CA2120048C - Pharmaceutical composition having analgesic activity - Google Patents
Pharmaceutical composition having analgesic activity Download PDFInfo
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- CA2120048C CA2120048C CA002120048A CA2120048A CA2120048C CA 2120048 C CA2120048 C CA 2120048C CA 002120048 A CA002120048 A CA 002120048A CA 2120048 A CA2120048 A CA 2120048A CA 2120048 C CA2120048 C CA 2120048C
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- pharmaceutical composition
- methoxy
- naphthyl
- propionic acid
- arginine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
Pharmaceutical compositions having analgesic activity containing (8)-2-(6-methoxy-2-naphthyl)-propionic acid as active ingredient and arginine, useful for the preparation of pharmaceutical forms for oral route, are described.
Description
---, PHARMACEUTICAL COMPOSITION HAVING ANALGESIC ACTIVITY
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The present invention relates to a pharmaceutical composition with analgesic activity and, more particularly, it relates to a pharma-ceutical composition containing tS>-2-t6-methoxy-2-naphthyl)propi-onic acid as active ingredient, useful for the preparation of phar-maceutical formulations for oral use.
cS)-2-t6-methoxy-2-naphthyl>propionic acid and its salts with phar-maceutically acceptable organic or inorganic bases have been de-scribed for the first time in US Patent No. 3,904,682 c8yntex Cor-poration).
Subsequently, the salts of some non-steroidal antiinflammatory drugs <NSAIDs) with basic ~inoacids have been described in US Patent No.
~5 4,279,926 tBPA-SocietA Prodotti Antibiotici S.p.A.) to be particu larly useful for the preparation of injectable pharmaceutical formu-lations because of their solubility in water giving neutral aqueous solutions.
Since several years, t8)-2-t6-methoxy-2-naphthyllpropionic acid, hereinafter indicated with the International Nonproprietary Name tINN) Naproxen, is used in therapy as free acid or as a salt, espe cially sodium or piperazine salt, for its analgesic, antiinflamaia tory and antipyretic properties tMerek Index, XI ed., No. 6337, page 1014).
Naproxen is orally administered at daily doses of 500-1500 mg. The maximum plasmatic concentration is generally between 49 and 90 ug/ml and it is reached in about two hours IVerbruggen and Moll, Nonelas-sical oral formulations of NSAIDs, page 391 - "Therapeutic Applica-tions of NSAIDs", edited by J.P. Famaey, Harold E. Paulus, Marcel Dekker Inc., New York, (1992)1.
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It is clear that the need of pharmaceutical compositions able to anticipate the onset of the pharmacological effect of non-steroidal antiinflammatory drugs is highly felt, particularly in the analgesic therapy.
US Patent No. 4,587,249 (Analgesic Associates> describes an anal-gesic and antiinflammatory composition containing an association of caffeine and a non-steroidal antiinflammatory drug able to increase the analgesic and antiinflammatory effect and to anticipate its onset.
Both caffeine and non-steroidal antiinflammatory drugs are commonly used in analgesic therapy.
US Patent No. 4,834,966 (Zambon S.p.A.> describes Ibuprofen water-soluble compositions containing 33-46x by weight of Ibuprofen, 34-51x by weight of L-arginine and 9-291c by weight of sodium bicar-bonate which allow to obtain an increase of Ibuprofen maximum plas-matic concentration and a remarkable anticipation of the onset time of the analgesic effect.
The molar ratio between arginine and Ibuprofen must be from 1.1 to 20 1~5 while the weight ratio between sodi~n bicarbonate and Ibuprofen is from 0.25 to 0.75.
We have now surprisingly found a pharmaceutical composition con-taining Naproxen and arginine able to significantly anticipate the onset of the analgesic effect after oral administration.
25 Therefore, object of the present invention is a pharmaceutical composition useful for the preparation of pharmaceutical formula tions for oral use consisting of a mixture of Naproxen and arginine in a molar ratio from 1:0.8 to 1:1.5 aril of an optional pharmaceu tically compatible auxiliary basic substance in a molar ratio up to 0.7 with respect to Naproxen, so that, if dissolved in water, the 212U04~
resultant aqueous solution has a pH value from 7.5 to 9Ø
Naproxen is used in the mixture in the form of free acid.
Arginine is preferably L-arginine.
The molar ratio between Naproxen and arginine is preferably between t:0.8 and 1:t.2, still more preferably it is t:t.t.
Specific examples of pharmaceutically compatible auxiliary basic substances are inorganic bases such as soditmn or potassium bicar-bonate, sodiwn or potassium carbonate, disodiim or dipotassium ~0 phosphate, sodium phosphate (Na=P04) or potassi~ phosphate (K~p04) or organic bases such as sodium or potassium citrate, sodium or potassium tartrate, N-methylglucamine, D-glucamine or glucosamine and mixtures thereof.
Exclusively for practical and economical reasons, sodium or potas-~5 sium bicarbonate is preferably used.
Preferably, the molar ratio between Naproxen and the pharmaceutical-ly compatible auxiliary basic substance, when present, is comprised from t:0.2 to t:0.4.
The pharmaceutical composition object of the present invention 20 allows to obtain a significant anticipation of the onset of the analgesic effect alter oral administration and it is particularly useful for the preparation of pharmaceutical formulations for oral use such as tablets, effervescent tablets, granulates, powders, syrups and solutions.
25 ~e peculiar characteristic of the composition object of the present invention is arginine.
It is worth underlining that arginine can be present also in stoi-chiometric delault with respect to the molar amount of Naproxen.
Furthermore, the pharmaceutical composition of the invention is hydrosoluble giving aqueous solutions with a pH from 7.5 to 9Ø
-3a-According to a further aspect of the present invention, there is provided a pharmaceutical composition, consisting essentially of: a) (S)-2-(6-methoxy-2-naphthyl)propionic acid; b) arginine; and c) a sufficient amount of a pharmaceutically acceptable auxiliary base, such that said pharmaceutical composition, when dissolved in water, affords an aqueous solution having a pH of from 7.5 to 9.0; wherein: i) said (S)-2-(6-methoxy-2-naphthy=L)propionic acid and said arginine are present. in relative amounts such that the molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid to arginine is ft-om 1:0.8 to 1:1.5; and ii) said pharmaceutically acceptable auxiliary base and said (S)-2-(6-methoxy-2-naphthyl)propionic acid are present in relative amounts such that the molar ratio of pharmaceutically acceptable auxiliary base to (S)-2-(6-methoxy-2-naphthyl)propionic acid is from 0:1 to 0.7:1.
According to a further aspect of the present invention, there is provided a pharmaceutical composition, consisting essentially of: a) (S)-2-(6-methoxy-2-naphthyl)propionic acid; b) arginine; and c) a sufficient amount of a pharmaceutically acceptable auxiliary base, such that said pharmaceutical composition, when dissolved in water, affords an aqueous solution having a pH of from 7.5 to 9.0; wherein: i) said (S)-2-(6-methoxy-2--naphthyl)propionic acid and said arginine are presE~nt. in relative amounts such that the molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid to arginine is from 1:l to 1:0.8; and ii) said pharmaceutically acceptable auxiliary base and said (S)-2-(6-methoxy-2-naphthy.l)propionic acid are present in relative amounts such that the molar ratio of -3b-pharmaceutically acceptable auxiliary base to (S)-2-(6-methoxy-2-naphthyl)prop:ionic acid is up to 0.7:1.
According to a further aspect of the present invention, there is provided a pharmaceutical composition, consisting essentially of: a) (S)-2-(6-methoxy-2-naphthyl)propionic acid; and b) arginine; and wherein:
said (S)-2-(6-methoxy-2-naphthyl)propionic acid and said arginine are presc:mt in relative amounts such that the molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid to arginine is at least 1:1.5 and said arginine is present in a sufficient molar excess over said (S)-2-(6-methoxy-2-naphthyl)prop:ion:ic acid such that said pharmaceutical composition, when dis:~olved in water, affords an aqueou::> solution having a pH of from 7.5 to 9Ø
---It is clear to the man skilled in the art that the pH value of the aqueous solution is mainly due to the presence of arginine and, consequently, when arginine is in a molar excess, the addition of the auxiliary basic substance may not be necessary.
The choice of the optional pharmaceutically compatible auxiliary basic substance has also the purpose of improving the characteristic of the finished pharmaceutical formulation.
For example, the use of an inorganic base such as sodium or potas-si~ bicarbonate improves the theological characteristics of the mixture making it particularly suitable for the granulation and the compression.
The preparation of the pharmaceutical compositions object of the present invention is carried out by mixing according to usual tech-piques.
As already underlined, the compositions object of the present inven-tion allow to obtain a significant anticipation of the onset of the analgesic effect with respect to formulations on the market con-taining sodium Naproxen (example 1b).
