|Title of Invention||
"A TRANSDERMAL PHARMACEUTICAL COMPOSITION"
|Abstract||A transdermal pharmaceutical composition comprising atleast 0.1% by weight of together with up to 99.9% by weight of a carrier, diluent and/or other auxiliary agent suitable for transdermal application, characterized in that the composition also comprises for 1 g of acetylsalicylic acid an alkali metal carbonate, ammonium carbonate, an alkali metal hydrocarbonate and/or ammonium hydrocarbonate in an amount equivalent to 0.01-1 g of carbon dioxide, and is buffered to pH 5.5 to 7 and optionally one or more antiphlogistic agent, analgesic agent, antirheumatic agent, muscle relaxant, local anaesthetic, pore dilatators and/or skin irritation alleviating agent as activity-complementing agent(s).|
|Full Text||The present invention relates to a transdermal pharmaceutical composition.
The invention relates to transdermally applicable aspirin-containing phar¬maceutical compositions which can be used in the therapy of calcification.
Calcification of cartilages, joints and interior organs is a disorder impending over everyone with the progress in lifetime; said disorder plays a causative role in the development of numerous diseases or medical conditions (such as joint in¬flammations, rheuma, locomotor diseases, deformations, etc.). Numerous therap¬eutical methods have been known for the treatment of calcification and its consequences. These methods include non-drug treatments (such as diet, curative gymnastics, massage, mud pack, balneotherapy, etc.) and various'drug therapies (such as administration of antiphlogistic, analgesic, muscle-relaxant etc. agents), which are frequently used in combination. An important representative of analgesic and antiphlogistic agents is acetylsalicylic acid (aspirin), which is used primarily for the treatment of rheumatic arthritis, rheumatoid arthritis and arthritis-like conditions usually in the form of orally administerable compositions or injections, but sometimes as a transdermal composition, too [Byoin Yakugaku 17(5), 335-340 (1991) (see C.A. 116, 158740q); Drugs of Today 33(%), 299-306 (1997); US patents Nos. 4,275,059, 5,260,066 and 5,612,382; GB patent No. 1,036,314; French patent No. 2,295,753]. Some of the papers listed above, furthermore Arch. Int. Pharmacodyn. 177(1), 211-223 (1969) also indicate that acetylsalicylic acid possesses anti-calcification effects. It is, however, well known that acetylsalicylic acid once entered the organism metabolises within a short period of time and decomposes to salicylic acid and acetic acid. Results of the tests performed by me have fully supported this quick me-
Although the two metabolites are also effective in reducing established
calcifications with the formation of calcium salicylate and calcium acetate [this effect
of salicylic acid has been discussed in Arch. Int. Pharmacodyn. 177(1), 211-223
(1969) cited above], the appearance of the formed two compounds, particularly of
calcium acetate, in the organism is highly objectionable from nephrological aspects,
due to its specific crystal structure. Presumably this explains why acetylsalicylic acid
has not been utilized in practice to cease already established calcification or to
reduce its extent, despite of its promising activity.
Now I have found that in a medium buffered to pH 5.5-7 and in the presence
of an alkali metal or ammonium carbonate or hydrocarbonate the metabolism of
acetylsalicylic acid can be slowed down to such an extent that at the area of calcification
the conversion of acetylsalicylic acid to calcium acetylsalicylate proceeds
much faster than its metabolism to salicylic acid and acetic acid. Acetylsalicilyc acid
which has been once bound in the form of calcium acetylsalicylate does not metabolise
further but is excreted from the organism in unchanged form without causing
This recojnition enables one to produce a nephrologically harmless pharmaceutical
composition suitable for the targeted treatment of calcification.
Thus the invention relates to a transdermal pharmaceutical composition
comprisinh acetylsalicylic acid together with a carrier, diluent and/or other auxiliary
agent suitable for transdermal application. The composition according to the invention
also comprises for 1 g of acetylsalicylic acid an alkali metal carbonate, ammonium
carbonate, an alkali metal hydrocarbonate and/or ammonium hydrocarbonate in
an amount equivalent to 0.01-1 g of carbon dioxide, and is buffered to pH 5.5 to 7.
Taking into account the equilibrium ion household of the organism, it is
preferred to use sodium carbonate or sodium hydrocarbonate as alkali metal
carbonate or hydrocarbonate.
The transdermal compositions according to the invention may comprise
acetylsalicylic acid in amounts usually applied in the known compositions of this
type. The compositions according to the invention may contain generally 0.1-30 %
by weight, suitably 0.5-20 % by weight, preferably 2-15 % by weight of acetylsalicylic
acid, calculated for the total weight of the composition. However, as it is well
known to one skilled in pharmacotechnology, the active agent content may also vary
with the actual type of the composition.
