3 Median 12.3
6.00 128 156 Maximum 30.2 8.00 252 263 ERF-2 (C1) N 7 7 7 6 Mean
14.2 -- 148 170 SD 8.87 -- 78.3 78.2 Minimum 4.41 1.50 39.7 51.5
Median 8.57 6.00 123 176 Maximum 26.6 8.00 259 265 ERF-2 (C2) N 7 7
7 6 Mean 12.5 -- 137 155 SD 8.02 -- 77.5 78.9 Minimum 4.88 1.00
44.6 49.8 Median 9.17 2.00 142 161 Maximum 26.3 10.00 270 277
Example 33
[0230] A phase I, randomized, single-blind, placebo-controlled,
multiple ascending dose tolerance trial of nalbuphine extended
release tablets (of Example 22) in healthy adult subjects in the
fasted state. Table 28 and 29 provides a summary of the observed
pharmacokinetic parameters.
TABLE-US-00029 TABLE 28 Single Dose Administration Pharmacokinetic
Data 60 mg 120 mg 180 mg 180 mg Parameter Statistics Period 1
Period 2 Period 3 Period 4 Cmax N 3 5 3 5 (ng/mL) Mean 7.920 15.574
27.800 23.420 SD 1.4722 8.4070 9.9000 10.6302 Min 7.360 14.900
27.800 21.600 Median 6.81 5.47 17.90 10.30 Max 9.59 27.80 37.70
39.80 Tmax (hr) N 3 5 3 5 Mean 5.67 3.60 5.67 3.00 SD 1.155 2.074
0.577 2.000 Min 5.00 4.00 6.00 3.00 Median 5.0 1.0 5.0 1.0 Max 7.0
6.0 6.0 5.0
TABLE-US-00030 TABLE 29 Multiple Doses Pharmacokinetic Data 60 mg
120 mg 180 mg 180 mg Treatment Statistics Period 1 Period 2 Period
3 Period 4 Cmax, ss N 3 5 3 5 (ng/mL) Mean 12.10 18.76 32.17 29.58
SD 1.217 1.806 8.810 11.107 Median 11.50 19.00 29.10 27.40 Min 11.3
15.9 25.3 18.4 Max 13.5 20.6 42.1 46.7 Tmax, ss (hr) N 3 5 3 5 Mean
5.00 3.40 4.33 5.60 SD 1.000 2.074 3.215 0.894 Median 5.00 3.00
3.00 5.00 Min 4.0 1.0 2.0 5.0 Max 6.0 6.0 8.0 7.0 Cmin, ss N 3 5 3
5 (ng/mL) Mean 3.263 5.974 12.067 7.232 SD 0.7966 0.9232 1.6653
2.1101 Median 3.450 6.300 12.600 7.440 Min 2.39 4.85 10.20 4.84 Max
3.95 7.08 13.40 10.20
Example 34
[0231] A phase I, randomized, single dose, five-period cross-over
study in healthy subjects to evaluate the intra-subject variability
of a nalbuphine extended release tablet formulation (of Example
23). Table 30 provides a summary of the observed pharmacokinetic
parameters.
