CA1208134A - Pranoprofen gelled ointment - Google Patents
Pranoprofen gelled ointmentInfo
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- CA1208134A CA1208134A CA000444225A CA444225A CA1208134A CA 1208134 A CA1208134 A CA 1208134A CA 000444225 A CA000444225 A CA 000444225A CA 444225 A CA444225 A CA 444225A CA 1208134 A CA1208134 A CA 1208134A
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Abstract
Pranoprofen Gelled Ointment ABSTRACT
An antiinflammatory and analgesic gelled ointment con-tains pranoprofen, at least one member selected from the group consisting of lower aliphatic alcohol, polyethylene glycol, methyl ethyl ketone and acetone, a gelling agent selected from the group consisting of carboxyvinyl polymer, hydroxyethyl cellulose, alginic acid and carboxymethyl cellulose, a water-soluble basic substance selected from the group consisting of ammonia, sodium hydroxide, potassium hydroxide, triethanolamine, diethanolamine, diisopropanolamine, triisopropanolamine and triethylamine, and water.
An antiinflammatory and analgesic gelled ointment con-tains pranoprofen, at least one member selected from the group consisting of lower aliphatic alcohol, polyethylene glycol, methyl ethyl ketone and acetone, a gelling agent selected from the group consisting of carboxyvinyl polymer, hydroxyethyl cellulose, alginic acid and carboxymethyl cellulose, a water-soluble basic substance selected from the group consisting of ammonia, sodium hydroxide, potassium hydroxide, triethanolamine, diethanolamine, diisopropanolamine, triisopropanolamine and triethylamine, and water.
Description
- 2 ~za~8~
1 This inven-tion relates -to an antiinflammatory and analgesic gelled ointment containing pranoprofen as an active ingredient.
Pranopro~en is a poten-t antiinflammatory, analgesic and antipyretic agent represented by the formula:
~ ~ ~ ~ CH-COOH
and described, for example, in U.S. Patent No. 3,931,205.
Pranoprofen is now sold by the present applicant in Japan in the form of capsules as antiinflammatory and analgesic agent for the treatment of chronic rheuma-tic arthritis, as analgesic and antipyretic agent for the treatment of acute upper air-way inflammation, and as antiinflammatory and analgesic agent for the treatment after tooth extraction.
The oral administration of pranoprofen may cause, though very rarely, adverse effects such as gastroenteric disorders as compared with indomethacin or other nonsteroid antiin-flammatory and analgesic agents.
In the treatment of local diseases such as arthritis, myalgia or pain a~ter trauma, the local route is more advan-tageous than the systemic route in effectiveness and inavoidance of unknown or unexpected adverse effects.
From these points of view, the development of pranoprofen ointments has been strongly desired.
The U.S. Patent No. 3,931,205 mentioned above describes that the pharmaceutical composition containing pranoprofen can take the Eorm of cream, ointment or jelly and that the
1 This inven-tion relates -to an antiinflammatory and analgesic gelled ointment containing pranoprofen as an active ingredient.
Pranopro~en is a poten-t antiinflammatory, analgesic and antipyretic agent represented by the formula:
~ ~ ~ ~ CH-COOH
and described, for example, in U.S. Patent No. 3,931,205.
Pranoprofen is now sold by the present applicant in Japan in the form of capsules as antiinflammatory and analgesic agent for the treatment of chronic rheuma-tic arthritis, as analgesic and antipyretic agent for the treatment of acute upper air-way inflammation, and as antiinflammatory and analgesic agent for the treatment after tooth extraction.
The oral administration of pranoprofen may cause, though very rarely, adverse effects such as gastroenteric disorders as compared with indomethacin or other nonsteroid antiin-flammatory and analgesic agents.
In the treatment of local diseases such as arthritis, myalgia or pain a~ter trauma, the local route is more advan-tageous than the systemic route in effectiveness and inavoidance of unknown or unexpected adverse effects.
From these points of view, the development of pranoprofen ointments has been strongly desired.
The U.S. Patent No. 3,931,205 mentioned above describes that the pharmaceutical composition containing pranoprofen can take the Eorm of cream, ointment or jelly and that the
- 3 12~1134 1 choice of carrier is determined by the preferred form of administration, the s-tability of the compounds and standard pharmaceutical practice. However, ointments prepared by mixing pranoprofen with the ointment bases such as vaseline, hydrophilic ointment base, ahsorptive oin-tment base and so on, which are usually used, exhibit insufficient pharmacological e~fects as shown in the following pharmacological experi.ment 1.
As a result of various investigations, the present in-ven-tors have found that gelled ointments prepared by mixing (a) 0.5-5% by weight of pranoprofen as an active ingredient with ointment bases comprising (b) 10-90% by weight oE at least one member selected from the group consisting of a mono-, bi- or -tri-hydric lower aliphat.ic alcohol, polyethylene glycol having an average molecular weight in the range of 200-1000, methyl ethyl ketone and acetone, (c) 0.1-5% by weight of a gelling agent selected from the group consisting o~ carboxyvinyl polymer, hydroxyethyl cellulose, alginic acid and carboxymethyl cellulose, (d) an adequate amount, which is sufficient to neutralize the ointments of the present invention, of a water-soluble basic substance selected from the group consisting ofammonia~ sodium hydroxide, potassium hydroxide, triethanolamine, diethanolamine, diisopropanolamine, triisopropanolamine and triethylamine, and (e) 10-90% by weight o~ water is more signi~icantly excellent than the indomethacin ointments used clinically iII the pharmaceutical effects and physical properties as ointments.