20 A significant anticipation of the onset of the analgesic effect due to an increase of the maximum plasmatic concentration is obtained with the compositions of the present invention also when compared to compositions containing an equivalent amount of Naproxen in the form of arginine salt (example 17).
25 It is worth noting that the AUC (Area Under Curve) is substantially the same in the compositions o! the invention and in formulations containing sodium Naproxen present on the market or in the formula-tion containing only the arginine salt of Naproxen.
From a practical point of view, this means that the analgesic effect begins in advance (generally after some minutes) and lasts longer.
- 5 - z~zoo4s It is not yet clear the mechanism through which the compositions of the invention give rise to such a remarkable anticipation of the onset of the analgesic effect of Naproxen with respect to commercial formulations of sodium Naproxen.
This result does not appear to be dependent on either partial or total salification of Naproxen so that the dissolution step is hastened at gastric level because it is known that the sodium salt of Naproxen is much more soluble, and consequently allows a much higher dissolution speed at gastric level, than the arginine salt IA.Fini et al., Pharm. Acta Helv., ~Q(2), 58-62, t1985)].
Tentatively, it could be argued that arginine has an active role at gastric level in the step of absorption of Naproxen in the form of free acid.
On the other hand, the compositions object of the present invention behave differently at gastric level in comparison with compositions containing the salt of Naproxen with arginine.
In fact, the presence of a slight excess of arginine or of small amounts of a pharmaceutically compatible auxiliary basic substance, 20 booking to the invention, allows to significantly increase the percentage of dissolved active ingredient (Naproxen) in the stomach in comparison with the gastric dissolution of the simple arginine salt (Example 18).
For the preparation of pharmaceutical formulations such as tablets, 25 effervescent tablets, granulates, powders, syrups and solutions, further excipients suitable for the pharmaceutical use such as, for example, sweetening agents, flavoring agents, effervescent mixtures and coloring agents, can be added to the composition object of the present invention.
Preferably, the pharmaceutical formulations will contain an amount _ 6 _ 212UU4~
of Naproxen equal to 125, 250 or 500 mg.
The preparation of the pharmaceutical formulations is carried out according to conventional techniques of granulation, compression and dilution.
In order to better illustrate the present invention, without lim-iting it, the following examples are now given.
Example 1 A mixture having the following composition Naproxen 500 g L-Arginine 416 g was prepared by mixing the two powders, separately sieved, in a mixer up to homogeneity.
The aqueous solution obtained by dissolving 0.916 g of the resultant ~5 mixture in 200 ml of water has pH=8.2.
Example 2 A mixture having the following composition Naproxen 500 g L-Arginine 416 g 20 was prepared by wet granulation and the granulate was dried in a static oven.
Example 3 A mixture having the following composition Naproxen 500 g 25 L ~ginine 302.5 g Sodium bicarbonate 73 g was prepared by mixing the three powders, separately sieved, in a mixer up to homogeneity.
Example 4 A mixture having the following composition _ 7 _ Naproxen 500 g L-Arginine 302.5 g Sodium bicarbonate 73 g was prepared by wet granulation and the granulate was dried in a static oven.
Example 5 A mixture having the following composition Naproxen 500 g L-Arginine 378.2 g Sodium bicarbonate 36.5 g was prepared by mixing the three powders, separately sieved, in a mixer up to homogeneity.
Example 6 ~5 A mixture having the following composition Naproxen 500 g L-Arginine 378.2 g Sodium bicarbonate 36.5 g was prepared by wet granulation and the granulate was dried in a 20 static oven.
Example 7 A mixture having the following composition Naproxen 500 g L-Arginine 560 g 25 was prepared by mixing the two powders, separately sieved, in a mixer up to homogeneity.
Alternatively, the mixture was granulated with water and the granu-late was dried in a static oven.
Example 8 A mixture having the following composition g _ U
Naproxen 500 g L-Arginine 378.2 g Sodium bicarbonate 54.7 g was prepared by wet granulation and the granulate was dried in a static oven.
Example 9 Saccharose 11939 sodiwn saccharin 120 g), aspartame g), 125 g) and mint flavour 1100 were added 'to a mixture prepared g) as described in Example 1.
The resultant mixture was shared into about 1000 sachets having the following composition t3 g in all) Naproxen 500 mg L-Arginine 416 mg Saccharose 1939 mg Sodium saccharin 20 mg Aspartame 25 mg Mint flavour 100 mg Example 10 20 ~ccharose 11939 sodium saccharin 120 g), aspartame g), 125 g) and mint flavour 1100 were added to a granulate prepared g) as described in Example 2.
The resultant mixture was shared into about 1000 paper-aluminum-polyethylene sachets having the following composition t3 g in all) 25 Naproxen 500 mg L-Arginine 416 mg Saccharose 1939 mg Sodium saccharin 20 mg Aspartame 25 mg Mint flavour 100 mg "~1 Alternatively, the mixture was shared into sachets containing 1.5 g or 0.?5 g, corresponding to 250 or 125 mg of Naproxen respectively.
Example 11 Microcrystalline cellulose (1t6 g), erosslinked polyvinylpyrrolidone (40 g) and magnesium stearate (8 g) were added to a granulate pre-pared as described in Example 2 and the resultant mixture was mixed up to homogeneity.
The mixture was compressed obtaining tablets (1.080 g) each con-taining 500 mg of Naproxen.
Alternatively, tablets weighing 0.540 g or 0.2?0 g each and con-taining 250 mg or 125 mg of Naproxen respectively were prepared.
Example 12 Sorbitol (1939 g), sodium saccharin (20 g), aspartame (60 g) and apricot tlavour (100 g) were added to a granulate prepared as de-scribed in Example 4.
The resultant mixture was shared into about 1000 paper-aluminum-polyethylene sachets at the rate of 3 g each.
Alternatively, the mixture was shared into sachets containing t.5 g 20 or 0.?5 g, corresponding to 250 or 125 mg of Naproxen respectively.
Example 13 Xylitol (900.3 g), sodium saccharin (25 g), aspartame (60 g> and anise flavour (100 g) were added to a mixture prepared as described in Example 6.
25 The resultant mixture was shared into about 1000 sachets having the following composition (2 g in all) Naproxen 500 mg L-Arginine 3?8.2 mg Sodium bicarbonate 36.5 mg Xylitol 900.3 mg -'~~- 2120048 Sodium saccharin 25 mg Aspartame 60 mg Anise flavour 100 mg Example 14 Sodium bicarbonate (800 g), sodium bitartrate (900 g), aspartame (40 g) and flavour (100 g) were added to a mixture prepared as described in Example 7.
The resultant mixture was compressed thus obtaining effervescent ~0 tablets (2.9 g) each containing 500 mg of Naproxen.
Alternatively, effervescent tablets weighing 1.45 g and each con-taining 250 mg of Naproxen were prepared.
Example 15 Sodium bicarbonate (800 g), sodium bitar:rate (900 g), saccharose ~r~ (1140 g) and flavour (100 g) were added to a mixture prepared as described in Example 7.
The resultant mixture was compressed obtaining effervescent tablets (4 g) each containing 500 mg of Naproxen.
Alternatively, effervescent tablets weighing 2 g or 1 g each and 20 containing 250 or 125 mg of Naproxen respectively were prepared.
Example 16 Aqueous solutions of a granulate prepared as described in Example t, containing 500 mg of Naproxen (treatment A) and of a sodium Naproxen commercial granulate, containing an equivalent aa~ount of active 25 lenient (treatment 8) were administered with a single dose by oral route to 12 subjects aged 32.514.05.
Each subject was apparently healthy, in particular as far as the renal, hepatic and hematopoietie functions were concerned.
Each subject received both preparations in two treatment sessions carried out two weeks apart, randomizing the order of r --.
- ~1 - 212004 administration.
During each session, basal samples of venous blood were drawn (in the morning) from each fasting subject, prior to oral administration . 5 of the preparation A or B. Further venous blood samples were also drawn 0.25, 0.50, 0.75, 1, 2, 3, 4, 8, 12 and 24 hours after treat-ment.
The analytical determination of Naproxen in the blood samples was carried out following the HPLC method hereinafter described.
~0 Chromatographie conditions:
- Apparatus Hp 1090 L equipped with a diode array detector HPLC column Hypersil ODS (5 yam, 100x2.1 mm) plus a precolwnn Hypersil OD8 (5 yam, 20x2.1 mm) Mobile phase: Na~HP0.~2H~0 0.03M (corrected to pH 3 with ~ 5 HaPO., : CHaOH=48: 52 ) - Flow: 0.5 ml/min - Column temperature: 40~C
Wavelength: 230.4 nm - Internal standard: a solution of Flurbiprofen in methanol (0.15 20 ~ml) The internal standard (0.2 ml) was added to plasma c0.1 ml). The whole was mixed and allowed to rest.
After 30 minutes, it was centrifuged at 4500 rounds per 10 minutes.
The clear surnatant (10 )r1) was injected into the HPLC system.
