(12) STANDARD PATENT (11) Application No.

AU 2009356961 B2
(19) AUSTRALIAN PATENT OFFICE

(54) Title
Effervescent L-carnitine-based composition

(51) International Patent Classification(s)

A61K 31/205 (2006.01) A61P 3/02 (2006.01)
A61K 9/46 (2006.01)

(21) Application No: 2009356961 (22) Date of Filing: 2009.12.14

(87) WIPO No: WO11/072320

(43) Publication Date: 2011.06.23

(44) Accepted Journal Date: 2016.05.19

(71) Applicant(s)
Jubilent Global Limited

(72) Inventor(s)
Ohl, Norman;Neuendorf, Cathrine

(74) Agent / Attorney

Cullens Pty Ltd, Level 32 239 George Street, Brisbane, QLD, 4000

(56) Related Art

WO 2009/071954 Al
WO 1998/000672 Al
US 4968517 A
DE 10119946 Al
CN 101439027 A
AU 57788/01 Al
 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization II

International Bureau
(10) International Publication Number
(43) International Publication Date
23 June 2011 (23.06.2011) PCT W O 2011/072320 Al

(51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
A61K31/205 (2006.01) A61P 3/02 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
A61K 9/46 (2006.01) DZ, EC, EE, EG, ES, Fl, GB, GD, GE, GH, GM, GT,
HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
(21) International Application Number: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
PCT/AU2009/001619 ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
(22) International Filing Date: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
14 December 2009 (14.12.2009) SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT,
TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
(25) Filing Language: English
(84) Designated States (unless otherwise indicated,for every
(26) Publication Language: English kind of regionalprotection available): ARIPO (BW, GH,
(71) Applicant (for all designated States except US): JUBI- GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
LENT GLOBAL LIMITED [ /VU]; Lolam House, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
Lini Highway, Port Vila, Vanuatu (VU). TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
ES, Fl, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
(72) Inventors; and MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM,
(75) Inventors/Applicants (for US only): OHL, Norman TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
[AU/AU]; 117 Fernberg Road, Paddington, Queensland ML, MR, NE, SN, TD, TG).
4064 (AU). NEUENDORF, Cathrine [AU/AU];
18 Published
Turner Street, Scarborough, Queensland 4020 (AU).
(74) Agent: CULLENS; Level 32, 239 George Street, Bris- with internationalsearch report (Art. 21(3))
bane, Queensland 4000 (AU). - with amended claims (Art. 19(1))
(81) Designated States (unless otherwise indicated,for every
kind of nationalprotection available): AE, AG, AL, AM,

(54) Title: EFFERVESCENT L-CARNITINE-BASED COMPOSITION

f4 (57) Abstract: This invention relates to an effervescent composition containing L-carnitine (levocarnitine) and to a method of
manufacturing said composition. In one aspect, the invention concerns an effervescent composition which effectively masks the
off-notes and poor taste normally associated with L-camitine as well as reducing 'fishy' odours and flatulence normally resulting
from L-carnitine ingestion and metabolism.
 WO 2011/072320 PCT/AU2009/001619
1

EFFERVESCENT L-CARNITINE-BASED COMPOSITION

TECHNICAL FIELD

This invention relates to an effervescent composition containing L-carnitine

(levocamitine) and to a method of manufacturing said composition. In one aspect, the
5 invention concerns an effervescent composition which effectively masks the off-notes and
poor taste normally associated with L-carnitine as well as reducing 'fishy' odours and
flatulence normally resulting from L-carnitine ingestion and metabolism.

BACKGROUND ART

Carnitine is a quaternary ammonium compound having the following chemical

10 structure:

OH O

The biologically active form is the isomer L-carnitine, which is essential for
energy production and fat metabolism in birds, fish and mammals. In such animals, L
carnitine plays a role in the transportation of long-chain fatty acids across the inner
15 mitochondrial membrane during the breakdown of fats and lipids, resulting in the
generation of metabolic energy in the form of ATP.