The mono-, bi- or tri-hydric lower aliphatic alcohol includes commonly used one in the ~ield o pharmaceu-tical
As a result of various investigations, the present in-ven-tors have found that gelled ointments prepared by mixing (a) 0.5-5% by weight of pranoprofen as an active ingredient with ointment bases comprising (b) 10-90% by weight oE at least one member selected from the group consisting of a mono-, bi- or -tri-hydric lower aliphat.ic alcohol, polyethylene glycol having an average molecular weight in the range of 200-1000, methyl ethyl ketone and acetone, (c) 0.1-5% by weight of a gelling agent selected from the group consisting o~ carboxyvinyl polymer, hydroxyethyl cellulose, alginic acid and carboxymethyl cellulose, (d) an adequate amount, which is sufficient to neutralize the ointments of the present invention, of a water-soluble basic substance selected from the group consisting ofammonia~ sodium hydroxide, potassium hydroxide, triethanolamine, diethanolamine, diisopropanolamine, triisopropanolamine and triethylamine, and (e) 10-90% by weight o~ water is more signi~icantly excellent than the indomethacin ointments used clinically iII the pharmaceutical effects and physical properties as ointments.
The mono-, bi- or tri-hydric lower aliphatic alcohol includes commonly used one in the ~ield o pharmaceu-tical
- 4 -~2~8~3~
1 practices such as, preferably, ethanol, isopropanol, propylene glycol or glycerol.
The preferable gelling agent is carboxyvinyl polymer.
The amount of the gelling agent may vary depending on the molecular weight, but it is generally in the range of 0.1-5%
by weight, preferably 0.5-2% by weight.
The preferable water-soluble basic substance is ammonia, potassium hydroxide, triethanolamine, diethanolamine, diisopropanolamine or triisopropanolamine, The wa-ter-soluble basic substance should be added sufficien-t amount to dissolve pranoprofen in the ointment base and to adjust the pH of the ointment base to 5-9, preferably 6-8. Water is purified water, preferably.
The effects of pranoprofen can be sufficiently expected by adding 0.5-5% by weight, especially 1-3~ by weight to the whole weight.
A percutaneous absorption enhancer such as isopropyl myristate, diisopropyl adipate, diethyl sebacate or ester of sebacic acid with propy]ene glycol, a stabilizer such as dibutylhydroxytoluene, a surfac-tant, a perfume or a preserva-tive may be added, if desired. Further, a local skin irritant such as nonylic acid vanillylamide may be added.
The ointments of the present invention can be prepared by dissolvin~ pranoprofen in at least one member selected from the group consisting oE the mono-, bi- or tri-hydric lower aliphatic alcohol, polyethylene glycol having an average melecular weight in the range of 200-1000, methyl ethyl ketone and acetone, a part of water and the wa-ter-soluble basic ~2'~B~3~ s , .
1 substance and then mixing the solution with the gelling agen-t previously swelled in the remaining water, but the order of mixing may be partly modified.
The p~esent invention will be better understood from the following pharmacological experiments and formulation examples, but they are not to be construed as limi-ting the present invention.
PharmacolocJical E~periment 1: ~ntiinf~a~matory action on ra-t carrageenin edema Male Donryu rats weighing about ].50 g, provided bv Clea Japan Inc., were divided into groups of 6-14 animals each.
After the foot volume of rat hind paw was measured by the water displacement method, the test ointment cantaining pranoprofen prepared in Formulation Example 2 was uniformly applied from the ankle of the hind paw to the tip of the toe (100 mg/paw). The ointment base was also applied to the control group.
The applied region was covered with a thin film (PARAFIL~1-k Amarican Can Co.) to prevent being licked by ra-t and subjected to the occulative dressing technique (O~). After 2 hours, PARAFILM was removed and the ointment was wiped off with a gauze immersed in warm water. To induce the edema, a 0.5%
methyl cellulose solution (5 ml/200 g) was administered orally and then immediately 0.05 rnl of a 1% carrageenin (PICNIN*A, Zushikagaku J,abora-tory, Inc.) in physiological saline was injected subcutaneously into the treated hind paw. Three hours af-ter the injection of carrageenin, the foot ~olume was measured to calculate the edema rate (%). The inhibitory *~r~rade MarJc 1~ .
- 6 -~2~34 1 rate (%) was determined as compared with the control group.
The results are s-tatis-tically analyzed by the one-way layou-t method.
From the results shown in Table 1, the ointment of the present invention is more potent than the ointment of pranoprofen mixed with ointment bases usually used.
Table 1 Ointmen-t Amount. of Number ¦ Edema rate (%) Inhibito base pranoprofen of rats (rnean i standard ra-te (%) (%) used error) _ The ointment of 0 14 1 65 0 1 3.2 the invention (Formulation _ 43.6 example 2) 1 14 36.6 + 3.1**
0 6 64.6 i 1.9 Vaseline* . ._ . 21.1 1 6 51.0 ~ ~.7 . _ _ _ Hydrophilic 51.3 i 5.6 24 6 ointment base 1 6 38.7 i 7.1 _ .
Polyethylene (5%) 0 6 57.6 ~ 6.9 Liquid paraffin . . _ 17.7 (95%) 1 6 47.4 -~ 6.5 _ _ _ Polyethylene (4 75%) 0 6 48.6 -t 3.3 (90.25"6) _ _ _ 23.4 Ester of fatty acid with glycerol . _ 37.2 -~ 4.1 **: p< 0.01 significant vs. control yroup *Trade Mark ,_ ..... .
