Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02550342 2006-06-16
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Effervescent preparation of a basic medicinally active substance
The present invention relates to an effervescent preparation comprising at
least one basic
medicinally active substance, characterized in that alkalization of the urine
and thus increased
accumulation of the basic medicinally active substance is avoided.
Effervescent preparations as medicaments have been known for a long time and
are used in the
form of effervescent powders, tablets or granules. They are as a rule solid
preparations comprising
an acid/base pair which react on contact with water to evolve COz (EP 0 474
040, EP 0 369 228,
P.C. Schmidt, I. Christin, Die Pharmazie, 1990, 45, 89-110). The effervescent
formulation leads to
faster disintegration of the dosage form and dissolution of the active
ingredient and may thus lead
to better and faster bioavailability of the medicament than a conventional
tablet formulation. For
active ingredients with a long absorption time or with a tendency to irritate
the gastric mucosa, for
example, effervescent preparations are a formulation form able to alleviate
the said
disadvantageous properties of the active ingredient. Medicaments comprising
effervescent
preparations are therefore becoming increasingly popular. .
When the advantages of an effervescent preparation were carried over to basic
medicaments, it was
found in a study (see below: study of the accumulation behaviour of
pseudoephedrine) that on
-multiple administration of an. effervescent preparation comprising for
example pseudoephedrine as
basic medicinally active substance using a conventional effervescent
composition comprising
sodium bicarbonate as basic component and citric acid as acidic component
there is accumulation
of the basic medicinally active substance in the patient which goes beyond the
intrinsic
accumulation behaviour in non-effervescent formulations. Optimal therapy is no
longer ensured
thereby, and there is an increasing risk of side effects occurring.
Under physiological conditions, basic medicaments are substantially in ionized
form and renal
excretion thereof is therefore sufficiently fast. Since the use of
conventional effervescent
formulations comprising bicarbonates or carbonates of singly charged cations
such as, for
example, sodium as base, and citric acid as acid, leads to alkalization of the
urine, more of the
basic medicaments is in the nonionized form. The elimination half life is
increased and the basic
active ingredient accumulates in the systemic circulation, possibly leading to
an altered benefit/risk
assessment of the basic medicament. The strong dependence of the elimination
half life of basic
active ingredients, for example of pseudoephedrine, on the pH of the urine is
verified in the
literature (I. Kanfer et al. Pharmacotherapy 1993, 13, 116S-128S).
The object was to find an effervescent formulation for basic active
ingredients which avoids
allcalization of the urine and thus accumulation of the basic active
ingredient, and hence ensures
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optimal therapy and can reduce the risk of side effects occurring.
It has now been found, surprisingly, that allcalization of the urine and thus
increased accumulation
of the basic medicinally active substance going far beyond the intrinsic
accumulation behaviour in
non-effervescent formulations is avoided through the effervescent preparation
according to the
invention.
The present invention relates to an effervescent preparation comprising an
effervescent
composition, at least one basic medicinally active substance and, where
appropriate, one or more
further active ingredients, characterized in that increased accumulation of
the basic medicinally
active substance is avoided.
Basic medicinally active substances for the purposes of the invention have a
protonatable basic
primary, secondary or tertiary nitrogen such as, for example, pseudoephedrine,
chlorphenamine,
phenylephrine, diphenhydramine, clemastine, bromphenamine, hydroxyzine,
tripelenamine,
pyrilamine, mequitazine, promethazine, cyproheptadine, doxylamine,
dexchlorphenamine, '
epinephrine, phenamine, trimeprazine, cyclizine, meclizine and azatadine, and
the physiologically
acceptable salts thereof. Pseudoephedrine, chlorphenamine, phenylephrine and
clemastine, and the
physiologically acceptable salts thereof, are preferred. Pseudoephedrine and
its physiologically
acceptable salts such as, for example, pseudoephedrine hydrochloride and
pseudoephedrine
sulphate are particularly preferred. The invention likewise encompasses
mixtures of the substances
mentioned.