TABLE-US-00031 TABLE 30 120 mg 120 mg Oral Oral Treatment Treatment
(Fast) (Fed) Solution Solution Parameter Statistics A1 A2 Treatment
A Treatment B Treatment C Treatment D Cmax N 12 12 12 12 12 12
(ng/mL) Mean 12.498 12.903 12.700 18.549 18.503 16.863 SD 7.1308
5.4062 5.7697 10.6560 7.8579 6.7619 Median 12.100 13.300 11.370
15.950 17.100 14.950 Min 4.03 3.83 3.93 5.79 8.53 8.62 Max 32.30
20.30 26.30 41.90 36.30 31.40 Tmax (hr) N 12 12 12 12 12 12 Mean
5.250 5.167 5.208 4.625 0.750 2.817 SD 3.4411 2.6572 2.3400 2.0352
0.3371 0.8055 Median 3.500 6.000 5.750 6.000 0.500 1.900 Min 2.00
1.00 2.00 1.50 0.50 1.00 Max 12.00 8.00 10.00 6.00 1.50 4.00 AUC
(0-last) N 12 12 12 12 12 12 (ng hr/mL) Mean 159.450 154.391
156.921 169.723 83.793 103.154 SD 60.2859 59.9296 54.7635 70.0775
24.1551 27.2275 Median 155.720 151.944 158.828 168.859 84.097
101.217 Min 56.97 54.32 55.65 56.76 51.24 63.89 Max 260.41 274.17
267.29 282.63 143.74 147.43 AUC (0-.infin.) N 8 8 8 8 8 8 (ng
hr/mL) Mean 160.790 161.532 161.161 170.590 85.926 103.053 SD
61.1655 54.6973 51.8638 69.3711 13.6623 29.5312 Median 152.985
166.487 167.257 162.708 90.056 96.558 Min 64.80 63.01 63.91 66.16
63.66 70.24 Max 238.44 258.27 213.18 272.16 104.20 151.97
Example 35
[0232] A phase I, open-label, single dose, five-period cross-over
study to determine the dose proportionality of 30, 60 120 and 180
mg nalbuphine extended release tablet formulations (of Examples
24-28). Table 31A-E provides a summary of the observed
pharmacokinetic parameters for the 60 mg, 120 mg and 180 mg
formulations of Examples 25, 26, 27 and 28, respectively.
TABLE-US-00032 TABLE 31A T.sub.max C.sub.max AUC.sub.last
AUC.sub.INF Treatment (hr) (ng/mL) (hr ng/mL) (hr ng/mL)
Description Parameter N = 22 N = 22 N = 22 N = 19 30 mg Mean 4.159
4.130 42.988 54.993 nalbuphine SD 1.996 2.338 20.135 20.681 HCl ER
Min 1.50 1.95 21.26 27.35 tablet Median 3.00 3.82 39.99 53.13 Max
8.00 12.70 110.41 117.08
TABLE-US-00033 TABLE 31B T.sub.max C.sub.max AUC.sub.last
AUC.sub.INF Treatment (hr) (ng/mL) (hr ng/mL) (hr ng/mL)
Description Parameter N = 24 N = 24 N = 24 N = 23 60 mg Mean 7.417
7.750 94.496 108.798 nalbuphine SD 2.962 6.034 40.001 38.737 HCl ER
Min 3.00 2.84 37.56 50.73 tablet Median 6.00 6.07 89.31 103.12 Max
12.00 29.90 186.60 196.41
TABLE-US-00034 TABLE 31C T.sub.max C.sub.max AUC.sub.last
AUC.sub.INF Treatment (hr) (ng/mL) (hr ng/mL) (hr ng/mL)
Description Parameter N = 19 N = 19 N = 19 N = 18 120 mg Mean 6.316
13.265 192.434 208.312 nalbuphine SD 2.709 6.458 82.867 90.778 HCl
ER Min 1.00 6.54 81.41 105.82 tablet Median 6.00 12.80 197.01
205.96 Max 12.00 34.80 463.17 503.93
TABLE-US-00035 TABLE 31D T.sub.max C.sub.max AUC.sub.last
AUC.sub.INF Treatment (hr) (ng/mL) (hr ng/mL) (hr ng/mL)
Description Parameter N = 15 N = 15 N = 15 N = 15 180 mg Mean 7.600
21.559 297.460 327.842 nalbuphine SD 3.043 23.526 154.701 164.674
HCl ER Min 2.00 5.89 138.35 148.67 tablet Median 6.00 16.30 274.64
288.86 (release 1) Max 12.00 102.00 722.79 760.86
TABLE-US-00036 TABLE 31E C.sub.max AUC.sub.last AUC.sub.INF
Treatment T.sub.max(hr) (ng/mL) (hr ng/mL) (hr ng/mL) Description
Parameter N = 19 N = 19 N = 19 N = 18 180 mg Mean 8.000 19.182
318.759 339.507 nalbuphine SD 4.604 11.007 167.371 117.176 HCl ER
Min 1.00 8.25 151.52 156.52 tablet Median 6.00 17.60 280.56 291.71
(release 2) Max 16.00 56.40 877.38 909.86
Example 36
[0233] A clinical study is performed to compare the anti-pruritic
efficacy of nalbuphine HCl ER to placebo in chronic uremic pruritus
subjects by measuring the difference between the active and placebo
arms in the change in the average worst daily itching intensity as
determined from Visual Analog Scale (VAS) score itch intensity
measurements.