9L2g~3~
l Pharmacological experiment 2: Comparison with clinically used lndomethacin ointment against carrageenin-induced foot edema The experiment was carried out in the similar manner as Experiment 1 excep-t that the inhibitory rate (%) was determined as compared with sham group treated with PARAFILM.
From the results shown in Table 2, the ointment of the present invention is significantly potent in comparison with the indomethacin ointment.
Table 2 Amount of Number Edema rate ~) Inhibitory Ointment pranoprofen of rats (mean ~ sta~dard rate (%) . . (%) used error) Ointment of 1 ¦ 14 36.6 i 3.1 44.2**,+
the invention Sham group 1 14 ! 65 6 -~ 4 1 Indomethacin 1 ¦ 14 46.9 ~ 1 3 28.5**
ointment . I
**: P< 0.01 significant vs. Sham group -~: P< 0.05 significant vs. indomethacin ointment Pharmacological experimen-t 3: Action on rat Eracture edema Male Donryu rats weighing about 130 g were divided into groups of 6 animals each. The -test ointment was appl.ied uniformly from -the ankle of -the hind leg to the tip o~ the toe (100 mg/paw). Then, the applied reyion was covered with PARAFILM and subjected to ODT. After 2 hours, the PARAFILM
was removed and the ointment was wiped oEf with a yauze immersed in warm water. Then~ a 0.5% me-thyl cellulose solution 1 (5 ml/200 g) was administered orally, and immedlately the hind leg of the rat was transversely fractured by being pinched with forceps. Three hours after the fracture, the foot volume was measured by the water displacement method. The rate of increase against the foot volume before the fracture was calculated, and the inhibitory rate (%) was determined as compared with the control group.
The inhibitory rate of the 1% pranoprofen gelled ointment of the present invention is 38%, whereas the rate of the indomethacin ointment is 31%.
Pharmacoloyical experiment 4: Action on rat increased vascular permeability induced by carrageenin.
Male Donryu rats weighing about 130 g were divided into groups of 7-8 animals each. The backs of the rats were shaved with an electric clipper and an electric shaver, and after 24 hours, 0.1 ml of 1% carrageenin in physiological saline was injected into the dorsal skin. Immedia-tely after the injection, 50 mg of the test ointment was applied. After 2.5 hours 1% Evans blue solu-tion in physiological saline (O.S ml/
100 g) was administered intravenously. After 30 minutes, the rat was bled to death and the dorsal skin was stripped off.
The region of the skin dyed blue was cut out and the amount of dye which had leaked (~g/site) was determined by ex-tracting the dye. The results are shown as an inhibitory rate in comparison with the control group~
In addition, to examine the duration oE action, carrageenin was injected 2~ hours after the test ointment ~as applied to another group and the same experiment was carried out. In this 9 ~ 34 1 experimen-t, the test ointment was removed at the 6th hour.
From the results summarlzed in Table 3, the 1% pranoprofen gelled ointment of the present invention exerts the same degree of inhibitory ac-tion as did the indomethacin ointment, and when carrageenin was given intradermally 24 hours after the application of the test ointmen-t, the gelled ointmen-t of the present invention inhibi-ted significantly increased vascular permeability, while the 1% indomethacin ointment did not show the si~nifican-t inhibitory action.
Table 3 Vascular permeability OintmentDose inhibition t~) .50 mg/site 3 hr. 24+3hr.
.
The ointment of the present invention 1.0% 62** 31*
~Formulation Example ll) Indomethacin oin~ment 1.0% 61** 24 . . .
*: P~ 0.05 significant vs. control group **: P< 0.01 significant vs. control group Test ointment was applied topically just before intraderma]
injection of carrageenin. Effects were measured 3 hours after the injection.
Pharmacological experiment 5: Therapeutic effects on rat adjuvant arthritis Male Lewis rats weighing 280-310 g were divided into groups of 8 animals each. The adjuvant was dead tubercle ~acilli suspended in liquid paraffin (0.5 mg/0.1 ml). It was - 1 o ~ 8~;~4 1 inoculated into the skin at the base of tail. Animals with arthritis were chosen on the 15th day, and the test ointment was applied to the site o~ the swelling on the right hind le~, 100 mg once a day for 7 consecutive days starting on the 15th day. It was removed at the 6th hour. The foot volume was measured by the water displacement method before the injection of adjuvant, just before the application of ointment on the 15th day, on the 3rd day after the first application (the 18th day) and on the 7th day (on the 22nd day).
The inhibitory rate was determined in comparison with the control group. The inhibitory rate of the lg~ pranoprofen gelled ointment of the present invention is 52%, whereas the rate of the 1% indomethacin ointment is 47%.
Pharmacological experiment 6: Action on prostaglandin E2 IPGE2) production in rat carrageenin air pouch Male Donryu rats weighing about 130 g were divided into groups of 6 animals each. The backs of the rats were shaved with an electric clipper and an electric shaver, and then an air pouch of 5 ml was made subcutaneously. After 24 hours, 8 ml of a 1% carrageenin solution in physiological saline was injected into the pouch. A given quantity of the ointment to be tested was immediately applied to the pouch surface, and the liquid in the pouch was recovered after 3 hours. From this solution, substances like PGE2 were extracted, bioassayed using a section of the gastric fundus, and the amount of PGE2-like substances was found by comparison with a standard preparation.