25 ~~er the described operative conditions, the retention times were as follows:
Naproxen=3.8 minutes Internal standard=8.7 minutes The obtained results are reported in the following table 1.
-v - ,2 - 2120048 Table 1 Mean plasma concentration of Naproxen after oral treatment with a solution of a pharmaceutical composition according to the present invention (treatment A) and after oral treatment with a commercial composition (treatment B).
Administered dose: 500 mg of active ingredient.
Plasma concentration of Naproxen (Ng/ml) ~0 Treatment Time after treatment (hours) 0.25 0.50 0.75 1 2 3 4 8 12 24 A 52.2 58.6 69.8 61.3 58.6 53.3 48.4 37.3 29.9 18.0 8 13.0 22.0 31.1 43.5 61.8 63.4 56.0 39.9 32.4 18.0 ~,5 ____________________________________________________________________ Pharmacokinetic parameters The following parameters were calculated and evaluated.
The area under curve of Naproxen plasma concentration from time "zero" to time 24 hours (AUCo~=AUCo~,",) expressed as yrg x h x 20 ml-' was calculated following the trapezoidal rule method (6ibaldi M. and Perrier D., "Pharmacokinetics", pages 293-296, Marcel Dekker Inc., New York 1975).
The area under curve of Naproxen plasma concentration from time "zero" to "infinite" (AllCeot) was calculated by the following formu 25 la AUCp.~,s4h + AUCz.,hi~.
wherein concentration at 24h AUC~4h'.e~-K, and K.= elimination constant The mean peak time expressed in hours was obtained by averaging the -, -13 _ 2120048 individual peak times.
The mean plasma concentration (Ca.") expressed as Ng/ml was calcu-lated by averaging the single peak values of the concentrations.
The lag time (hours) is the delay between the drug administration and the beginning of the absorption.
The values of the above specified pharmacokinetic parameters are reported in the following table 2.
Table 2 Pharmacokinetic parameters obtained after oral treatment with a solution of a pharmaceutical composition according to the invention (preparation A) and after oral treatment with a solution of a com-mercial composition (preparation B).
Administered dose: 500 mg of active ingredient.
__-_________________________________________________________________ Pharmacokinetie parameters Preparation A Preparation B
AUCeb~ (Ng x h x ml'') 812 835 AUCeet (!Ig X h x ml'') 1192 1041 Peak time (hours) 1.22 2.63 20.
c",~ ( Ng/ml ) 75 . 4 70. 6 Lag time (hours) 0.02 0.12 From the values reported in the table, it is evident that the compo sitions object of the present invention show a remarkable anticipa tion of the onset of the analgesic effect.
In Tact, the peak time and the lag time are significantly lower than those of a commercial composition of sodium Naproxen and the maxianm concentration (C"""~) is higher.
Example 17 Aqueous solutions of a granulate prepared as described in Example 6, containing 250 mg of Naproxen, arginine and sodium bicarbonate (treatment A> and of a granulate, containing an equivalent amount of active ingredient but in the form of arginine salt and without sodium bicarbonate (treatment e) were administered with a single dose by oral route to 6 healthy adult male volunteers in fasting conditions.
The solutions were administered in both cases according to an open, ~~ balanced, randomized, cross-over design. A wash out period of 7 days was observed between the treatments.
For each treatment, a basal sample of venous blood was drawn from each fasting subject, prior to oral administration of the prepara-tion A or B. Further venous blood samples were also drawn 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 30 and 36 hours after treatment.
The analytical determination of Naproxen in the blood samples was carried out by HPLC with U.V. detection.
Chromatographic conditions:
20 - PLC column Hypersil ODS (5 Nm, 100x2.1 mm) plus a precolumn Hypersil ODS (5 )rm, 20x2.1 mm) - Mobile phase: Na,HP04~2H~0 0.03M (corrected to pH 3 with Hap04:CH,OH=48:52) Flow: 0.5 ml/min 25 - Column temperature: 40~C
- Wavelength: 230.4 rm Internal standard: a solution of Flurbiprolen in methanol (0.15 mg/ml) The internal standard (0.2 ml) was added to plasma (0.1 ml). The whole was mixed and allowed to rest at 4~C.
3a - ,5 - 212UU48 After 30 minutes, it was centrifuged at 4500 rounds per 10 minutes.
The clear surnatant t0.1 ml) was injected into the HPLC system.
The obtained results are reported in the following table 3.
Table 3 Mean plasma concentration of Naproxen after oral treatment with a solution of a pharmaceutical composition according to the present invention ttreatment A) and after oral treatment with a composition containing only Naproxen in the form of arginine salt ttreatment B).
~0 Administered dose: 250 mg of active ingredient.
Naproxen plasma concentration tNg/ml) Time after treatment Treatment A Treatment B
(hours) 15 0~17 20.0 19.1 0.33 28.5 I 27.7 0.5 30.4 29.3 0.75 35.2 31.2 1 33.6 30.6 20 1~5 32.0 29.5 2 30.6 29.3 2.5 28.5 27.9 3 26.5 26.7 25.1 24.2 25 8 19.8 18.7 12 16.6 15.0 24 10~8 9.02 30 6.b5 6.31 36 3.60 4.20 zlzoo~s Pharmacokinetie parameters The following parameters were calculated and evaluated.
The area under curve of Naproxen plasma concentration from time "zero" to time 36 hours (AUCo~cAUCo--ash) expressed as ug x h x ml-' was calculated following the trapezoidal rule method (6ibaldi M. and Perrier D., "Pharmacokinetics", pages 293-296, Marcel Dekker Inc., New York 1975).
The area under curve of Naproxen plasma concentration from time "ze-ro" to "infinite" (AUCtot) was calculated by the following formula AUCo.-)asp, + AUCa.n-~~
wherein AUCa",~.= concentration at 36h K.
and K,= elimination constant The mean peak time expressed in hours was obtained by averaging the individual peak times.
The mean plasma concentration (C","~) expressed as yrg/ml was calcu-lated by averaging the single peak values of the concentrations.
The elimination half-life (t~) expressed in hours.
The values of the above specified pharmacokinetic parameters are reported in the following table 4.
Table 4 Pharmacokinetic parameters obtained after oral treatment with a solution of a pharmaceutical composition according to the invention (Preparation A) and after oral treatment with a solution of a compo sition containing only an equivalent amount of Naproxen in the form of arginine salt (preparation B).
Administered dose: 250 mg of active ingredient.
17 - 212004$
Pharmacokinetic parameters Preparation A Preparation B
AUCo,,o ty~g x h x m1_' ) 570 493 AUCtot tllg X h X m1_') 592 Peak time thours) 0.70 0.68 C~ (!ag/ml ) 36. 8 32. 4 t~ thours) ~ 1t.8 12.0 -________________________ ________________________________________ From the values reported in the table, it is evident that a composi-tion containing Naproxen, arginine and sodium bicarbonate in the ratio 1:1:0.2, according to the present invention, allows to obtain a maximum plasmatic concentration tC",.,~) meaningfully higher than ~5 that of a composition containing only the arginine salt of Naproxen.
This means that the analgesic effect of the composition of the present invention is greater and faster.
Example 18 Aqueous solutions tt00 ml) of a granulate prepared as described in ~~le 8, containing 200 mg of Naproxen, arginine and sodium bicar bonate tpreparation A) and of a granulate, containing an equivalent amount of active ingredient but in the form of arginine salt and without sodium bicarbonate tpreparation B) were treated with HCl 0.03N t30 ml) in order to simulate the acidity produced by the gastric juice.
The resultant suspensions were filtered through a Millipore filter membrane t0.8 um).
A quantitative determination of Naproxen present in the starting suspension, in the filtered solution and in the residue on the filter was carried out according to the following procedure.
_ ,8 _ 2120048 Apparatus: Hewlett-Packard liquid chromatograph (mod. 1050 and mod.
1090A) with U.V, detector at changeable wavelength.
Hewlett-Packard data recorder system (mod.3359A).
Column: Hewlett-Paekard RP-18, 200x4.6 rm, 5 yam.
Chromatographic conditions:
- mobile phase: tetrabutylammonium hydroxide 0.005M corrected to pH
7.0 with phosphoric acid:acetonitrile=62:38 flow: 2.0 ml/minutes - wavelength: 270 rm - eluent temperature: room temperature - column temperature: 40~C
- injected volume: 10 Nl - retention time: 2.2 minutes Preparation of the standard solution: Naproxen (200 mg) was dis-solved in the mobile phase up to volume (100~m1). M aliquot (5 ml), of the resultant solution was further diluted with the mobile phase up to volume c20 ml).
Preparation of the sample solution: the starting suspension and the 20 solution obtained after filtering the starting suspension were suit ably diluted with the mobile phase in order to obtain a theoretical Naproxen concentration as equal as possible to the concentration of the standard solution labout 0.5 mg/ml). The filtered residue was dissolved with the mobile phase up to a volume corresponding as much 25 as possible to the theoretical Naproxen concentration of the stan-dard solution.
