Title of Invention

ALKALOID FORMULATIONS

Abstract The invention discloses an alkaloid formulation comprising a complex of an alkaloid having a tertiary amine and a phosphorylated electron transfer agent selected from the group consisting of mono-tocopheryl phosphates, di-tocopheryl phosphates, and mixtures thereof. The invention is also for a method for preparation of said alkaloid formulation.
Full Text Field of the invention
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
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.
Alkaloids
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:-
• tertiary amines which:-
• are alicyclic with the nitrogen atom as a common member of three
rings (eg. Morphine, Atropine, Quinine ); or
• are cyclic where the nitrogen is incorporated into a single ring and
alkylated (eg. Nicotine, Fenspiride); or
• have no cyclic structure incorporating the nitrogen (eg. Flurazepan);

• secondary amines where the nitrogen is incorporated into an alicyclic
structure (eg Conline, Fendiline) or a linear structure (eg. Epinephrine);
• primary amines (eg. Ephidrine);
• pyridines (eg Nicotine);
• methamidine derivatives;
• quinolines (eg. Cinchonine); and
• guanidines (eg. Arginine).
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.
Topical administration
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).
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.

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.
Transdermal delivery has been recognized to offer several potential benefits including
achieving blood levels similar to those achieved by slow intravenous infusion hut 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.
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.
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.
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 ina 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.
Oral administration
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
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.
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.
Preferably, the phosphate derivative of a electron transfer agent is selected from the group
comprising one or more phosphate derivatives of tocopherol.
Preferably, the alkaloid formulation is administered topically or orally.
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.
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.
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.
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.

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 Kl 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 R1, R2 and R3 may be hydrogen or methyl
groups, that is, the α-5:7:8 tri-methyl; β-5:8 di-methyl; 7-7:8 di-methyl; and 5 8 methyl
derivatives. In the tocopherols, R4 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, R4 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 a-tocopherol.


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.
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.
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.
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 R1R2N(CH2)nOH wherein n is an integer

between 1 and 6 and R1 and R2 may be either H or short alkyl chains with 3 or less
carbons. R1 and R2 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.
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.
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.
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
Figure 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.
Figure 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.
Figure 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.
Figure 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.
Figure 5: Effect of treatment and time flinch response after heat probe application
Figure 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
Various embodiments/aspects of the invention will now be described with reference to the
following non-limiting examples.

Example 1
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.
Methods and materials
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% Triethanolarmne, 0.1% Surcide DMDMH and
Deionized Water up to 100%.
Compositions G 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. Compositions F and H
are reference compositions.


Ten male crossbred (Large white x 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 x 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).
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.
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 cm2 (75x230 mm). Feed was then offered
at 100 g/kg liveweight0.75 (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 (10x12 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.






Discussion and conclusion
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.

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.
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.
Further, the formulation according to the invention caused no inflammation, thus it appears
possible to allow prolonged dermal contact without causing irritation.
Example 2
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.
This study was designed to assess the level of analgesia as measured by a delay in the tail
flinch response to a heat (62°C) placed on the rump following the transdermal delivery to
pigs of morphine.
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.


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
(Figure 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.
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.


Standard error of the difference for time x treatment. For treatment and time effects
multiply by 0.511 and 0.497, respectively.
Example 3
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.
Methods
Animals: Conscious Sprague Dawley Rats (~ 280 g) n=6 per group.
Transdermal Formulation Preparation: Morphine HC1, 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 HC1 could not be used with creams, so free base was used).

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.


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.
Test Method:
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 (~45°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°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.
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 (~400 grams) received morphine at a dose of 10 mg morphine HC1
per kg body weight. The formulation contained 10% wAv morphine.HCl, 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.
Results:
Figure 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)
Conclusion:
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.
Figure 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.

We claim:
1. An alkaloid formulation comprising :
(i) an alkaloid having a tertiary amine group such as herein described; and
(ii) one or more phosphate derivatives of one or more electron transfer agents which
is a mixture of mono-tocopheryl phosphate and di-tocopheryl phosphate, wherein 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.
2. The alkaloid formulation as claimed in claim 1 wherein the tocopheryl
phosphate is in the form of a salt selected from the group consisting of sodium,
magnesium, potassium, and calcium.
3. The alkaloid formulation as claimed in claim 1 wherein the formulation is a
topical formulation.
4. The alkaloid formulation as claimed in claim 3 wherein the topical formulation
is for dermal or transdermal delivery.
5. The alkaloid formulation as claimed in claim 1 wherein the formulation is an
oral formulation.
6. The alkaloid formulation as claimed in claim 5 wherein the oral formulation has
an enteric coating.
7. The alkaloid formulation as claimed in claim 5 wherein the oral 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.

8. The alkaloid formulation as claimed in claim 1 wherein the formulation is a
buccal formulation.
9. The alkaloid formulation as claimed in claim 1 wherein the tocopheryl
phosphate is α-tocopheryl phosphate.
10. The alkaloid formulation as claimed in claim 1 wherein the alkaloid having a
tertiary amine is selected from the group consisting of alicyclic tertiary amines wherein
the nitrogen atom is a common member of three rings; cyclic tertiary amines wherein
the nitrogen is incorporated into a single ring and alkylated; and non-cyclic tertiary
amines wherein the nitrogen is not incorporated into a ring.
11. The alkaloid formulation as claimed in claim 1 wherein the alkaloid is an opioid.
12. The alkaloid formulation as claimed in claim 1 wherein the alkaloid is selected
from the group consisting of atropine, quinine, fentanyl, nicotine, fenspiride,
flurazepan, morphine, and codeine.
13. The alkaloid formulation as claimed in claim 12 wherein the alkaloid is atropine.
14. The alkaloid formulation as claimed in claim 12 wherein the alkaloid is
morphine.
15. The alkaloid formulation as claimed in claim 1 comprising atropine complexed
with a mixture of mono-tocopheryl phosphate and di-tocopheryl phosphate.
16. The alkaloid formulation as claimed in claim 1 comprising morphine complexed
with a mixture of mono-tocopheryl phosphate and di-tocopheryl phosphate.
17. An alkaloid formulation as claimed in claim 1 wherein the alkaloid formulation
is in the form of a pharmaceutical composition.
18. A method for the preparation of an alkaloid formulation as claimed in claim 1,
said method comprising the step of reacting an alkaloid having a tertiary amine with a

phosphorylated electron transfer agent selected from the group consisting of mono-
tocopheryl phosphates, di-tocopheryl phosphates, and mixtures thereof.


