U.S. patent application number 10/551203 was filed with the patent office on 2006-12-14 for alkaloid formulations.
Invention is credited to Robert Gianello, Esra Ogru, Simon Michael West.
Application Number | 20060281716 10/551203 |
Document ID | / |
Family ID | 34921028 |
Filed Date | 2006-12-14 |
United States Patent
Application |
20060281716 |
Kind Code |
A1 |
West; Simon Michael ; et
al. |
December 14, 2006 |
Alkaloid formulations
Abstract
There is provided an alkaloid formulation comprising the
reaction product of one or more alkaloids with one or more
phosphate derivatives of one or more electron transfer agents.
Inventors: |
West; Simon Michael;
(Williamstown, AU) ; Ogru; Esra; (Glen Waverley,
AU) ; Gianello; Robert; (Olinda, AU) |
Correspondence
Address: |
REED SMITH LLP
P.O. BOX 488
PITTSBURGH
PA
15230-0488
US
|
Family ID: |
34921028 |
Appl. No.: |
10/551203 |
Filed: |
March 3, 2005 |
PCT Filed: |
March 3, 2005 |
PCT NO: |
PCT/AU05/00307 |
371 Date: |
June 29, 2006 |
Current U.S.
Class: |
514/100 ;
514/221; 514/282; 514/283; 514/304; 514/317 |
Current CPC
Class: |
A61K 31/46 20130101;
A61K 31/485 20130101; A61K 31/355 20130101; A61P 25/04 20180101;
A61K 9/0014 20130101; A61K 9/06 20130101; A61K 31/66 20130101; A61P
29/00 20180101 |
Class at
Publication: |
514/100 ;
514/282; 514/283; 514/304; 514/317; 514/221 |
International
Class: |
A61K 31/675 20060101
A61K031/675; A61K 31/665 20060101 A61K031/665; A61K 31/5513
20060101 A61K031/5513; A61K 31/485 20060101 A61K031/485; A61K 31/46
20060101 A61K031/46; A61K 31/44 20060101 A61K031/44; A61K 31/445
20060101 A61K031/445 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 3, 2004 |
AU |
2004901107 |
Aug 3, 2004 |
AU |
2004904367 |
Claims
1. An alkaloid formulation comprising the reaction product of one
or more alkaloids with one or more phosphate derivatives of one or
more electron transfer agents.
2. The alkaloid formulation according to claim 1 wherein the
phosphate derivative of a electron transfer agent is selected from
the group comprising one or more phosphate derivatives of
tocopherol.
3. The alkaloid formulation according to claim 1 wherein the
formulation is a topical formulation.
4. The alkaloid formulation according to claim 1 wherein the
formulation is an oral formulation.
5. The alkaloid formulation according to claim 4 further comprising
an enteric coating.
6. The alkaloid formulation according to claim 4 wherein the
formulation is selected from the group consisting of tablets,
powders, chewable tablets, capsules, oral suspensions, suspensions,
emulsions or fluids, children's formulations, enteral feeds,
nutraceuticals, and functional foods.
7. The alkaloid formulation according to claim 1 wherein the
formulation is a buccal formulation.
8. The alkaloid formulation according to claim 1 wherein the
electron transfer agent is selected from the group consisting of
hydroxy chromans including alpha, beta, gamma and delta tocols in
enantiomeric and racemic forms; quinols being the reduced forms of
vitamin K1 and ubiquinone; hydroxy carotenoids including retinol;
calciferol, ascorbic acid and mixtures thereof.
9. The alkaloid formulation according to claim 8 wherein the
electron transfer agent is selected from the group consisting of
tocopherol and other tocols, retinol, vitamin K1 and mixtures
thereof.
10. The alkaloid formulation according to claim 9 wherein the
electron transfer agent is selected from the group consisting of
the tocols and mixtures thereof
11. The alkaloid formulation according to claim 10 wherein the
electron transfer agent is .alpha.-tocopherol.
12. The alkaloid formulation according to claim 11 wherein the one
or more phosphate derivatives of one or more electron transfer
agents is selected from the group consisting of mono-tocopheryl
phosphate, di-tocopheryl phosphate and mixtures thereof
13. The alkaloid formulation according to claim 12 wherein the one
or more phosphate derivatives of one or more electron transfer
agents is a mixture of mono-tocopheryl phosphate and di-tocopheryl
phosphate.
14. The alkaloid formulation according to claim 1 wherein the one
or more phosphate derivatives of one or more electron transfer
agents is a phosphatide.
15. The alkaloid formulation according to claim 1 wherein the
alkaloid is selected from the group consisting of tertiary amines
which are alicyclic with the nitrogen atom as a common member of
three rings; are cyclic where the nitrogen is incorporated into a
single ring and alkylated; or have no cyclic structure
incorporating the nitrogen; and mixtures thereof.