Pranoprofen gelled ointment of the present invention ~8~34L
l inhibited the production of PGE2 in carrageenin air pouches in a concen-tration-dependent way at 1-3%, showing stronger inhibition than the l~ indomethacin ointmen-t. The 1%
pranoprofen gelled ointment inhibited the production of PEG2 in carrageenin air pouches in a dose-dependent way when 50-200 mg was applied, showing stronger activit~ than the 1% indomethacin ointment.
Pharmacological experiment 7: Action on bradykinin-induced nervous-discharge acceleration in cats Cats weighing 2-3 kg were used regardless of sex. Under mixed anesthesia of laughing gas and halothane, the animals were ixed to a brain-orientation-fixing apparatus, then cut at the Ll or L2 level, and a splral specimen was prepared.
Next, a polyethylene canula for the arterial injection of bradykinin (BKl was inserted into a side branch of the femoral artery of the right hind leg and a similar canula for the intravenous injection of galamine into the median cephalic vein of the left foreleg.
After the completion~of the operation, the animal was immobilized with galamine, and the experiment was made with artificial respira-tion without anesthesia. From the dipole electrode fitted to the saphenous nerve, the action potential of pain nerve was induced, and the action of the test oin-tment was examined, taking as an index the acceleration of nervous discharge frec~uency 10-~0 seconds after the arterial injection of BK (20 g/0.2 ml~. The test ointment (1~5 g) was applied to the skin of the xight hind leg, and measurement was periodically made.
-- 12 ~ 3~
1 The 3% pranoprofen gel strongly inhibited the acceleration of nervous discharge after the arterial adminis-tration of BK, starting 90 minutes after its application.
Pharmacological experiment 8: Percutaneous absorption and excre-tion Male Donryu rats weighing 120-140 g were divided into groups of 4 animals each. The backs of the rats were shaved with an elec-tric clipper and an electric shaver. On the exposed part, aluminum foil (3 x 4 cm) to which 1% l~C-pranoprofen gelled ointment (60 mg3 had been applied was placed, sealed hermetically with an adhesive plaster, and then massaged from the above for about 1 minute.
After this application, the test ointment remaining was wiped off at a sek time with absorbent cotton mois-tened with 50% ethanol. The contained l~C was eluted with methanol and determined by conventional methods.
An adhesive plaster a li-ttle larger (3 x 4 cm) than the application area (2 x 3 cm) was applied after 24 hours.
After applying 60 mg of the 1% 14C-pranoprofen gelled ~0 ointment, the blood level rapidly rose and nearly reached a plateau (about 1.5 g/ml) in ahout 3 hours. After removing the unabsorbed ointment 16 hours after application) the blood level rapidly fell at the half-life of abou-t 5 hours.
Pranoprofen gelled ointment is absorbed rapidly by rat skin, with the absorption rate up to the six-th hour aEter application estimated to be 28.3-33%.
; Absorbed pranoprofen disappears from blood at the half life of about 5 hours. It is excreted mainly into urine and feces.
i.
-13 ~ 3~ ~
1 The results of pharmacological experimen-ts suggest that pranoproEen gelled oin-tment of the present invention rapidly permea-tes into the site of inflammation after topical application, inhibits the production of prostaglandin E2 at that sitel and has s-trong antiinflammatory and analgesic ac-tivities by antagonizing the pain-inducing effect of bradykinin. Moreover, pranoprofen gelled ointment is believed to have the characteristic of excellent penetration into deep regions with inflamma-tlon such as joints, and to have long-sustained action. These activities of pranoprofen gelled ointment are superior to those of indomethacin ointment and its safety is also grea-ter.
In conclusion, pranoprofen gelled ointment of the present invention is expected to be clinically useful.
Formulation Example 1 To 52 g of ethanol are added 1 g of pranoprofen and 2 g of triisopropanolamine. To the mixture are added 30 g o~ a
1 practices such as, preferably, ethanol, isopropanol, propylene glycol or glycerol.
The preferable gelling agent is carboxyvinyl polymer.
The amount of the gelling agent may vary depending on the molecular weight, but it is generally in the range of 0.1-5%
by weight, preferably 0.5-2% by weight.
The preferable water-soluble basic substance is ammonia, potassium hydroxide, triethanolamine, diethanolamine, diisopropanolamine or triisopropanolamine, The wa-ter-soluble basic substance should be added sufficien-t amount to dissolve pranoprofen in the ointment base and to adjust the pH of the ointment base to 5-9, preferably 6-8. Water is purified water, preferably.
The effects of pranoprofen can be sufficiently expected by adding 0.5-5% by weight, especially 1-3~ by weight to the whole weight.
A percutaneous absorption enhancer such as isopropyl myristate, diisopropyl adipate, diethyl sebacate or ester of sebacic acid with propy]ene glycol, a stabilizer such as dibutylhydroxytoluene, a surfac-tant, a perfume or a preserva-tive may be added, if desired. Further, a local skin irritant such as nonylic acid vanillylamide may be added.
The ointments of the present invention can be prepared by dissolvin~ pranoprofen in at least one member selected from the group consisting oE the mono-, bi- or tri-hydric lower aliphatic alcohol, polyethylene glycol having an average melecular weight in the range of 200-1000, methyl ethyl ketone and acetone, a part of water and the wa-ter-soluble basic ~2'~B~3~ s , .
1 substance and then mixing the solution with the gelling agen-t previously swelled in the remaining water, but the order of mixing may be partly modified.
The p~esent invention will be better understood from the following pharmacological experiments and formulation examples, but they are not to be construed as limi-ting the present invention.
