U.S. patent application number 13/670865 was filed with the patent office on 2013-05-16 for transdermally deliverable opioid prodrugs, abuse-resistant compositions and methods of using opioid prodrugs.
This patent application is currently assigned to AllTranz Inc.. The applicant listed for this patent is AllTranz Inc.. Invention is credited to Miroslaw Jerzy GOLINSKI, Dana Carmel HAMMELL, Jeffery Lynn HOWARD, Audra Lynn STINCHCOMB.
Application Number | 20130123292 13/670865 |
Document ID | / |
Family ID | 39043182 |
Filed Date | 2013-05-16 |
United States Patent
Application |
20130123292 |
Kind Code |
A1 |
STINCHCOMB; Audra Lynn ; et
al. |
May 16, 2013 |
TRANSDERMALLY DELIVERABLE OPIOID PRODRUGS, ABUSE-RESISTANT
COMPOSITIONS AND METHODS OF USING OPIOID PRODRUGS
Abstract
Described herein are opioid prodrugs, methods of making opioid
prodrugs, formulations comprising opioid prodrugs, and methods of
using opioid prodrugs. One embodiment described herein relates to
the transdermal administration of a buprenorphine prodrug in an
abuse-resistant formulation for treating and preventing diseases
and/or disorders.
Inventors: |
STINCHCOMB; Audra Lynn;
(Lexington, KY) ; GOLINSKI; Miroslaw Jerzy;
(Lexington, KY) ; HAMMELL; Dana Carmel;
(Georgetown, KY) ; HOWARD; Jeffery Lynn;
(Richmond, KY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AllTranz Inc.; |
Lexington |
KY |
US |
|
|
Assignee: |
AllTranz Inc.
Lexington
KY
|
Family ID: |
39043182 |
Appl. No.: |
13/670865 |
Filed: |
November 7, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12388891 |
Feb 19, 2009 |
8309568 |
|
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13670865 |
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11860432 |
Sep 24, 2007 |
7511054 |
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12388891 |
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60826603 |
Sep 22, 2006 |
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Current U.S.
Class: |
514/282 ;
514/279; 546/39 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61P 25/04 20180101; A61P 25/32 20180101; A61P 25/36 20180101; A61P
23/00 20180101; A61K 31/439 20130101; C07D 489/02 20130101; A61K
31/485 20130101; A61K 31/439 20130101; A61K 2300/00 20130101; A61K
31/485 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/282 ;
514/279; 546/39 |
International
Class: |
A61K 9/00 20060101
A61K009/00 |
Claims
1. A compound having the formula: ##STR00023## wherein R.sub.1 is
selected from the group consisting of oxygenated alkyl carbonate,
alkyl carbonate and oxygenated ester.
2. A method of treating a medical condition in a mammal comprising
the step of transdermally administering a buprenorphine prodrug
from the group consisting of: ##STR00024## ##STR00025##
3. The method of claim 2 wherein the medical condition is selected
from the group consisting of: opioid dependence, alcohol dependence
and pain.
4. The method of claim 2 further comprising the step of
transdermally administering a second compound having the formula:
##STR00026## wherein R.sub.3 is selected from the group consisting
of: H; --COC(CH.sub.3).sub.3; --COCH(CH.sub.3).sub.2;
--COCH.sub.2CH(CH.sub.3).sub.2; --COCH(CH.sub.2CH.sub.3).sub.2;
--CON(CH.sub.2CH.sub.3).sub.2; --CON(CH(CH.sub.3).sub.2).sub.2;
COOCH(CH.sub.3).sub.2; ##STR00027## and
--CO(CH.sub.2).sub.2OCH.sub.3.
5. The method of claim 4 wherein the medical condition is selected
from the group consisting of: opioid dependence; alcohol dependence
and pain.
6. The method of claim 2 further comprising the step of
transdermally administering a second compound selected from the
group consisting of: naltrexone; 3-O-pivalyl naltrexone;
3-O-isovaleryl naltrexone; 3-O-(2'-ethylbutyryl)naltrexone;
3-O-isobutyryl naltrexone; 3-O-isopropyloxycarbonyl naltrexone;
3-O-tertiarybutyloxycarbonyl naltrexone; N,N-dimethyl-3-O-carbamate
naltrexone; N,N-diethyl-3-O-carbamate naltrexone; and
N,N-diisopropyl-3-O-carbamate naltrexone.
7. A method for transdermally delivering a buprenorphine prodrug to
a mammal comprising the steps of: (a) selecting a buprenorphine
prodrug from the group consisting of: ##STR00028## ##STR00029## (b)
selecting a naltrexone prodrug of having the formula ##STR00030##
wherein R.sub.3 is selected from the group consisting of: H;
--COC(CH.sub.3).sub.3; --COCH(CH.sub.3).sub.2;
--COCH.sub.2CH(CH.sub.3).sub.2; --COCH(CH.sub.2CH.sub.3).sub.2;
--CON(CH.sub.2CH.sub.3).sub.2; --CON(CH(CH.sub.3).sub.2).sub.2;
COOCH(CH.sub.3).sub.2; ##STR00031## and
--CO(CH.sub.2).sub.2OCH.sub.3; (c) combining the compounds selected
in (a) and (b) with a pharmaceutically acceptable excipient to form
a pharmaceutical composition; and (d) contacting the pharmaceutical
composition with the skin of the mammal.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 12/388,122, filed on Feb. 19, 2009, which is a continuation of
U.S. application Ser. No. 11/860,432, filed on Sep. 24, 2007, now
U.S. Pat. No. 7,511,054, which claims the benefit of U.S.
Provisional Application Ser. No. 60/826,603 filed Sep. 22, 2006.
These applications, in their entirety, are hereby incorporated by
reference.
FIELD
[0002] Described herein are pharmaceutically active agents suitable
for transdermal delivery to a mammal, compositions for transdermal
delivery of pharmaceutically active agents and methods of using
such compositions in treating and preventing diseases and
disorders.
BACKGROUND
[0003] Pain is the most frequently reported symptom and is a common
clinical problem which confronts the clinician. Millions of people
in the United States suffer from severe pain that, according to
numerous recent reports, is chronically under-treated or
inappropriately managed.
[0004] Opioids have long been recognized as one of the most
effective treatments of pain. However, they also have a high
potential of abuse. In fact, opioid and narcotic abuse are major
worldwide problems connected with tremendous social and personal
strife. As of 1992, the estimated United States economic cost of
drug and alcohol abuse was $246 billion. The latest National
Household Survey on Drug Abuse survey conducted by the Substance
Abuse and Mental Health Services Administration reported in July
2007 that nearly one in twelve full-time workers in the United
States have serious enough drug/alcohol problems to require medical
treatment. Providing recovery assistance for drug addicts and
alcoholics with pharmacological interventions has proven
helpful.
[0005] Certain opioids, such as buprenorphine, butorphanol,
dezocine, meptazinol, nalbuphine, and pentazocine, have both
agonist and antagonist qualities. For example, the main
agonist/antagonist effect of buprenorphine is through its binding
to .mu.-opioid and .kappa.-opioid receptors, acting clinically as
an agonist at lower doses and as an antagonist at higher doses. The
dual agonist-antagonist activity of these opioids make them
effective at not only treating pain, but also at reducing the
severity of the withdrawal symptoms experienced when a former
abuser begins to eliminate opioid and/or alcohol. Buprenorphine is
currently available as a sublingual dosage form, both alone
(Subutex.RTM.) and in combination with naloxone (Suboxone.RTM.) for
the treatment of pain and opioid dependence. Because they are
administered sublingually, both have clinically relevant drawbacks.
For example, the necessity of taking multiple daily doses, or even
once-daily dosing, decreases patient compliance. In addition, the
daily and multiple daily dosing necessary with sublingual dosage
forms may cause more frequent and more extreme peaks and troughs in
the blood-plasma concentration of the active medications, thereby,
increasing the potential for a patient to experience both the
adverse effects associated with supra-therapeutic concentrations
and ineffective relief associated with a sub-therapeutic
concentrations.
[0006] Further, lack of appetite, nausea and/or frequent emesis are
commonly experienced by patients undergoing withdrawal from
narcotic or alcohol abuse and those suffering from chronic,
under-treated or intractable pain. As such, oral and sublingual
therapies for these patients are often either poorly tolerated or
fail to provide an effective therapeutic dose.
[0007] For these patients, transdermal administration can provide a
favorable route of administration. Transdermal dosing, provides the
patient with a desirable systemic delivery profile which can
minimize or eliminate any "highs" (dizziness and drowsiness)
associated with more rapid absorption and can reduce the side
effects associated with oral administration of a drug such as
abdominal pain, nausea and vomiting. Additionally, transdermal
administration avoids first-pass metabolism which can allow for
higher therapeutic concentrations to be achieved. Transdermal
delivery also offers a patient freedom from injections and surgical
implantations. Transdermal delivery can also improve patient
compliance by reducing the dose frequency. A transdermal patch can
offer sustained release of a drug for an extended period (e.g., one
week) while transdermal gels are also an accepted dosage form for
convenient daily application.
[0008] Because of the inherent potential for abuse, it is important
that any pharmaceutical composition containing an opioid agonist be
made as abuse-resistant or abuse-deterrent as possible. This is
particularly true with extended release opioid products, including
transdermal applications. Illicit users often will attempt to
circumvent the extended release properties of these dosage forms by
injecting or otherwise misusing the product in order to achieve an
immediate release of the opioid agonist.
[0009] Not all opioids however are capable of dermal absorption.
Buprenorphine, for example, has been evaluated for transdermal
delivery, but has generally been found to be too hydrophobic to
cross the skin at a therapeutic rate through a reasonably-sized
transdermal patch. However, as transdermal pharmaceutical
compositions pass through the epidermis and dermis of many mammals,
such as humans and guinea pigs, they are exposed to enzymes which
are capable of metabolizing active pharmaceutical agents. The
metabolic processes occurring in the skin of mammals, such as
humans, can be utilized to deliver pharmaceutically effective
quantities of opioids to a mammal in need thereof, by metabolizing
prodrugs into active pharmaceutical compounds. Thus, it would be
desirable to deliver prodrugs of buprenorphine through the skin at
a higher rate than buprenorphine while taking advantage of the
rapid hydrolysis of the buprenorphine prodrug to buprenorphine
during transport into and through the skin. It would be further
desirable to combine the buprenorphine prodrug with a non-dermally
absorbable prodrug of an opioid antagonist, such as naltrexone, in
order to increase the abuse deterrence of the composition.
SUMMARY
[0010] Some embodiments described herein are prodrugs of opioids,
including buprenorphine, methods of making prodrugs of
buprenorphine, compositions comprising prodrugs of buprenorphine
and methods of using prodrugs of buprenorphine.
[0011] Other embodiments, objects, features and advantages will be
set forth in the detailed description of the embodiments that
follow, and in part will be apparent from the description, or may
be learned by practice, of the claimed invention. These objects and
advantages will be realized and attained by the processes and
compositions particularly pointed out in the written description
and claims hereof. The foregoing Summary has been made with the
understanding that it is to be considered as a brief and general
synopsis of some of the embodiments disclosed herein, is provided
solely for the benefit and convenience of the reader, and is not
intended to limit in any manner the scope, or range of equivalents,
to which the appended claims are lawfully entitled.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 shows the twenty-four hour permeation profile of
buprenorphine (n=3) in a propylene glycol formulation.
[0013] FIG. 2 shows the forty-eight hour permeation profile of
buprenorphine (n=3) in a propylene glycol formulation.
[0014] FIG. 3 shows the permeation profile of buprenorphine (n=3),
ALL00106 (n=4) and ALL00107 (n=3) in a propylene glycol
formulation.
[0015] FIG. 4 is a bar graph illustrating the skin disposition of
buprenorphine (n=3), ALL00106 (n=4) and ALL00107 (n=3) in a
propylene glycol formulation.
[0016] FIG. 5 shows the permeation profile of buprenorphine (n=2),
ALL00107 (n=3) and ALL00108 (n=2) in a propylene glycol
formulation.
[0017] FIG. 6 is a bar graph illustrating the skin disposition of
buprenorphine (n=2), ALL00107 (n=3) and ALL00108 (n=2) in a
propylene glycol formulation.
[0018] FIG. 7 shows the permeation profile of buprenorphine (n=2),
ALL00106 (n=3), ALL00107 (n=3), and ALL00108 (n=3) in a gel
formulation.
[0019] FIG. 8 shows the permeation profile of buprenorphine (n=3),
ALL00106 (n=3), and ALL00110 (n=2) in a propylene glycol
formulation.
[0020] FIG. 9 shows the permeation profile of buprenorphine (n=3),
ALL00108 (n=2), ALL00114 (n=2), and ALL00115 (n=2) in a propylene
glycol formulation.
[0021] FIG. 10 shows the permeation profile of buprenorphine (n=3),
ALL00110 (n=3), ALL00114 (n=3), and ALL00115 (n=2) in a gel
formulation.
[0022] FIG. 11 shows the permeation profile of buprenorphine (n=3)
and ALL00116 (n=3) in propylene glycol/ethanol [96/4]
formulation.
[0023] FIG. 12 shows the permeation profile of buprenorphine (n=2),
ALL00113 (n=3), and ALL00116 (n=3) in a gel formulation.
DESCRIPTION
[0024] While the present invention is capable of being embodied in
various forms, the description below of several embodiments is made
with the understanding that the present disclosure is to be
considered as an exemplification of the claimed subject matter, and
is not intended to limit the appended claims to the specific
embodiments illustrated. The headings used throughout this
disclosure are provided for convenience only and are not to be
construed to limit the claims in any way. Embodiments illustrated
under any heading may be combined with embodiments illustrated
under any other heading.
[0025] The term prodrug as used herein refers to a
pharmacologically inert chemical derivative that can be converted,
enzymatically or non-enzymatically, in vivo or in vitro, to an
active drug molecule, which is capable of exerting one or more
physiological effects.