The resulting detected amounts of Naproxen are reported in the following table 5.
Table 5 Amounts of Naproxen dissolved under simulated gastric conditions obtained from a granulate according to the invention (preparation A) and from a granulate containing an equivalent amount of active ingredient (preparation B).
Naproxen amount (x) Preparation A Preparation B
Starting suspension 100 Filtered solution 28.45 6.15 Filtered residue 71.55 93.85 From the above data it clearly results that, under conditions simulating the gastric acidity, the composition of the present invention allows the dissolution of a higher amount of active ingre-dient than a composition containing an equivalent amount of Naproxen in the form of arginine salt.
w~r~rw~rx~»~r~r~r~~r~r~xxxxrw»»
The present invention relates to a pharmaceutical composition with analgesic activity and, more particularly, it relates to a pharma-ceutical composition containing tS>-2-t6-methoxy-2-naphthyl)propi-onic acid as active ingredient, useful for the preparation of phar-maceutical formulations for oral use.
cS)-2-t6-methoxy-2-naphthyl>propionic acid and its salts with phar-maceutically acceptable organic or inorganic bases have been de-scribed for the first time in US Patent No. 3,904,682 c8yntex Cor-poration).
Subsequently, the salts of some non-steroidal antiinflammatory drugs <NSAIDs) with basic ~inoacids have been described in US Patent No.
~5 4,279,926 tBPA-SocietA Prodotti Antibiotici S.p.A.) to be particu larly useful for the preparation of injectable pharmaceutical formu-lations because of their solubility in water giving neutral aqueous solutions.
Since several years, t8)-2-t6-methoxy-2-naphthyllpropionic acid, hereinafter indicated with the International Nonproprietary Name tINN) Naproxen, is used in therapy as free acid or as a salt, espe cially sodium or piperazine salt, for its analgesic, antiinflamaia tory and antipyretic properties tMerek Index, XI ed., No. 6337, page 1014).
Naproxen is orally administered at daily doses of 500-1500 mg. The maximum plasmatic concentration is generally between 49 and 90 ug/ml and it is reached in about two hours IVerbruggen and Moll, Nonelas-sical oral formulations of NSAIDs, page 391 - "Therapeutic Applica-tions of NSAIDs", edited by J.P. Famaey, Harold E. Paulus, Marcel Dekker Inc., New York, (1992)1.
.. .
zl2oo~~
It is clear that the need of pharmaceutical compositions able to anticipate the onset of the pharmacological effect of non-steroidal antiinflammatory drugs is highly felt, particularly in the analgesic therapy.
US Patent No. 4,587,249 (Analgesic Associates> describes an anal-gesic and antiinflammatory composition containing an association of caffeine and a non-steroidal antiinflammatory drug able to increase the analgesic and antiinflammatory effect and to anticipate its onset.
Both caffeine and non-steroidal antiinflammatory drugs are commonly used in analgesic therapy.
US Patent No. 4,834,966 (Zambon S.p.A.> describes Ibuprofen water-soluble compositions containing 33-46x by weight of Ibuprofen, 34-51x by weight of L-arginine and 9-291c by weight of sodium bicar-bonate which allow to obtain an increase of Ibuprofen maximum plas-matic concentration and a remarkable anticipation of the onset time of the analgesic effect.
The molar ratio between arginine and Ibuprofen must be from 1.1 to 20 1~5 while the weight ratio between sodi~n bicarbonate and Ibuprofen is from 0.25 to 0.75.
We have now surprisingly found a pharmaceutical composition con-taining Naproxen and arginine able to significantly anticipate the onset of the analgesic effect after oral administration.
25 Therefore, object of the present invention is a pharmaceutical composition useful for the preparation of pharmaceutical formula tions for oral use consisting of a mixture of Naproxen and arginine in a molar ratio from 1:0.8 to 1:1.5 aril of an optional pharmaceu tically compatible auxiliary basic substance in a molar ratio up to 0.7 with respect to Naproxen, so that, if dissolved in water, the 212U04~
resultant aqueous solution has a pH value from 7.5 to 9Ø
Naproxen is used in the mixture in the form of free acid.
Arginine is preferably L-arginine.
The molar ratio between Naproxen and arginine is preferably between t:0.8 and 1:t.2, still more preferably it is t:t.t.
Specific examples of pharmaceutically compatible auxiliary basic substances are inorganic bases such as soditmn or potassium bicar-bonate, sodiwn or potassium carbonate, disodiim or dipotassium ~0 phosphate, sodium phosphate (Na=P04) or potassi~ phosphate (K~p04) or organic bases such as sodium or potassium citrate, sodium or potassium tartrate, N-methylglucamine, D-glucamine or glucosamine and mixtures thereof.
Exclusively for practical and economical reasons, sodium or potas-~5 sium bicarbonate is preferably used.
Preferably, the molar ratio between Naproxen and the pharmaceutical-ly compatible auxiliary basic substance, when present, is comprised from t:0.2 to t:0.4.
The pharmaceutical composition object of the present invention 20 allows to obtain a significant anticipation of the onset of the analgesic effect alter oral administration and it is particularly useful for the preparation of pharmaceutical formulations for oral use such as tablets, effervescent tablets, granulates, powders, syrups and solutions.
25 ~e peculiar characteristic of the composition object of the present invention is arginine.
It is worth underlining that arginine can be present also in stoi-chiometric delault with respect to the molar amount of Naproxen.
Furthermore, the pharmaceutical composition of the invention is hydrosoluble giving aqueous solutions with a pH from 7.5 to 9Ø
-3a-According to a further aspect of the present invention, there is provided a pharmaceutical composition, consisting essentially of: a) (S)-2-(6-methoxy-2-naphthyl)propionic acid; b) arginine; and c) a sufficient amount of a pharmaceutically acceptable auxiliary base, such that said pharmaceutical composition, when dissolved in water, affords an aqueous solution having a pH of from 7.5 to 9.0; wherein: i) said (S)-2-(6-methoxy-2-naphthy=L)propionic acid and said arginine are present. in relative amounts such that the molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid to arginine is ft-om 1:0.8 to 1:1.5; and ii) said pharmaceutically acceptable auxiliary base and said (S)-2-(6-methoxy-2-naphthyl)propionic acid are present in relative amounts such that the molar ratio of pharmaceutically acceptable auxiliary base to (S)-2-(6-methoxy-2-naphthyl)propionic acid is from 0:1 to 0.7:1.
According to a further aspect of the present invention, there is provided a pharmaceutical composition, consisting essentially of: a) (S)-2-(6-methoxy-2-naphthyl)propionic acid; b) arginine; and c) a sufficient amount of a pharmaceutically acceptable auxiliary base, such that said pharmaceutical composition, when dissolved in water, affords an aqueous solution having a pH of from 7.5 to 9.0; wherein: i) said (S)-2-(6-methoxy-2--naphthyl)propionic acid and said arginine are presE~nt. in relative amounts such that the molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid to arginine is from 1:l to 1:0.8; and ii) said pharmaceutically acceptable auxiliary base and said (S)-2-(6-methoxy-2-naphthy.l)propionic acid are present in relative amounts such that the molar ratio of -3b-pharmaceutically acceptable auxiliary base to (S)-2-(6-methoxy-2-naphthyl)prop:ionic acid is up to 0.7:1.
According to a further aspect of the present invention, there is provided a pharmaceutical composition, consisting essentially of: a) (S)-2-(6-methoxy-2-naphthyl)propionic acid; and b) arginine; and wherein:
said (S)-2-(6-methoxy-2-naphthyl)propionic acid and said arginine are presc:mt in relative amounts such that the molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid to arginine is at least 1:1.5 and said arginine is present in a sufficient molar excess over said (S)-2-(6-methoxy-2-naphthyl)prop:ion:ic acid such that said pharmaceutical composition, when dis:~olved in water, affords an aqueou::> solution having a pH of from 7.5 to 9Ø
---It is clear to the man skilled in the art that the pH value of the aqueous solution is mainly due to the presence of arginine and, consequently, when arginine is in a molar excess, the addition of the auxiliary basic substance may not be necessary.
The choice of the optional pharmaceutically compatible auxiliary basic substance has also the purpose of improving the characteristic of the finished pharmaceutical formulation.
For example, the use of an inorganic base such as sodium or potas-si~ bicarbonate improves the theological characteristics of the mixture making it particularly suitable for the granulation and the compression.
The preparation of the pharmaceutical compositions object of the present invention is carried out by mixing according to usual tech-piques.
As already underlined, the compositions object of the present inven-tion allow to obtain a significant anticipation of the onset of the analgesic effect with respect to formulations on the market con-taining sodium Naproxen (example 1b).