[0234] The Primary Efficacy Endpoint is the difference between the
active and placebo arms in the change from the last week of the
Open Label Titration Period to the last 2 weeks of the Double Blind
Treatment and Evaluation Period in the average worst daily itching
intensity
[0235] Secondary objectives include evaluating the tolerability and
safety of Nalbuphine HCl ER; evaluating the dosing titration
regimen for the efficacy and Safety of Nalbuphine HCl ER in chronic
uremic pruritus; and assessing the effect of Nalbuphine HCL ER on
pruritus-specific subject-reported outcomes (PRO) including Brief
itch inventory, Skindex 10, Patient Assessed Disease Severity Scale
(ABC categorical scale), Itch MOS Sleep Scale; assessing the effect
of Nalbuphine HCL ER on the affective state of subjects with
chronic uremic pruritus using the Beck Depression Index; and
exploring the exposure-effect relationship between plasma
nalbuphine levels and anti-pruritic effect(s).
[0236] The Study has Baseline Run-in Period, Open Label Titration
Period, Double Blind Treatment and Evaluation Period and Post-Dose
Evaluation Period.
Run-in Period
[0237] The Run-in Period consists of 6 dialysis center visits over
2 weeks. During this period, there is an initial Screening Visit
(Visit 1) in which subjects provide informed consent and
eligibility requirements are reviewed.
[0238] Over the following five consecutive dialysis visits (V2-6)
the intensity of pruritus is ascertained to determine if the
subject meets the VAS intensity Inclusion Criteria and subjects are
enrolled in the Open Label Titration Period provided the subject
also meets all other Inclusion and Exclusion Criteria. In addition
during the Run-in Period subjects undergo training on the PRO
instruments at 2 dialysis center visits (V1 and V2).
Open-Label Titration Period
[0239] The Open-Label Titration Period lasts no fewer than 11 days
and no longer than 51 days. The purpose of the open-label titration
period is to achieve an anti-pruritic effect in a subject titrated
to a stable dose of nalbuphine HCl ER. Stabilization is defined as:
[0240] 1) An average daily worst itch intensity .ltoreq.40 mm on
the VAS from 3 consecutive dialysis visits during the Open Label
Titration Period. Average daily worst itch intensity is calculated
as follows: during dialysis, the subject completes 2 VAS scale
measures per visit to the dialysis center--one describing the night
time itching intensity and one describing the daytime itching
intensity from the previous day. The highest value ("daily worst
itch intensity") on the VAS score is used to compute the "average
daily worst itch intensity". [0241] 2) The daily dose of nalbuphine
HCl ER is not changed for 4 consecutive days. [0242] 3) Does not
require a supplemental anti-pruritic medication for 4 consecutive
days immediately prior to randomization.
[0243] Subjects who successfully achieve a stabilized dose of
nalbuphine HCl ER during the Open Label Titration Period are
immediately randomized to the Double-Blind Treatment and Evaluation
Period.
Double-Blind Treatment and Evaluation Period
[0244] Eligible subjects are randomized to the Double-Blind
Treatment Period at their final dose from the Open-Label Titration
Period or placebo in a 1:1 ratio. The Double-Blind Treatment Period
lasts no longer than 37 days. The purpose of the Double-Blind
Treatment and Evaluation Period is: [0245] 1. Evaluate the primary
endpoint, secondary endpoints and safety parameters during the
double blind period in the active arm relative to placebo. [0246]
2. Evaluate the durability of drug response to any change in
primary endpoint and secondary endpoints in the active arm relative
to placebo.