[0026] Compounds described herein include pharmaceutically
acceptable prodrugs of buprenorphine. One embodiment described
herein includes pharmaceutically acceptable prodrugs of
buprenorphine which are suitable for transdermal administration.
The buprenorphine prodrugs described herein may be in any form
suitable for administration to a mammal, such as in the form of a
free base, free acid, salt, ester, hydrate, anhydrate, enantiomer,
isomer, tautomer, polymorph, derivative, or the like, provided that
the free base, salt, ester, hydrate, enantiomer, isomer, tautomer,
or any other pharmacologically suitable derivative is able to
undergo conversion to a therapeutically active form of
buprenorphine.
[0027] Compositions described herein comprise at least one
pharmaceutically acceptable prodrug of buprenorphine. The
pharmaceutically acceptable prodrugs of buprenorphine may be in any
suitable form for administration to a mammal such as in the form of
a free base, free acid, salt, ester, hydrate, anhydrate, amide,
enantiomer, isomer, tautomer, polymorph, derivative, or the like,
provided that the free base, salt, ester, hydrate, amide,
enantiomer, isomer, tautomer, or any other pharmacologically
suitable derivative is able to undergo conversion to a
therapeutically active form of buprenorphine.
[0028] Compositions described herein also include those which are
suitable for transdermal administration of prodrugs of
buprenorphine and optionally include a vehicle or carrier for the
transdermal administration of a prodrug of buprenorphine as well as
further comprising one or more of the following: pharmacologically
active agents, solvents, thickening agents, penetration enhancers,
wetting agents, lubricants, emollients, substances added to mask or
counteract a disagreeable odor, fragrances, and substances added to
improve appearance or texture of the composition as well as other
excipients.
[0029] Methods of treating one or more medical conditions such as
opioid dependence, alcohol dependence or pain are described herein
and comprise administering a pharmaceutically acceptable prodrug of
buprenorphine. One embodiment described herein includes
pharmaceutically acceptable prodrugs of buprenorphine which are
suitable for transdermal administration. The buprenorphine prodrugs
described herein may be in any form suitable for administration to
a mammal, such as in the form of a free base, free acid, salt,
ester, hydrate, anhydrate, enantiomer, isomer, tautomer, polymorph,
derivative, or the like, provided that the free base, salt, ester,
hydrate, enantiomer, isomer, tautomer, or any other
pharmacologically suitable derivative is able to undergo conversion
to a therapeutically active form of buprenorphine.
[0030] "Pharmaceutically acceptable salts," or "salts," include the
salts of buprenorphine prodrugs, suitable for administration to a
mammal and includes those prepared from 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, methanesulfonic,
ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic,
2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic,
beta-hydroxybutyric, galactaric and galacturonic acids. The
following list of pharmaceutically acceptable salts is not meant to
be exhaustive but merely illustrative as person of ordinary skill
in the art would appreciate that other pharmaceutically acceptable
salts of buprenorphine and buprenorphine prodrugs may be
prepared.
[0031] In one embodiment, acid addition salts can be prepared from
the free base forms through a reaction of the free base with a
suitable acid. Suitable acids for preparing acid addition salts
include both organic acids, e.g., acetic acid, propionic acid,
glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid,
succinic acid, maleic acid, fumaric acid, tartaric acid, citric
acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,
and the like, as well as inorganic acids, e.g., hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and
the like. The following list of organic and inorganic acids is not
meant to be exhaustive but merely illustrative as person of
ordinary skill in the art would appreciate that other acids may be
used to create pharmaceutically acceptable salts of buprenorphine
and prodrugs of buprenorphine. In other embodiments, an acid
addition salt is reconverted to the free base by treatment with a
suitable base. In still other embodiments, the basic salts are
alkali metal salts, e.g., sodium salt.
[0032] In one embodiment, an alkyl carbonate or an oxygenated alkyl
carbonate is prepared by functionalizing the 3-phenolic hydroxyl
group present within the molecular structure of buprenorphine. In
another embodiment, the oxygenated alkyl carbonate is a
hydroxylated alkyl carbonate. In a further embodiment the
oxygenated alkyl carbonate is an oxa-carbonate. In another
embodiment the oxa-carbonate is a pegylated carbonate. In an
additional embodiment the alkyl carbonate is methyl carbonate. In
further embodiments, the oxygenated alkyl carbonate can have 1
alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5
alkyl carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9
alkyl carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl
carbons, 13 alkyl carbons, or 14 alkyl carbons. In a further
embodiments, the alkyl carbonate has 2 alkyl carbons, 3 alkyl
carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkyl
carbons or 8 alkyl carbons. In further embodiments the pegylated
carbonate can have 1 ethylene glycol repeat unit, 2 ethylene glycol
repeat units, 3 ethylene glycol repeat units, 4 ethylene glycol
repeat units, 5 ethylene glycol repeat units, 6 ethylene glycol
repeat units, 7 ethylene glycol repeat units or 8 ethylene glycol
repeat units. In further embodiments, the oxygenated alkyl
carbonate has 1 oxygen atom, 2 oxygen atoms, 3 oxygen atoms, 4
oxygen atoms, 5 oxygen atoms, 6 oxygen atoms, 7 oxygen atoms, 8
oxygen atoms, 9 oxygen atoms, 10 oxygen atoms, 11 oxygen atoms or
12 oxygen atoms.
[0033] In a further embodiment, oxygenated esters are prepared by
functionalizing the 3-phenolic hydroxyl group present within the
molecular structure of buprenorphine. In a further embodiment the
oxygenated esters are oxa-esters. In a further embodiment the
oxa-ester is a pegylated ester. In further embodiments the
pegylated oxa-esters can have 1 ethylene glycol repeat unit, 2
ethylene glycol repeat units, 3 ethylene glycol repeat units, 4
ethylene glycol repeat units, 5 ethylene glycol repeat units, 6
ethylene glycol repeat units, 7 ethylene glycol repeat units or 8
ethylene glycol repeat units. In a further embodiment, the
oxygenated ester is an oxygenated alkyl ester. In a further
embodiment the oxygenated alkyl ester can be a hydroxylated alkyl
ester. In further embodiments, the oxygenated alkyl ester can have
1 alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons,
5 alkyl carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons,
9 alkyl carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl
carbons, 13 alkyl carbons, or 14 alkyl carbons. In further
embodiments, the oxygenated esters have 1 oxygen atom, 2 oxygen
atoms, 3 oxygen atoms, 4 oxygen atoms, 5 oxygen atoms, 6 oxygen
atoms, 7 oxygen atoms, 8 oxygen atoms, 9 oxygen atoms, 10 oxygen
atoms, 11 oxygen atoms or 12 oxygen atoms.
[0034] In one embodiment, illustrative opioid prodrugs include
those compounds of Formula (I):
##STR00001##
wherein R.sub.1 is comprised of a bio-labile linker (e.g. ester,
carbonate, carbamate or other suitable bio-labile linking
structure) and further comprising moieties which can be selected in
order to control the rate and extent of transdermal absorption and
metabolism. Several options for R.sub.1 are disclosed herein. Also
included herein is the free base, salt, ester, hydrate, amide,
enantiomer, isomer, tautomer, polymorph and derivative of compounds
of Formula I.
[0035] In additional embodiments of compounds of Formula (I),
R.sub.1 is an alkyl carbonate or an oxygenated alkyl carbonate. In
a further embodiment R.sub.1 is a hydroxylated alkyl carbonate. In
another embodiment R.sub.1 is an oxa-carbonate. In a further
embodiment R.sub.1 is a pegylated carbonate. In an additional
embodiment R.sub.1 is methyl carbonate. In further embodiments,
R.sub.1 can be an oxygenated alkyl carbonate and have 1 alkyl
carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkyl
carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkyl
carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl carbons, 13
alkyl carbons, or 14 alkyl carbons. In a further embodiments,
R.sub.1 can be an alkyl carbonate and have 2 alkyl carbons, 3 alkyl
carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkyl
carbons or 8 alkyl carbons. In further embodiments, R.sub.1 can be
a pegylated carbonate having 1 ethylene glycol repeat unit, 2
ethylene glycol repeat units, 3 ethylene glycol repeat units, 4
ethylene glycol repeat units, 5 ethylene glycol repeat units, 6
ethylene glycol repeat units, 7 ethylene glycol repeat units or 8
ethylene glycol repeat units. In further embodiments, the
oxygenated alkyl carbonate has 1 oxygen atom, 2 oxygen atoms, 3
oxygen atoms, 4 oxygen atoms, 5 oxygen atoms, 6 oxygen atoms, 7
oxygen atoms, 8 oxygen atoms, 9 oxygen atoms, 10 oxygen atoms, 11
oxygen atoms or 12 oxygen atoms.
[0036] In a further embodiment R.sub.1 is an oxygenated ester. In a
further embodiment R.sub.1 is an oxa-ester. In a further embodiment
R.sub.1 is a pegylated oxa-ester. In further embodiments, R.sub.1
is a pegylated oxa-ester having 1 ethylene glycol repeat unit, 2
ethylene glycol repeat units, 3 ethylene glycol repeat units, 4
ethylene glycol repeat units, 5 ethylene glycol repeat units, 6
ethylene glycol repeat units, 7 ethylene glycol repeat units or 8
ethylene glycol repeat units. In a further embodiment, R.sub.1 is
an oxygenated alkyl ester. In a further embodiment R.sub.1 is a
hydroxylated alkyl ester. In further embodiments, R.sub.1 is an
oxygenated alkyl ester having 1 alkyl carbon, 2 alkyl carbons, 3
alkyl carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7
alkyl carbons, 8 alkyl carbons, 9 alkyl carbons, 10 alkyl carbons,
11 alkyl carbons, 12 alkyl carbons, 13 alkyl carbons, or 14 alkyl
carbons. In further embodiments, the oxygenated esters have 1
oxygen atom, 2 oxygen atoms, 3 oxygen atoms, 4 oxygen atoms, 5
oxygen atoms, 6 oxygen atoms, 7 oxygen atoms, 8 oxygen atoms, 9
oxygen atoms, 10 oxygen atoms, 11 oxygen atoms or 12 oxygen
atoms.
TABLE-US-00001 Reference Formula Name Chemical Name II ALL00106
Buprenorphine 3,6,9-trioxadecyl carbonate III ALL00107
Buprenorphine methyl carbonate IV ALL00108 Buprenorphine
2-[2-(2-methoxy- ethoxy)ethoxy]acetyl ester V ALL00110
Buprenorphine 3,4-dihydroxybutyl carbonate VI ALL00113
Buprenorphine 3,6-dioxaheptyl carbonate VII ALL00114 Buprenorphine
2-(2-methoxyethoxy)acetyl ester VIII ALL00115 Buprenorphine
3,6,9,12-tetraoxatridecyl carbonate IX ALL00116 Buprenorphine
3,6,9,12-tetraoxatridecanoyl ester
[0037] In a further embodiment, one or more buprenorphine prodrugs
are selected from the group consisting of:
##STR00002## ##STR00003##
[0038] Further embodiments described herein are pharmaceutical
compositions comprising
(a) a buprenorphine prodrug selected from the group consisting
of:
##STR00004## ##STR00005##
and (b) a pharmaceutical excipient.
[0039] Additional embodiments include methods of transdermally
delivering a buprenorphine prodrug to a mammal comprising the steps
of selecting a buprenorphine prodrug from the group consisting
of:
##STR00006## ##STR00007##
combining the selected compound with a pharmaceutically acceptable
excipient to form a pharmaceutical composition and contacting the
pharmaceutical composition with the skin of the mammal.
[0040] A further embodiment is a method of treating a medical
condition in a mammal comprising the steps of administering a
buprenorphine prodrug selected from the group consisting of:
##STR00008## ##STR00009##
[0041] In a further embodiment the medical condition is selected
from the group consisting of: opioid dependence, alcohol dependence
and pain.
[0042] Abuse-Resistant Compositions
[0043] Due to the potential for opioid agonists and
agonist-antagonists drugs to be abused by individuals addicted to
opioids, it is desirable to incorporate such compounds into
abuse-resistant or abuse-deterrent formulations and dosage forms so
that the possibility of abuse through intravenous administration,
inhalation, oral ingestion or other methods is substantially
reduced or eliminated. For example, with transdermal
administration, it is desirable to use poorly absorbed forms of
opioid antagonists to minimize the effect of the opioid antagonist
during transdermal use, but preserving the antagonist properties in
the event that abuse of the dosage form is attempted.
[0044] In one embodiment, the pharmaceutical composition contains
an opioid agonist or agonist/antagonist such as buprenorphine or
prodrugs of an opioid agonist or agonist/antagonist, such as a
prodrug of buprenorphine and an opioid antagonist. In a further
embodiment, the opioid antagonist is selected from the group
consisting of: naltrexone, 6-beta-naltrexol, nalmefene, naloxone
and prodrugs of the foregoing.
[0045] In a further embodiment, the opioid antagonist would be
insoluble in the dosage form and/or not absorbable at a therapeutic
rate across the skin.