16. The alkaloid formulation according to claim 15 wherein the
alkaloid is selected from the group consisting of atropine,
quinine, opioids, fentanyl, nicotine, fenspiride, flurazepan and
codeine.
17. The alkaloid formulation according to claim 1 wherein the
alkaloid is atropine.
18. The alkaloid formulation according to claim 1, wherein the
alkaloid is morphine.
19. A method for improving the efficacy of an alkaloid, said method
comprising the step of reacting the alkaloid with one or more
phosphate derivative of one or more electron transfer agents.
20. Use of the reaction product of one or more alkaloids with one
or more phosphate derivatives of one or more electron transfer
agents, together with excipients in the manufacture of a
formulation.
21. A pharmaceutical composition comprising the reaction product of
one or more alkaloids with one or more phosphate derivatives of one
or more electron transfer agents.
22. A pharmaceutical composition according to claim 21 wherein the
electron transfer agent is tocopherol.
Description
FIELD OF THE INVENTION
[0001] The present invention is directed to formulations comprising
one or more alkaloids. More specifically but not exclusively it
relates to formulations comprising one or more alkaloids and one or
more phosphate derivatives of electron transfer agents.
BACKGROUND OF THE INVENTION
[0002] In this specification, where a document, act or item of
knowledge is referred to or discussed, this reference or discussion
is not an admission that the document, act or item of knowledge or
any combination thereof was at the priority date: part of common
general knowledge, or known to be relevant to an attempt to solve
any problem with which this specification is concerned.
[0003] Alkaloids
[0004] There is a long history of the use of alkaloids for
medicine. These compounds were originally extracted from plants and
include nitrogenous compounds having physiological actions on
humans as drugs and poisons. The term "alkaloids" as used in this
description and in the claims includes all natural and synthetic
active compounds containing primary, secondary or tertiary amine
substituents. The amine may be incorporated into one or two rings,
but non-cyclic structures are also included. For example, this
includes: [0005] tertiary amines which: [0006] are alicyclic with
the nitrogen atom as a common member of three rings (eg. Morphine,
Atropine, Quinine); or [0007] are cyclic where the nitrogen is
incorporated into a single ring and alkylated (eg. Nicotine,
Fenspiride); or [0008] have no cyclic structure incorporating the
nitrogen (eg. Flurazepan); [0009] secondary amines where the
nitrogen is incorporated into an alicyclic structure (eg Conline,
Fendiline) or a linear structure (eg. Epinephrine); [0010] primary
amines (eg. Ephidrine); [0011] pyridines (eg Nicotine); [0012]
methamidine derivatives; [0013] quinolines (eg. Cinchonine); and
[0014] guanidines (eg. Arginine).
[0015] Most alkaloids are not water soluble but are soluble in
organic solvents. However, all alkaloids are basic and will combine
with acids to form crystalline salts which are usually at least
partially water soluble. Typically, alkaloids are administered as
salts either orally or by intravenous injection. The alkaloids are
a class of drugs that are not commonly administered transdermally
because the hydrophilic nature of the salts usually limits
transdermal transport. Morphine and atropine are examples of
clinically useful alkaloids that are not administered
transdermally. Further, it is desirable to improve oral delivery of
alkaloids since some of them are thought to act through the
lymphatic system.
[0016] Topical Administration
[0017] Topical administration refers to the application of a drug
directly to a part of the body and includes transdermal
administration (application to the skin) and buccal administration
(application to the inside of the mouth).
[0018] The skin is the largest organ of the body and functions to
protect the internal organs from external chemical, physical and
pathological hazards. Normal skin is divided into three layers: the
epidermis, the dermis, and subcutaneous tissue. The outer cornified
layer of the epidermis, the stratum corneum, possesses properties
of strength, flexibility, high electrical impedance and dryness
that retards penetration and proliferation of micro-organisms. The
stratum corneum is also the principle barrier to transdermal drug
absorption.
[0019] The art of transdermal delivery includes the application of
drugs in the pure state or as formulations which typically include
substances that enhance the rate of transport through the skin.
Historically transdermal delivery was as ointments, creams,
poultices and plasters to give effective contact with the skin.
More recently, the technology has been improved by making the
plaster into a "patch" which has better adhesion to the skin and
improved control over the rate of transport.
[0020] Transdermal delivery has been recognized to offer several
potential benefits including achieving blood levels similar to
those achieved by slow intravenous infusion but without the
inconvenience; better control of absorption and metabolism compared
to oral administration; continuity of drug effect especially of
drugs with short half lives; equivalent efficacy with reduced drug
dosage due to by-pass of hepatic first pass elimination; lower risk
of under or overdosing; and better patient compliance through
simplification of a dosage regime.