PharmacolocJical E~periment 1: ~ntiinf~a~matory action on ra-t carrageenin edema Male Donryu rats weighing about ].50 g, provided bv Clea Japan Inc., were divided into groups of 6-14 animals each.
After the foot volume of rat hind paw was measured by the water displacement method, the test ointment cantaining pranoprofen prepared in Formulation Example 2 was uniformly applied from the ankle of the hind paw to the tip of the toe (100 mg/paw). The ointment base was also applied to the control group.
The applied region was covered with a thin film (PARAFIL~1-k Amarican Can Co.) to prevent being licked by ra-t and subjected to the occulative dressing technique (O~). After 2 hours, PARAFILM was removed and the ointment was wiped off with a gauze immersed in warm water. To induce the edema, a 0.5%
methyl cellulose solution (5 ml/200 g) was administered orally and then immediately 0.05 rnl of a 1% carrageenin (PICNIN*A, Zushikagaku J,abora-tory, Inc.) in physiological saline was injected subcutaneously into the treated hind paw. Three hours af-ter the injection of carrageenin, the foot ~olume was measured to calculate the edema rate (%). The inhibitory *~r~rade MarJc 1~ .
- 6 -~2~34 1 rate (%) was determined as compared with the control group.
The results are s-tatis-tically analyzed by the one-way layou-t method.
From the results shown in Table 1, the ointment of the present invention is more potent than the ointment of pranoprofen mixed with ointment bases usually used.
Table 1 Ointmen-t Amount. of Number ¦ Edema rate (%) Inhibito base pranoprofen of rats (rnean i standard ra-te (%) (%) used error) _ The ointment of 0 14 1 65 0 1 3.2 the invention (Formulation _ 43.6 example 2) 1 14 36.6 + 3.1**
0 6 64.6 i 1.9 Vaseline* . ._ . 21.1 1 6 51.0 ~ ~.7 . _ _ _ Hydrophilic 51.3 i 5.6 24 6 ointment base 1 6 38.7 i 7.1 _ .
Polyethylene (5%) 0 6 57.6 ~ 6.9 Liquid paraffin . . _ 17.7 (95%) 1 6 47.4 -~ 6.5 _ _ _ Polyethylene (4 75%) 0 6 48.6 -t 3.3 (90.25"6) _ _ _ 23.4 Ester of fatty acid with glycerol . _ 37.2 -~ 4.1 **: p< 0.01 significant vs. control yroup *Trade Mark ,_ ..... .
9L2g~3~
l Pharmacological experiment 2: Comparison with clinically used lndomethacin ointment against carrageenin-induced foot edema The experiment was carried out in the similar manner as Experiment 1 excep-t that the inhibitory rate (%) was determined as compared with sham group treated with PARAFILM.
From the results shown in Table 2, the ointment of the present invention is significantly potent in comparison with the indomethacin ointment.
Table 2 Amount of Number Edema rate ~) Inhibitory Ointment pranoprofen of rats (mean ~ sta~dard rate (%) . . (%) used error) Ointment of 1 ¦ 14 36.6 i 3.1 44.2**,+
the invention Sham group 1 14 ! 65 6 -~ 4 1 Indomethacin 1 ¦ 14 46.9 ~ 1 3 28.5**
ointment . I
**: P< 0.01 significant vs. Sham group -~: P< 0.05 significant vs. indomethacin ointment Pharmacological experimen-t 3: Action on rat Eracture edema Male Donryu rats weighing about 130 g were divided into groups of 6 animals each. The -test ointment was appl.ied uniformly from -the ankle of -the hind leg to the tip o~ the toe (100 mg/paw). Then, the applied reyion was covered with PARAFILM and subjected to ODT. After 2 hours, the PARAFILM
was removed and the ointment was wiped oEf with a yauze immersed in warm water. Then~ a 0.5% me-thyl cellulose solution 1 (5 ml/200 g) was administered orally, and immedlately the hind leg of the rat was transversely fractured by being pinched with forceps. Three hours after the fracture, the foot volume was measured by the water displacement method. The rate of increase against the foot volume before the fracture was calculated, and the inhibitory rate (%) was determined as compared with the control group.
The inhibitory rate of the 1% pranoprofen gelled ointment of the present invention is 38%, whereas the rate of the indomethacin ointment is 31%.
Pharmacoloyical experiment 4: Action on rat increased vascular permeability induced by carrageenin.
Male Donryu rats weighing about 130 g were divided into groups of 7-8 animals each. The backs of the rats were shaved with an electric clipper and an electric shaver, and after 24 hours, 0.1 ml of 1% carrageenin in physiological saline was injected into the dorsal skin. Immedia-tely after the injection, 50 mg of the test ointment was applied. After 2.5 hours 1% Evans blue solu-tion in physiological saline (O.S ml/
100 g) was administered intravenously. After 30 minutes, the rat was bled to death and the dorsal skin was stripped off.
The region of the skin dyed blue was cut out and the amount of dye which had leaked (~g/site) was determined by ex-tracting the dye. The results are shown as an inhibitory rate in comparison with the control group~
In addition, to examine the duration oE action, carrageenin was injected 2~ hours after the test ointment ~as applied to another group and the same experiment was carried out. In this 9 ~ 34 1 experimen-t, the test ointment was removed at the 6th hour.
From the results summarlzed in Table 3, the 1% pranoprofen gelled ointment of the present invention exerts the same degree of inhibitory ac-tion as did the indomethacin ointment, and when carrageenin was given intradermally 24 hours after the application of the test ointmen-t, the gelled ointmen-t of the present invention inhibi-ted significantly increased vascular permeability, while the 1% indomethacin ointment did not show the si~nifican-t inhibitory action.