The basic medicinally active substance is employed in therapeutically
effective amounts.
Preference is given to pseudoephedrine hydrochloride or pseudoephedrine-
sulphate in a dosage of
from 10 to 100 mg, particularly preferably in a dosage of from 20 to 70 mg.
The effervescent preparation comprises where appropriate one or more further
active ingredients
such as, for example, analgesics, antibiotics, antihistamines,
antidepressants, antidiabetics,
antihypertensives, anticoagulants, lipid-lowering agents, antineoplastics,
antiviral substances, anti-
inflammatory substances, antitussives, expectorants, muscle relaxants,
anticonvulsants,
antidiarrhoeals, antiasthmatics and antidiuretics. Analgesics may be mentioned
as preferred.
The analgesics include, for example, acetylsalicylic acid, paracetamol,
ibuprofen, naproxen,
diclofenac, propyphenazone, metamizole and COX-2 inhibitors such as, for
example, celecoxib
and rofecoxib. Representative antibiotics are, for example, beta-lactam
antibiotics,
chloramphenicol, neomycin, tetracyclines, cephalosporins, erythromycin,
ciprofloxacin,
moxifloxacin, norfloxacin and enrofloxacin. Representative antihistamines are,
for example,
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fexofenadine, dimethindene, cromoglicic acid, cetirizine, loratadine,
pyrilamine, chlorphenamine,
tetrahydrozoline and antazoline. Representative antidepressants are, for
example, amitriptyline,
fluoxetine, doxepine, maprotiline and imipramine. Representative antidiabetics
are, for example,
- acarbose, chlorpropamide, glibenclamide and tolbutamide. Representative
antihypertensives are,
for example, amlodipine, nifedipine, felodipine, enalapril, ramipril,
captopril, cilazapril,
trandolapril, fosinopril, quinapril, moexipril, lisinopril and perindopril,
losartan, candesartan,
irbesartan and telmisartan. Representative anticoagulants are, for example,
bishydroxycoumarin
and warfarin. Representative lipid-lowering agents are, for example,
pravastatin, lovastatin,
simvastatin, atorvastatin, fluvastatin, itavastatin, pitavastatin,
rosuvastatin and cerivastatin.
Representative antineoplastics are, for example, Adriamycin, fluorouracil and
methotrexate. A
representative antiviral substance is, for example, acyclovir. Representative
antiinflammatory
substances are, for example, cortisone, hydrocortisone, betamethasone,
dexamethasone and
prednisolone. Representative antitussives are, for example, codeine,
dihydrocodeine,
dextromethorphan and clobutinol. Representative expectorants are, for example,
ambroxol,
acetylcysteine, bromhexine and carbocysteine. Representative muscle relaxants
are, for example,
diazepam, dantrolene, cyclobenzaprine and methocarbamol. Representative
anticonvulsants are,
for example, diphenylhydantoin and barbiturates. Representative
antidiarrhoeals are, for example,
loperamide and diphenoxylate. Representative antiasthmatics are, for example,
theophylline,
beclomethasone and epinephrine. Representative diuretics are, for example,
chlorthalid'one,
indapamide, bendroflumethiazide, metolazone, cyclopenthiazide, polythiazide,
mefruside,
xipamide, chlorothiazide and hydrochlorothiazide. The listed examples are
likewise understood to
include the corresponding physiologically acceptable salts. The invention
likewise encompasses
mixtures of the active ingredients mentioned.
Further active ingredients which may be mentioned as preferred are, for
example, acetylsalicylic
acid, paracetamol, ibuprofen, diclofenac, metamizole and COX-2 inhibitors such
as, for example,
celecoxib and rofecoxib and the physiologically acceptable salts thereof.
Acetylsalicylic acid,
ibuprofen, paracetamol, naproxen and the physiologically acceptable salts
thereof are particularly
preferred. The invention likewise encompasses mixtures of the active
ingredients mentioned.