The invention discloses an alkaloid formulation comprising a complex of an alkaloid
having a tertiary amine and a phosphorylated electron transfer agent selected from the
group consisting of mono-tocopheryl phosphates, di-tocopheryl phosphates, and
mixtures thereof.
The invention is also for a method for preparation of said alkaloid formulation.

Documents:

02507-kolnp-2006-abstract.pdf

02507-kolnp-2006-claims.pdf

02507-kolnp-2006-correspondence others-1.1.pdf

02507-kolnp-2006-correspondence others.pdf

02507-kolnp-2006-description(complete).pdf

02507-kolnp-2006-drawings.pdf

02507-kolnp-2006-form-1.pdf

02507-kolnp-2006-form-3-1.1.pdf

02507-kolnp-2006-form-3.pdf

02507-kolnp-2006-form-5.pdf

02507-kolnp-2006-gpa.pdf

02507-kolnp-2006-international publication.pdf

02507-kolnp-2006-international search authority report.pdf

02507-kolnp-2006-pct request.pdf

02507-kolnp-2006-priority document.pdf

2507-kolnp-2006-abstract 1.1.pdf

2507-KOLNP-2006-ABSTRACT.pdf

2507-kolnp-2006-amanded claims 1.1.pdf

2507-KOLNP-2006-AMANDED CLAIMS.pdf

2507-KOLNP-2006-ASSIGNMENT.pdf

2507-kolnp-2006-correspondence 1.1.pdf

2507-KOLNP-2006-CORRESPONDENCE 1.2.pdf

2507-KOLNP-2006-CORRESPONDENCE.pdf

2507-kolnp-2006-description (complete) 1.1.pdf

2507-KOLNP-2006-DESCRIPTION (COMPLETE).pdf

2507-kolnp-2006-drawings 1.1.pdf

2507-KOLNP-2006-DRAWINGS.pdf

2507-KOLNP-2006-EXAMINATION REPORT REPLY RECIEVED.pdf

2507-KOLNP-2006-EXAMINATION REPORT.pdf

2507-kolnp-2006-form 1-1.1.pdf

2507-KOLNP-2006-FORM 1.pdf

2507-KOLNP-2006-FORM 13 1.2.pdf

2507-KOLNP-2006-FORM 13.pdf

2507-KOLNP-2006-FORM 18 2.pdf

2507-kolnp-2006-form 18.pdf

2507-kolnp-2006-form 2-1.1.pdf

2507-KOLNP-2006-FORM 2.pdf

2507-kolnp-2006-form 3-1.1.pdf

2507-KOLNP-2006-FORM 3.pdf

2507-KOLNP-2006-FORM 5.pdf

2507-KOLNP-2006-FORM-27.pdf

2507-KOLNP-2006-GPA.pdf

2507-KOLNP-2006-GRANTED-ABSTRACT.pdf

2507-KOLNP-2006-GRANTED-CLAIMS.pdf

2507-KOLNP-2006-GRANTED-DESCRIPTION (COMPLETE).pdf

2507-KOLNP-2006-GRANTED-DRAWINGS.pdf

2507-KOLNP-2006-GRANTED-FORM 1.pdf

2507-KOLNP-2006-GRANTED-FORM 2.pdf

2507-KOLNP-2006-GRANTED-SPECIFICATION.pdf

2507-KOLNP-2006-OTHERS (CHINESE, EUROPEAN.ISRAELI,NEW ZEALAND,RUSSIAN,U.S. PATENT APPLN).pdf

2507-KOLNP-2006-OTHERS-1.1.pdf

2507-kolnp-2006-others-1.2.pdf

2507-KOLNP-2006-OTHERS.pdf

2507-kolnp-2006-petition under rule 137-1.1.pdf

2507-KOLNP-2006-PETITION UNDER RULE 137.pdf

2507-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf


Patent Number 249675
Indian Patent Application Number 2507/KOLNP/2006
PG Journal Number 44/2011
Publication Date 04-Nov-2011
Grant Date 02-Nov-2011
Date of Filing 01-Sep-2006
Name of Patentee VITAL HEALTH SCIENCES PTY LTD.
Applicant Address LEVEL 2 , 90 WILLIAM STREET, MELBOURNE VIC 3000, AUSTRALIA
Inventors:
# Inventor's Name Inventor's Address
1 WEST, SIMON, MICHAEL 3 VERDON STREET, WILLIAMSTOWN, VIC 3016, AUSTRALIA
2 GIANELLO, ROBERT 34 OLINDA CRESCENT, OLINDA, VI 3788, AUSTRALIA
3 OGRU, ESRA 1/6 EDITH STREET, GLEN WAVERLY, VIC 3150, AUSTRALIA
PCT International Classification Number A61K 31/46
PCT International Application Number PCT/AU2005/000307
PCT International Filing date 2005-03-03
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2004901107 2004-03-03 Australia
2 2004904367 2004-08-03 Australia