Table 3 Vascular permeability OintmentDose inhibition t~) .50 mg/site 3 hr. 24+3hr.
.
The ointment of the present invention 1.0% 62** 31*
~Formulation Example ll) Indomethacin oin~ment 1.0% 61** 24 . . .
*: P~ 0.05 significant vs. control group **: P< 0.01 significant vs. control group Test ointment was applied topically just before intraderma]
injection of carrageenin. Effects were measured 3 hours after the injection.
Pharmacological experiment 5: Therapeutic effects on rat adjuvant arthritis Male Lewis rats weighing 280-310 g were divided into groups of 8 animals each. The adjuvant was dead tubercle ~acilli suspended in liquid paraffin (0.5 mg/0.1 ml). It was - 1 o ~ 8~;~4 1 inoculated into the skin at the base of tail. Animals with arthritis were chosen on the 15th day, and the test ointment was applied to the site o~ the swelling on the right hind le~, 100 mg once a day for 7 consecutive days starting on the 15th day. It was removed at the 6th hour. The foot volume was measured by the water displacement method before the injection of adjuvant, just before the application of ointment on the 15th day, on the 3rd day after the first application (the 18th day) and on the 7th day (on the 22nd day).
The inhibitory rate was determined in comparison with the control group. The inhibitory rate of the lg~ pranoprofen gelled ointment of the present invention is 52%, whereas the rate of the 1% indomethacin ointment is 47%.
Pharmacological experiment 6: Action on prostaglandin E2 IPGE2) production in rat carrageenin air pouch Male Donryu rats weighing about 130 g were divided into groups of 6 animals each. The backs of the rats were shaved with an electric clipper and an electric shaver, and then an air pouch of 5 ml was made subcutaneously. After 24 hours, 8 ml of a 1% carrageenin solution in physiological saline was injected into the pouch. A given quantity of the ointment to be tested was immediately applied to the pouch surface, and the liquid in the pouch was recovered after 3 hours. From this solution, substances like PGE2 were extracted, bioassayed using a section of the gastric fundus, and the amount of PGE2-like substances was found by comparison with a standard preparation.
Pranoprofen gelled ointment of the present invention ~8~34L
l inhibited the production of PGE2 in carrageenin air pouches in a concen-tration-dependent way at 1-3%, showing stronger inhibition than the l~ indomethacin ointmen-t. The 1%
pranoprofen gelled ointment inhibited the production of PEG2 in carrageenin air pouches in a dose-dependent way when 50-200 mg was applied, showing stronger activit~ than the 1% indomethacin ointment.
Pharmacological experiment 7: Action on bradykinin-induced nervous-discharge acceleration in cats Cats weighing 2-3 kg were used regardless of sex. Under mixed anesthesia of laughing gas and halothane, the animals were ixed to a brain-orientation-fixing apparatus, then cut at the Ll or L2 level, and a splral specimen was prepared.
Next, a polyethylene canula for the arterial injection of bradykinin (BKl was inserted into a side branch of the femoral artery of the right hind leg and a similar canula for the intravenous injection of galamine into the median cephalic vein of the left foreleg.
After the completion~of the operation, the animal was immobilized with galamine, and the experiment was made with artificial respira-tion without anesthesia. From the dipole electrode fitted to the saphenous nerve, the action potential of pain nerve was induced, and the action of the test oin-tment was examined, taking as an index the acceleration of nervous discharge frec~uency 10-~0 seconds after the arterial injection of BK (20 g/0.2 ml~. The test ointment (1~5 g) was applied to the skin of the xight hind leg, and measurement was periodically made.
-- 12 ~ 3~
1 The 3% pranoprofen gel strongly inhibited the acceleration of nervous discharge after the arterial adminis-tration of BK, starting 90 minutes after its application.
Pharmacological experiment 8: Percutaneous absorption and excre-tion Male Donryu rats weighing 120-140 g were divided into groups of 4 animals each. The backs of the rats were shaved with an elec-tric clipper and an electric shaver. On the exposed part, aluminum foil (3 x 4 cm) to which 1% l~C-pranoprofen gelled ointment (60 mg3 had been applied was placed, sealed hermetically with an adhesive plaster, and then massaged from the above for about 1 minute.
After this application, the test ointment remaining was wiped off at a sek time with absorbent cotton mois-tened with 50% ethanol. The contained l~C was eluted with methanol and determined by conventional methods.
An adhesive plaster a li-ttle larger (3 x 4 cm) than the application area (2 x 3 cm) was applied after 24 hours.
After applying 60 mg of the 1% 14C-pranoprofen gelled ~0 ointment, the blood level rapidly rose and nearly reached a plateau (about 1.5 g/ml) in ahout 3 hours. After removing the unabsorbed ointment 16 hours after application) the blood level rapidly fell at the half-life of abou-t 5 hours.
Pranoprofen gelled ointment is absorbed rapidly by rat skin, with the absorption rate up to the six-th hour aEter application estimated to be 28.3-33%.
; Absorbed pranoprofen disappears from blood at the half life of about 5 hours. It is excreted mainly into urine and feces.
i.