[0021] Not every drug can be administered transdermally at a rate
sufficiently high enough to achieve blood levels that are
therapeutically beneficial for systemic medication. Drugs with
similar molecular weights and sizes for example may absorb across
the skin at different rates. Skin enhancers and various formulation
techniques have been developed to improve drug absorption through
the skin. But concern has been raised with respect to long term
risk because increased drug permeability is achieved at the cost of
damaging a fundamentally important protective layer of the
skin.
[0022] Current strategies to improve transdermal therapy have not
been universally successful and there is scope for further
improvement. In particular, there is a need for use of transdermal
delivery systems capable of delivering alkaloids.
[0023] There has also been increased interest in buccal delivery
since this method of delivery avoids metabolism by the liver which
can be a problem when drugs are administered orally. Typically, the
drug is formulated in a lozenge which is placed under the tongue.
The lining of the mouth does not have an equivalent of the stratum
corneum on the skin so it is not as difficult to administer drugs
by buccal delivery, but this method of administration is not
commonly used because the rate of transport may be low, achieving
an ineffective result if the buccal membranes do not allow
permeation or active transport. Efforts have been made in the past
to improve the topical administration of drugs. For example,
international patent application no PCT/AU03/00998 discloses a
carrier for pharmaceuticals wherein the carrier comprises a complex
of a phosphate derivative of a pharmaceutically acceptable
compound, for example, laurylaminodipropionic acid tocopheryl
phosphates. PCT/AU03/00998 discloses that the tocopheryl phosphate
is complexed to a complexing agent selected from the group
consisting of amphoteric surfactants, cationic surfactants, amino
acids having nitrogen functional groups and proteins rich in these
amino acids. This carrier has been shown to improve the topical
administration of testosterone, estrogen, atropine and morphine.
However, in relation to morphine and atropine, further improvement
in skin penetration was desired.
[0024] Oral Administration
[0025] Many drugs are administered orally, but a large number of
potentially useful drugs are rejected because they are unable to
pass through the intestinal walls. It is understood that substances
such as fats are efficiently transported through the intestines,
but many others such as tocopherol are poorly transported. There is
thus a need for systems which enable improved oral administration
of alkaloids.
SUMMARY OF THE INVENTION
[0026] It has been found that there is a significant improvement in
administration when an alkaloid compound is complexed directly to a
phosphate derivative of an electron transfer agent. For example,
the administration of morphine was improved when it was complexed
directly to tocopheryl phosphate.
[0027] According to the present invention, there is provided an
alkaloid formulation comprising the reaction product of one or more
alkaloids with one or more phosphate derivatives of one or more
electron transfer agents.
[0028] Preferably, the phosphate derivative of a electron transfer
agent is selected from the group comprising one or more phosphate
derivatives of tocopherol.
[0029] Preferably, the alkaloid formulation is administered
topically or orally.
[0030] According to a second aspect of the invention, there is
provided a method for improving the efficacy of an alkaloid, said
method comprising the step of reacting the alkaloid with one or
more phosphate derivative of one or more electron transfer
agents.
[0031] The present invention also provides for the use of the
reaction product of one or more alkaloids with one or more
phosphate derivatives of one or more electron transfer agents,
together with excipients in the manufacture of a formulation.
[0032] The present invention also provides a pharmaceutical
composition comprising the reaction product of one or more
alkaloids with one or more phosphate derivatives of one or more
electron transfer agents, such as phosphate derivatives of
tocopherol.
[0033] Preferably, the alkaloid is selected from the group
consisting of tertiary amines which are (1) alicyclic with the
nitrogen atom as a common member of three rings ( eg. Morphine,
Atropine, Quinine ); (2) are cyclic where the nitrogen is
incorporated into a single ring and alkylated (eg. Nicotine,
Fenspiride ); or (3) have no cyclic structure incorporating the
nitrogen (eg. Flurazepan). More preferably, the alkaloid is
selected from the group consisting of atropine, quinine, opioids
such as morphine, fentanyl, nicotine, fenspiride, flurazepan and
codeine.
[0034] The term "electron transfer agents" is used herein to refer
to the class of chemicals which may be phosphorylated and which (in
the non-phosphorylated form) can accept an electron to generate a
relatively stable molecular radical or accept two electrons to
allow the compound to participate in a reversible redox system.
Examples of classes of electron transfer agent compounds that may
be phosphorylated include hydroxy chromans including alpha, beta,
gamma and delta tocols in enantiomeric and racemic forms; quinols
being the reduced forms of vitamin K1 and ubiquinone; hydroxy
carotenoids including retinol; calciferol and ascorbic acid.