In view of its biological activity, it is no surprise that L-carnitine is widely sold

and used as an orally taken dietary supplement for treating various physiological
conditions, and in particular for reducing body fat, enhancing lean muscle mass, fighting
20 fatigue and increasing stamina. However, since L-carnitine is a highly hygroscopic
compound, the preparation of oral formulations containing L-carnitine and the storage of
such formulations has been problematic.

Another problem with known L-carnitine based oral formulations is that L

carnitine has an unpleasant odor and unpleasant taste, which are both difficult to mask.

25 Further problems arising with use of L-carnitine as a dietary supplement relate to a

known metabolite, trimethylamine. Trimethylamine has a 'fishy' odour and as a result of
 WO 2011/072320 PCT/AU2009/001619
2

the metabolism of the L-carnitine, some individuals taking L-carnitine may develop a
'fishy' odor in their breath and sweat. A build-up of 'fishy' gas in the bowel can also
result, leading to flatulence.

DETAILED DESCRIPTION OF THE INVENTION

5 It is an object of the present invention to minimise or overcome one or more of the

problems described above, or to provide the public with a useful or commercial choice.

The inventors have discovered that L-carnitine, when taken orally in an

effervescent form/composition (which preferably creates an acidic environment when in
solution), can reduce the physiological problems normally observed with L-carnitine
10 ingestion and metabolism, namely 'fishy' odour and flatulence.

The inventors have also discovered that the effervescent form/composition,

particularly when further containing a sweetening agent and/or flavouring agent, can
effectively mask the off-notes and poor taste normally associated with L-carnitine.

The inventors have further discovered that the effervescent form/composition is

15 less problematic to prepare and store than other types of L-carnitine compositions as it
tends to be less hygroscopic.

Broadly, the invention concerns an effervescent L-carnitine based composition for

treating a physiological condition yet minimising a physiological problem normally
resulting from L-carnitine metabolism, said composition comprising:

20 an effective amount of L-carnitine for treating said physiological condition; and

effervescent agents.

According to a first aspect of the present invention, there is provided an

effervescent L-carnitine based composition for treating a physiological condition yet
minimising a physiological problem normally resulting from L-carnitine metabolism, said
25 composition comprising:

an effective amount of L-carnitine for treating said physiological condition; and

 WO 2011/072320 PCT/AU2009/001619
3

effervescent agents for creating an acidic environment when the composition is in

solution.

Any suitable amount and form of L-carnitine may be used in the composition,
provided that it is ingestable and can provide the desired physiological effect. For

5 instance, the L-carnitine may be in the form of a free base or salt. Preferably,
approximately 40-60% w/w L-carnitine is used, and more preferably about 52% w/w.

Any suitable types and amounts of effervescent agents may be used in the
composition. Typically, this will be a combination of at least one type of acid and base.
The acid may be one or more of the following: citric, malic, tartaric, adipic, and fumaric
10 acid. Preferably, the composition comprises approximately 15-40 % w/w anhydrous citric
acid, and more preferably about 29% w/w. The base may be one or more of the following:
sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.
Preferably, the composition comprises approximately 10-30% w/w sodium bicarbonate,
and more preferably about 19% w/w.

15 Preferably, the acid environment has a pH of approximately 4 to 5, and more

preferably, a pH of about 4.7 (in 100 mL water) or 4.8 (200 mL water).

The composition can further comprise a sweetening agent and/or flavouring agent
for further masking the off-notes and poor taste normally associated with L-carnitine.
Any suitable type and amount of sweetening agent and/or flavouring agent may be used.
20 The sweetening agent may be a natural or artificial sweetener, or a mixture of both.
Preferably, the sweetening agent is a non-calorific natural sweetener such as stevia or
sucralose. Preferably, the composition comprises approximately 0.2-0.8% w/w sucralose,
and more preferably about 0.4% w/w.