The further active ingredients) present where appropriate are employed in
therapeutically
effective amounts. Dosages of from 0.5 to 5 mmol are preferred. Dosages of
from 0.8 to 3 mmol
are particularly preferred.
Preference is given to acetylsalicylic acid in a dosage of from 100 to 1000
mg, paracetamol in a
dosage of from 100 to 1000 mg, ibuprofen in a dosage of from 100 to 1000 mg,
naproxen in a
dosage of from 100 to 1000 mg or mixtures of these active ingredients in a
total dosage of from
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100 to 1000 mg.
Particular preference is given to acetylsalicylic acid in a dosage of from 250
to 500 mg,
_ paracetamol in a dosage of from 250 to 500 mg, ibuprofen in a dosage of from
100 to 300 mg,
naproxen in a dosage of from 250 to 500 mg or mixtures of these active
ingredients in a total
dosage of from 200 to 500 mg.
A preferred effervescent preparation is characterized in that an effervescent
composition,
pseudoephedrine and one or more analgesics such as, for example,
acetylsalicylic acid,
paracetamol, naproxen and ibuprofen and/or one or more antitussives such as,
for example, dextro-
methorphan and/or one or more expectorants such as, for example ambroxol and
acetylcysteine are
present, with avoidance of alkalization of the urine and thus increased
accumulation of the basic
medicinally active substance. Antihistamines such as, for example,
chlorpheniramine can be added
where appropriate. The ingredients can also be in the form of their
physiologically acceptable
salts.
A particularly preferred effervescent preparation is characterized in that an
effervescent
composition, pseudoephedrine and one or more active ingredients from the group
of acetylsalicylic
acid, paracetamol and ibuprofen are present, with avoidance of alkalization of
the urine and thus
increased accumulation of the basic medicinally active substance, and it being
possible for the
ingredients also to be in the form of their physiologically acceptable salts.
The effervescent composition reacts on contact with water or saliva to evolve
COz and consists of
at least one basic and of at least one acidic component.
Carbonates may he mentioned as basic component of the effervescent
composition. Carbonates
mean for the purposes of the invention carbonates, sesquicarbonates and
bicarbonates. Preference
is given to ammonium carbonate, ammonium bicarbonate and alkalimetal and
alkaline earth metal
carbonates and bicarbonates such as, for example, sodium carbonate, sodium
bicarbonate,
potassium carbonate, potassium bicarbonate, calcium carbonate, calcium
bicarbonate, calcium
magnesium carbonate, magnesium carbonate, magnesium bicarbonate and magnesium
hydroxycarbonate. Particular preference is given to sodium carbonate, sodium
bicarbonate,
potassium carbonate, potassium bicarbonate, calcium carbonate, calcium
bicarbonate, magnesium
carbonate, magnesium bicarbonate and magnesium hydroxycarbonate. It is
likewise possible to
employ mixtures of the basic components mentioned.
The basic components) of the effervescent composition are employed in a total
dosage of from 1
to 20 mmol, preferably in a total dosage of from 2 to 15 mmol, particularly
preferably in a total
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dosage of from 2 to 10 mmol.
The acidic component may have more than one dissociation constant, meaning it
may have more
than one acidic functional group. The acidic component may be an organic or
inorganic acid in the
form of its anhydride, of its free acid or of its acidic salt in which, if
there is a plurality of acidic
functional groups, some of the protons can be replaced by a cation or cations.
Examples which
may be mentioned as acidic component are tartaric acid, succinic acid, malic
acid, malonic acid,
malefic acid, fumaric acid, adipic acid, lactic acid, glycolic acid, alpha-
hydroxy acids, ascorbic
acid, isoascorbic acid, glutaric acid, amino acids, phosphoric acid,
diphosphoric acid,
triphosphoric acid, metaphosphoric acid, pyrophosphoric acid, polyphosphoric
acids, sulphuric
acid, disulphuric acid and the acidic salts thereof such as, for example,
potassium hydrogentarirate
or sodium hydrogenphosphate, and other physiologically acceptable salts.