Preferably, the electron transfer agent is selected from the group
consisting of tocopherol and other tocols, retinol, vitamin K1 and
mixtures thereof. More preferably, the electron transfer agent is
selected from the group consisting of the tocols and mixtures
thereof. The tocols include all isomers of derivatives of 6:hydoxy
2:methyl chroman (see structure below) where R.sub.1, R.sub.2 and
R.sub.3 may be hydrogen or methyl groups, that is, the
.alpha.-5:7:8 tri-methyl; .beta.-5:8 di-methyl; .gamma.-7:8
di-methyl; and .delta. 8 methyl derivatives. In the tocopherols,
R.sub.4 is substituted by 4:8:12 tri-methyl tridecyl group and
includes various stereoisomers and optical isomers (chiral centres
are indicted by the *). In the tocotrienols, R.sub.4 is substituted
by 4:8:12 tri-methyl trideca-3:7:11 triene group and the 2 position
may be stereoactive as R or S stereoisomers. Most preferably, the
electron transfer agent is .alpha.-tocopherol. ##STR1##
[0035] The term "phosphate derivatives" is used herein to refer to
compounds covalently bound by means of an oxygen to the phosphorus
atom of a phosphate group thus forming a
carbon--oxygen--phosphorous bond. The oxygen atom is typically
derived from a hydroxyl group on the electron transfer agent. The
term includes the acid forms of phosphorylated electron transfer
agents, salts of the phosphates including metal salts such as
sodium, magnesium, potassium and calcium and any other derivative
where the phosphate proton is replaced by other substituents such
as ethyl or methyl groups or phosphatidyl groups. The term includes
mixtures of phosphate derivatives, especially those which result
from phosphorylation reactions, as well as each of the phosphate
derivatives alone. For example, the term includes a mixture of
mono-tocopheryl phosphate (TP) and di-tocopheryl phosphate (T2P) as
well as each of TP and T2P alone. Suitable mixtures are described
in international patent application no PCT/AU01/01475.
[0036] The term "phosphate derivatives" does not include complexes
of the phosphate derivatives with a complexing agent selected from
the group consisting of amphoteric surfactants, cationic
surfactants, amino acids having nitrogen functional groups and
proteins rich in these amino acids.
[0037] Preferably, the one or more phosphate derivatives of one or
more electron transfer agents is selected from the group consisting
of mono-tocopheryl phosphate, di-tocopheryl phosphate and mixtures
thereof. Most preferably, the one or more phosphate derivatives of
one or more electron transfer agents is a mixture of
mono-tocopheryl phosphate and di-tocopheryl phosphate.
[0038] In some situations, it may be necessary to use a phosphate
derivative such as a phosphatide where additional properties such
as increased water solubility are preferred. Phosphatidyl
derivatives are amino alkyl derivatives of organic phosphates.
These derivatives may be prepared from amines having a structure of
R.sub.1R.sub.2N(CH.sub.2).sub.nOH wherein n is an integer between 1
and 6 and R.sub.1 and R.sub.2 may be either H or short alkyl chains
with 3 or less carbons. R.sub.1 and R.sub.2 may be the same or
different. The phosphatidyl derivatives are prepared by displacing
the hydroxyl proton of the electron transfer agent with a phosphate
entity that is then reacted with an amine, such as ethanolamine or
N,N' dimethylethanolamine, to generate the phosphatidyl derivative
of the electron transfer agent. One method of preparation of the
phosphatidyl derivatives uses a basic solvent such as pyridine or
triethylamine with phosphorous oxychloride to prepare the
intermediate which is then reacted with the hydroxy group of the
amine to produce the corresponding phosphatidyl derivative, such as
P cholyl P tocopheryl dihydrogen phosphate.
[0039] The alkaloid formulation may be administered to humans or
animals through a variety of dose forms such as supplements,
enteral feeds, parenteral dose forms, suppositories, nasal delivery
forms, dermal delivery including patches and creams, buccal
delivery forms. Oral or buccal delivery may specifically suit
alkaloids which have low water solubility.
[0040] Preferably, oral alkaloid formulations according to the
invention further comprise an enteric coating. The enteric coating
protects the complexes from the acidic environment in the stomach.
Oral formulations may take the form of tablets, powders, chewable
tablets, capsules, oral suspensions, suspensions, emulsions or
fluids, children's formulations, enteral feeds, nutraceuticals, and
functional foods.
[0041] The dose form may further include any additives routinely
used in preparation of that dose form such as starch or polymeric
binders, sweeteners, coloring agents, emulsifiers, coatings and the
like. Another suitable additive is a complex of a phosphate
derivative of an electron transfer agents may also be utilized
where additional properties such as improved stability or
deliverability may be useful. The term "complexes of phosphate
derivatives" refers to the reaction product of one or more
phosphate derivatives of electron transfer agents with one or more
complexing agents selected from the group consisting of amphoteric
surfactants, cationic surfactants, amino acids having nitrogen
functional groups and proteins rich in these amino acids as
disclosed in international patent application no PCT/AU01/01476,
incorporated herein by reference. If such an additive was used, it
would be important to ensure that there was excess electron
transfer agent present in the formulation. Other suitable additives
will be readily apparent to those skilled in the art.