The compositions according to the invention may comprise the alkali metal
carbonate, ammonium carbonate, alkali metal hydrocarbonate and/or ammonium
carbonate in an amount equivalent to preferably 0.01-0.5 g, more preferably 0.02-
0.3 g, particularly preferably 0.02-0.2 g of carbon dioxide, calculated for 1 g of
A further feature of the composition according to the invention is that its pH is
of 5.5 to 7, preferably about 6.5. For aqueous compositions, such as emulsions,
gels, creams etc. comprising at least 5 % by weight of water, these figures represent
the pH measured in the composition itself. For nonaqueous compositions, such as
fatty creams or plasters carrying the pharmacons in a dried layer, these figures represent
the pH of the composition when contacted with water (e.g. smeared onto
wet skin surface or immersed into water). Any of the conventional non-toxic, pharmaceutically
acceptable buffers can be used to adjust the pH of the composition to
the prescribed value. Of these buffers tertiary amines (such as triethanol amine),
salts of tertiary amines and quaternary ammonium salts are preferred.
The compositions according to the invention can be presented in any form
suitable for topical use, such as as solutions, emulsions, suspensions, ointments,
creams, lotions, shake-up mixtures, gels, plasters, etc. These composition also
comprise carriers, diluents and/or other auxiliary agents conventionally applied in
such compositions beside the acetylsalicylic acid active agent, the metabolism .
delaying agent (alkali metal or ammonium carbonate and/or hydrocarbonate) and
the buffer. Examples of such carriers, diluents and other auxiliary agents are as
follows: ointment bases, such as vaseline and lanoline; solvents and liquid diluents,
such as water, alcohols and glycerol; thickeners and gellifying agents, such as polyvinyl
alcohol, polyvinyl acetate and polymeric cellulose derivatives; ionic and nonionic
tenzides; odourants; substances for adjusting osmotic pressure; colourants and
dyestuffs. Preferred representatives of the compositions are those comprising a
thickener, optionally along with a stabilizer, since they enable one to apply a
relatively high local dose onto the area to be treated. The only specific requirement
made on the auxiliary agents is that they should not react with acetylsalicylic acid.
The compositions may optionally also comprise other biologically active substances
as activity-complementing agents, examples of which are as follows: antiphlogistic
agents, analgesic agents, antirheumatic agents, muscle relaxants, local
anaesthetics, pore dilatators and/or skin irritation alleviating agents. The activitycomplementing
agents also comprise active agents utilized in conventional formulations
for the topical treatment of joint and rheumatic pains, such as camphor,
menthol, lidocain, diclofenac, snake venom extract, and the like. Preferably the compositions
also comprise agents for dilatating skin pores and/or vasopermeability
increasing agents as activity-complementing substances, examples of which are
capsaicine, histamine and cantharis extract.
If any of the components of the composition comprises alkali metal or
ammonium ions, the required amount of alkali metal or ammonium carbonate and/or
hydrocarbonate or a part thereof can also be formed from this component by adding
a calculated amount of carbon dioxide.
In order to treat calcification, the composition according to the invention is
applied onto the body part to be treated. The composition exerts its effect transdermally.
If the composition is a nonaqueous one, presence of water should also be
provided for e.g. by wetting the area to be treated or by immersing the plaster into
water before application.
Further details of the invention are illustrated by the following non-limiting
Gels with the compositions given below have been prepared by conventional
Acetylsalicylic acid 5 g
Diclofenac-Na 4 g
Sodium hydrocarbonate 3 g
Cetyl-trimethyl-ammonium bromide 2 g
Ethyl-methyl-cellulose 5 g
Ethanol 25 g
Distilled water 52 g
pH of the gel is 6.1.
Acetylsalicylic acid 10 g
Triethanol amine 3g
Lidocain 3 g
Methyl cellulose 4 g
Ammonium carbonate 5 g
Ethanol 30 g
Distilled water 45 g
pH of the gel is 6.7.
Acetylsalicylic acid 10 g
Sodium carbonate 2 g
Lidocain 4 g
Tinctura capsaicini 0.5 g
Triethanol amine 3 g
Polyvinyl alcohol 5 g
Ethanol 22 g
Distilled water 53.5 g
pH of the gel is 6.5.
Biological activity tests and their results
(A) Examination of the metabolism of acetylsalicylic acid
The tests were performed on 6 weeks old male New-Zealand giant white
rabbits. Before testing the animals were subjected to radiography to ascertain that
they do not suffer from calcification. The hair was shaved off from the backs of the
animals, and 0.6 g of a gel with the following composition was applied onto the skin:
acetylsalicylic acid 0.05 g
ethanol 0.05 g
methyl cellulose 0.02 g
distilled water 0.48 g
Blood samples were taken periodically, as given in Table 1, from the jugular
veins of the animals, the samples were centrifuged to separate the plasm, and the
acetylsalicylic acid (ASA) and salicylic acid (SA) contents of the samples were
measured by HPLC. The centrifuged plasms were stored at -22°C until analysis in
order to avoid the occurrence of any ex vivo metabolism upon the effect of esterases
present in the plasm.