[0046] In a further embodiment, illustrative opioid antagonist
prodrugs include those compounds of Formula (X):
##STR00010##
wherein R.sub.3 is comprised of a bio-labile linker (e.g. ester,
carbonate, carbamate, or other suitable bio-labile linking
structure) and further comprising moieties which can be selected in
order to control the rate and extent of transdermal absorption and
metabolism. Several options for R.sub.3 are disclosed herein. Also
included herein is the free base, salt, ester, hydrate, amide,
enantiomer, isomer, tautomer, polymorph, or derivative thereof of
compounds of Formula (X)
[0047] In one embodiment, R.sub.3 is selected from the group
consisting of Formula (X), wherein R.sub.3 is selected from the
group consisting of:
--COC(CH.sub.3).sub.3; Formula (XI):
--COCH(CH.sub.3).sub.2; Formula (XII):
--COCH.sub.2CH(CH.sub.3).sub.2; Formula (XIII):
--COCH(CH.sub.2CH.sub.3).sub.2; Formula (XIV):
--CON(CH.sub.2CH.sub.3).sub.2; Formula (XV):
CON(CH(CH.sub.3).sub.2).sub.2; Formula (XVI):
--COOCH(CH.sub.3).sub.2; Formula (XVII):
##STR00011## and
--CO(CH.sub.2).sub.2OCH.sub.3. Formula (XIX):
[0048] In one embodiment the opioid antagonist is selected from the
group consisting of 3-O-pivalyl naltrexone, 3-O-isovaleryl
naltrexone, 3-O-(2'-ethylbutyryl)naltrexone, 3-O-isobutyryl
naltrexone, 3-O-isopropyloxycarbonyl naltrexone,
3-O-tertiarybutyloxycarbonyl naltrexone, N,N-dimethyl-3-O-carbamate
naltrexone, N,N-diethyl-3-O-carbamate naltrexone, and
N,N-diisopropyl-3-O-carbamate naltrexone. Other prodrugs of
naltrexone, opioid antagonist prodrugs or opioid antagonists can
also be used.
[0049] Further embodiments are pharmaceutical compositions
comprising:
[0050] (a) a buprenorphine prodrug selected from the group
consisting of:
##STR00012## ##STR00013##
[0051] (b) a naltrexone prodrug of Formula (X), wherein R.sub.3 is
selected from:
--COC(CH.sub.3).sub.3; Formula (XI):
--COCH(CH.sub.3).sub.2; Formula (XII):
--COCH.sub.2CH(CH.sub.3).sub.2; Formula (XIII):
--COCH(CH.sub.2CH.sub.3).sub.2; Formula (XIV):
--CON(CH.sub.2CH.sub.3).sub.2; Formula (XV):
CON(CH(CH.sub.3).sub.2).sub.2; Formula (XVI):
--COOCH(CH.sub.3).sub.2; Formula (XVII):
##STR00014## and
--CO(CH.sub.2).sub.2OCH.sub.3; and Formula (XIX):
[0052] (c) a pharmaceutical excipient.
[0053] Further embodiments include methods for transdermally
delivering a buprenorphine prodrug to a mammal comprising the steps
of:
[0054] (a) selecting a buprenorphine prodrug from the group
consisting of:
##STR00015## ##STR00016##
[0055] (b) selecting a naltrexone prodrug of Formula (X), wherein
R.sub.3 is selected from:
--COC(CH.sub.3).sub.3; Formula (XI):
--COCH(CH.sub.3).sub.2; Formula (XII):
--COCH.sub.2CH(CH.sub.3).sub.2; Formula (XIII):
--COCH(CH.sub.2CH.sub.3).sub.2; Formula (XIV):
--CON(CH.sub.2CH.sub.3).sub.2; Formula (XV):
CON(CH(CH.sub.3).sub.2).sub.2; Formula (XVI):
--COOCH(CH.sub.3).sub.2; Formula (XVII):
##STR00017## and
--CO(CH.sub.2).sub.2OCH.sub.3; Formula (XIX):
[0056] (c) combining the compounds selected in (a) and (b) with a
pharmaceutically acceptable excipient to form a pharmaceutical
composition; and
[0057] (d) contacting the pharmaceutical composition with the skin
of the mammal.
[0058] Further embodiments include methods of treating a medical
condition in a mammal comprising the step of:
[0059] (a) administering a buprenorphine prodrug selected from the
group consisting of:
##STR00018## ##STR00019##
and;
[0060] (b) administering a naltrexone prodrug of Formula (X),
wherein R.sub.3 is selected from the group consisting of:
--COC(CH.sub.3).sub.3; Formula (XI):
--COCH(CH.sub.3).sub.2; Formula (XII):
--COCH.sub.2CH(CH.sub.3).sub.2; Formula (XIII):
--COCH(CH.sub.2CH.sub.3).sub.2; Formula (XIV):
--CON(CH.sub.2CH.sub.3).sub.2; Formula (XV):
CON(CH(CH.sub.3).sub.2).sub.2; Formula (XVI):
--COOCH(CH.sub.3).sub.2; Formula (XVII):
##STR00020## and
--CO(CH.sub.2).sub.2OCH.sub.3. Formula (XIX):
[0061] In a further embodiment, the medical condition is selected
from the group consisting of: opioid dependence, alcohol dependence
and pain.
[0062] Combination with Non-Opioid Agents
[0063] In one embodiment, the pharmaceutical composition containing
the opioid or opioid prodrug could also be combined with an
optional second non-opioid pharmacologically active agent for the
treatment of pain and/or polydrug abuse, including, for example, a
cannabinoid (agonist, antagonist, or inverse agonist), bupropion,
hydroxybupropion, nicotine, nornicotine, varenicline, doxepin,
acetaminophen, aspirin, or another non-steroidal anti-inflammatory
drug. The cannabinoid could consist of one or more of the drugs or
prodrugs as described in U.S. patent application Ser. No.
11/157,034 and U.S. Provisional Pat. App. No. 60/952,746. The
previous listing of suitable compounds for use as an optional
second non-opioid pharmacologically active agent is not meant to be
exhaustive, as a person of ordinary skill in the art would
understand that other compounds (such as those found in the Merck
Index, Thirteenth Edition and the Physicians Desk Reference,
58.sup.th ed.) would be suitable for use as the optional second
non-opioid pharmacologically active agent in the invention
disclosed herein.
[0064] Pharmaceutical Excipients
[0065] The pharmaceutical compositions described herein can, if
desired, include one or more pharmaceutically acceptable
excipients. The term "excipient" herein means any substance, not
itself a therapeutic agent, used as a carrier or vehicle for
delivery of a therapeutic agent to a subject or added to a
pharmaceutical composition to improve its handling or storage
properties or to permit or facilitate formation of a dose unit of
the composition. Excipients include, by way of illustration and not
limitation, solvents, thickening agents, penetration enhancers,
wetting agents, lubricants, emollients, substances added to mask or
counteract a disagreeable odor or flavor, fragrances, and
substances added to improve appearance or texture of the
composition. Any such excipients can be used in any dosage forms of
the present disclosure. The foregoing list of excipients is not
meant to be exhaustive but merely illustrative as a person of
ordinary skill in the art would recognize that additional
excipients could be utilized.
[0066] Compositions described herein containing excipients can be
prepared by any technique known to a person of ordinary skill in
the art of pharmacy, pharmaceutics, drug delivery,
pharmacokinetics, medicine or other related discipline that
comprises admixing one or more excipients with a therapeutic
agent.
[0067] Non-limiting examples of penetration enhancing agents
include C8-C22 fatty acids such as isostearic acid, octanoic acid,
and oleic acid; C8-C22 fatty alcohols such as oleyl alcohol and
lauryl alcohol; lower alkyl esters of C8-C22 fatty acids such as
ethyl oleate, isopropyl myristate, butyl stearate, and methyl
laurate; di(lower)alkyl esters of C6-C22 diacids such as
diisopropyl adipate; monoglycerides of C8-C22 fatty acids such as
glyceryl monolaurate; tetrahydrofurfuryl alcohol polyethylene
glycol ether; polyethylene glycol, propylene glycol;
2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ether;
alkylaryl ethers of polyethylene oxide; polyethylene oxide
monomethyl ethers; polyethylene oxide dimethyl ethers; dimethyl
sulfoxide; glycerol; ethyl acetate; acetoacetic ester;
N-alkylpyrrolidone; and terpenes. Additional penetration enhancers
suitable for use can also be found in U.S. patent application Ser.
No. 10/032,163.
[0068] The thickening agents (aka gelling agents) used herein may
include anionic polymers such as polyacrylic acid (CARBOPOL.RTM. by
Noveon, Inc., Cleveland, Ohio), carboxypolymethylene,
carboxymethylcellulose and the like, including derivatives of
Carbopol.RTM. polymers, such as Carbopol.RTM. Ultrez 10,
Carbopol.RTM. 940, Carbopol.RTM. 941, Carbopol.RTM. 954,
Carbopol.RTM. 980, Carbopol.RTM. 981, Carbopol.RTM. ETD 2001,
Carbopol.RTM. EZ-2 and Carbopol.RTM. EZ-3, and other polymers such
as Pemulen.RTM. polymeric emulsifiers, and Noveon.RTM.
polycarbophils. Additional thickening agents, enhancers and
adjuvants may generally be found in Remington's The Science and
Practice of Pharmacy as well as the Handbook of Pharmaceutical
Excipients, Arthur H. Kibbe ed. 2000. Thickening agents or gelling
agents are present in an amount sufficient to provide the desired
rheological properties of the composition. Illustratively, one or
more pharmaceutically acceptable thickening agent or gelling agent
are present in a total amount by weight of about 0.1%, about 0.25%,
about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about
1.75%, about 2.0%, about 2.25%, about 2.5%, about 2.75%, about
3.0%, about 3.25%, about 3.5%, about 3.75%, about 4.0%, about
4.25%, about 4.5%, about 4.75%, about 5.0%, about 5.25%, about
5.5%, about 5.75%, about 6.0%, about 6.25%, about 6.5%, about
6.75%, about 7.0%, about 7.25%, about 7.5%, about 7.75%, about
8.0%, about 8.25%, about 8.5%, about 8.75%, about 9.0%, about
9.25%, about 9.5%, about 9.75%, about 10%, about 11%, about 11.5%,
about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about
14.5% or about 15%.
[0069] In one embodiment a neutralizing agent is optionally present
to assist in forming a gel. Suitable neutralizing agents include
sodium hydroxide (e.g., as an aqueous mixture), potassium hydroxide
(e.g., as an aqueous mixture), ammonium hydroxide (e.g., as an
aqueous mixture), triethanolamine, tromethamine (2-amino
2-hydroxymethyl-1,3 propanediol), aminomethyl propanol (AMP),
tetrahydroxypropyl ethylene diamine, diisopropanolamine, Ethomeen
C-25 (Armac Industrial Division), Di-2 (ethylhexyl) amine
(BASF-Wyandotte Corp., Intermediate Chemicals Division),
triamylamine, Jeffamine D-1000 (Jefferson Chemical Co.),
b-Dimethylaminopropionitrite (American Cyanamid Co.), Armeen CD
(Armac Industrial Division), Alamine 7D (Henkel Corporation),
dodecylamine and morpholine. The neutralizing agent is present in
an amount sufficient to form a gel which is suitable for contact
with the skin of a mammal.
[0070] In a further embodiment, the formulation is a gel, an
ointment, a cream or a patch and comprises a buprenorphine prodrug,
optionally one or more penetration enhancing agent, thickening
agent, lower alcohol, such as ethanol or isopropanol; or water. In
another embodiment, the formulation is a gel, an ointment, a cream
or a patch, further comprised of sodium hydroxide or
triethanolamine or potassium hydroxide, or a combination thereof,
in an amount sufficient, as is known in the art, to assist the
gelling agent in forming a gel suitable for contact with the skin
of a mammal.
[0071] Compositions described herein optionally comprise one or
more pharmaceutically acceptable wetting agents as excipients.
Non-limiting examples of surfactants that can be used as wetting
agents in compositions of the disclosure include quaternary
ammonium compounds, for example benzalkonium chloride, benzethonium
chloride and cetylpyridinium chloride, dioctyl sodium
sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example
nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers
(polyoxyethylene and polyoxypropylene block copolymers),
polyoxyethylene fatty acid glycerides and oils, for example
polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g.,
Labrasol.TM. of Gattefosse), polyoxyethylene (35) castor oil and
polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl
ethers, for example polyoxyethylene (20) cetostearyl ether,
polyoxyethylene fatty acid esters, for example polyoxyethylene (40)
stearate, polyoxyethylene sorbitan esters, for example polysorbate
20 and polysorbate 80 (e.g., Tween.TM. 80 of ICI), propylene glycol
fatty acid esters, for example propylene glycol laurate (e.g.,
Lauroglycol.TM. of Gattefosse), sodium lauryl sulfate, fatty acids
and salts thereof, for example oleic acid, sodium oleate and
triethanolamine oleate, glyceryl fatty acid esters, for example
glyceryl monostearate, sorbitan esters, for example sorbitan
monolaurate, sorbitan monooleate, sorbitan monopalmitate and
sorbitan monostearate, tyloxapol, and mixtures thereof. Such
wetting agents, if present, constitute in total about 0.25% to
about 15%, about 0.4% to about 10%, or about 0.5% to about 5%, of
the total weight of the composition. Illustratively, one or more
pharmaceutically acceptable wetting agents are present in a total
amount by weight of about 0.25%, about 0.5%, about 0.75%, about 1%,
about 1.25%, about 1.5%, about 1.75%, about 2.0%, about 2.25%,
about 2.5%, about 2.75%, about 3.0%, about 3.25%, about 3.5%, about
3.75%, about 4.0%, about 4.25%, about 4.5%, about 4.75%, about
5.0%, about 5.25%, about 5.5%, about 5.75%, about 6.0%, about
6.25%, about 6.5%, about 6.75%, about 7.0%, about 7.25%, about
7.5%, about 7.75%, about 8.0%, about 8.25%, about 8.5%, about
8.75%, about 9.0%, about 9.25%, about 9.5%, about 9.75% or about
10%.