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] FIG. 1: Effect of various atropine formulations on heart
rate in pigs. Data are cumulative averages over 10 minute periods
and have been corrected for basal (average of 1 h before
application) using covariate analyses.
[0043] FIG. 2: Typical differential of heart rate versus time
curve. Data are from pig 1 during replicate 1 who was treated with
preparation C (ie the very first pig used). The treatment
application commenced at 0 minutes and continued for 6 minutes. The
period over which differentials were averaged is indicated by the
straight lines.
[0044] FIG. 3: Effect of various base creams on heart rate in pigs.
Data are cumulative averages over 10 minutes periods and have been
corrected for basal (average of 1 h before application) using
covariate analyses.
[0045] FIG. 4: Typical heart rate versus time curve. Data are from
pig 1 during replicate 1 who was treated with preparation C (ie the
very pig used). The treatment application commenced at 0 minutes
and continued for 6 minutes. The period over which differentials
were averaged is indicated by the straight lines.
[0046] FIG. 5: Effect of treatment and time flinch response after
heat probe application
[0047] FIG. 6: Effect of morphine 1.35, 2.7 and 5.4 mg/kg in
TPM-01/M formulation on paw withdrawal latency, tested up to 8
hours.
EXAMPLES
[0048] Various embodiments/aspects of the invention will now be
described with reference to the following non-limiting
examples.
Example 1
[0049] This example investigates the transdermal delivery to pigs
of atropine in a formulation according to the invention. This
experiment investigated the effects of dermal penetration of
atropine when applied in gel form on heart rate of pigs.
[0050] Methods and Materials
[0051] Atropine (20 mg/kg) was formulated in the following base
creams for testing. In addition to the components specified below,
all of the creams contained the following: 12% Ultrez-10
Carbomer-3% solution, 0.25% Triethanolamine, 0.1% Surcide DMDMH and
Deionized Water up to 100%.
[0052] Compositions f, H and J when combined with atropine produce
a formulation according to the invention. Compositions B, D and E
produce formulations according to the prior art and compositions A,
C and I illustrate the effect of the excipients. TABLE-US-00001
Code Composition A 1.27% Deriphat 160 B 7.5% of 40% disodium
lauryliminodipropionate monotocopheryl phosphate and
lauryliminodipropionate ditocopheryl phosphate C 0.77% Arginine D
7.5% of 40% arginine monotocopheryl phosphate and arginine
ditocopheryl phosphate E 7.5% of 40% arginine mono tocopheryl
phosphate F 3% mono tocopheryl phosphate G 3% mono tocopheryl
phosphate and ditocopheryl phosphate H 7.5% disodium
lauryliminodipropionate mono tocopheryl phosphate I 1.5%
Triethanolamine J Tocopheryl phosphate and di-tocopheryl
phosphate
[0053] Ten male crossbred (Large white.times.Landrace) pigs
(initial average weight 51.5 kg and final average weight of 61.0
kg) were utilised in this experiment. Four days prior to the study
fourteen pigs were weighed and randomly allocated to individual
pens (1.75 m.times.0.65 m) in the experimental facility for an
acclimatisation period. During this period the hair on the back of
the pigs was removed with animal clippers (Oster--U.S.A) followed
by regular shaving with an electric human shaver (Philishave
HQ5041--Philips Aust Pty Ltd).
[0054] Elastic belts were also placed around the chest of the pigs
to accustom them to wearing the heart rate monitors. At the start
of the experiment the ten pigs that adapted best to the environment
and regular handling were selected and housed such that there were
no pigs in adjacent pens. This physical separation of the pigs
avoided any potential conflict between signals from the heart rate
monitors which all operated at the same frequency. The ten pigs
were divided into two groups of five (odd and even numbers) and
utilised on alternate days in the experiment. An experimental
replicate was therefore performed over two consecutive treatment
days. Within each replicate the ten pigs were randomly assigned to
one of the ten treatment groups, therefore each pig was used for
data capture on five occasions, and each treatment was applied five
times.