The composition may be of any suitable form, including in the form of an

25 effervescent powder, granule or tablet. The composition may be packaged in the form of
a capsule. The capsule can be any suitable capsule known in the art, including hard or
soft gelatine prepared from beef and/or pork gelatin. Alternatively, the capsule, whether
hard or soft, can be prepared from plant-based gelling substances so as to be suitable for
persons on a vegetarian diet. Plant-based gelling substances suitable for the preparation
30 of vegetarian capsules include carrageenans or modified forms of starch and cellulose.
 WO 2011/072320 PCT/AU2009/001619
4

Depending on the form of the composition, the composition may further comprise
one or more of the following: a binding agent, buffering agent, disintegrating agent,
lubricant, glidant and flow regulating agent.

The composition may further comprise other types of ingredients such as, for
5 example, a colouring agent. The colouring agent may be any suitable natural and/or
artificial colouring agent. Preferably, the composition comprises approximately 0.01
0.3% w/w carminic acid (cochineal), and more preferably about 0.1% w/w.

According to a preferred embodiment, the effervescent L-carnitine based

composition comprises:

10 approximately 52.08% w/w L-carnitine;

approximately 28.65% w/w anhydrous citric acid;

approximately 18.78% w/w sodium bicarbonate;

approximately 00.39% w/w sucralose; and

approximately 00.10% w/w cochineal.

15 According to a second aspect of the present invention, there is provided a method

of treating a physiological condition of an individual with an effervescent L-carnitine
based composition yet minimising a physiological problem normally resulting from L
carnitine metabolism by the individual, said method comprising the step of orally
administering to the individual an effervescent L-carnitine based composition comprising:

20 a physiologically effective amount of L-carnitine for treating said physiological

condition; and

effervescent agents, preferably for creating an acidic environment when the

composition is in solution.

According to a third aspect of the present invention, there is provided the use of a
25 physiologically effective amount of L-carnitine in combination with effervescent agents,
for creating an acidic environment when the L-carnitine is in solution, in the preparation
of a medicament (composition) for treating a physiological condition of an individual yet
 WO 2011/072320 PCT/AU2009/001619
5

minimising a physiological problem normally resulting from L-carnitine metabolism by

the individual.

The composition may be used to treat any suitable type of physiological condition.
For instance, the composition may be used to reduce body fat, enhance lean muscle mass,
5 fight fatigue and increase stamina.

The physiological problem normally observed with L-carnitine ingestion and

metabolism may be the 'fishy' odour of the individual's sweat or breath or flatulence.

Any suitable administration regime may be used for the individual. Preferably,
the composition is dissolved in water and ingested twice daily. Preferably, approximately
10 3-4 g of the composition of the preferred embodiment described above is dissolved in
100-200 mL water and ingested twice daily (morning and afternoon).

According to a fourth aspect of the present invention, there is provided a method

of preparing an effervescent L-carnitine based composition for treating a physiological
condition yet minimising a physiological problem normally resulting from L-carnitine
15 metabolism, said method comprising the step of:

blending an effective amount of L-carnitine for treating said physiological

condition with effervescent agents, preferably for creating an acidic environment when
the L-carnitine is in solution.

Preferably, the method further comprises the step of blending at least one
20 sweetening agent with the effervescent agents prior to blending with L-carnitine.

Preferably, the effervescent agents are dried prior to addition to the sweetening
agent or L-carnitine. In a particularly preferred embodiment, the blending is undertaken
in a low relative humidity (RH) environment, preferably at less than about 20% RH.

Preferably, the method further comprises the step of blending in a colouring agent.

25 In order that the invention may be more readily understood and put into practice,
one or more preferred embodiments thereof will now be described, by way of example
only.
 WO 2011/072320 PCT/AU2009/001619
6

BEST MODE FOR CARRYING OUT THE INVENTION

As mentioned above, the inventors have discovered that L-carnitine, when taken
orally in an effervescent form/composition, which preferably creates an acidic
environment when in solution, can reduce the physiological problems normally observed
5 with L-carnitine ingestion and metabolism. The inventors have also discovered that the
effervescent form/composition, particularly when further containing a sweetening agent
and/or flavouring agent, can effectively mask the off-notes and poor taste normally
associated with L-carnitine. The inventors have further discovered that the effervescent
form/composition is less problematic to prepare and store than other types of L-carnitine
10 compositions as it tends to be less hygroscopic.