[0072] Compositions described herein optionally comprise one or
more pharmaceutically acceptable lubricants (including
anti-adherents and/or glidants) as excipients. Suitable lubricants
include, either individually or in combination, glyceryl behapate
(e.g., Compritol.TM. 888); stearic acid and salts thereof,
including magnesium (magnesium stearate), calcium and sodium
stearates; hydrogenated vegetable oils (e.g., Sterotex.TM.);
colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium
acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g.,
Carbowax.TM. 4000 and Carbowax.TM. 6000); sodium oleate; sodium
lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if
present, constitute in total about 0.1% to about 10%, about 0.2% to
about 8%, or about 0.25% to about 5%, of the total weight of the
composition. Illustratively, one or more pharmaceutically
acceptable lubricants are present in a total amount by weight of
about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about
0.6%, about 0.7%, about 0.8%, about 0.9%, 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 2.1%, about 2.2%,
about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about
2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, about 3.3%,
about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about
3.9%, about 4.0%, about 4.1%, about 4.2%, about 4.3%, about 4.4%,
about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about
5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%,
about 5.6%, about 5.7%, about 5.8%, about 5.9%, about 6.0%, about
6.1%, about 6.2%, about 6.3%, about 6.4%, about 6.5%, about 6.6%,
about 6.7%, about 6.8%, about 6.9%, about 7.0%, about 7.1%, about
7.2%, about 7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%,
about 7.8%, about 7.9%, about 8.0%, about 8.1%, about 8.2%, about
8.3%, about 8.4%, about 8.5%, about 8.6%, about 8.7%, about 8.8%,
about 8.9%, about 9.0%, about 9.1%, about 9.2%, about 9.3%, about
9.4%, about 9.5%, about 9.6%, about 9.7%, about 9.8%, about 9.9% or
about 10.0%.
[0073] In another embodiment, the compositions described herein
optionally comprise an emollient. Illustrative emollients include
mineral oil, mixtures of mineral oil and lanolin alcohols, cetyl
alcohol, cetostearyl alcohol, petrolatum, petrolatum and lanolin
alcohols, cetyl esters wax, cholesterol, glycerin, glyceryl
monostearate, isopropyl myristate, isopropyl palmitate, lecithin,
allyl caproate, althea officinalis extract, arachidyl alcohol,
argobase EUC, Butylene glycol dicaprylate/dicaprate, acacia,
allantoin, carrageenan, cetyl dimethicone, cyclomethicone, diethyl
succinate, dihydroabietyl behenate, dioctyl adipate, ethyl laurate,
ethyl palmitate, ethyl stearate, isoamyl laurate, octanoate, PEG-75
lanolin, sorbitan laurate, walnut oil, wheat germ oil super refined
almond, super refined sesame, super refined soybean, octyl
palmitate, caprylic/capric triglyceride and glyceryl cocoate.
[0074] An emollient, if present, is present in the compositions
described herein in an amount of about 1% to about 30%, about 3% to
about 25%, or about 5% to about 15%, by weight. Illustratively, one
or more emollients are present in a total amount by weight of about
1%, about 2%, about 3%, about 4%, 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 26%, about 27%, about 28%, about 29%, or about 30%.
[0075] In one embodiment, a composition comprises an antimicrobial
preservative. Illustrative anti-microbial preservatives include
acids, including but not limited to benzoic acid, phenolic acid,
sorbic acids, alcohols, benzethonium chloride, bronopol,
butylparaben, cetrimide, chlorhexidine, chlorobutanol,
chlorocresol, cresol, ethylparaben, imidurea, methylparaben,
phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric
acetate, phenylmercuric borate, phenylmercuric nitrate, potassium
sorbate, propylparaben, sodium propionate, or thimerosal. The
anti-microbial preservative, if present, is present in an amount of
about 0.1% to about 5%, about 0.2% to about 3%, or about 0.3% to
about 2%, by weight, for example about 0.2%, 0.4%, 0.6%, 0.8%, 1%,
1.2%, 1.4%, 1.6%, 1.8%, 2%, 2.4%, 2.6%. 2.8%, 3.0%, 3.2%, 3.4%,
3.6%, 3.8%, 4%, 4.2%, 4.4%, 4.6%, 4.8%, or 5%.
[0076] Compositions described herein optionally compromise one or
more emulsifying agents. The term "emulsifying agent" refers to an
agent capable of lowering surface tension between a non-polar and
polar phase and includes compounds defined as "self emulsifying"
agents. Suitable emulsifying agents can come from any class of
pharmaceutically acceptable emulsifying agents including
carbohydrates, proteins, high molecular weight alcohols, wetting
agents, waxes and finely divided solids. The optional emulsifying
agent, if present, is present in a composition in a total amount of
about 1% to about 15%, about 1% to about 12%, about 1% to about
10%, or about 1% to about 5% by weight of the composition.
Illustratively, one or more emulsifying agents are present in a
total amount by weight of about 1%, about 2%, about 3%, about 4%,
about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about
11%, about 12%, about 13%, about 14%, or about 15%.
[0077] In another embodiment, the water immiscible solvent
comprises propylene glycol, and is present in a composition in an
amount of about 1% to about 99%, by weight of the composition, for
example about 1%, about 2%, about 3%, about 4%, about 5%, about 6%,
about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about
20%, about 25%, about 30%, about 35%, about 40%, about 45%, about
50%, about 55%, about 60%, about 65%, about 70%, about 75%, about
80%, about 85%, about 90%, about 95% or about 99%.
[0078] Pharmaceutical Dosage Forms
[0079] In one embodiment, compositions described herein are
suitable for transdermal administration. In another embodiment,
transdermally administrable compositions are adapted for
administration in and/or around the abdomen, back, chest, legs,
arms, scalp or other suitable skin surface and maybe formulated as
patches, ointments, creams, suspensions, lotions, pastes, gels,
sprays, foams, oils or other form suitable for transdermal
administration.
[0080] In another embodiment, compositions described herein which
are transdermally administrable include opioid prodrugs, including
prodrugs of buprenorphine, placed in a propylene glycol or gel
formulation.
[0081] In another embodiment, a single dosage unit comprises a
therapeutically effective amount or a therapeutically and/or
prophylactically effective amount of buprenorphine or buprenorphine
prodrug. The term "therapeutically effective amount" or
"therapeutically and/or prophylactically effective amount" as used
herein refers to an amount of compound or agent that is sufficient
to elicit the required or desired therapeutic and/or prophylactic
response, as the particular treatment context may require. Single
dosage unit as used herein includes individual sachets containing a
single dose, metered pumps designed to dispense a predetermined
quantity of material for application to the skin as well as other
means for dispensing a single or multiple doses for application to
the skin.
[0082] It will be understood that a therapeutically and/or
prophylactically effective amount of a drug for a subject is
dependent inter alia on the body weight of the subject as well as
other factors known to a person of ordinary skill in the art. A
"subject" herein to which a therapeutic agent or composition
thereof can be administered includes mammals such as a human
subject of either sex and of any age, and also includes any
nonhuman animal, particularly a domestic, farm or companion animal,
illustratively a cat, cow, pig, dog or a horse as well as
laboratory animals such as guinea pigs and primates.
[0083] In another embodiment, compositions disclosed herein
comprise one or more opioid prodrugs, including prodrugs of
buprenorphine, in a total amount of about of between about 0.1% and
about 95% by weight of the composition, for example about 0.1%,
about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about
0.7%, about 0.8%, about 0.9%, about 1%, 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%, about 2.1%, about 2.2%, about 2.3%,
about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about
2.9%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%,
about 9%, about 10%, about 11%, about 12%, about 13%, about 14%,
about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,
about 45%, about 50%, about 55%, about 60%, about 65%, about 70%,
about 75%, about 80%, about 85%, about 90% or about 95%.
[0084] A therapeutically effective dose of a opioid prodrug
composition described herein is that amount of the composition or
opioid prodrug delivered to a mammal for the treatment of a symptom
or condition.
[0085] The terms "treat", "treated", "treating" and "treatment" are
to be broadly understood as referring to any response to, or
anticipation of, a medical condition in a mammal, particularly a
human, and includes but is not limited to: [0086] (i) preventing
the medical condition from occurring in a subject, which may or may
not be predisposed to the condition, but has not yet been diagnosed
with the condition and, accordingly, the treatment constitutes
prophylactic treatment for the medical condition; [0087] (ii)
inhibiting the medical condition, i.e., arresting, slowing or
delaying the on-set, development or progression of the medical
condition; or [0088] (iii) relieving the medical condition, i.e.,
causing regression of the medical condition.
[0089] Gel Formulations
[0090] Alcoholic gels and emulsions have become more popular for
systemic delivery of pharmacologically active agents. Testosterone
and estradiol products are examples of products on the market now
which are gaining market share relative to competitive patch
products. Typically patches have been the mainstay for systemic
transdermal drug delivery. Ironically, the original transdermal
dosage form was a nitroglycerin ointment that was measured out to
provide the correct dose. For modern transdermal systemic delivery,
many gels and creams have unit dose packaging and calibrated pump
dispensers designed to provide the correct dose for application to
the skin of the subject. Systemic gel treatments take advantage of
the fact that much larger skin surface areas can be covered with
the drug, which will improve the chances of therapeutic blood level
success. Patches can usually only be made at a maximum area of 50
cm.sup.2; however, this is not a desirable size. Alcoholic gels can
be made and can optionally include a gelling agent such as ethyl
cellulose or a Carbopol. Optionally, appropriate levels of
penetration enhancers can be incorporated into the gel.
[0091] Additional embodiments which can be prepared include the
following compositions:
[0092] Gel Formulation Used for Rubbing into Skin
TABLE-US-00002 92% absolute ethanol, USP/NF 5% Propylene glycol 2%
Klucel .RTM. hydroxypropylcellulose 1% buprenorphine or prodrug of
buprenorphine
[0093] Gel Formulation
TABLE-US-00003 92% absolute ethanol, USP/NF 5% ethylene glycol, USP
2% Klucel .RTM. hydroxypropylcellulose 1% buprenorphine or prodrug
of buprenorphine
[0094] Gel Formulation
TABLE-US-00004 91.75% absolute ethanol, USP/NF 5.0% ethylene
glycol, USP .sup. 1% buprenorphine or prodrug of buprenorphine
1.25% Di-2 (ethylhexyl) amine 0.5% Carbopol 980 .RTM., NF 0.5%
isopropyl myristate, USP/NF
[0095] Patch Formulation
[0096] The compounds and pharmaceutical compositions described
herein are suitable for use in transdermal delivery devices such as
patches and the like. For example, the compounds and compositions
described herein are suitable for use in a membrane-modulated
transdermal delivery system. In this system, the reservoir
containing the compound to be transdermally administered to the
patient is encapsulated in a shallow compartment molded from a drug
impermeable backing and a rate controlling polymeric membrane
through which the compound to be delivered passes in a controlled
manner. In one embodiment, the external surface of the membrane has
a thin layer of a drug-compatible, hypoallergenic adhesive polymer
(e.g., silicone or polyacrylate adhesive) which is applied to
achieve intimate contact of the transdermal system with the
skin.
[0097] The compounds and pharmaceutical compositions described
herein are also suitable for use in adhesive-diffusion controlled
transdermal systems. In these embodiments, the drug reservoir is
formulated by directly dispersing the drug (or drugs) to be
delivered in an adhesive polymer and then spreading the medicated
adhesive onto a flat sheet of drug-impermeable backing membrane to
form a thin drug reservoir layer. Optionally, on top of the drug
reservoir layer, additional layers of non-medicated rate
controlling adhesive polymer of constant thickness are placed to
produce an adhesive diffusion-controlled drug-delivery system.
[0098] The compounds and pharmaceutical compositions described
herein are also suitable for use in matrix dispersion-type systems.
In these systems, the drug reservoir is formed by homogeneously
dispersing the drugs in a hydrophilic or lipophilic polymer matrix,
and the medicated polymer then is molded into a medicated disc with
a defined surface area and controlled thickness. The disc then is
glued onto an occlusive baseplate in a compartment fabricated from
a drug-impermeable backing. The adhesive polymer is spread along
the circumference to form a strip of adhesive rim around the
medicated disc.
[0099] The compounds and pharmaceutical compositions described
herein are also suitable for use in microreservoir systems. In
these systems, the drug reservoir is formed by first suspending the
drug particles in an aqueous solution of water-soluble polymer and
then dispersing it homogeneously in a lipophilic polymer by
high-shear mechanical force to form a large number of unleachable,
microscopic spheres of drug reservoirs. This unstable dispersion is
quickly stabilized by immediately cross-linking the which produces
a medicated polymer disc with a constant surface area and fixed
thickness. A transdermal therapeutic system is produced in which
the medicated disc is positioned at the center and surrounded by an
adhesive rim.
[0100] Patch formulations can be optimized using in vitro human
skin diffusion testing prior to the selection of two or three
patches for stability testing. In one embodiment, the drug and
adhesive are formulated into one monolithic layer. The drug can be
mixed with an adhesive (e.g. silicone type, available from Dow
Corning and other manufacturers) in a solvent (e.g. methylene
chloride or ethyl acetate). This drug mixture would then be
extruded onto a polyester backing film to a uniform thickness of
about 100 microns or greater with a precision wet film applicator.
The solvent is allowed to evaporate in a drying oven and the
resulting "patch" is trimmed to fit the diffusion cell donor
chamber. Various patch formulations will be made until the desired
steady-state flux rate and adhesive properties are obtained.
Different adhesives can be tried, as well as varying the amount of
adhesive in the formulation (Nalluri, Milligan et al. 2005).
Suitable results have been obtained by making monolithic patches
with DURO-TAK 387-2051, which is an acrylate-vinyl acetate
non-curing pressure sensitive adhesive from the National Starch
Chemical Company. Different solvents (e.g. isopropyl myristate,
propylene glycol) can optionally be incorporated into the
formulation in an attempt to optimize the delivery rate. In a
further embodiment, reservoir patches can be made if it appears,
for example, that the drugs are not compatible with a monolithic
matrix patch formulation. In the reservoir system, the active
ingredient(s) and any excipient(s) could be formulated into a gel
and sealed between a release layer and an impermeable backing
material such as polyester or other suitable material known to a
person of skill in the art. Ethyl vinyl acetate membranes with
acrylic adhesives have been found to be suitable.
[0101] Adhesive patch formulations can be prepared containing
different loadings of a buprenorphine prodrug and optionally an
opioid antagonist by using DURO-TAK adhesives (National Starch and
Chemical Company, USA). Appropriate amounts of adhesive and drug
can be sonicated for ten minutes, cast onto the release liner (9742
Scotchpak, 3M, St. Paul, Minn.) with a wet film applicator (Paul N.