[0055] On each measurement day by about 08:00 the five pigs under
experiment were weighed, fitted with heart rate monitors and
recording of heart rate at 1-minute intervals commenced. Human
heart rate monitors (Polar Sport Tester PE4000--Polar Electro
Finland) were used to capture heart rate data. Chest belts with
in-built sensors and transmitters were fitted around the pig's
chest just behind the front legs. These belts had a liberal coating
of an ultra-sonic gel (Virbac Aust Pty Ltd) applied to the sensor
contact areas to ensure a good heart rate signal was obtained. A
second belt fabricated from 100 mm wide elastic and velcro was
placed around the pigs over the transmitter belt. This belt
protected the transmitter from physical damage and included a
pocket for storage of the monitor recording unit (similar to a
wristwatch) during the recording period. An area on the back of the
pigs was then shaved with the electric human shaver. Within this
shaved area a template and permanent marker was used to outline a
rectangular treatment application area of 172.5 cm.sup.2
(75.times.230 mm). Feed was then offered at 100 g/kg
liveweight.sup.0.75 (eg: 55 kg pig=2020 g/d). Treatment application
was begun at least 1 h after the commencement of heart rate
recording. Three staff wearing protective rubber gloves applied
each of the test formulations in 5 ml syringes. This involved
rubbing the products into the skin of the pig while an assistant
directed warm air from an electric hair dryer onto the treatment
area. Rubbing was discontinued after approximately 8 to 10 minutes
when the skin surface became tacky to touch. Three (10.times.12 cm)
transparent dressings (Tegaderm--3M Health Care U.S.A.) were then
applied over the treatment area. Following treatment application
the pigs were left undisturbed for the remaining 6 to 7 hours of
the recording period. Syringes and gloves used in treatment
applications were weighed before and after application to enable
accurate calculation of the actual doses applied to the pigs. At
the conclusion of the recording period, the heart rate monitors and
the transparent dressings were removed and the treatment
application area was washed down with warm water containing a small
quantity of a liquid handwash.
[0056] Results TABLE-US-00002 TABLE 1 Effect of various atropine
preparations on average heart rate over 60 minute intervals. A B C
D E F G H I J sed .chi..sup.2 Heart rate (bpm) -60-0 min 148 147
148 154 148 152 151 149 150 146 5.52 0.916 0-60 min 173 155 176 155
165 162 180 170 155 154 9.33 0.007 60-120 min 186 170 184 169 170
175 196 190 164 165 10.91 0.011 120-180 min 161 156 162 154 148 165
168 171 144 153 10.46 0.124 180-240 min 145 148 146 149 139 156 152
164 144 149 9.87 0.353 240-300 min 144 146 150 142 147 147 146 155
139 136 7.93 0.471 300-360 min 143 142 144 131 137 142 147 150 135
136 7.60 0.271 Difference from baseline (bpm) 0-60 min 24.2 8.7
28.5 1.1 16.1 10.3 30.7 20.0 4.9 7.1 10.41 0.021 60-120 min 37.8
22.8 35.6 14.1 21.7 22.6 46.8 40.9 13.2 19.0 12.58 0.045 120-180
min 13.0 8.9 13.2 -1.4 -0.8 12.8 20.1 21.2 -6.8 8.0 11.71 0.196
[0057] TABLE-US-00003 TABLE 2 Effect of various atropine
preparations on average heart rate over 60 minute intervals. A B C
D E F Log peak 2.341 2.307 2.33 2.29 2.313 2.326 rate (bpm) (219)
(203) (214) (195) (206) (212) Log time to 1.790 1.904 1.762 1.872
1.726 1.787 peak (min) (61.7) (80.2) (57.8) (74.5) (53.2) (61.2)
Log 0.125 0.003 0.171 -0.060 0.061 0.229 ascending slope.sup.1
(1.33) (1.01) (1.48) (0.87) (1.15) (1.69) Log -0.244 -0.312 -0.206
-0.124 -0.186 -0.393 descending slope.sup.1,2 (0.57) (0.49) (0.62)
(0.75) (0.65) (0.40) Log ratio 0.354 0.292 0.393 0.072 0.264 0.624
of slopes.sup.2 (2.26) (1.96) (2.47) (1.18) (1.84) (4.21) G H I J
sed .chi..sup.2 Log peak 2.351 2.321 2.301 2.288 0.0233 0.078 rate
(bpm) (224) (209) (200) (194) Log time to 1.738 1.734 1.764 1.786
0.0953 0.452 peak (min) (54.7) (54.2) (58.1) (61.1) Log 0.434 0.250
0.211 0.117 0.1568 <0.001 ascending slope.sup.1 (2.72) (1.78)
(1.62) (1.31) Log -0.375 -0.427 -0.299 -0.049 0.1095 <0.001
descending slope.sup.1,2 (0.42) (0.37) (0.50) (0.89) Log ratio
0.808 0.680 0.495 0.196 0.2052 <0.001 of slopes.sup.2 (6.43)
(4.79) (3.13) (1.57) .sup.1units are bpm per min .sup.2units should
be negative but were multiplied by -1 so that a log transformation
could be performed.