-13 ~ 3~ ~
1 The results of pharmacological experimen-ts suggest that pranoproEen gelled oin-tment of the present invention rapidly permea-tes into the site of inflammation after topical application, inhibits the production of prostaglandin E2 at that sitel and has s-trong antiinflammatory and analgesic ac-tivities by antagonizing the pain-inducing effect of bradykinin. Moreover, pranoprofen gelled ointment is believed to have the characteristic of excellent penetration into deep regions with inflamma-tlon such as joints, and to have long-sustained action. These activities of pranoprofen gelled ointment are superior to those of indomethacin ointment and its safety is also grea-ter.
In conclusion, pranoprofen gelled ointment of the present invention is expected to be clinically useful.
Formulation Example 1 To 52 g of ethanol are added 1 g of pranoprofen and 2 g of triisopropanolamine. To the mixture are added 30 g o~ a
5~ carboxyvinyl polymer solution ~HIVISWAK~ 104, Wako Pure Chemical Industries, Ltd.) and 15 g of puriried water.
The pH oE ointment thus obtained is 6.6 and the viscosity which is measured at 20C and 20 rpm by using a BH type viscometer (Tokyo Keiki Seisakusho KK.) provided ~-ith Roter No. 7, is 460 poises.
This ointment .is transparent, spreads well on the skin, gives an impression of refreshment, and is stable when kept at room -temperature.
Formulation Example 2 A solu-tion of 1 g o~ pranoprofen in a mixture of 2 g of diisopropanolamine, 8 g of propy]ene glycol, 2 g of diisopropyl *Trade ~lark ~.~
L2~8~l34 1 adipate and 37 g of ethanol is mixed with a solution of 2 g of carboxyvinyl polymer (CARBOPOL* 934, ~oodrich Chemical Co.) in 48 g of purified water to give an ointment with a pH o~
The pH oE ointment thus obtained is 6.6 and the viscosity which is measured at 20C and 20 rpm by using a BH type viscometer (Tokyo Keiki Seisakusho KK.) provided ~-ith Roter No. 7, is 460 poises.
This ointment .is transparent, spreads well on the skin, gives an impression of refreshment, and is stable when kept at room -temperature.
Formulation Example 2 A solu-tion of 1 g o~ pranoprofen in a mixture of 2 g of diisopropanolamine, 8 g of propy]ene glycol, 2 g of diisopropyl *Trade ~lark ~.~
L2~8~l34 1 adipate and 37 g of ethanol is mixed with a solution of 2 g of carboxyvinyl polymer (CARBOPOL* 934, ~oodrich Chemical Co.) in 48 g of purified water to give an ointment with a pH o~
6.4 and a viscosity of 980 poises.
Formulation Example 3 A solution of 1 g of pranoprofen in 14 g of 2N potassium hydroxide is mixed with 30 g of a 5% HIVISWAKO 10~ solution, and then with 12 g of ethanol and 43 g of purified water -to give an ointment with a pH of 8.0 and a viscosity of 670 poises.
Formulation Example 4 A solution of 3 g of pranoprofen and 5 g of triisopropanolamine in a mixture of polyethylene glycol 400 and 32 g of ethanol is mixed with 40 g of a 4~ HIVISWAKO 104 solution to give an ointmen-t with a pH of 7.2 and a viscosity of 250 poises.
Formulation Example 5 A solution of 3 g of pranoprofen and 5 g of triisopropanolamine in a mixture of 20 g of glycerol and 32 g of ethanol is mixed with 30 g of a 5% HIVISWAKO 104 solution and 0.1 g of dibu-tyl-hydroxy-toluene. To the mixture is added ~rifled water to make the whole quantity to 100 g.
The pH of the ointment -thus obtained is 6.7 and the viscosity is 610 poises.
Formulation Example 6 A solution of 2 g of pranoproEen and 4 g of triiso-propanolamine in 34 g of acetone is mixed with 20 g of a 5 HIVISWAKO 104 solution to give ointment with a pH of 7.3 and a viscosity of 310 poises.
Formulation Example 7 *Trade Mark ! \
, - 15 - ~2~8~3~
1 A solution of 0.5 g of pranoprofen and 2 g of tri-ethanolamine in a mixture of 20 g of methyl ethyl ketone and 17.5 g of ethanol is mixed with a 5% HIVISWAKo 104 solution and 40 g of purified water to give an ointment with a pH of
Formulation Example 3 A solution of 1 g of pranoprofen in 14 g of 2N potassium hydroxide is mixed with 30 g of a 5% HIVISWAKO 10~ solution, and then with 12 g of ethanol and 43 g of purified water -to give an ointment with a pH of 8.0 and a viscosity of 670 poises.
Formulation Example 4 A solution of 3 g of pranoprofen and 5 g of triisopropanolamine in a mixture of polyethylene glycol 400 and 32 g of ethanol is mixed with 40 g of a 4~ HIVISWAKO 104 solution to give an ointmen-t with a pH of 7.2 and a viscosity of 250 poises.
Formulation Example 5 A solution of 3 g of pranoprofen and 5 g of triisopropanolamine in a mixture of 20 g of glycerol and 32 g of ethanol is mixed with 30 g of a 5% HIVISWAKO 104 solution and 0.1 g of dibu-tyl-hydroxy-toluene. To the mixture is added ~rifled water to make the whole quantity to 100 g.
The pH of the ointment -thus obtained is 6.7 and the viscosity is 610 poises.
Formulation Example 6 A solution of 2 g of pranoproEen and 4 g of triiso-propanolamine in 34 g of acetone is mixed with 20 g of a 5 HIVISWAKO 104 solution to give ointment with a pH of 7.3 and a viscosity of 310 poises.