Gardner Company, Inc., Pompano Beach, Fla.) set at a 40 mil
thickness, and kept at room temperature for one hour and then at
70.degree. C. in an oven for ten minutes (to remove any residual
solvent). The patches would then be covered with backing membrane
(CoTran 9722, 3M, St. Paul, Minn.), will be cut into appropriate
sizes, and then can be stored in a desiccator for further
study.
[0102] In further embodiments, additional adhesives which are
suitable for preparing patch formulations and transdermal delivery
devices such as patches include polyisobutylenes, acrylates,
silicone and combinations of the foregoing. Additional adhesives
can be found in U.S. Provisional Patent Application No.
60/852,394.
[0103] In another illustrative embodiment, the transdermal patch
can be one which is capable of controlling the release of the
buprenorphine or buprenorphine prodrug such that transdermal
delivery of the buprenorphine or buprenorphine prodrug to the
subject is substantially uniform and sustained over a period of
about 6 hours, about 12 hours, about 24 hours, about 48 hours or
about 7 days. Such transdermal patch which can be used in the
practice of the methods described herein can take the form of an
occlusive body. In practice, the occlusive body which includes the
buprenorphine or buprenorphine prodrug is positioned on the
subject's skin under conditions effective to transdermally deliver
the buprenorphine or buprenorphine prodrug to the subject.
[0104] In addition to using the compounds and pharmaceutical
compositions described herein in the transdermal delivery systems
previously described, they are also suitable for use in conjunction
with microneedles for transdermal drug delivery which create
micrometer-scale transport pathways. Microneedles provide a
minimally invasive means to transport molecules into the skin, as
the channels they create are extremely small on a clinical level.
However, because the channels are much larger than even
macromolecules, such channels should dramatically increase skin
permeability.
[0105] Microneedles can be made from materials such as silicon,
biodegradable polymers, and stainless steel as well as other
bio-compatible materials and can be solid or hollow. Solid
microneedles can be used to create holes in the skin, followed by
application of a transdermal patch to the skin surface.
Alternatively, solid microneedles can be first coated with a drug
and then inserted into the skin. Hollow microneedles can also be
used, to facilitate active fluid flow through the needle bore and
into the skin. See, e.g., Prausnitz, Adv. Drug. Deliv. Rev. 56
(2004) 581-587, for a review.
[0106] Numerous studies have demonstrated that solid microneedles
can increase skin permeability by up to four orders of magnitude
for compounds ranging in size from small molecules to proteins to
nanoparticles (Henry et al., J. Pharm. Sci. 87 (1988) 922-925;
McAllister et al., PNAS 100 (2003) 13755-13760; Lin et al., Pharm.
Res. 18 (2001) 1787-1793; and Cormier et al., J. Control. Release.
97 (2004) 503-511). Hollow microneedles have also been shown to
deliver insulin and reduce blood glucose levels (McAllister et al.,
PNAS 100 (2003) 13755-13760; Martanto et al., Pharm. Res. 21 (2004)
947-952). Kaushik et al. studied the effects of pain associated
with microneedle insertion in human volunteers and showed that the
sensation was no more than that of a smooth surface applied to the
skin or the "sensation of a piece of tape" applied to the skin
(Kaushik et al., Anesth. Analg. 92 (2004) 502-504).
[0107] Suitable microneedle arrangements for use with the compounds
and compositions described herein can be found in the foregoing
references as well as in U.S. patent application Ser. No.
11/812,249.
EXAMPLES
Example 1
Section I
Summary
[0108] The objective was to synthesize buprenorphine and
buprenorphine prodrugs and assess the permeation of buprenorphine
and its prodrugs through human abdominal skin in vitro.
Buprenorphine base and eight buprenorphine prodrugs were
synthesized and tested. Flow through diffusion cells were used for
the permeation studies. An aqueous ethanol solution of 25% was used
for the receiver solution. Donor compartment was comprised of 100%
propylene glycol solution, 96% propylene glycol with 4% ethanol or
a gel formulation. The flux and lag time values of buprenorphine
and buprenorphine prodrugs were obtained from the permeation
profiles. Drug accumulation in the skin after a 24 h diffusion
experiment was determined as .mu.mol/g wet tissue weight.
Section II
Methodology
[0109] 1.0 Purpose:
[0110] Synthesize buprenorphine prodrugs and assess the human skin
permeation of buprenorphine and buprenorphine prodrugs in vitro.
The following compounds were studied:
##STR00021## ##STR00022##
[0111] 2.0 Skin Details
[0112] The skin samples used in the following experiments were
obtained from the abdominal reduction surgery and dermatomed to a
thickness of approximately 200 .mu.m. The skin samples used herein
were frozen at -20.degree. C. for less than one year.
[0113] 3.0 Chemicals
[0114] Acetonitrile (HPLC grade), trifluoroacetic acid,
triethylamine, 4-(2-hydroxy ethyl)-piperzine ethane sulfonic acid
(HEPES), gentamicin sulfate, acetone, sodium hydroxide,
4-dimethylaminopyridine, and sodium bicarbonate were obtained
through Fisher Scientific (Fair Lawn, N.J.). Methanol (HPLC grade),
acetonitrile (HPLC grade), N--N'-dicyclohexylcarbodiamide, and
polyethylene glycol 400 (PEG 400) were obtained through VWR (West
Chester, Pa.). Propylene glycol (PG), triethylene glycol,
buprenorphine hydrochloride, triphosgene, methylchloroformate,
butenyl chloroformate, osmium tetraoxide, and Hanks' balanced salts
modified powder were purchased from Sigma-Aldrich (St. Louis, Mo.).
Petroleum ether, ethyl acetate, hexane, chloroform, anhydrous
sodium sulfate, hexane, methylene chloride, and dichloromethane
were obtained from the Chemical Stores (Lexington, Ky.). Argon and
nitrogen were purchased through Scott Gross Company, Inc.
(Lexington, Ky.). Nanopure water was obtained from a Barnstead
NANOpure.RTM. Diamond.TM. Ultrapure water system (Barnstead
International, Dubuque, Iowa).
[0115] 4.0 Synthesis of Buprenorphine Base and Buprenorphine
Prodrugs
[0116] 4.1 Synthesis of Buprenorphine Base
[0117] Buprenorphine hydrochloride (200 mg, 0.0004 mol) was
suspended in about 10 mL of dichloromethane. Triethylamine (80 mg,
0.0008 mol) was added drop-by-drop. The solution was stirred until
all material had dissolved. The solution was transferred to a 60-mL
reparatory funnel with rinses of dichloromethane. About 10 mL of
water was added to the funnel and the contents agitated well by
hand. The two phases were allowed to separate. The methylene
chloride layer was removed and dried over anhydrous sodium sulfate
for several hours. The methylene chloride was removed and combined
with dichloromethane rinses of the sodium sulfate. The solvent was
removed by a stream and nitrogen and the final product dried under
vacuum.
[0118] 4.2 Synthesis of ALL00106 (Buprenorphine 3,6,9-trioxadecyl
carbonate)
[0119] Triethylene glycol monomethyl ether (60 mg, 0.0004 mol) was
dissolved in dichloromethane and the solution chilled in an ice
bath. Triphosgene (36 mg, 0.00013 mol) was dissolved in
dichloromethane and this solution slowly added to the triethylene
glycol solution with stirring and while maintained at 0.degree. C.
The mixture was kept under argon and stirred for 3 hours.
[0120] Buprenorphine hydrochloride (200 mg, 0.0004 mol) was
suspended in about 10 mL of dichloromethane. Triethylamine (80 mg,
0.0008 mol) was added drop-by-drop. The solution was sealed and
stirred for 3 hours.
[0121] The two solutions were combined and allowed to come to
ambient temperature. The mixture was placed under argon and allowed
to stir overnight. The solvent was reduced to a small volume under
nitrogen and hexane was added to precipitate the product. The
product was removed by filtration and dried under vacuum. The
resulting product was a white, slightly sticky powder.
[0122] 4.3 Synthesis of ALL00107 (Buprenorphine methyl
carbonate)
[0123] Buprenorphine hydrochloride (204 mg, 0.0004 mol) was
suspended in 10 mL of dichloromethane contained in a glass vial.
The vial was placed in an ice bath and the contents chilled to
0.degree. C. Triethylamine (121 mg, 0.0012 mol) was added slowly
while stirring. Methylchloroformate (75.6 mg, 0.0008 mol) was added
drop-wise while stirring. The solution was allowed to come to
ambient temperature and left to stir overnight. The solution was
reduced to about 1 mL under a stream of nitrogen. About 5 mL of
hexane were added to precipitate the product. Solvent was removed
under a stream of nitrogen and then by vacuum until constant weight
for the product was obtained. The resultant product was a white
powder.
[0124] For ALL00107, the .sup.1H NMR (400 MHz, CDCl.sub.3) was as
follows: .delta.=6.86 (1H, d, J=8.0); 6.60 (1H, d, J=8.0); 5.90
(1H, s, H-5); 4.46 (1H, d, J=1.8); 3.85 (3H, s, OCO.sub.2CH.sub.3);
3.49 (s, 3H); 3.06-2.98 (2H, m); 2.93-2.84 (1H, m); 2.62 (1H, dd,
J1=11.9, J2=5.1); 2.38-2.21 (4H, m); 2.12 (1H, t, J=9.9); 1.98 (1H,
dt, J1=12.7, J2=5.6); 1.94-1.78 (2H, m); 1.71 (1H, dd, J1=12.9,
J2=2.2); 1.35 (3H, s, CH.sub.3C), 1.32 (1H, dd, J1=13.2, J2=9.4);
1.12-1.03 (1H, m); 1.03 (9H, s, C(CH.sub.3).sub.3); 0.85-0.74 (1H,
m); 0.72-0.62 (1H, m); 0.55-0.43 (2H, m, c-Pr); 0.16-0.07 (2H, m,
c-Pr).
[0125] 4.4 Synthesis of ALL00108 (Buprenorphine
2-[2-(2-methoxyethoxy)ethoxy]acetyl ester)
[0126] 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (37 mg, 0.0002
mol), N--N'-dicyclohexylcarbodiamide (62 mg, 0.0003 mol) and
4-dimethylaminopyridine (2.4 mg, 0.00002 mol) were combined in
dichloromethane and covered with argon. The mixture was allowed to
stir at ambient temperature for 3 hours.
[0127] Buprenorphine hydrochloride (100 mg, 0.0002 mol) was
suspended in dichloromethane. The above mixture was slowly added.
The mixture was kept under argon and stirred at ambient temperature
overnight.
[0128] The solvent was reduced to a small volume under nitrogen and
hexane was added to precipitate the product. The product was
removed by filtration and dried under vacuum. The resulting product
was an off-white powder.
[0129] For ALL00108, the .sup.1H NMR (400 MHz, CDCl.sub.3) was as
follows: .delta.=6.83 (1H, d, J=8.0); 6.62 (1H, d, J=8.0); 5.88
(1H, s, H-5); 4.45 (1H, d); 4.39 (2H, s, OCH.sub.2CO.sub.2);
3.80-3.76 (2H, m, PEG); 3.73-3.63 (4H, m, PEG); 3.57-3.53 (2H, m,
PEG); 3.45 (s, 3H); 3.38 (s, 3H, CH.sub.2OCH.sub.3); 3.06-2.98 (2H,
m); 2.93-2.84 (1H, m); 2.62 (1H, dd, J1=11.9, J2=5.1); 2.38-2.21
(4H, m); 2.12 (1H, t, J=9.9); 1.98 (1H, dt, J1=12.7, J2=5.6);
1.94-1.78 (2H, m); 1.71 (1H, dd, J1=12.9, J2=2.2); 1.35 (3H, s,
CH.sub.3C), 1.32 (1H, dd, J1=13.2, J2=9.4); 1.12-1.03 (1H, m); 1.04
(9H, s, C(CH.sub.3).sub.3); 0.85-0.74 (1H, m); 0.72-0.62 (1H, m);
0.55-0.43 (2H, m, c-Pr); 0.16-0.07 (2H, m, c-Pr).
[0130] 4.5 Synthesis of ALL00110 (Buprenorphine 3,4-dihydroxybutyl
carbonate)
[0131] Buprenorphine hydrochloride (300 mg, 0.0006 mol) was
suspended in dichloromethane. Triethylamine (171 mg, 0.0012 mol)
was added slowly with stirring. After all material had dissolved,
3-butenyl chloroformate (81 mg, 0.0006 mol) was added slowly under
argon with stirring. The mixture was allowed to stir overnight
under argon at ambient temperature. The solution volume was reduced
to about 2 mL under a stream of nitrogen. Hexane was added to
precipitate the product (3-butenyl carbonate of buprenorphine),
which was recovered by filtration and dried under vacuum. The
recovered 3-butenyl carbonate of buprenorphine (360 mg, 0.0007 mol)
was dissolved in 10% water in acetone. Pyridine (53 mg, 0.0007 mol)
was slowly added under argon with stirring, followed by
N-methylmorpholine N-oxide (189 mg, 0.0014 mol) and the mixture
brought to 0.degree. C. in an ice bath. Osmium tetraoxide (48 mg,
0.0007 mol) was dissolved in 10% water in acetone and added slowly
under argon at 0.degree. C. with stirring. The mixture was allowed
to come to ambient temperature and continue to stir overnight. The
solution was transferred to separatory funnel and additional water
added. Dichloromethane was added and the two phases mixed
thoroughly by manual shaking. After phase separation, the methylene
chloride layer was removed and dried for several hours over
anhydrous sodium sulfate. The solution volume was reduced under a
stream of nitrogen and hexane was added to precipitate the final
product. The product was recovered by filtration and dried under
vacuum.