[0058] TABLE-US-00004 TABLE 3 Effect of various base cream
preparations on average heart rate over 60 minute intervals. A B C
D E F G H I J sed .chi..sup.2 Heart rate (bpm) -60-0 min 146 147
147 143 145 127 145 135 124 132 11.1 0.283 0-60 min 139 140 129 144
138 123 142 120 123 128 10.7 0.141 60-120 min 125 132 124 137 134
122 139 120 120 132 10.9 0.587 120-180 min 128 126 126 131 135 119
130 125 119 124 6.7 <0.001 180-240 min 125 121 132 134 129 121
132 122 114 122 8.7 0.358 240-300 min 137 122 130 132 120 112 139
130 121 122 9.0 0.040 300-360 min 131 120 132 127 116 110 134 126
110 125 6.0 <0.001 Difference from baseline (bpm) 0-60 min -4.4
-5.1 -16.5 1.4 -6.6 -6.3 -2.7 -12.5 -0.9 -5.8 6.16 0.162 60-120 min
-16.7 -15.3 -20.1 -3.8 -10.3 -7.0 -6.5 -13.7 -5.5 -4.4 11.44 0.708
120-180 min -15.0 -16.0 -21.1 -9.9 -9.8 -9.8 -15.8 -8.3 -4.1 -8.6
12.62 0.971
[0059] Discussion and Conclusion
[0060] The data suggests that transdermal application of atropine
will increase heart rate in the pig with the peak occurring
approximately 60 minutes after application. The data also suggests
that the base creams alone do not increase heart rate and that the
affects of the preparations are due to the atropine itself.
[0061] Formulation G which contains the tocopheryl
phosphate/di-tocopheryl phosphate mixture provided the best
delivery system for atropine. The heart rate increased and remained
sustained for longer periods compared to the other formulations.
This is shown in table 1, where under the heading "Differences from
baseline" the values at the 0-60 min and 60-120 min are greatest
with G. Table 1 demonstrates that Formulation G is consistently
more effective than a similar concentration of atropine in
compositions containing the lauryliminodipropionate-tocopheryl
phosphates.
[0062] The evaluation of the data in Table 2 shows that there is a
consistent increased efficacy of formulation G versus formulation H
for log peak rate, log time to peak and, importantly, log ascending
slope and log descending slope.
[0063] Further, the formulation according to the invention caused
no inflammation, thus it appears possible to allow prolonged dermal
contact without causing irritation.
Example 2
[0064] This example investigated the effect of transdermal delivery
to pigs of morphine. The skin of pigs has similar properties to
human skin and as such the pig is an excellent model for studying
dermal delivery of drugs.
[0065] This study was designed to assess the level of analgesia as
measured by a delay in the tail flinch response to a heat
(62.degree. C.) placed on the rump following the transdermal
delivery to pigs of morphine.
[0066] Flinch test data were analysed by REML (Residual maximum
likelihood) with treatment and time as the fixed model and pig,
replicate and flinch time at time zero as the random model. Data
were initially analysed raw but because there were some skewed data
at 6 h they were also log-transformed for analyses. Either analyses
provided essentially the same interpretation.
[0067] The following formulations were tested: TABLE-US-00005 Code
Composition AGM Morphine in formulation G as per Example 1. AG
Formulation G with no morphine AHM Morphine in formulation H as per
Example 1. AH Formulation H with no morphine.
[0068] Overall, the flinch time for pigs treated with preparation
AGM had a greater flinch time than any of the other treatments
(2.63, 2.88, 4.82 and 3.17 seconds for treatments AG, AH, AGM and
AHM, Table 4). Interestingly, the response was greatest at 6 h
after treatment (FIG. 5) suggesting a sustained effect,
particularly when compared to the control AG. In this context the
flinch test was 133% greater at 6 h in pigs treated with AGM
compared to AG. There was an indication that AHM had a greater
flinch time at 2 h after treatment when compared to the control AH,
but this was not sustained. AHM did not provide the sustained
results which were obtained with AGM.
[0069] In conclusion, the data demonstrates that transdermal
delivery of morphine in a formulation according to the invention
(AGM) provides rapid and sustained analgesia as measured by a delay
in the tail flinch response to a heat treatment at 1 to 6 h.
Further, the formulation according to the invention caused no
inflammation, thus it appears possible to allow prolonged dermal
contact without causing irritation. TABLE-US-00006 TABLE 4 Effect
of treatment and time flinch response after heat probe application
(seconds).sup.1 Time after treatment (h) Significance (.chi..sup.2)
1 2 4 6 sed.sup.1 Treat Time Tr .times. Ti AG 1.83 2.69 3.26 2.75
1.087 <0.001 0.062 0.45 AH 2.10 2.34 3.60 3.50 AGM 3.96 3.40
5.49 6.42 AHM 2.85 3.87 2.97 3.00 AG (0.260) (0.411) (0.461)
(0.413) 0.0858 0.003 0.011 0.85 AH (0.313) (0.335) (0.465) (0.438)
AGM (0.460) (0.470) (0.570) (0.622) AHM (0.410) (0.466) (0.440)
(0.458) .sup.1Values in parentheses are log transformed.