Particular preference is
given to ascorbic acid, isoascorbic acid, tartaric acid, phosphoric acid and
the acidic salts thereof.
It is likewise possible to employ mixtures of the acidic components mentioned.
The acidic components) of the effervescent composition are employed in a total
dosage of from-1
to 20 mmol, preferably in a total dosage of from 2 to 15 mmol.
It is possible to employ citric acid as acidic component if the basic
component of the effervescent
composition consists exclusively of alkaline earth metal carbonates and/or
bicarbonates such as,
for example, calcium carbonate, calcium bicarbonate, magnesium carbonate,
magnesium
bicarbonate and magnesium hydroxycarbonate or mixtures thereof. A preferred
effervescent
composition comprises citric acid as acidic component and calcium carbonate as
basic component.
The ratio of equivalents between the equivalents of citric acid and the total
of the equivalents of
the allcaline earth metal carbonates and/or bicarbonates is not more than 2:1,
preferably not more
than 1:1.
It is possible to employ citric acid and alkali metal carbonates and/or
bicarbonates if the equivalent
ratio between the equivalents of citric acid and the total of the equivalents
of the alkali metal
carbonates and/or bicarbonates is not more than 1:3, preferably not more than
1:4, particularly
preferably not more than 1:5.
If the further active ingredients) which are present where appropriate is an
acid, the acidic active
ingredients) such as, for example, acetylsalicylic acid, paracetamol and
ibuprofen may partly or
completely replace the acidic component in the effervescent composition.
Likewise preferred as effervescent composition is a combination of at least
one acidic and of at
least one basic component, where the equivalent ratio between the total of the
equivalents of the
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acidic and the total of the equivalents of the basic component is from 1:1 to
3:1, preferably 1:l to
2.5:1 and particularly preferably 1:1 to 1.5:1.
- Preference is likewise given to an effervescent preparation characterized in
that an effervescent
composition comprising citric acid and calcium carbonate, pseudoephedrine and
one or more
further active ingredients from the group of acetylsalicylic acid, paracetamol
and ibuprofen are
present, with avoidance of alkalization of the urine and thus increased
accumulation of the basic
medicinally active substance, and it being possible for the ingredients also
to be in the form of
their physiologically acceptable salts.
The invention further relates to a medicament comprising the effervescent
preparation according to
the invention and at least one further excipient.
Pharmaceutical excipients familiar to the skilled person are also described
for example in the
following handbook: "Handbook of Pharmaceutical Excipients", Wade, A. &
Welter, P.J.,
American Pharmaceutical Association, Washington, 2nd edition 1994.
Further excipients which may be mentioned for example are binders, lubricants,
flavourings,
wetting agents, sweeteners, antifoams, diluents, colours and stabilizers.
finders which may be mentioned for example are glycol, polyethylene glycol,
dextrose, sucrose,
sugar, starch, invert sugar, mannitol, cellulose, methylcellulose and
derivatives thereof.
Lubricants which may be mentioned for example are magnesium stearate, stearic
acid, talc,
paraffin, hydrogenated castor oil, polyethylene glycol, fumaric acid, adipic
acid, sodium benzoate,
sodium stearylfumarate and the salts thereof. Preferred examples are the
sodium, potassium,
ammonium, calcium and magnesium salts of fumaric acid and of adipic acid.
Flavourings which may be mentioned for example are synthetic and natural
flavourings which are
suitable for food products. Preferred examples are orange flavour, lime
flavour, Optarom orange,
eucalyptus oil, peppermint oil, vanilla and lemon flavour. Particularly
preferred examples are
orange flavour, lime flavour and Optarom orange.
Wetting agents which may be mentioned for example are dioctyl sodium
sulphosuccinate and
sodium lauryl sulphate.