[0132] 4.6 Synthesis of ALL00113 (Buprenorphine 3,6-dioxaheptyl
carbonate)
[0133] The same procedure as for ALL00106, starting from diethylene
glycol monomethyl ether (36 mg, 0.3 mmol), triphosgene (26.7 mg,
0.09 mmol), Buprenorphine hydrochloride (150 mg, 0.3 mmol) and
triethylamine (60.6 mg, 0.6 mmol), afforded 8 mg (4%) of
ALL00113.
[0134] 4.7 Synthesis of ALL00114 (Buprenorphine
2-(2-methoxyethoxy)acetyl ester)
[0135] The same procedure as for ALL00116, starting from
Buprenorphine hydrochloride (150 mg, 0.3 mmol), triethylamine (33.3
mg, 0.33 mmol), 2-(2-methoxyethoxy)acetic acid (40.2 mg, 0.3 mmol),
4-dimethylaminopyridine (3.7 mg, 0.03 mmol) and
N--N'-dicyclohexylcarbodiimide (92.8 mg, 0.45 mmol), afforded 98 mg
(56%) of ALL00114 as an off-white oil.
[0136] For ALL00114, the .sup.1H NMR (400 MHz, CDCl.sub.3) was as
follows: .delta.=6.81 (1H, d, J=8.2); 6.60 (1H, d, J=8.2); 5.88
(1H, s, H-5); 4.43 (1H, d, J=1.8); 4.39 (2H, s, OCH.sub.2CO.sub.2);
3.79-3.75 (2H, m, OCH.sub.2CH.sub.2O); 3.62-3.57 (2H, m,
OCH.sub.2CH.sub.2O); 3.46 (s, 3H); 3.38 (s, 3H, CH.sub.2OCH.sub.3);
3.05-2.99 (2H, m); 2.96-2.84 (1H, m); 2.63 (1H, dd); 2.39-2.22 (4H,
m); 2.12 (1H, t); 1.98 (1H, dt); 1.94-1.77 (2H, m); 1.71 (1H, dd,
J1=13.0, J2=2.5); 1.36 (3H, s, CH.sub.3C), 1.32 (1H, dd, J1=13.2,
J2=9.4); 1.13-1.01 (1H, m); 1.04 (9H, s, C(CH.sub.3).sub.3);
0.86-0.75 (1H, m); 0.75-0.64 (1H, m); 0.55-0.44 (2H, m, c-Pr);
0.16-0.08 (2H, m, c-Pr).
[0137] 4.8 Synthesis of ALL00115 (Buprenorphine
3,6,9,12-tetraoxamidecyl carbonate)
[0138] The same procedure as for ALL00106, starting from
tetraethylene glycol monomethyl ether (62.4 mg, 0.3 mmol),
triphosgene (26.7 mg, 0.09 mmol), Buprenorphine hydrochloride (150
mg, 0.3 mmol) and triethylamine (60.6 mg, 0.6 mmol), afforded 107
mg (51%) of ALL00115 as a white sticky solid.
[0139] 4.9 Synthesis of ALL00116 (Buprenorphine
3,6,9,12-tetraoxamidecanoyl ester)
[0140] Buprenorphine hydrochloride (75.6 mg, 0.15 mmol) was
suspended in dichloromethane (2 mL) followed by triethylamine (16.7
mg, 0.165 mmol). The mixture was stirred at ambient temperature for
5 min. 3,6,9,12-Tetraoxamidecanoic acid (43.3 mg, 0.195 mmol) in
dichloromethane (1.75 mL) was added followed by
4-dimethylaminopyridine (1.8 mg, 0.015 mmol) and
N--N'-dicyclohexylcarbodiimide (49.5 mg, 0.24 mmol). The mixture
was stirred at ambient temperature overnight. The mixture was
filtered, concentrated under a reduced pressure and chromatographed
on silica gel with hexane-ethyl acetate (gradient 4:1, 2:1, 1:1,
0:1). Fractions containing the product were concentrated under a
reduced pressure, dissolved in hexane with a few drops of ethyl
acetate, filtered and concentrated again to afford ALL00116 (65.5
mg, 65%) as a colorless oil.
[0141] For ALL00116, the .sup.1H NMR (400 MHz, CDCl.sub.3) was as
follows: .delta.=6.81 (1H, d, J=8.2); 6.61 (1H, d, J=8.2); 5.89
(1H, s, H-5); 4.43 (1H, d, J=1.8); 4.40 (2H, s, OCH.sub.2CO.sub.2);
3.80-3.76 (2H, m, PEG); 3.73-3.63 (8H, m, PEG); 3.57-3.53 (2H, m,
PEG); 3.46 (s, 3H); 3.38 (s, 3H, CH.sub.2OCH.sub.3); 3.06-2.98 (2H,
m); 2.94-2.84 (1H, m); 2.63 (1H, dd); 2.39-2.22 (4H, m); 2.12 (1H,
t); 1.98 (1H, dt); 1.94-1.77 (2H, m); 1.71 (1H, dd, J1=13.0,
J2=2.5); 1.36 (3H, s, CH.sub.3C), 1.32 (1H, dd, J1=13.2, J2=9.4);
1.13-1.01 (1H, m); 1.04 (9H, s, C(CH.sub.3).sub.3); 0.86-0.75 (1H,
m); 0.75-0.64 (1H, m); 0.55-0.44 (2H, m, c-Pr); 0.16-0.08 (2H, m,
c-Pr).
[0142] 5.0 In Vitro Skin Permeation Studies
[0143] 5.1 Preparation of Receiver Fluid 1
[0144] One liter of receiver fluid was prepared by measuring 1 L of
nanopure water into a graduated cylinder. Ninety percent of the
water was added to an Erlenmeyer flask. One bottle of Hanks' salts
was added to the water along with 5.96 g of HEPES and 0.35 g of
sodium bicarbonate. The pH of the solution was adjusted with 1 N
sodium hydroxide solution to pH 7.4. The remaining water was added
and the receiver fluid was filtered through a 0.2.mu. filter
(Millipore, Billerica, Mass.). Fifty milligrams of gentamicin was
added to the filtered receiver fluid and 400 mL of the receiver
fluid was removed and replaced with 400 mL of PEG 400.
[0145] 5.2 Preparation of Receiver Fluid 2
[0146] One liter of receiver fluid was prepared by measuring 857 mL
or 714 mL of nanopure water into a graduated cylinder. Ethanol
(70%) was added (143 mL or 286 mL). The receiver fluid was filtered
through a 0.2.mu. filter (Millipore, Billerica, Mass.).
[0147] 5.3 Preparation of the Formulations
[0148] Each compound was made up in 100% propylene glycol (PG). For
the PG solution, approximately 25-35 mg of the appropriate compound
was weighed into a glass culture tube. Propylene glycol was added
to give about 102 mg/mL solution. For the gel formulation, the
appropriate drug was weighed out (1% of the formulation). To the
drug, absolute ethanol was added (92% of the formulation). The
solution was vortexed and propylene glycol was added (5% of the
formulation). The solution was vortexed and the gelling agent
[Klucel.RTM. hydroxypropylcellulose] was added (2% of the
formulation). Other formulations included propylene glycol/ethanol
[96/4].
[0149] 5.4 Permeation Experiments
[0150] Dermatomed skin harvested from abdominoplasty, stored at
-20.degree. C., was used for the experiments. A PermeGear
flow-through (In-Line, Riegelsville, Pa.) diffusion cell system was
used for the skin permeation studies.
[0151] Diffusion cells were kept at 32.degree. C. with a
circulating water bath. Human epidermal skin was arranged in the
diffusion cell with stratum corneum (upper layer of skin) facing
the donor compartment. The permeation area of the skin was 0.95
cm.sup.2. Data was collected from a human skin donor with three to
four diffusion cells per treatment.
[0152] Receiver solution was HEPES-buffered Hanks' balanced salts
with gentamicin containing 40% PEG 400 at a pH of 7.4 or aqueous
ethanol and flow rate was adjusted to 0.8 mL/h. Each cell was
charged with 0.050 mL, 0.075 mL or 0.10 mL of the respective drug
formulation (donor solution). The formulation was applied to ensure
complete coverage. Diffusion cells were covered with a cap for the
duration of the study.
[0153] Samples were collected into scintillation vials in 3 hour
increments for 24 hours, except for the initial diffusion study
which was conducted for 48 hours. All the samples were stored at
4.degree. C. until extracted. An aliquot (0.5 mL) of the diffusion
sample was placed into a HPLC vial and 0.5 mL of acetonitrile was
added to the sample, capped and vortexed. For diffusion studies
conducted with aqueous ethanol as the receiver fluid, 0.9 mL of the
collected sample was placed into HPLC vials for analysis without
dilution.
[0154] At the end of the experiment, the skin tissue was removed
from the diffusion cell, rinsed with nanopure water, and blotted
dry with a paper towel. The skin was tape stripped twice using book
tape (Scotch.TM., 3M, St. Paul, Minn.) to remove drug formulation
adhering to the tissue surface. The area of skin in contact with
the drug was cut out, chopped up and placed in a pre-weighed
scintillation vial. Ten mL of acetonitrile was added to the vial
and drug was extracted from the skin by shaking at room temperature
overnight. The following day a 1 mL aliquot was removed and added
into a HPLC vial for analysis.
[0155] At the end of the experiment, a 0.01 mL aliquot of the PG
donor solution was removed and added to a scintillation vial
containing 10 mL of acetonitrile. The vials were vortexed and then
sonicated for 15 min. An aliquot of 1 mL was removed and
transferred into a HPLC vial for analysis.
[0156] 6.0 Analytical Method
TABLE-US-00005 Column Brownlee .RTM. C.sub.8 reversed phase Spheri
5 .mu.m, (4.6 .times. 220 mm) column with a Brownlee .RTM. C.sub.8
reversed phase 7 .mu.m (3.2 x 150 mm) guard column Mobile 80:20
(acetonitrile:0.05% trifluroacetic acid with phase 5%
acetonitrile), 80:20 (acetonitrile:0.10% trifluroacetic acid with
5% acetonitrile) or 70:30 (acetonitrile:0.10% trifluroacetic acid
with 5% acetonitrile) Flow rate 1.5 mL/min Wavelength 210 or 220 nm
Injection 100 .mu.L (diffusion samples and respective standards)
volume 20 .mu.L (skin samples, donor samples, and respective
standards) Run time 6-18 min Retention buprenorphine = 4.3, 4.5,
5.0, or 9.1 min times ALL00106 = 6.0, 7.2-7.4 or 14.2 min ALL00107
= 5.5, 5.7, 7.5, or 11.2 min ALL00108 = 5.0-5.2 or 5.7 min ALL00110
= 3.6 min ALL00113 = 5.1-5.2 min ALL00114 = 5.2 min ALL00115 = 5.3
min ALL00116 = 5.1 or 5.4 min
[0157] 7.0 Data Analysis
[0158] The cumulative quantity of drug collected in the receiver
compartment was plotted as a function of time. The flux value for a
given experiment was obtained from the slope of a steady state
portion of the cumulative amount of drug permeated vs. time plot.
Lag time was obtained from the x-intercept of the steady state
portion of the cumulative amount of drug permeated vs. time plot.
In the Tables, the combined results of the delivered prodrug and
buprenorphine from the prodrug are listed as "total buprenorphine".
These values represent the data as total buprenorphine equivalents
delivered in the form of buprenorphine and/or prodrug.
Section III
Results
[0159] Originally the Hanks' buffer was used for the receiver
fluid; however, the receiver fluid was changed to the aqueous
ethanol to improve the sensitivity of the HPLC assay. With the
Hanks' buffer, ALL00106 and ALL00107 permeated through the human
skin as buprenorphine. Intact prodrug was found in the diffusion
samples for ALL00106 but it was only for the initial 3 h sample or
it was below the limit of detection after the initial sample. Both
buprenorphine and intact prodrug were found in the skin samples.
ALL00106 and ALL00107 had higher total buprenorphine in the skin
compared to buprenorphine base. A lower flux enhancement was seen
with ALL00106 or ALL00107. With the aqueous ethanol buffer,
ALL00107 and ALL00108 permeated through the skin as buprenorphine
and intact prodrug. Intact prodrug and buprenorphine were also
found in the skin samples. ALL00108 had a flux enhancement of 2.35
relative to the buprenorphine base and a cumulative amount (nmol)
4.times. higher than the buprenorphine base.
[0160] In Table 8, ALL00108 had a flux enhancement compared to the
parent compound with the gel formulation. ALL00107 and ALL00108
also had higher cumulative amount of total drug (nmol) at the end
of the 24 h study compared to buprenorphine base. In Table 10,
ALL00114 and ALL00115 both had improved flux values compared to the
parent drug and had higher cumulative amount of total drug (nmol)
at the end of the 24 h study. There appeared to be some depletion
of drug with the gel formulation studies toward the last couple of
time points but this would be improved by adding more drug/gel
formulation.
[0161] In Table 9 and 11 with the propylene glycol donor solution,
ALL00106, ALL00108, ALL00110, ALL00114, and ALL00115 all had flux
enhancements compared to the parent compound. The five prodrugs
also had higher cumulative amounts at the end of the study compared
to the parent compound.
[0162] With both the gel formulation and propylene glycol, ALL00115
was mostly detected as intact prodrug in the receiver fluid with
only trace amounts of the parent compound. For the remainder of the
prodrugs, they were primarily detected as the parent drug in
receiver fluid.
[0163] ALL00116 had a flux enhancement of 9.2 over the parent
compound, buprenorphine base. The flux values of buprenorphine base
was 0.3.+-.0.2 nmol/cm.sup.2/h and the total buprenorphine from
ALL00116 was 2.7.+-.0.7 nmol/cm.sup.2/h. The cumulative amount of
drug (nmol) for buprenorphine base was 3.4.+-.2.8 compared to total
buprenorphine from ALL00116 which was 30.4.+-.7.0. Skin
concentrations for buprenorphine base were 1.1.+-.0.6 .mu.mol/g
compared to total buprenorphine from ALL00116 which was
22.7.+-.6.8.