20 A significant anticipation of the onset of the analgesic effect due to an increase of the maximum plasmatic concentration is obtained with the compositions of the present invention also when compared to compositions containing an equivalent amount of Naproxen in the form of arginine salt (example 17).
25 It is worth noting that the AUC (Area Under Curve) is substantially the same in the compositions o! the invention and in formulations containing sodium Naproxen present on the market or in the formula-tion containing only the arginine salt of Naproxen.
From a practical point of view, this means that the analgesic effect begins in advance (generally after some minutes) and lasts longer.
- 5 - z~zoo4s It is not yet clear the mechanism through which the compositions of the invention give rise to such a remarkable anticipation of the onset of the analgesic effect of Naproxen with respect to commercial formulations of sodium Naproxen.
This result does not appear to be dependent on either partial or total salification of Naproxen so that the dissolution step is hastened at gastric level because it is known that the sodium salt of Naproxen is much more soluble, and consequently allows a much higher dissolution speed at gastric level, than the arginine salt IA.Fini et al., Pharm. Acta Helv., ~Q(2), 58-62, t1985)].
Tentatively, it could be argued that arginine has an active role at gastric level in the step of absorption of Naproxen in the form of free acid.
On the other hand, the compositions object of the present invention behave differently at gastric level in comparison with compositions containing the salt of Naproxen with arginine.
In fact, the presence of a slight excess of arginine or of small amounts of a pharmaceutically compatible auxiliary basic substance, 20 booking to the invention, allows to significantly increase the percentage of dissolved active ingredient (Naproxen) in the stomach in comparison with the gastric dissolution of the simple arginine salt (Example 18).
For the preparation of pharmaceutical formulations such as tablets, 25 effervescent tablets, granulates, powders, syrups and solutions, further excipients suitable for the pharmaceutical use such as, for example, sweetening agents, flavoring agents, effervescent mixtures and coloring agents, can be added to the composition object of the present invention.
Preferably, the pharmaceutical formulations will contain an amount _ 6 _ 212UU4~
of Naproxen equal to 125, 250 or 500 mg.
The preparation of the pharmaceutical formulations is carried out according to conventional techniques of granulation, compression and dilution.
In order to better illustrate the present invention, without lim-iting it, the following examples are now given.
Example 1 A mixture having the following composition Naproxen 500 g L-Arginine 416 g was prepared by mixing the two powders, separately sieved, in a mixer up to homogeneity.
The aqueous solution obtained by dissolving 0.916 g of the resultant ~5 mixture in 200 ml of water has pH=8.2.
Example 2 A mixture having the following composition Naproxen 500 g L-Arginine 416 g 20 was prepared by wet granulation and the granulate was dried in a static oven.
Example 3 A mixture having the following composition Naproxen 500 g 25 L ~ginine 302.5 g Sodium bicarbonate 73 g was prepared by mixing the three powders, separately sieved, in a mixer up to homogeneity.
Example 4 A mixture having the following composition _ 7 _ Naproxen 500 g L-Arginine 302.5 g Sodium bicarbonate 73 g was prepared by wet granulation and the granulate was dried in a static oven.
Example 5 A mixture having the following composition Naproxen 500 g L-Arginine 378.2 g Sodium bicarbonate 36.5 g was prepared by mixing the three powders, separately sieved, in a mixer up to homogeneity.
Example 6 ~5 A mixture having the following composition Naproxen 500 g L-Arginine 378.2 g Sodium bicarbonate 36.5 g was prepared by wet granulation and the granulate was dried in a 20 static oven.
Example 7 A mixture having the following composition Naproxen 500 g L-Arginine 560 g 25 was prepared by mixing the two powders, separately sieved, in a mixer up to homogeneity.
Alternatively, the mixture was granulated with water and the granu-late was dried in a static oven.
Example 8 A mixture having the following composition g _ U
Naproxen 500 g L-Arginine 378.2 g Sodium bicarbonate 54.7 g was prepared by wet granulation and the granulate was dried in a static oven.
Example 9 Saccharose 11939 sodiwn saccharin 120 g), aspartame g), 125 g) and mint flavour 1100 were added 'to a mixture prepared g) as described in Example 1.
The resultant mixture was shared into about 1000 sachets having the following composition t3 g in all) Naproxen 500 mg L-Arginine 416 mg Saccharose 1939 mg Sodium saccharin 20 mg Aspartame 25 mg Mint flavour 100 mg Example 10 20 ~ccharose 11939 sodium saccharin 120 g), aspartame g), 125 g) and mint flavour 1100 were added to a granulate prepared g) as described in Example 2.
The resultant mixture was shared into about 1000 paper-aluminum-polyethylene sachets having the following composition t3 g in all) 25 Naproxen 500 mg L-Arginine 416 mg Saccharose 1939 mg Sodium saccharin 20 mg Aspartame 25 mg Mint flavour 100 mg "~1 Alternatively, the mixture was shared into sachets containing 1.5 g or 0.?5 g, corresponding to 250 or 125 mg of Naproxen respectively.
Example 11 Microcrystalline cellulose (1t6 g), erosslinked polyvinylpyrrolidone (40 g) and magnesium stearate (8 g) were added to a granulate pre-pared as described in Example 2 and the resultant mixture was mixed up to homogeneity.
The mixture was compressed obtaining tablets (1.080 g) each con-taining 500 mg of Naproxen.
Alternatively, tablets weighing 0.540 g or 0.2?0 g each and con-taining 250 mg or 125 mg of Naproxen respectively were prepared.
Example 12 Sorbitol (1939 g), sodium saccharin (20 g), aspartame (60 g) and apricot tlavour (100 g) were added to a granulate prepared as de-scribed in Example 4.
The resultant mixture was shared into about 1000 paper-aluminum-polyethylene sachets at the rate of 3 g each.
Alternatively, the mixture was shared into sachets containing t.5 g 20 or 0.?5 g, corresponding to 250 or 125 mg of Naproxen respectively.
Example 13 Xylitol (900.3 g), sodium saccharin (25 g), aspartame (60 g> and anise flavour (100 g) were added to a mixture prepared as described in Example 6.
25 The resultant mixture was shared into about 1000 sachets having the following composition (2 g in all) Naproxen 500 mg L-Arginine 3?8.2 mg Sodium bicarbonate 36.5 mg Xylitol 900.3 mg -'~~- 2120048 Sodium saccharin 25 mg Aspartame 60 mg Anise flavour 100 mg Example 14 Sodium bicarbonate (800 g), sodium bitartrate (900 g), aspartame (40 g) and flavour (100 g) were added to a mixture prepared as described in Example 7.
The resultant mixture was compressed thus obtaining effervescent ~0 tablets (2.9 g) each containing 500 mg of Naproxen.
Alternatively, effervescent tablets weighing 1.45 g and each con-taining 250 mg of Naproxen were prepared.
Example 15 Sodium bicarbonate (800 g), sodium bitar:rate (900 g), saccharose ~r~ (1140 g) and flavour (100 g) were added to a mixture prepared as described in Example 7.
The resultant mixture was compressed obtaining effervescent tablets (4 g) each containing 500 mg of Naproxen.
Alternatively, effervescent tablets weighing 2 g or 1 g each and 20 containing 250 or 125 mg of Naproxen respectively were prepared.
Example 16 Aqueous solutions of a granulate prepared as described in Example t, containing 500 mg of Naproxen (treatment A) and of a sodium Naproxen commercial granulate, containing an equivalent aa~ount of active 25 lenient (treatment 8) were administered with a single dose by oral route to 12 subjects aged 32.514.05.
Each subject was apparently healthy, in particular as far as the renal, hepatic and hematopoietie functions were concerned.
Each subject received both preparations in two treatment sessions carried out two weeks apart, randomizing the order of r --.
- ~1 - 212004 administration.
During each session, basal samples of venous blood were drawn (in the morning) from each fasting subject, prior to oral administration . 5 of the preparation A or B. Further venous blood samples were also drawn 0.25, 0.50, 0.75, 1, 2, 3, 4, 8, 12 and 24 hours after treat-ment.
The analytical determination of Naproxen in the blood samples was carried out following the HPLC method hereinafter described.
~0 Chromatographie conditions:
- Apparatus Hp 1090 L equipped with a diode array detector HPLC column Hypersil ODS (5 yam, 100x2.1 mm) plus a precolwnn Hypersil OD8 (5 yam, 20x2.1 mm) Mobile phase: Na~HP0.~2H~0 0.03M (corrected to pH 3 with ~ 5 HaPO., : CHaOH=48: 52 ) - Flow: 0.5 ml/min - Column temperature: 40~C
Wavelength: 230.4 nm - Internal standard: a solution of Flurbiprofen in methanol (0.15 20 ~ml) The internal standard (0.2 ml) was added to plasma c0.1 ml). The whole was mixed and allowed to rest.
After 30 minutes, it was centrifuged at 4500 rounds per 10 minutes.
The clear surnatant (10 )r1) was injected into the HPLC system.