Sweeteners which may be mentioned for example are sodium saccharin, cyclamate,
invert sugar
and aspartame.
An antifoam which may be mentioned for example is silicone oil.
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Diluents which may be mentioned for example are starch and cellulose.
Colours which may be mentioned for example are titanium dioxide, beetroot
powder, beta-carotene
and all colours suitable for food products.
Stabilizers which may be mentioned for example are polyvinyl alcohol,
polyvinylpyrrolidone,
polyethylene glycol and derivatives thereof.
Physiologically acceptable salts for the puzposes of the invention may be acid
addition salts of the
compounds with mineral acids, carboxylic acids or sulphonic acids.
Particularly preferred salts are,
for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid,
phosphoric acid,
methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,
benzenesulphonic acid,
naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid,
tartaric acid, citric acid, fumaric
acid, malefic acid or benzoic acid
However, salts which may be mentioned are also salts with conventional bases,
such as, for example,
alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal
salts (e.g. calcium 'or
magnesium salts) or ammonium salts derived from ammonia or organic amines such
as, for example,
diethylamine, triethylamine, ethyldiisopropylamine, procain, dibenzylamine, N-
methylmorpholine,
dehydroabietylamine, 1-ephenamine or methylpiperidine.
The invention further relates to the use of the effervescent preparation for
the treatment of
diseases. Depending on the active ingredients present in the effervescent
preparation, the
effervescent preparation is preferably used for the treatment of influenza)
infections, bacterial
infections, fevers, nasal catarrhs, coughs, colds or allergies.
The invention further relates to a process for producing the effervescent
preparation according to
the invention, characterized in that the components of the effervescent
preparation are formulated
in a pharmaceutical form conventional in the area of pharmaceutical
preparations. Powders,
granules, beads, pellets or tablets may be mentioned as preferred. Powders,
granules and tablets are
particularly preferred. Suitable known processes are used to produce the
medicaments according to
the invention.
The present invention likewise encompasses all combinations of the preferred
ranges.
Test to determine the accumulation behaviour:
To investigate the accumulation behaviour of a basic medicinally active
substance in effervescent
preparations, the basic medicinally active substance is administered in an
identical therapeutically
effective amount in each case in the following three preparations: preparation
A as effervescent
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preparation to be investigated, preparation B as non-effervescent preparation
and preparation C as
standard effervescent preparation, where preparation B contains no
effervescent components, and
preparation C contains a conventional effervescent composition consisting
exclusively of 600 mg
- of sodium bicarbonate and 1000 mg of citric acid. The three preparations are
administered at the
same time on each of 5 consecutive days, with the number of dosages per day
depending on the
basic medicinally active substance employed, and the dosage of this substance
corresponding to a
conventional use. After 5 days, the respective plasma levels A, B and C of the
basic medicinally
active substance are measured. Plasma level B reflects the intrinsic
accumulation behaviour of the
basic medicinally active substance. Increased accumulation of the basic
medicinally active
substance occurs if the difference between plasma level A and plasma level B
is in an
accumulation ratio of more than 1:2, preferably of more than 1:3, particularly
preferably of more
than 1:4 relative to the difference between plasma level C and plasma level B.
The accumulation
ratio is equal to the difference between plasma level A and plasma level B
divided by the
difference between plasma level C and plasma level B.
A preferred effervescent preparation comprises an effervescent composition, at
least one basic
medicinally active substance and, where appropriate, one or more further
active ingredients,
characterized in that the accumulation ratio is less than 1:2, preferably less
than 1:3, particularly
preferably less than 1:4.