Post-Dose Evaluation Period
[0247] The purpose of the Post-Dose Evaluation Period is to assess
the status of the subject's pruritus off blinded study drug for 7
days following the end of drug treatment.
Efficacy
[0248] Patients who are on active treatment with nalbuphine have a
statistically significant reduction in moderate to severe uremic
pruritus related itch intensity relative to patients who receive
placebo. This conclusion is based on the difference between active
and placebo arms in the primary endpoint of "Quantitative change in
the average worst daily itching intensity". This primary endpoint
is calculated from Visual Analog Scale ("VAS") score itch intensity
measurements (VAS measurement on a scale of 0 mm "no itching" to
100 mm "worst possible itching").
[0249] Average daily worst itch intensity is calculated as follows:
during dialysis, the subject completes 2 VAS scale measures per
visit to the dialysis center--one describing the night time itching
intensity and one describing the daytime itching intensity from the
previous day. The highest value ("daily worst itch intensity") on
the VAS score is used to compute the "average daily worst itch
intensity". Moderate to severe itch intensity is defined as average
daily worst itch intensity .gtoreq.50 mm on a VAS scale collected
during the last five consecutive dialysis visits.
[0250] Patients on active treatment with nalbuphine have
statistically significant reduction in pruritus specific patient
reported outcome scales that measure the impact of pruritus on
functional activities, quality of life, psychological affect and
sleep. These patient reported outcome scales include: [0251] Brief
itch inventory [0252] Skindex 10 [0253] Patient Assessed Disease
Severity Scale (ABC categorical scale) [0254] Itch MOS Sleep Scale
[0255] Beck Depression Index
[0256] Patients are capable of safely titrating the drug nalbuphine
to a dose that achieves statistically significant reduction in
pruritus relative to the placebo arm patients. This reduction in
pruritus is measured by the ability of a specific nalbuphine dose
to diminish the an average daily worst itch intensity to .ltoreq.40
mm on the VAS for 3 consecutive dialysis visits (e.g., 3 dialysis
visits is equivalent to 5 days).
[0257] Dosing ranges are between 15 to 360 mg for a single daily
dose of nalbuphine, or 15 mg to 180 mg per dose for twice-daily
dosing. The mean dose found to be efficacious is nalbuphine 60 mg
twice daily. The daily dose ranges from nalbuphine 15 mg once a day
to 180 mg twice a day. The time of titration to a dose to receive
an optimal effect is as short as upon taking the first dose of drug
on day 1, to as long as 30 days to the titrate the drug to a stable
dose.
Durability
[0258] A stable dose of nalbuphine is capable of achieving a
statistically significant reduction in uremic pruritus symptoms
that can endure for at least one month at any stable dose of drug
between nalbuphine 15 mg once daily to nalbuphine 180 mg twice
daily.
Safety
[0259] Nalbuphine HCl ER is safe and well tolerated. Adverse Events
("AEs") reported are characteristic of those commonly noted with
opiate treatment and are mostly reported as mild or moderate in
intensity. The most commonly reported AEs are nausea, somnolence,
dizziness, vomiting, headache, and insomnia, all of which are
reported by a higher percentage of patients in the nalbuphine HCl
ER group than in the placebo group.
Example 37
[0260] The tablet of Example 29 was tested for % release according
to USP Procedure Drug Release General Chapter <711>
Dissolution, using apparatus USP Type III/250 mL. The test was
performed at pH 6.8 and pH 6.8, 37.degree. C./15 dpm (dips per
minute) in 100 mM ammonium phosphate buffer. The results are shown
in Table 32.
TABLE-US-00037 TABLE 32 Dissolution Time pH 4.5 pH 6.8 (hours) (%
dissolution) (% dissolution) 0 0 0 1 30 41 3 58 64 4 68 71 6 81 84
8 89 92 12 97 101
[0261] The embodiments described herein and illustrated by the
foregoing examples should be understood to be illustrative of the
present invention, and should not be construed as limiting. On the
contrary, the present disclosure embraces alternatives and
equivalents thereof, as embodied by the appended claims. Each
reference disclosed herein is incorporated by reference herein in
its entirety.
* * * * *