25 ~~er the described operative conditions, the retention times were as follows:
Naproxen=3.8 minutes Internal standard=8.7 minutes The obtained results are reported in the following table 1.
-v - ,2 - 2120048 Table 1 Mean plasma concentration of Naproxen after oral treatment with a solution of a pharmaceutical composition according to the present invention (treatment A) and after oral treatment with a commercial composition (treatment B).
Administered dose: 500 mg of active ingredient.
Plasma concentration of Naproxen (Ng/ml) ~0 Treatment Time after treatment (hours) 0.25 0.50 0.75 1 2 3 4 8 12 24 A 52.2 58.6 69.8 61.3 58.6 53.3 48.4 37.3 29.9 18.0 8 13.0 22.0 31.1 43.5 61.8 63.4 56.0 39.9 32.4 18.0 ~,5 ____________________________________________________________________ Pharmacokinetic parameters The following parameters were calculated and evaluated.
The area under curve of Naproxen plasma concentration from time "zero" to time 24 hours (AUCo~=AUCo~,",) expressed as yrg x h x 20 ml-' was calculated following the trapezoidal rule method (6ibaldi M. and Perrier D., "Pharmacokinetics", pages 293-296, Marcel Dekker Inc., New York 1975).
The area under curve of Naproxen plasma concentration from time "zero" to "infinite" (AllCeot) was calculated by the following formu 25 la AUCp.~,s4h + AUCz.,hi~.
wherein concentration at 24h AUC~4h'.e~-K, and K.= elimination constant The mean peak time expressed in hours was obtained by averaging the -, -13 _ 2120048 individual peak times.
The mean plasma concentration (Ca.") expressed as Ng/ml was calcu-lated by averaging the single peak values of the concentrations.
The lag time (hours) is the delay between the drug administration and the beginning of the absorption.
The values of the above specified pharmacokinetic parameters are reported in the following table 2.
Table 2 Pharmacokinetic parameters obtained after oral treatment with a solution of a pharmaceutical composition according to the invention (preparation A) and after oral treatment with a solution of a com-mercial composition (preparation B).
Administered dose: 500 mg of active ingredient.
__-_________________________________________________________________ Pharmacokinetie parameters Preparation A Preparation B
AUCeb~ (Ng x h x ml'') 812 835 AUCeet (!Ig X h x ml'') 1192 1041 Peak time (hours) 1.22 2.63 20.
c",~ ( Ng/ml ) 75 . 4 70. 6 Lag time (hours) 0.02 0.12 From the values reported in the table, it is evident that the compo sitions object of the present invention show a remarkable anticipa tion of the onset of the analgesic effect.
In Tact, the peak time and the lag time are significantly lower than those of a commercial composition of sodium Naproxen and the maxianm concentration (C"""~) is higher.
Example 17 Aqueous solutions of a granulate prepared as described in Example 6, containing 250 mg of Naproxen, arginine and sodium bicarbonate (treatment A> and of a granulate, containing an equivalent amount of active ingredient but in the form of arginine salt and without sodium bicarbonate (treatment e) were administered with a single dose by oral route to 6 healthy adult male volunteers in fasting conditions.
The solutions were administered in both cases according to an open, ~~ balanced, randomized, cross-over design. A wash out period of 7 days was observed between the treatments.
For each treatment, a basal sample of venous blood was drawn from each fasting subject, prior to oral administration of the prepara-tion A or B. Further venous blood samples were also drawn 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 30 and 36 hours after treatment.
The analytical determination of Naproxen in the blood samples was carried out by HPLC with U.V. detection.
Chromatographic conditions:
20 - PLC column Hypersil ODS (5 Nm, 100x2.1 mm) plus a precolumn Hypersil ODS (5 )rm, 20x2.1 mm) - Mobile phase: Na,HP04~2H~0 0.03M (corrected to pH 3 with Hap04:CH,OH=48:52) Flow: 0.5 ml/min 25 - Column temperature: 40~C
- Wavelength: 230.4 rm Internal standard: a solution of Flurbiprolen in methanol (0.15 mg/ml) The internal standard (0.2 ml) was added to plasma (0.1 ml). The whole was mixed and allowed to rest at 4~C.
3a - ,5 - 212UU48 After 30 minutes, it was centrifuged at 4500 rounds per 10 minutes.
The clear surnatant t0.1 ml) was injected into the HPLC system.
The obtained results are reported in the following table 3.
Table 3 Mean plasma concentration of Naproxen after oral treatment with a solution of a pharmaceutical composition according to the present invention ttreatment A) and after oral treatment with a composition containing only Naproxen in the form of arginine salt ttreatment B).
~0 Administered dose: 250 mg of active ingredient.
Naproxen plasma concentration tNg/ml) Time after treatment Treatment A Treatment B
(hours) 15 0~17 20.0 19.1 0.33 28.5 I 27.7 0.5 30.4 29.3 0.75 35.2 31.2 1 33.6 30.6 20 1~5 32.0 29.5 2 30.6 29.3 2.5 28.5 27.9 3 26.5 26.7 25.1 24.2 25 8 19.8 18.7 12 16.6 15.0 24 10~8 9.02 30 6.b5 6.31 36 3.60 4.20 zlzoo~s Pharmacokinetie parameters The following parameters were calculated and evaluated.
The area under curve of Naproxen plasma concentration from time "zero" to time 36 hours (AUCo~cAUCo--ash) expressed as ug x h x ml-' was calculated following the trapezoidal rule method (6ibaldi M. and Perrier D., "Pharmacokinetics", pages 293-296, Marcel Dekker Inc., New York 1975).
The area under curve of Naproxen plasma concentration from time "ze-ro" to "infinite" (AUCtot) was calculated by the following formula AUCo.-)asp, + AUCa.n-~~
wherein AUCa",~.= concentration at 36h K.
and K,= elimination constant The mean peak time expressed in hours was obtained by averaging the individual peak times.
The mean plasma concentration (C","~) expressed as yrg/ml was calcu-lated by averaging the single peak values of the concentrations.
The elimination half-life (t~) expressed in hours.
The values of the above specified pharmacokinetic parameters are reported in the following table 4.
Table 4 Pharmacokinetic parameters obtained after oral treatment with a solution of a pharmaceutical composition according to the invention (Preparation A) and after oral treatment with a solution of a compo sition containing only an equivalent amount of Naproxen in the form of arginine salt (preparation B).
Administered dose: 250 mg of active ingredient.
17 - 212004$
Pharmacokinetic parameters Preparation A Preparation B
AUCo,,o ty~g x h x m1_' ) 570 493 AUCtot tllg X h X m1_') 592 Peak time thours) 0.70 0.68 C~ (!ag/ml ) 36. 8 32. 4 t~ thours) ~ 1t.8 12.0 -________________________ ________________________________________ From the values reported in the table, it is evident that a composi-tion containing Naproxen, arginine and sodium bicarbonate in the ratio 1:1:0.2, according to the present invention, allows to obtain a maximum plasmatic concentration tC",.,~) meaningfully higher than ~5 that of a composition containing only the arginine salt of Naproxen.
This means that the analgesic effect of the composition of the present invention is greater and faster.
Example 18 Aqueous solutions tt00 ml) of a granulate prepared as described in ~~le 8, containing 200 mg of Naproxen, arginine and sodium bicar bonate tpreparation A) and of a granulate, containing an equivalent amount of active ingredient but in the form of arginine salt and without sodium bicarbonate tpreparation B) were treated with HCl 0.03N t30 ml) in order to simulate the acidity produced by the gastric juice.
The resultant suspensions were filtered through a Millipore filter membrane t0.8 um).
A quantitative determination of Naproxen present in the starting suspension, in the filtered solution and in the residue on the filter was carried out according to the following procedure.
_ ,8 _ 2120048 Apparatus: Hewlett-Packard liquid chromatograph (mod. 1050 and mod.
1090A) with U.V, detector at changeable wavelength.
Hewlett-Packard data recorder system (mod.3359A).
Column: Hewlett-Paekard RP-18, 200x4.6 rm, 5 yam.
Chromatographic conditions:
- mobile phase: tetrabutylammonium hydroxide 0.005M corrected to pH
7.0 with phosphoric acid:acetonitrile=62:38 flow: 2.0 ml/minutes - wavelength: 270 rm - eluent temperature: room temperature - column temperature: 40~C
- injected volume: 10 Nl - retention time: 2.2 minutes Preparation of the standard solution: Naproxen (200 mg) was dis-solved in the mobile phase up to volume (100~m1). M aliquot (5 ml), of the resultant solution was further diluted with the mobile phase up to volume c20 ml).
Preparation of the sample solution: the starting suspension and the 20 solution obtained after filtering the starting suspension were suit ably diluted with the mobile phase in order to obtain a theoretical Naproxen concentration as equal as possible to the concentration of the standard solution labout 0.5 mg/ml). The filtered residue was dissolved with the mobile phase up to a volume corresponding as much 25 as possible to the theoretical Naproxen concentration of the stan-dard solution.