In a particularly preferred embodiment of the invention (shown in TABLE 1), the

composition comprises L-carnitine in combination with the effervescent agents anhydrous
citric acid and sodium bicarbonate, the sweetening agent sucralose, and the colouring
agent carminic acid to colour the composition pink. The composition is preferably in
15 powder form.

The masking of the poor taste and off-notes of L-carnitine is believed to be

provided by the citric acid and sodium bicarbonate combination, further enhanced by the
sweetening agent sucralose. The stoichiometry of this combination, when dissolved in
water, creates a pleasant tasting and non-odourous solution that can be easily consumed.

20 In addition, the effervescent agents produce an acidic environment when the

composition is in solution, such as in water. Not wishing to be bound by theory, the
inventors believe that the effervescent agents produce a low pH environment in the portal
circulation of the individual to whom the composition is administered. As a result of this
low pH environment, there are reduced amounts of amines such as ammonia in the portal
25 circulation, as the ammonia is converted to ammonium ions in the low pH environment,
which are readily excreted without the odor associated with free amines. The individual
therefore does not suffer from a build-up of 'fishy' gas in the bowel nor 'fishy' odor in
their breath and sweat.

In an acidic environment free H+ are readily available to create NH 3 * + H* ->

30 NH 4* and in a more neutral or alkaline environment in the digestive process there may be
 WO 2011/072320 PCT/AU2009/001619
7

insufficient free hydrogen donors available to drive the conversion of free ammonia in the
lower gastrointestinal tract to the ammonium group which can be readily excreted. One
theory to explain the reported removal of the 'fishy' flatulence would be the excessive
excretion of free NH 3+ via the systemic circulation.

5 Normally, 3.84 g of the composition (ie. single sachet) as described in TABLE 1

was dissolved in 100-200 mL water and taken orally by an individual twice daily
(morning and afternoon). When combined with tap water having a pH of 7.5, L-camitine
in 100 mL of tap water yielded a pH of 4.7, whereas L-carnitine in 200 mL of tap water
yielded a pH of 4.8.

10 Individuals who had been taking commercially available L-carnitine dietary

supplements, such as the MusahiTM carnitine supplement, and then the composition as
herein exemplified noted the differences in taste, smell and 'fishy' flatulence. In
particular, individuals generally noted that the composition as herein exemplified was
pleasant tasting and smelling, and removed the 'fishy' flatulence that resulted from taking
15 commercially available supplements.

A general procedure for the preparation of the L-camitine based composition

preferably entails the following steps:

(i) dispensing all ingredients of the composition in a low RH environment;

(ii) drying the effervescent agents to remove any excess moisture;

20 (iii) blending the sweetening agent and the effervescent agents;

(iv) adding L-carnitine to the blend of step (iii) and

(v) blending to achieve homogeneity of the composition.

To minimise the absorption of atmospheric moisture, it is preferable for the

resultant blend to be formed into the appropriate form (powder, granulate or tablet) and
25 packed relatively soon after preparation. It is particularly preferred for the packing to be
undertaken within 5-8 hours of blending the composition.

A detailed description of the preparation of the preferred L-carnitine based

composition follows.
 WO 2011/072320 PCT/AU2009/001619
8

Step 1

L-carnitine USP (260.40 kg) was dispensed in a controlled RH (no more than 30%) and
temperature (no more than 25 *C) atmosphere.

Step 2

5 Two batches of sodium bicarbonate BP (each of 46.95 kg) and citric acid BP (143.25 kg)
were separately dried in an oven at 50 "C until the moisture content of each compound
was no more than 0.3%. The compounds were then transferred to a controlled RH (no
more than 30%) and temperature (no more than 25 *C) atmosphere.

Step 3

10 One batch of sodium bicarbonate from Step 2 was sieved through a stainless steel mesh
#22 with cochineal C175470 (0.25 kg) and sucralose USP (0.975 kg). The sieved
materials were mixed for five minutes on a drum roller.