[0164] The graphs show the cumulative amount (nmol) of
parent/prodrug permeated over the 24 h study period.
Section IV
Tables
TABLE-US-00006 [0165] TABLE 1 Buprenorphine and buprenorphine
prodrugs Molecular Molecular Melting Compound formula weight point
buprenorphine C.sub.29H.sub.41NO.sub.4 467.64 212-215.degree. C.
ALL00106 C.sub.37H.sub.55NO.sub.9 657.83 -- ALL00107
C.sub.31H.sub.43NO.sub.6 525.68 184-188.degree. C. ALL00108
C.sub.36H.sub.53NO.sub.8 627.81 195-198.degree. C. ALL00110
C.sub.34H.sub.49NO.sub.8 599.75 --
[0166] Table 1 shows the molecular formula, molecular weight and
some melting points for several compounds including buprenorphine
and four prodrugs of buprenorphine identified as ALL00106,
ALL00107, ALL00108 and ALL00109. The molecular structure for each
of these buprenorphine prodrugs is shown in as Formulas II-V.
TABLE-US-00007 TABLE 2 Permeation data of buprenorphine (n = 3) in
propylene glycol 24 h 24 h 48 h Lag skin conc cumulative cumulative
Flux time Compound (.mu.mol/g) amt (nmol) amt (nmol)
(nmol/cm.sup.2/h) (h) buprenorphine 1.1 .+-. 0.2 18.9 .+-. 8.0 35.3
.+-. 8.7 0.70 .+-. 0.06 5.7 .+-. 0.0
[0167] Table 2 shows the in vitro permeation of buprenorphine in a
propylene glycol carrier. The data in Table 2 provides the 24 h
skin concentration in .mu.mol of buprenorphine per gram of skin,
the 24 h and 48 h cumulative amount of buprenorphine which has
permeated the skin sample (nmol), the buprenorphine flux in units
of nmol/cm.sup.2/h and the lag time in hours. The flux is a measure
of the amount of substance (buprenorphine in Table 2) to pass
through a predetermined area (1 cm.sup.2 in Table 2) per unit time.
The lag time is a measure of the length of time for a drug to
establish a uniform concentration gradient in the skin.
TABLE-US-00008 TABLE 3 Permeation data of buprenorphine (n = 3),
ALL00106 (n = 4), and ALL00107 (n = 3) in propylene glycol 24 h 24
h Lag skin conc* cumulative Flux Flux time Compound (.mu.mol/g) amt
(nmol) (nmol/cm.sup.2/h) enhancement (h) buprenorphine 0.7 .+-. 0.4
9.8 .+-. 1.4 0.45 .+-. 0.04 -- 2.0 .+-. 1.4 ALL00106 0.2 .+-. 0.1
(Bup) 11.4 .+-. 0.8 0.54 .+-. 0.07 1.20 NA 2.1 .+-. 1.5 (PD)
ALL00107 0.1 .+-. 0.0 (Bup) 11.5 .+-. 1.8 0.53 .+-. 0.07 1.18 0.4
.+-. 0.2 1.6 .+-. 0.7 (PD) *In the skin of prodrug treated cells,
both intact prodrug and the parent drug was measured
[0168] Table 3 shows the in vitro permeation of buprenorphine and
buprenorphine prodrugs in a propylene glycol carrier. The data in
Table 3 provides the 24 h skin concentration in .mu.mol of
buprenorphine and prodrug (if administered) per gram of skin, the
24 h cumulative amount of buprenorphine which has permeated the
skin sample (nmol), the total buprenorphine flux in units of
nmol/cm.sup.2/h, the flux enhancement and the lag time in hours.
The flux enhancement values of 1.20 for ALL00106
(0.54.+-.0.07/0.45.+-.0.04) and 1.18 (0.53.+-.0.07/0.45.+-.0.04)
for ALL00107 show the increase in flux for buprenorphine prodrugs
ALL00106 and ALL00107 relative to flux for buprenorphine. Also
shown in Table 3 is an increase in both the 24 h skin concentration
(.mu.mol/g) and the 24 h cumulative amount (nmol) of buprenorphine
prodrugs ALL00106 and ALL00107 relative to that of
buprenorphine.
TABLE-US-00009 TABLE 4 Permeation data of buprenorphine (n = 3) in
propylene glycol (10% aq. ethanol receiver fluid) 24 h 24 h Lag
skin conc cumulative Flux time Compound (.mu.mol/g) amt (nmol)
(nmol/cm.sup.2/h) (h) buprenorphine 0.3 .+-. 0.2 0.6 .+-. 0.2 0.08
.+-. 0.02 16.8 .+-. 0.2
[0169] Table 4 shows the in vitro permeation of buprenorphine in a
propylene glycol carrier with a 10% aqueous ethanol receiver fluid.
The data in Table 4 provides the 24 h skin concentration in .mu.mol
of buprenorphine per gram of skin, the 24 h cumulative amount of
buprenorphine which has permeated the skin sample (nmol), the
buprenorphine flux in units of nmol/cm.sup.2/h and the lag time in
hours. The flux and lag time have the meaning as set forth with
respect to Table 2.
TABLE-US-00010 TABLE 5 Permeation data of buprenorphine (n = 3) in
propylene glycol (25% aq. ethanol receiver fluid) 24 h 24 h Lag
skin conc cumulative Flux time Compound (.mu.mol/g) amt (nmol)
(nmol/cm.sup.2/h) (h) buprenorphine 0.5 .+-. 0.1 0.7 .+-. 0.2 0.08
.+-. 0.03 13.6 .+-. 2.5
[0170] Table 5 shows the in vitro permeation of buprenorphine in a
propylene glycol carrier with a 25% aqueous ethanol receiver fluid.
The data in Table 5 provides the 24 h skin concentration in .mu.mol
of buprenorphine per gram of skin, the 24 h cumulative amount of
buprenorphine which has permeated the skin sample (nmol), the
buprenorphine flux in units of nmol/cm.sup.2/h and the lag time in
hours. The flux and lag time have the meaning as set forth with
respect to Table 2.
TABLE-US-00011 TABLE 6 Permeation data of buprenorphine (n = 2),
ALL00107 (n = 3), and ALL00108 (n = 2) in propylene glycol (25% aq.
ethanol receiver fluid) 24 h 24 h Lag skin conc cumulative Flux
Flux time Compound (.mu.mol/g) amt (nmol) (nmol/cm.sup.2/h)
enhancement (h) buprenorphine 0.4 .+-. 0.1 4.2 .+-. 0.6 0.43 .+-.
0.03 -- 14.0 .+-. 0.9 Total buprenorphine (ALL00107) 2.0 .+-. 0.7
1.5 .+-. 0.8 0.17 .+-. 0.06 0.40 15.0 .+-. 1.2 Buprenorphine from
ALL00107 0.1 .+-. 0.0 0.6 .+-. 0.0 0.06 .+-. 0.00 13.0 .+-. 0.4
ALL00107 1.9 .+-. 0.7 0.9 .+-. 0.8 -- -- Total buprenorphine
(ALL00108) 1.4 .+-. 0.4 17.3 .+-. 1.6 1.01 .+-. 0.07 2.35 6.0 .+-.
0.5 Buprenorphine from ALL00108 0.4 .+-. 0.1 9.7 .+-. 0.4 0.90 .+-.
0.07 12.5 .+-. 1.3 ALL00108 1.0 .+-. 0.3 7.6 .+-. 2.0 -- -- * total
buprenorphine = total buprenorphine equivalents delivered in the
form of buprenorphine and/or prodrug
[0171] Table 6 shows the in vitro permeation of buprenorphine in a
propylene glycol carrier with a 25% aqueous ethanol receiver fluid.
The data in Table 6 provides the 24 h skin concentration in .mu.mol
of buprenorphine and prodrug (if administered) per gram of skin,
the 24 h cumulative amount of buprenorphine which has permeated the
skin sample (nmol), the buprenorphine flux in units of
nmol/cm.sup.2/h, the flux enhancement and the lag time in hours.
The flux enhancement values of 0.40 for ALL00107
(0.17.+-.0.06/0.43.+-.0.03) and 2.35 (1.01.+-.0.07/0.43.+-.0.03)
for ALL00108 show the increase in flux for buprenorphine prodrug
ALL00108 relative to flux for buprenorphine while the flux
decreases for ALL00107 relative to buprenorphine as the flux
enhancement is less than one. Also shown in Table 6 is an increase
in both the 24 h skin concentration (.mu.mol/g) and the 24 h
cumulative amount (nmol) of buprenorphine prodrug ALL00108 relative
to that of buprenorphine.
TABLE-US-00012 TABLE 7 Additional buprenorphine prodrugs Molecular
Molecular Compound formula weight ALL00113 C.sub.35H.sub.51NO.sub.8
613.78 ALL00114 C.sub.34H.sub.49NO.sub.7 583.76 ALL00115
C.sub.39H.sub.59NO.sub.10 701.89 ALL00116 C.sub.38H.sub.57NO.sub.9
671.86
[0172] Table 7 shows the molecular formula and molecular weight for
four prodrugs of buprenorphine identified as ALL00113, ALL00114,
ALL00115 and ALL00116. The molecular structure for each of these
buprenorphine prodrugs is shown in as Formulas VI-IX.
TABLE-US-00013 TABLE 8 Permeation data of buprenorphine (n = 2),
ALL00106 (n = 3), ALL00107 (n = 3), and ALL00108 (n = 3) in gel
formulation 24 h 24 h Lag skin conc cumulative Flux Flux time
Compound (.mu.mol/g) amt (nmol) (nmol/cm.sup.2/h) enhancement (h)
buprenorphine 6.3 .+-. 1.3 12.4 .+-. 3.1 0.9 .+-. 0.2 -- 3.3 .+-.
0.6 Total buprenorphine (ALL00106) 12.2 .+-. 3.6 5.5 .+-. 0.5 0.4
.+-. 0.1 0.4 6.5 .+-. 1.1 Buprenorphine from ALL00106 0.3 .+-. 0.1
1.7 .+-. 0.3 0.2 .+-. 0.1 4.7 .+-. 1.5 ALL00106 11.9 .+-. 3.6 3.8
.+-. 0.3 0.3 .+-. 0.0 8.2 .+-. 0.8 Total buprenorphine (ALL00107)
4.1 .+-. 0.4 16.9 .+-. 2.6 0.8 .+-. 0.2 0.9 6.7 .+-. 0.0
Buprenorphine from ALL00107 0.5 .+-. 0.0 2.7 .+-. 0.5 0.1 .+-. 0.0
5.1 .+-. 0.0 ALL00107 4.0 .+-. 0.1 14.2 .+-. 2.4 0.7 .+-. 0.1 3.5
.+-. 4.8 Total buprenorphine (ALL00108) 2.2 .+-. 1.8 21.0 .+-. 6.7
1.2 .+-. 0.6 1.3 7.8 .+-. 0.8 Buprenorphine from ALL00108 0.2 .+-.
0.2 21.0 .+-. 6.7 1.2 .+-. 0.6 7.8 .+-. 0.8 ALL00108 1.9 .+-. 1.6
-- -- -- * total buprenorphine = total buprenorphine equivalents
delivered in the form of buprenorphine and/or prodrug
[0173] Table 8 shows the in vitro permeation of buprenorphine and
buprenorphine prodrugs in a gel formulation. The data in Table 8
provides the 24 h skin concentration in .mu.mol of buprenorphine
and prodrug (if administered) per gram of skin, the 24 h cumulative
amount of buprenorphine which has permeated the skin sample (nmol),
the total buprenorphine flux in units of nmol/cm.sup.2/h, the flux
enhancement and the lag time in hours. The flux enhancement value
of 1.3 for ALL00108 (1.2.+-.0.6/0.9.+-.0.2) shows the increase in
flux for buprenorphine prodrug ALL00108 relative to flux for
buprenorphine. Also shown in Table 8 is an increase in the 24 h
skin concentration (.mu.mol/g) of total buprenorphine for
buprenorphine prodrug ALL00106 and the 24 h cumulative amount
(nmol) of total buprenorphine for buprenorphine prodrugs ALL00107
and ALL00108 relative to that of buprenorphine.
TABLE-US-00014 TABLE 9 Permeation data of buprenorphine (n = 3),
ALL00106 (n = 3), and ALL00110 (n = 2) in propylene glycol 24 h 24
h Lag skin conc cumulative Flux Flux time Compound (.mu.mol/g) amt
(nmol) (nmol/cm.sup.2/h) enhancement (h) buprenorphine 1.6 .+-. 1.6
15.9 .+-. 2.3 1.2 .+-. 0.2 -- 11.4 .+-. 1.5 Total buprenorphine
(ALL00106) 11.9 .+-. 4.4 48.9 .+-. 17.6 3.8 .+-. 1.1 3.2 10.6 .+-.
1.3 Buprenorphine from ALL00106 1.6 .+-. 0.4 30.1 .+-. 13.2 2.3
.+-. 0.8 10.2 .+-. 1.4 ALL00106 10.4 .+-. 4.0 18.8 .+-. 4.6 1.5
.+-. 0.3 11.1 .+-. 1.2 Total buprenorphine (ALL00110) 14.1 .+-. 3.2
27.0 .+-. 2.4 2.4 .+-. 0.3 2.0 11.9 .+-. 2.7 Buprenorphine from
ALL00110 2.5 .+-. 0.4 27.0 .+-. 2.4 2.4 .+-. 0.3 11.9 .+-. 2.7
ALL00110 11.6 .+-. 2.8 -- -- -- * total buprenorphine = total
buprenorphine equivalents delivered in the form of buprenorphine
and/or prodrug
[0174] Table 9 shows the in vitro permeation of buprenorphine and
buprenorphine prodrugs in a propylene glycol carrier. The data in
Table 9 provides the 24 h skin concentration in .mu.mol of
buprenorphine and prodrug (if administered) per gram of skin, the
24 h cumulative amount of buprenorphine which has permeated the
skin sample (nmol), the total buprenorphine flux in units of
nmol/cm.sup.2/h, the flux enhancement and the lag time in hours.