The resulting detected amounts of Naproxen are reported in the following table 5.
Table 5 Amounts of Naproxen dissolved under simulated gastric conditions obtained from a granulate according to the invention (preparation A) and from a granulate containing an equivalent amount of active ingredient (preparation B).
Naproxen amount (x) Preparation A Preparation B
Starting suspension 100 Filtered solution 28.45 6.15 Filtered residue 71.55 93.85 From the above data it clearly results that, under conditions simulating the gastric acidity, the composition of the present invention allows the dissolution of a higher amount of active ingre-dient than a composition containing an equivalent amount of Naproxen in the form of arginine salt.
Claims (27)
1) A pharmaceutical composition, consisting essentially of:
a) (S)-2-(6-methoxy-2-naphthyl)propionic acid;
b) arginine; and c) a sufficient amount of a pharmaceutically acceptable auxiliary base, such that said pharmaceutical composition, when dissolved in water, affords an aqueous solution having a pH of from 7.5 to 9.0;
wherein:
i) said (S)-2-(6-methoxy-2-naphthyl)propionic acid and said arginine are present in relative amounts such that the molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid to arginine is from 1:0.8 to 1:1.5; and ii) said pharmaceutically acceptable auxiliary base and said (S)-2-(6-methoxy-2-naphthyl)propionic acid are present in relative amounts such that the molar ratio of pharmaceutically acceptable auxiliary base to (S)-2-(6-methoxy-2-naphthyl)propionic acid is from 0:1 to 0.7:1.
a) (S)-2-(6-methoxy-2-naphthyl)propionic acid;
b) arginine; and c) a sufficient amount of a pharmaceutically acceptable auxiliary base, such that said pharmaceutical composition, when dissolved in water, affords an aqueous solution having a pH of from 7.5 to 9.0;
wherein:
i) said (S)-2-(6-methoxy-2-naphthyl)propionic acid and said arginine are present in relative amounts such that the molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid to arginine is from 1:0.8 to 1:1.5; and ii) said pharmaceutically acceptable auxiliary base and said (S)-2-(6-methoxy-2-naphthyl)propionic acid are present in relative amounts such that the molar ratio of pharmaceutically acceptable auxiliary base to (S)-2-(6-methoxy-2-naphthyl)propionic acid is from 0:1 to 0.7:1.
2) The pharmaceutical composition of claim 1, wherein said arginine is L-arginine.
3) The pharmaceutical composition of claim 1, wherein said molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid to arginine is from 1:0.8 to 1:1.2.
4) The pharmaceutical composition of claim 1, wherein said molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid to arginine is 1:1.1.
5) The pharmaceutical composition of claim 1, wherein said pharmaceutically acceptable auxiliary base is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, disodium phosphate, dipotassium phosphate, sodium phosphate(Na3 PO4), potassium phosphate (K3 PO4), sodium citrate, potassium citrate, sodium tartrate, potassium tartrate, N-methylglucamine, D-glucamine, glucosamine, and mixtures thereof.
6) The pharmaceutical composition of claim 1, wherein said pharmaceutically acceptable auxiliary base is sodium bicarbonate or potassium bicarbonate.
7) The pharmaceutical composition of claim 1, wherein said molar ratio of pharmaceutically acceptable auxiliary base to (S)-2-(6-methoxy-2-naphthyl)propionic acid is from 0.2:1 to 0.4:1.
8) The pharmaceutical composition of claim 1, wherein said (S)-2-(6-methoxy-2-naphthyl)propionic acid is present in an amount of 125 mg.
9) The pharmaceutical composition of claim 1, wherein said (S)-2-(6-methoxy-2-naphthyl)propionic acid is present in an amount of 250 mg.
10) The pharmaceutical composition of claim 1, wherein said (S)-2-(6-methoxy-2-naphthyl)propionic acid is present in an amount of 500 mg.
11) The pharmaceutical composition of claim 1, further consisting essentially of a pharmaceutically acceptable excipient.
12) A pharmaceutical composition, consisting essentially of:
a) (S)-2-(6-methoxy-2-naphthyl)propionic acid;
b) arginine; and c) a sufficient amount of a pharmaceutically acceptable auxiliary base, such that said pharmaceutical composition, when dissolved in water, affords an aqueous solution having a pH of from 7.5 to 9.0;
wherein:
i) said (S)-2-(6-methoxy-2-naphthyl)propionic acid and said arginine are present in relative amounts such that the molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid to arginine is from 1:1 to 1:08; and ii) said pharmaceutically acceptable auxiliary base and said (S)-2-(6-methoxy-2-naphthyl)propionic acid are present in relative amounts such that the molar ratio of pharmaceutically acceptable auxiliary base to (S)-2-(6-methoxy-2-naphthyl)propionic acid is up to 0.7:1.
a) (S)-2-(6-methoxy-2-naphthyl)propionic acid;
b) arginine; and c) a sufficient amount of a pharmaceutically acceptable auxiliary base, such that said pharmaceutical composition, when dissolved in water, affords an aqueous solution having a pH of from 7.5 to 9.0;
wherein:
i) said (S)-2-(6-methoxy-2-naphthyl)propionic acid and said arginine are present in relative amounts such that the molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid to arginine is from 1:1 to 1:08; and ii) said pharmaceutically acceptable auxiliary base and said (S)-2-(6-methoxy-2-naphthyl)propionic acid are present in relative amounts such that the molar ratio of pharmaceutically acceptable auxiliary base to (S)-2-(6-methoxy-2-naphthyl)propionic acid is up to 0.7:1.
13) The pharmaceutical composition of claim 12, wherein said arginine is L-arginine.
14) The pharmaceutical composition of claim 12, wherein said pharmaceutically acceptable auxiliary base is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, disodium phosphate, dipotassium phosphate, sodium phosphate (Na3 PO4), potassium phosphate (K3 PO4), sodium citrate, potassium citrate, sodium tartrate, potassium tartrate, N-methylglucamine, D-glucamine, glucosamine, and mixtures thereof.
15) The pharmaceutical composition of claim 12, wherein said pharmaceutically acceptable auxiliary base is sodium bicarbonate or potassium bicarbonate.
16) The pharmaceutical composition of claim 12, wherein said molar ratio of pharmaceutically acceptable auxiliary base to (S)-2-(6-methoxy-2-naphthyl)propionic acid is from 0.2:1 to 0.4:1.
17) The pharmaceutical composition of claim 12, wherein said (S)-2-(6-methoxy-2-naphthyl)propionic acid is present in an amount of 125 mg.
18) The pharmaceutical composition of claim 12, wherein said (S)-2-(6-methoxy-2-naphthyl)propionic acid is present in an amount of 250 mg.
19) The pharmaceutical composition of claim 12, wherein said (S)-2-(6-methoxy-2-naphthyl)propionic acid is present in an amount of 500 mg.
20) The pharmaceutical composition of claim 12, further consisting essentially of a pharmaceutically acceptable excipient.
21) A pharmaceutical composition, consisting essentially of:
a) (S)-2-(6-methoxy-2-naphthyl)propionic acid; and b) arginine; and wherein:
i) said (S)-2-(6-methoxy-2-naphthyl)propionic acid and said arginine are present in relative amounts such that the molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid to arginine is at least 1:1.5 and said arginine is present in a sufficient molar exceeds over said (S)-2-(6-methoxy-2-naphthyl)propionic acid such that said pharmaceutical composition, when dissolved in water, affords an aqueous solution having a pH of from 7.5 to 9Ø
a) (S)-2-(6-methoxy-2-naphthyl)propionic acid; and b) arginine; and wherein:
i) said (S)-2-(6-methoxy-2-naphthyl)propionic acid and said arginine are present in relative amounts such that the molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid to arginine is at least 1:1.5 and said arginine is present in a sufficient molar exceeds over said (S)-2-(6-methoxy-2-naphthyl)propionic acid such that said pharmaceutical composition, when dissolved in water, affords an aqueous solution having a pH of from 7.5 to 9Ø
22) The pharmaceutical composition of claim 21, wherein said arginine is L-arginine.
23) The pharmaceutical composition of claim 21, wherein said molar ratio of (S)-2-(6-methoxy-2-naphthyl)propionic acid and arginine 1:1.1.
24) The pharmaceutical composition of claim 21, wherein said (S)-2-(6-methoxy-2-naphthyl)propionic acid is present in an amount of 125 mg.
25) The pharmaceutical composition of claim 21, wherein said (S)-2-(6-methoxy-2-naphthyl)propionic acid is present in an amount of 250 mg.
26) The pharmaceutical composition of claim 21, wherein said (S)-2-(6-methoxy-2-naphthyl)propionic acid is present in an amount of 500 mg.