Step 4

The second batch of sodium bicarbonate from Step 2 was sieved through a stainless steel
15 mesh #22 with cochineal C175470 (0.25 kg) and sucralose USP (0.975 kg). The sieved
materials were mixed for five minutes on a drum roller.

Step 5

The L-camitine from Step 1 was sieved through a stainless steel mesh #12.

Step 6

20 The citric acid from Step 2 was sieved through a stainless steel mesh #12.

Step 7

The mixes resulting from Step 3 and Step 4 and the L-carnitine from Step 5 were
combined and mixed for 5 minutes using a bin mixer.
 WO 2011/072320 PCT/AU2009/001619
9

Step 8

The citric acid from Step 6 was combined with the mix from Step 7 and mixed for ten
minutes using a bin mixer. Five samples were removed and tested to ensure that the
moisture content was not more than 0.5%. The blend was then mixed for a further five
5 minutes using a bin mixer. A further five samples were removed and tested to ensure that
the moisture content was not more than 0.5%.

Step 9

The blended product was then stored at 14-19% RH in readiness for packing.

Step 10

10 Packing was undertaken in a controlled atmosphere of 15% RH and 20 *C into sachets

containing 3.84 g of the effervescent composition.

Each 3.84 g sachet comprised the following composition:

TABLE 1

Ingredient status % g

L-carnitine active 52.08 2.000

anhydrous citric acid effervescent agent 28.65 1.100

sodium bicarbonate effervescent agent 18.78 0.721

sucralose non-calorie natural source sweetening agent 00.39 0.015

cochineal natural red colour agent 00.10 0.004

It is clear from the foregoing that the invention provides novel compositions
15 comprising L-carnitine which overcome or at least ameliorate some of the problems
associated with known L-carnitine based supplements.

The foregoing embodiments are illustrative only of the principles of the invention,
and various modifications and changes will readily occur to those skilled in the art. The
 WO 2011/072320 PCT/AU2009/001619
10

invention is capable of being practiced and carried out in various ways and in other
embodiments. It is also to be understood that the terminology employed herein is for the
purpose of description and should not be regarded as limiting.

The term "comprise" and variants of the term such as "comprises" or

5 "comprising" are used herein to denote the inclusion of a stated integer or stated integers
but not to exclude any other integer or any other integers, unless in the context or usage
an exclusive interpretation of the term is required.
 -11

CLAIMS

1. An effervescent L-carnitine based composition for treating a physiological condition yet

minimising a physiological problem normally resulting from L-carnitine metabolism, said
composition comprising:
approximately 40-60% w/w of L-carnitine for treating said physiological condition; and
effervescent agents for creating an acidic environment when the composition is in
solution.

2. The composition of claim 1, wherein the effervescent agents comprise a combination of

at least one type of acid and base selected from the group consisting of citric acid, malic acid,
tartaric acid, adipic adic, fuiaric acid, sodium bicarbonate, potassium bicarbonate, sodium
carbonate and potassium carbonate.

3. The composition of claim 2, wherein the effervescent agents comprise approximately

15-40% w/w anhydrous citric acid and approximately 10-30% w/w sodium bicarbonate.

4. The composition of claim I further comprising a sweetening agent and/or flavouring

agent for further masking the off-notes and poor taste normally associated with L-carnitine.

5. The composition of claim 4, wherein the composition comprises approximately 0.2

0.8% w/w sucralose as the sweetening agent.

6. The composition of claim 1, wherein the composition is in the form of an effervescent

powder, granule, tablet or capsule.

7. The composition of claim 6, wherein the composition is in the form of an effervescent

powder, and when dissolved in tap water the acidic environment has a pH of about 4.7 or 4.8.