The results are summarized in Table 1.
. The data of Table 1 clearly demonstrate that the salicylic acid content of the
blood samples was always at least the hundredfold of the acetylsalicylic acid
content. The results of the meassurements performed in every 15 minutes verify that
acetylsalicylic acid metabolises in the living organism within 15 minutes with the
formation of salicylic acid and acetic acid.
The above test was repeated on the same animals with the difference that
0.01 g of sodium carbonate was also added to the gel and the gel was buffered to
pH 6.5. The results are listed in Table 2.
From the data of Table 2 it appears that the amount of acetylsalicylic acid
present in the blood of the animals stabilized after a short induction period. An
extreme slow down in the metabolism of acetylsalicylic acid could be observed.
Metabolism started essentially at about the third-fourth hour, however, 25 % of
acetylsalicylic acid remained unmetabolised even after 4 hours. It should be
stressed here that this test was performed on healthy animals, where no dissolution
of calcification and no formation of calcium acetylsalicylate due to this dissolution
proceeds. Taking into account that acetylsalicylic acid once reacted with the calcified
area and thus converted to calcium acetylsalicylate can no more be metabolised but
is excreted from the organism in unchanged form (which was checked by urine
analyses performed on rabbits kept on specific calcium-rich diet), undesired calcium
acetate formation can safely be avoided when a calcified organ is treated with the
composition according to the invention.
(B) Examination of calcification-dissolving effects under ex vivo conditions
The tests were performed on intact pig joints. One marble chip, about 5 mrn in
diameter and about 1 -1.5 g in weight, was placed onto each of the joints, and the
chips were smeared with a gel of the composition as given in point (A) of Example 1.
After 8 hours this treatment was repeated, and then the joints were allowed to stand
overnight. Next day the effects were assessed visually. No marble residue could be
observed on any of the joints. Upon subjecting the joints to surgical and radiographic
examination no damage of the bone, of the synovial membrane or of the medullary •
substance could be detected, either.
1. A transdermal pharmaceutical composition comprising atleast 0.1% by weight of acetylsalicylic acid together with up to 99.9% by weight of a carrier, diluent and/or other auxiliary agent suitable for transdermal application, characterized in that the composition also comprises for 1 g of acetylsalicylic acid an alkali metal carbonate, ammonium carbonate, an alkali metal hydrocarbonate and/or ammonium hydrocarbonate in an amount equivalent to 0.01 to 1 g of carbon dioxide, and is buffered to pH 5.5 to 7 and optionally one or more antiphlogistic agent, analgesic agent, antirheumatic agent, muscle relaxant, local anaesthetic, pore dilatators and/or skin irritation alleviating agent as activity-complementing agent(s).
2. A composition as claimed in claim 1, which comprises 0.1 to 30 % by weight of acetylsalicylic acid calculated for the total weight of the composition.
3. A composition as claimed in claim 1 or 2, which comprises for 1 g of acetylsalicylic acid an alkali metal carbonate, ammonium carbonate, an alkali metal hydrocarbonate and/or ammonium hydrocarbonate in an amount equivalent to 0.01 to 0.5 g of carbon dioxide.
4. A composition as claimed in claim 3, which comprises for 1 g of acetylsalicylic acid an alkali metal carbonate, ammonium carbonate, an alkali metal hydrocarbonate and/or ammonium hydrocarbonate in an amount equivalent to 0.02 to 0.3 g of carbon dioxide.
5. A composition as claimed in claim 4, which comprises for 1 g of acetylsalicylic acid an alkali metal carbonate, ammonium carbonate, an alkali metal hydrocarbonate and/or ammonium hydrocarbonate in an amount equivalent to 0.02 to 0.2 g of carbon dioxide.
6. A composition as claimed in any of claims 1 to 5, which comprises sodium carbonate as alkali metal carbonate and sodium hydrocarbonate as alkali metal hydrocarbonate.
7. A composition as claimed in any of claims 1 to 6, which comprises as buffer for adjusting the pH to 5.5 to 7 a tertiary amine, a tertiary amine salt or a quaternary ammonium salt.
8. A composition as claimed in claim 7, which comprises Methanol amine as buffer.
|Indian Patent Application Number||1372/DELNP/2004|
|PG Journal Number||03/2009|
|Date of Filing||21-May-2004|
|Name of Patentee||ZOLTAN DARDAI|
|Applicant Address||ERDOKERULO UT 27, H-1157 BUDAPEST, HUNGARY.|
|PCT International Classification Number||A61K 47/02|
|PCT International Application Number||PCT/HU02/00112|
|PCT International Filing date||2002-10-31|