27) The pharmaceutical composition of claim 21, further consisting essentially of a pharmaceutically acceptable excipient
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI930582A IT1272149B (en) | 1993-03-26 | 1993-03-26 | PHARMECEUTICAL COMPOSITION WITH ANALGESIC ACTIVITY |
| ITMI93A000582 | 1993-03-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2120048A1 CA2120048A1 (en) | 1994-09-27 |
| CA2120048C true CA2120048C (en) | 2004-01-27 |
Family
ID=11365508
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002120048A Expired - Fee Related CA2120048C (en) | 1993-03-26 | 1994-03-25 | Pharmaceutical composition having analgesic activity |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US5693312A (en) |
| JP (1) | JP3784843B2 (en) |
| BE (1) | BE1006718A3 (en) |
| CA (1) | CA2120048C (en) |
| CH (1) | CH686403A5 (en) |
| DE (1) | DE4410470A1 (en) |
| ES (1) | ES2109131B1 (en) |
| FR (1) | FR2703249B1 (en) |
| GB (1) | GB2276545B (en) |
| IT (1) | IT1272149B (en) |
| NL (1) | NL194390C (en) |
| SE (1) | SE517006C2 (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1301966B1 (en) | 1998-07-30 | 2000-07-20 | Zambon Spa | PHARMACEUTICAL COMPOSITIONS WITH ANALGESIC ACTIVITY |
| GB9924636D0 (en) * | 1999-10-18 | 1999-12-22 | Norgine Bv | Laxative preparation |
| US20030235629A1 (en) * | 1999-11-06 | 2003-12-25 | Janmarie Hornack | Dietary supplement containing alkaline electrolyte buffers |
| US6727286B2 (en) | 2001-11-02 | 2004-04-27 | Cumberland Pharmaceuticals Inc. | Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid |
| ES2253326T3 (en) * | 2001-11-02 | 2006-06-01 | Cumberland Pharmaceuticals Inc. | PHARMACEUTICAL ACID COMPOSITION 2- (4-ISOBUTILFENILO) PROPIONICO |
| BRPI0409127A (en) * | 2003-04-11 | 2006-03-28 | Pfizer | pharmaceutical combination comprising electriptan and sodium bicarbonate |
| US20050008699A1 (en) * | 2003-07-11 | 2005-01-13 | Fred Wehling | Effervescent glucosamine composition |
| PE20050445A1 (en) * | 2003-10-30 | 2005-06-18 | Bayer Consumer Care Ag | PRESENTATION FORM OF SODIUM NAPROXEN |
| US20050137262A1 (en) * | 2003-12-22 | 2005-06-23 | Hu Patrick C. | Highly concentrated pourable aqueous solutions of potassium ibuprofen, their preparation and their uses |
| ATE489077T1 (en) | 2006-09-28 | 2010-12-15 | Losan Pharma Gmbh | QUICKLY SOLUBLE FORMULATION OF NON-STEROIDAL ANTIPHLOGISTICS |
| US8828452B2 (en) * | 2007-05-22 | 2014-09-09 | Glenn Abrahmsohn | Method for pain control |
| CA2688863A1 (en) * | 2007-05-22 | 2008-11-27 | Glenn Abrahmsohn | Method for pain control |
| BRPI0800951A2 (en) * | 2008-04-09 | 2012-02-22 | Ems Sa | new taurine-derived compounds and their uses, their preparation process and pharmaceutical compositions containing them |
| JP7163015B2 (en) * | 2016-10-31 | 2022-10-31 | エスエス製薬株式会社 | oral solid composition |
| JP7163014B2 (en) * | 2016-10-31 | 2022-10-31 | エスエス製薬株式会社 | cold medicine |
| US11779541B2 (en) * | 2019-03-26 | 2023-10-10 | Johnson & Johnson Consumer Inc. | Immediate release dosage form |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3904682A (en) * | 1967-01-13 | 1975-09-09 | Syntex Corp | 2-(6{40 -Methoxy-2{40 -naphthyl)acetic acid |
| GB1497044A (en) * | 1974-03-07 | 1978-01-05 | Prodotti Antibiotici Spa | Salts of phenyl-alkanoic acids |
| US4344929A (en) * | 1980-04-25 | 1982-08-17 | Alza Corporation | Method of delivering drug with aid of effervescent activity generated in environment of use |
| US4587249A (en) * | 1982-07-22 | 1986-05-06 | Analgesic Associates | Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same |
| US5053396A (en) * | 1985-08-27 | 1991-10-01 | Blass David H | Therapeutic composition |
| IT1209667B (en) * | 1985-11-12 | 1989-08-30 | Zambon Spa | EFFEVERSCENT COMPOSITION ANALGESIC ADAPTITY. |
| IT1207994B (en) * | 1986-01-03 | 1989-06-01 | Therapicon Srl | WATER SOLUBLE SALTS OF ANTI-INFLAMMATORY AND ANALGESIC ADAPTITY COMPOUNDS, THEIR PREPARATION AND USE IN PHARMACEUTICAL COMPOSITIONS. |
| IT1197038B (en) * | 1986-08-01 | 1988-11-25 | Zambon Spa | PHARMACEUTICAL COMPOSITION WITH ANALGESIC ACTIVITY |
| SE463541B (en) * | 1987-08-31 | 1990-12-10 | Lejus Medical Ab | GRANULATED PRODUCT TRANSFER OF A MELT OF ITSELF AND THE PROCEDURE FOR ITS PREPARATION |
| GB8724763D0 (en) * | 1987-10-22 | 1987-11-25 | Aps Research Ltd | Sustained-release formulations |
| GB8813682D0 (en) * | 1988-06-09 | 1988-07-13 | Reckitt & Colmann Prod Ltd | Pharmaceutical compositions |
| KR920700613A (en) * | 1989-05-16 | 1992-08-10 | 지구르트 퓌터 | Pharmaceutical |
| US5262179A (en) * | 1989-09-13 | 1993-11-16 | Nicholas Kiwi Pty Ltd. | Non-effervescent ibuprofen compositions |
| HUT59656A (en) * | 1990-11-15 | 1992-06-29 | Puetter Medice Chem Pharm | Process for producing s/+/-phenyl-alkanoic acids and alpha-amino-acids containing complexes and pharmaceutical compositions containing them as active components |
| HUT59692A (en) * | 1990-11-15 | 1992-06-29 | Puetter Medice Chem Pharm | Process for producing complexes containing s/+/-phenyl-alkanoic acids and aminosugars |
-
1993
- 1993-03-26 IT ITMI930582A patent/IT1272149B/en active IP Right Grant
-
1994
- 1994-03-10 CH CH71194A patent/CH686403A5/en not_active IP Right Cessation
- 1994-03-15 FR FR9402977A patent/FR2703249B1/en not_active Expired - Fee Related
- 1994-03-17 BE BE9400290A patent/BE1006718A3/en not_active IP Right Cessation
- 1994-03-18 GB GB9405420A patent/GB2276545B/en not_active Expired - Fee Related
- 1994-03-25 CA CA002120048A patent/CA2120048C/en not_active Expired - Fee Related
- 1994-03-25 JP JP05571694A patent/JP3784843B2/en not_active Expired - Fee Related
- 1994-03-25 ES ES09400644A patent/ES2109131B1/en not_active Expired - Fee Related
- 1994-03-25 DE DE4410470A patent/DE4410470A1/en not_active Withdrawn
- 1994-03-25 SE SE9401005A patent/SE517006C2/en not_active IP Right Cessation
- 1994-03-25 NL NL9400481A patent/NL194390C/en not_active IP Right Cessation
-
1995
- 1995-06-06 US US08/470,143 patent/US5693312A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP3784843B2 (en) | 2006-06-14 |
| ITMI930582A1 (en) | 1994-09-26 |
| ES2109131A1 (en) | 1998-01-01 |
| BE1006718A3 (en) | 1994-11-22 |
| JPH06321777A (en) | 1994-11-22 |
| DE4410470A1 (en) | 1994-09-29 |
| GB2276545A (en) | 1994-10-05 |
| FR2703249A1 (en) | 1994-10-07 |
| IT1272149B (en) | 1997-06-11 |
| ITMI930582A0 (en) | 1993-03-26 |
| NL9400481A (en) | 1994-10-17 |
| SE517006C2 (en) | 2002-04-02 |
| SE9401005L (en) | 1994-09-27 |
| SE9401005D0 (en) | 1994-03-25 |
| GB9405420D0 (en) | 1994-05-04 |
| US5693312A (en) | 1997-12-02 |
| FR2703249B1 (en) | 1995-07-13 |
| ES2109131B1 (en) | 1998-08-16 |
| NL194390B (en) | 2001-11-01 |
| CA2120048A1 (en) | 1994-09-27 |
| GB2276545B (en) | 1996-08-14 |
| CH686403A5 (en) | 1996-03-29 |
| NL194390C (en) | 2002-03-04 |
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| EEER | Examination request | ||
| MKLA | Lapsed |