8. An L-camitine based composition comprising:

approximately 52.08% w/w L-carnitine;
approximately 28.65% w/w anhydrous citric acid;
approximately 18.78% w/w sodium bicarbonate;
approximately 00.39% w/w sucralose; and
approximately 00.10% w/w cochineal.
 - 12

9. A method of treating a physiological condition of an individual with an effervescent L

camitine based composition yet minimising a physiological problem normally resulting from L
carnitine metabolism by the individual, said method comprising the step of orally administering
to the individual an effervescent L-carnitine based composition comprising:
approximately 40-60% w/w of L-carnitine for treating said physiological condition; and
effervescent agents for creating an acidic environment when the composition is in
solution.

10. The method of claim 9, wherein the effervescent agents comprise a combination of at
least one type of acid and base selected from the group consisting of citric acid, malic acid,
tartaric acid, adipic adic, fumaric acid, sodium bicarbonate, potassium bicarbonate, sodium
carbonate and potassium carbonate.

11. The method of claim 10, wherein the effervescent agents comprise approximately 15
40 % w/w anhydrous citric acid and approximately 10-30% w/w sodium bicarbonate.

12. The method of claim 9, wherein the composition further comprises a sweetening agent
and/or flavouring agent for further masking the off-notes and poor taste normally associated
with L-carnitine.

13. The method of claim 12, wherein the composition comprises approximately 0.2-0.8%
w/w sucralose as the sweetening agent.

14. The method of claim 9, wherein the composition is in the form of an effervescent
powder, granule, tablet or capsule.

15. The method of claim 14, wherein the composition is in the form of an effervescent
powder, and when dissolved in tap water the acidic environment has a pH of about 4.7 or 4.8.

16. The method of claim 9, wherein the composition comprises:

approximately 52.08% w/w L-carnitine;
approximately 28.65% w/w anhydrous citric acid;
approximately 18.78% w/w sodium bicarbonate;
approximately 00.39% w/w sucralose; and
approximately 00.10% w/w cochineal.
 -13

17. The method of claim 9, wherein the composition is dissolved in water and ingested
twice daily.

18, The method of claim 16, wherein approximately 3-4 g of the composition is dissolved in
100-200 mL water and ingested twice daily.

19, The method of claim 9, wherein the composition is used to reduce body fat, enhance
lean muscle mass, fight fatigue or increase stamina,

20. The method of claim 9. wherein the physiological problem normally observed with L
carnitine ingestion and metabolism is 'fishy' odour of the individual's sweat or breath or
flatulence,

21. The use of approximately 40-60% w/w of L-carnitine in combination with effervescent
agents, for creating an acidic environment when the L-carnitine is in solution, in the preparation
of a medicament for treating a physiological condition of an individual yet minimising a
physiological problem normally resulting from L-carnitine metabolism by the individual,

22. A method of preparing an effervescent L-carnitine based composition for treating a

physiological condition yet minimising a physiological problem normally resulting from L
carnitine metabolism, said method comprising the step of:
blending approximately 40-60% w/w of L-carnitine for treating said physiological
condition with effervescent agents for creating an acidic environment when the L-carnitine is in
solution.

23. The method of claim 22, wherein the method further comprises the step of blending at
least one sweetening agent with the effervescent agents prior to blending with L-carnitine.

24. The method of claim 22, wherein the effervescent agents are dried prior to addition to
the sweetening agent or L-carnitine.

25. An effervescent L-carnitine based composition for treating a physiological condition yet
minimising a physiological problem normally resulting from L-carnitine -metabolism, said
composition comprising:
approximately 40-60% w/w of L-camnitine for treating said physiological condition; and
effervescent agents.
 - 14

26. A method of treating a physiological condition of an individual with an effervescent L

carnitine based composition yet minimising a physiological problem normally resulting from L
carnitine metabolism by the individual, said method comprising the step of orally administering
to the individual an effervescent L-carnitine based composition comprising:
approximately 40-60% w/w of L-carnitine for treating said physiological condition; and
effervescent agents.

27. A method of preparing an effervescent L-carnitine based composition for treating a

physiological condition yet minimising a physiological problem normally resulting from L
carnitine metabolism, said method comprising the step of:
blending approximately 40-60% w/w of L-carnitine for treating said physiological
condition with effervescent agents.