Study of the accumulation behaviour of pseudoephedrine:
The accumulation behaviour of pseudoephedrine as basic medicinally active
substance was
investigated in two different preparations. Preparation 1 contained 60 mg of
pseudoephedrine HCl,
500 mg of acetaminophen and 1 tablet of Alka-Seltzer Cold & Cough ANC 6
(containing 600 mg
of citric acid and 1000 mg of sodium bicarbonate), preparation 2 contained 20
ml of Sudafed~
children's nasal decongestant liquid medication (equivalent to 60 mg of
pseudoephedrine HCl). In
17 consecutive single dosages, every 6 hours the two preparations were each
dissolved in 120 ml
of water and administered within 2 minutes to 32 test subjects in each case,
so that 4 dosages were
administered on each of the first to fourth day, and one dosage was
administered on the fifth day.
The pseudoephedrine plasma level was measured 12 hours after the last dosage
and averaged
236.9 ng/ml in the group of test subjects who received preparation l, and
averaged 120.23 ng/ml in
the group of test subjects who received preparation 2. The plasma levels
demonstrate increased
accumulation of pseudoephedrine.
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Exemplary embodiments:
Example 1:
- Effervescent tablet comprising:
1. Acetylsalicylic acid500 mg
Pseudoephedrine HCl 30 mg
2.
3. Citric acid 1000 mg
4. Calcium carbonate 555 mg
5. Mannitol 803 mg
6. Sorbitol 100 mg
Povidone (K30) 0.5 mg
7.
8. Sodium lauryl sulphate0.5 mg
Example 2:
Effervescent tablet comprising:
1. Acetylsalicylic acid500 mg
Pseudoephedrine HCI 30 mg
2.
3. Ascorbic acid 200 mg
4. Citric acid 800 mg
5. Calcium carbonate 555 mg
6. Mannitol 803 mg
Sorbitol 100 mg
7.
8. Povidone (K30) 0.5 mg
9. Sodium lauryl sulphate0.5 mg
Example 3:
Effervescent granules comprising:
Acetylsalicylic 500 mg
1. acid
2. Pseudoephedrine 30 mg
HCl
3. Sucrose 5.120 mg
4. Ascorbic acid 30 mg _
5. Tartaric acid 750 mg
Sodium bicarbonate690 mg
6.
7. Sodium carbonate 150 mg
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8. Clarity Premix 2 mg
9. Orange flavour 30 mg
Example 4:
Effervescent tablet comprising:
1. Acetylsalicylic acid 500 mg
2. Pseudoephedrine HCl 30 mg
3. Ascorbic acid 240 mg
4. Sodium dihydrogenphosphate900 mg
5. Sodium bicarbonate 450 mg
Sodium carbonate 100 mg
6.
Example 5:
Effervescent granules comprising:
1. Ibuprofen 200 mg
2. Pseudoephedrine 30 mg
HCl
Citric acid 400 mg
3.
4. Calcium carbonate 200 mg
5. Aspartame 13 mg
6. Orange flavour 100 mg
7. Lime flavour 20 mg
Optarom Orange* 200 mg
8.
*Lemonade base for taste optimization
Example 6:
Effervescent tablet comprising:
1. Acetylsalicylic acid 250 mg
2. Paracetamol 250 mg
3. Pseudoephedrine sulphate 30 mg
4. Citric acid 800 mg
5. Calcium carbonate 400 mg
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Example 7:
Effervescent granules comprising:
- 1. Acetylsalicylic acid 500 mg
2. Pseudoephedrine HCl 30 mg
3. Citric acid 180 mg
4. Sodium dihydrogenphosphate900 mg
5. Sodium bicarbonate 450 mg
6. Sodium carbonate 100 mg
Example
8:
Effervescent
tablet
comprising:
1. Acetylsalicylic acid 500 mg
2. Pseudoephedrine HCl 30 mg
3. Sodium carbonate 280 mg
Example 9:
Effervescent tablet comprising:
1. Pseudoephedrine HCl 30 mg
2. Citric acid 2882 mg
3. Calcium carbonate 750 mg
Example 10:
Effervescent tablet comprising:
1. Pseudoephedrine HCl 30 mg
2. Ascorbic acid 1321 mg
3. Sodium bicarbonate 630 mg