.sup.2standard error of the difference for time .times. treatment.
For treatment and time effects multiply by 0.511 and 0.497,
respectively.
Example 3
[0070] This example investigates the effect of different
formulations according to invention when compared to a control
using complexed tocopheryl phosphate on transdermal delivery of
morphine to rats.
[0071] Methods
[0072] Animals: Conscious Sprague Dawley Rats (.about.280 g) n=6
per group.
[0073] Transdermal Formulation Preparation: Morphine HCl, Glaxo
Australia Pty Ltd (catalogue number 22284). Morphine free base was
derived from HCL form in aqueous solution by the addition of
potassium carbonate. This process was completed at Monash
University. (Morphine HCl could not be used with creams, so free
base was used).
[0074] Morphine (10 mg/kg) was applied in each of the formulations
set out in Table 5. The effect was measured by the delayed response
of the rat to heat with the delay in time taken to withdraw the pat
taken as the action of morphine. TABLE-US-00007 TABLE 5
Formulations of tocopheryl phosphates TPM- Ingredient Purpose
Vital-ET .TM. TP/T.sub.2P TPM-01 01/M Disodium tocopheryl
Transdermal 2.00% 2.00% 2.00% 7.20% phosphate agents Di-tocopheryl
1.00% 1.00% 1.00% 3.60% phosphate Lauryldiaminopropionic Complexing
3.00% -- -- -- acid agent Morphine HCl USP- Active -- -- -- 5.4% NF
Ingredient Ultrez-10 carbomer- Excipient 0.36% 0.36% -- -- 3%
solution Carbomer 934 USP- -- -- -- 0.36% 0.36% NF Triethanolamine
Excipient 0.25% 0.25% 0.25% 0.25% (trolamine) USP Surcide DMDMH
preservative 0.10% 0.10% -- -- Germall 115 preservative -- -- -- --
Methylparaben USP- preservative 0.10% -- 0.10% 0.10% NF, BP
Purified water USP- Solvent QS 100% QS 100% QS 100% QS 100% NF
[0075] The base gels used as controls contained all of the
ingredients except for the tocopheryl phosphate. Vital ET was not
used in this experiment and is listed here as a comparison of the
components between Vital ET and the formulation of the
invention.
[0076] Test Method:
[0077] The plantar analgesiometer is designed for rapid and
efficient screening of analgesia levels in small laboratory
animals. The device is used to apply a heat source
(.about.45.degree. C. from an infrared light) to the animal's hind
paw and the time taken to withdraw the paw is measured (paw
withdrawal latency). The hot plate provides a constant surface
temperature, with a built-in digital thermometer with an accuracy
of 0.1.degree. C. and a timer with an accuracy of 0.1 second. The
animal is placed on a hot plate, confined by a clear acrylic cage
which surrounds the plate and paw-lick response is monitored. An
increased time period before paw-lick response indicating
analgesia.
[0078] Rats had a hair removal cream applied to a dorsal
hindquarter area of skin (under anaesthesia) at least 24 hours
prior to any transdermal patch application. Conscious Sprague
Dawley rats (.about.400 grams) received morphine at a dose of 10 mg
morphine HCl per kg body weight. The formulation contained 10% w/w
morphine.HCI, and for a 0.2 kg rat the amount applied was 20 mg of
formulation that contained 2 mg morphine.HCl. A single application
was used in the morning, with measures of the analgesia made at
various time-points. The skin area exposed to drug/vehicle was then
covered with a Tegaderm patch. All animals underwent analgesic
testing before and after morphine administration.
[0079] Results:
[0080] FIG. 6 illustrates the results achieved with each of the
formulations. The results show an increase in response time,
indicating analgesia, in a dose-dependant manner. The control test
of gel with morphine but no TPM show the essential requirement of
TPM for the transdermal route to work. Results are expressed as
change in withdrawal time compared to controls, where control
values are from rats treated with incomplete formulations (i.e., no
morphine or no TPM), as well as the zero-time values for rats
treated with complete the formulation, TPM-01/M)
[0081] Conclusion:
[0082] The formulation used in this study contains TP/T2P mix (or
TPM), morphine.HCl and other excipients as listed in table 5. The
formulation did not contain any lauryldiaminoproprionic acid.
[0083] FIG. 6 shows a clear dose-response and a sustained affect.
When compared to the 2 types of control (ie, a control gel with
base excipients only, and no morphine and no TP/T2P mix, and a
control gel with base excipients and morphine but no TP/T2P) the
results show that morphine is best delivered when formulated with
the TP/T2P mix. The word `comprising` and forms of the word
`comprising` as used in this description and in the claims does not
limit the invention claimed to exclude any variants or additions.
Modifications and improvements to the invention will be readily
apparent to those skilled in the art. Such modifications and
improvements are intended to be within the scope of this
invention.
* * * * *