The flux enhancement value of 3.2 for ALL00106
(3.8.+-.1.1/1.2.+-.0.2) and 2.0 for ALL00110
(2.4.+-.0.3/1.2.+-.0.2) shows the increase in flux for
buprenorphine prodrugs ALL00106 and ALL00110 relative to flux for
buprenorphine. Also shown in Table 9 is an increase in the 24 h
skin concentration (.mu.mol/g) and the 24 h cumulative amount
(nmol) of total buprenorphine for buprenorphine prodrugs ALL00106
and ALL00110 relative to that of buprenorphine.
TABLE-US-00015 TABLE 10 Permeation data of buprenorphine (n = 3),
ALL00110 (n = 3), ALL00114 (n = 3), and ALL00115 (n = 2) in gel
formulation 24 h 24 h Lag skin conc cumulative Flux Flux time
Compound (.mu.mol/g) amt (nmol) (nmol/cm.sup.2/h) enhancement (h)
buprenorphine 8.3 .+-. 4.0 2.5 .+-. 1.0 0.2 .+-. 0.0 -- 6.0 .+-.
1.8 Total buprenorphine (ALL00110) 7.8 .+-. 7.5 1.9 .+-. 1.0 0.1
.+-. 0.1 0.7 12.4 .+-. 4.1 Buprenorphine from ALL00110 0.7 .+-. 0.6
1.9 .+-. 1.0 0.1 .+-. 0.1 12.4 .+-. 4.1 ALL00110 7.1 .+-. 6.9 -- --
-- Total buprenorphine (ALL00114) 7.4 .+-. 2.8 6.3 .+-. 1.7 0.5
.+-. 0.2 2.5 11.3 .+-. 5.8 Buprenorphine from ALL00114 0.2 .+-. 0.1
6.3 .+-. 1.7 0.5 .+-. 0.2 11.3 .+-. 5.8 ALL00114 7.1 .+-. 2.8 -- --
-- Total buprenorphine (ALL00115) 1.4 .+-. 0.4 4.5 .+-. 1.3 0.2
.+-. 0.1 1.2 7.6 .+-. 0.5 Buprenorphine from ALL00115 0.1 .+-. 0.0
TA -- -- ALL00115 3.4 .+-. 0.6 4.5 .+-. 1.3 0.2 .+-. 0.1 7.6 .+-.
0.5 * total buprenorphine = total buprenorphine equivalents
delivered in the form of buprenorphine and/or prodrug
[0175] Table 10 shows the in vitro permeation of buprenorphine and
buprenorphine prodrugs in a gel formulation. The data in Table 10
provides the 24 h skin concentration in .mu.mol of buprenorphine
and prodrug (if administered) per gram of skin, the 24 h cumulative
amount of buprenorphine which has permeated the skin sample (nmol),
the total buprenorphine flux in units of nmol/cm.sup.2/h, the flux
enhancement and the lag time in hours. The flux enhancement value
of 2.5 for ALL00114 (0.5.+-.0.2/0.2.+-.0.0) and 1.2 for ALL00115
(0.2.+-.0.1/0.2.+-.0.0) shows the increase in flux for
buprenorphine prodrugs ALL00114 and ALL00115 relative to flux for
buprenorphine. Also shown in Table 10 is an increase in the 24 h
cumulative amount (nmol) of total buprenorphine for buprenorphine
prodrugs ALL00114 and ALL00115 relative to that of
buprenorphine.
TABLE-US-00016 TABLE 11 Permeation data of buprenorphine (n = 3),
ALL00108 (n = 2), ALL00114 (n = 2), and ALL00115 (n = 2) in
propylene glycol 24 h 24 h Lag skin conc cumulative Flux Flux time
Compound (.mu.mol/g) amt (nmol) (nmol/cm.sup.2/h) enhancement (h)
buprenorphine 1.1 .+-. 0.1 3.0 .+-. 0.7 0.3 .+-. 0.1 -- 13.8 .+-.
0.8 Total buprenorphine (ALL00108) 2.4 .+-. 0.7 5.8 .+-. 0.7 0.5
.+-. 0.0 1.7 10.9 .+-. 2.4 Buprenorphine from ALL00108 ND 5.8 .+-.
0.7 0.5 .+-. 0.0 10.9 .+-. 2.4 ALL00108 2.4 .+-. 0.7 -- -- -- Total
buprenorphine (ALL00114) 20.0 .+-. 0.9 8.8 .+-. 0.0 0.9 .+-. 0.1
3.0 13.2 .+-. 0.9 Buprenorphine from ALL00114 0.9 .+-. 0.0 8.8 .+-.
0.0 0.9 .+-. 0.1 13.2 .+-. 0.9 ALL00114 19.1 .+-. 0.9 -- -- --
Total buprenorphine (ALL00115) 0.8 .+-. 0.2 6.0 .+-. 1.3 0.7 .+-.
0.2 2.3 9.4 .+-. 8.5 Buprenorphine from ALL00115 ND TA -- --
ALL00115 0.8 .+-. 0.2 6.0 .+-. 1.3 -- -- * total buprenorphine =
total buprenorphine equivalents delivered in the form of
buprenorphine and/or prodrug
[0176] Table 11 shows the in vitro permeation of buprenorphine and
buprenorphine prodrugs in a propylene glycol carrier. The data in
Table 11 provides the 24 h skin concentration in .mu.mol of
buprenorphine and prodrug (if administered) per gram of skin, the
24 h cumulative amount of buprenorphine which has permeated the
skin sample (nmol), the total buprenorphine flux in units of
nmol/cm.sup.2/h, the flux enhancement and the lag time in hours.
The flux enhancement value of 1.7 for ALL00108
(0.5.+-.0.0/0.3.+-.0.1), 3.0 for ALL00114 (0.9.+-.0.1/0.3.+-.0.1)
and 2.3 for ALL00115 (0.7.+-.0.2/0.3.+-.0.1) shows the increase in
flux for buprenorphine prodrugs ALL00108, ALL00114 and ALL00115
relative to flux for buprenorphine. Also shown in Table 11 is an
increase in the 24 h skin concentration (.mu.mol/g) for
buprenorphine prodrugs ALL00108 and ALL00114 and the 24 h
cumulative amount (nmol) of total buprenorphine for buprenorphine
prodrugs ALL00108, ALL00114 and ALL00115 relative to that of
buprenorphine.
TABLE-US-00017 TABLE 12 Permeation data of buprenorphine (n = 3)
and ALL00116 (n = 3) in Propylene glycol/ethanol [96:4] 24 h 24 h
Lag skin conc cumulative Flux Flux time Compound (.mu.mol/g) amt
(nmol) (nmol/cm.sup.2/h) enhancement (h) buprenorphine 1.1 .+-. 0.6
3.4 .+-. 2.8 0.3 .+-. 0.2 -- 12.5 .+-. 2.1 Total buprenorphine
(ALL00116) 22.7 .+-. 6.8 30.4 .+-. 7.0 2.7 .+-. 0.7 9.2 12.3 .+-.
1.2 Buprenorphine from ALL00116 2.4 .+-. 0.9 8.7 .+-. 1.2 0.8 .+-.
0.2 13.2 .+-. 0.8 ALL00116 20.4 .+-. 5.8 21.7 .+-. 6.7 1.9 .+-. 0.6
11.8 .+-. 1.4 * total buprenorphine = total buprenorphine
equivalents delivered in the form of buprenorphine and/or
prodrug
[0177] Table 12 shows the in vitro permeation of buprenorphine and
a buprenorphine prodrug in a propylene glycol/ethanol [96/4]
carrier. The data in Table 12 provides the 24 h skin concentration
in .mu.mol of buprenorphine and prodrug (if administered) per gram
of skin, the 24 h cumulative amount of buprenorphine which has
permeated the skin sample (nmol), the total buprenorphine flux in
units of nmol/cm.sup.2/h, the flux enhancement and the lag time in
hours. The flux enhancement value of 9.2 for ALL00116
(2.7.+-.0.7/0.3.+-.0.2) shows the increase in flux for
buprenorphine prodrug ALL00116 relative to flux for buprenorphine.
Also shown in Table 11 is an increase in the 24 h skin
concentration (.mu.mol/g) and the 24 h cumulative amount (nmol) of
total buprenorphine for buprenorphine prodrug ALL00116 relative to
that of buprenorphine.
TABLE-US-00018 TABLE 13 Permeation data of buprenorphine (n = 2),
ALL00113 (n = 3), and ALL00116 (n = 3) in gel formulation 24 h 24 h
Lag skin conc cumulative Flux Flux time Compound (.mu.mol/g) amt
(nmol) (nmol/cm.sup.2/h) enhancement (h) buprenorphine 10.7 .+-.
5.3 3.5 .+-. 1.8 0.4 .+-. 0.1 -- 3.6 .+-. 1.3 Total buprenorphine
(ALL00113) 0.9 .+-. 0.2 0.9 .+-. 0.2 0.05 .+-. 0.01 0.1 7.9 .+-.
0.9 Buprenorphine from ALL00113 0.1 .+-. 0.1 0.9 .+-. 0.2 0.05 .+-.
0.01 7.9 .+-. 0.9 ALL00113 0.8 .+-. 0.1 -- -- -- Total
buprenorphine (ALL00116) 3.5 .+-. 0.9 5.5 .+-. 0.6 0.4 .+-. 0.1 1.2
7.2 .+-. 0.6 Buprenorphine from ALL00116 0.2 .+-. 0.0 5.5 .+-. 0.6
0.4 .+-. 0.1 7.2 .+-. 0.6 ALL00116 3.3 .+-. 0.8 -- -- -- * total
buprenorphine = total buprenorphine equivalents delivered in the
form of buprenorphine and/or prodrug
[0178] Table 13 shows the in vitro permeation of buprenorphine and
a buprenorphine prodrugs in a gel formulation. The data in Table 13
provides the 24 h skin concentration in .mu.mol of buprenorphine
and prodrug (if administered) per gram of skin, the 24 h cumulative
amount of buprenorphine which has permeated the skin sample (nmol),
the total buprenorphine flux in units of nmol/cm.sup.2/h, the flux
enhancement and the lag time in hours. The flux enhancement value
of 1.2 for ALL00116 (0.4.+-.0.1/0.4.+-.0.1) shows the increase in
flux for buprenorphine prodrug ALL00116 relative to flux for
buprenorphine. Also shown in Table 12 is an increase in the 24 h
cumulative amount (nmol) of total buprenorphine for buprenorphine
prodrug ALL00116 relative to that of buprenorphine.
[0179] All references, including printed publications, patent
applications, and patents, cited herein are hereby incorporated by
reference to the same extent as if each reference were individually
and specifically indicated to be incorporated by reference and were
set forth in its entirety herein.
[0180] The use of the terms "a" and "an" and "the" and similar
references in the context of this disclosure (especially in the
context of the following claims) are to be construed to cover both
the singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. All methods and individual method
steps described herein can be performed in any suitable order or
simultaneously unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g., such as, preferred, preferably)
provided herein, is intended merely to further illustrate the
content of the disclosure and does not pose a limitation on the
scope of the claims. No language in the specification should be
construed as indicating any non-claimed element as essential to the
practice of the present disclosure.
[0181] Alternative embodiments of the claimed disclosure are
described herein, including the best mode known to the inventors
for practicing the claimed invention. Of these, variations of the
disclosed embodiments will become apparent to those of ordinary
skill in the art upon reading the foregoing disclosure. The
inventors expect skilled artisans to employ such variations as
appropriate (e.g., altering or combining features or embodiments),
and the inventors intend for the invention to be practiced
otherwise than as specifically described herein.
[0182] Accordingly, this invention includes all modifications and
equivalents of the subject matter recited in the claims appended
hereto as permitted by applicable law. Moreover, any combination of
the above described elements in all possible variations thereof is
encompassed by the invention unless otherwise indicated herein or
otherwise clearly contradicted by context.
[0183] The use of individual numerical values are stated as
approximations as though the values were preceded by the word
"about" or "approximately." Similarly, the numerical values in the
various ranges specified in this application, unless expressly
indicated otherwise, are stated as approximations as though the
minimum and maximum values within the stated ranges were both
preceded by the word "about" or "approximately." In this manner,
variations above and below the stated ranges can be used to achieve
substantially the same results as values within the ranges. As used
herein, the terms "about" and "approximately" when referring to a
numerical value shall have their plain and ordinary meanings to a
person of ordinary skill in the art to which the disclosed subject
matter is most closely related or the art relevant to the range or
element at issue. The amount of broadening from the strict
numerical boundary depends upon many factors. For example, some of
the factors which may be considered include the criticality of the
element and/or the effect a given amount of variation will have on
the performance of the claimed subject matter, as well as other
considerations known to those of skill in the art. As used herein,
the use of differing amounts of significant digits for different
numerical values is not meant to limit how the use of the words
"about" or "approximately" will serve to broaden a particular
numerical value or range. Thus, as a general matter, "about" or
"approximately" broaden the numerical value. Also, the disclosure
of ranges is intended as a continuous range including every value
between the minimum and maximum values plus the broadening of the
range afforded by the use of the term "about" or "approximately."
Thus, recitation of ranges of values herein are merely intended to
serve as a shorthand method of referring individually to each
separate value falling within the range, unless otherwise indicated
herein, and each separate value is incorporated into the
specification as if it were individually recited herein.
[0184] It is to be understood that any ranges, ratios and ranges of
rations that can be formed by, or derived from, any of the data
disclosed herein represents further embodiments of the present
disclosure and are included as a part of the disclosure as though
they were explicitly set forth. This includes ranges that can be
formed that do or do not include a finite upper and/or lower
boundary. Accordingly, a person of ordinary skill in the art most
closely related to a particular range, ratio or range of ratios
will appreciate that such values are unambiguously derivable from
the data presented herein.
* * * * *