Formulation Example 7 *Trade Mark ! \
, - 15 - ~2~8~3~
1 A solution of 0.5 g of pranoprofen and 2 g of tri-ethanolamine in a mixture of 20 g of methyl ethyl ketone and 17.5 g of ethanol is mixed with a 5% HIVISWAKo 104 solution and 40 g of purified water to give an ointment with a pH of
7.3 and a viscosity of 220 poises.
Formulation Example 8 To a solution of 1 g of pranoprofen in 10 g of a 5%
ammonia solution are added 40 g of purified water and 20 g of isopropanol. The solution is mixed with 20 g of a 5%
CARBOPOL 934 solution to give an ointment with a pH of 8.7 and a viscosity of 164 poises.
Formulation Example 9 A solution of 0.5 g of pranoprofen and 1.5 g of di-ethanolamine in 46 g of ethanol and 30 g of propylene gl~col is mixed with a gelling agent comprising 1 g of HIVISWAKO
104 and 1 g of hydroxyethyl. cellulose in 20 g of purified water to give an ointment with a pH of 6.7 and a viscosity of 360 poises.
Formulation Example 10 A solution of 0.5 g of pranoprofen and 2 g of diiso-propanolamine in 20 g of ethanol is mixed with a mixture of 2 g of ~IIVISWAKO 104 in 10 g of purified water and ~0 g of glycerol.
To the mixture is added glycerol to make the whole quantity to 100 g. The pH of the ointment is 6.8 and the viscosity is 580 poises.
Formulation Example 11 A solution of 1 g of HIVISWAKO 104 .in a mi~ture of 56.5 g - 16 ~ 8~3~
1 of purified water and 30 g of e-thanol is mixed with 5 g of propylene glycol and 2 g of diethyl sebacate. After 1 g of pranoprofen is suspended in the mixture, 3.5 g of triiso-propanolamine is added to the suspension and then 1 g of polyethylene glycol 4000 is added to give an ointment with a pH of 7.6 and a viscosity of 400 poises.
Formulation Example 8 To a solution of 1 g of pranoprofen in 10 g of a 5%
ammonia solution are added 40 g of purified water and 20 g of isopropanol. The solution is mixed with 20 g of a 5%
CARBOPOL 934 solution to give an ointment with a pH of 8.7 and a viscosity of 164 poises.
Formulation Example 9 A solution of 0.5 g of pranoprofen and 1.5 g of di-ethanolamine in 46 g of ethanol and 30 g of propylene gl~col is mixed with a gelling agent comprising 1 g of HIVISWAKO
104 and 1 g of hydroxyethyl. cellulose in 20 g of purified water to give an ointment with a pH of 6.7 and a viscosity of 360 poises.
Formulation Example 10 A solution of 0.5 g of pranoprofen and 2 g of diiso-propanolamine in 20 g of ethanol is mixed with a mixture of 2 g of ~IIVISWAKO 104 in 10 g of purified water and ~0 g of glycerol.
To the mixture is added glycerol to make the whole quantity to 100 g. The pH of the ointment is 6.8 and the viscosity is 580 poises.
Formulation Example 11 A solution of 1 g of HIVISWAKO 104 .in a mi~ture of 56.5 g - 16 ~ 8~3~
1 of purified water and 30 g of e-thanol is mixed with 5 g of propylene glycol and 2 g of diethyl sebacate. After 1 g of pranoprofen is suspended in the mixture, 3.5 g of triiso-propanolamine is added to the suspension and then 1 g of polyethylene glycol 4000 is added to give an ointment with a pH of 7.6 and a viscosity of 400 poises.
Claims (5)
1. An antiinflammatory and analgesic gelled ointment containing 0.5-5% by weigh-t of pranoprofen, 10-90% by weight of at least one member selected from the group consisting of a mono-, bi- or tri-hydric lower aliphatic alcohol, polyethylene glycol having an average molecular weight in the range of 200-1000, methyl ethyl ketone and acetone, 0.1-5% by weight of a gelling agent selected from the group consisting of carboxyvinyl polymer, hydroxyethyl cellulose, alginic acid and carboxymethyl cellulose, an adequate amount of a water-soluble basic substance selected from the group consisting of ammonia, sodium hydroxide, potassium hydroxide, triethanolamine, diethanolamine, diisopropanolamine, tri-isopropanolamine and triethylamine, and 10-90% by weight of water.
2. The ointment of Claim 1 wherein the mono-, bi- or tri-hydric lower aliphatic alcohol is ethanol, isopropanol, propylene glycol or glycerol.
3. The ointment of Claim 1 wherein the gelling agent is carboxyvinyl polymer.
4. The ointment of Claim 1 wherein the water-soluble basic substance is ammonia, potassium hydroxide, triethanolamine, diethanolamine, diisopropanolamine or triisopropanolamine.
5. The ointment of Claim 1 which further contains a percutaneous absorption enhancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000444225A CA1208134A (en) | 1983-12-23 | 1983-12-23 | Pranoprofen gelled ointment |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000444225A CA1208134A (en) | 1983-12-23 | 1983-12-23 | Pranoprofen gelled ointment |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1208134A true CA1208134A (en) | 1986-07-22 |
Family
ID=4126814
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000444225A Expired CA1208134A (en) | 1983-12-23 | 1983-12-23 | Pranoprofen gelled ointment |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1208134A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019070134A3 (en) * | 2017-10-03 | 2020-01-02 | Aquafortus Technologies Limited | A salt recovery solution and processes of use thereof |
| US11826704B2 (en) | 2016-10-04 | 2023-11-28 | Aquafortus Technologies Limited | Thermo-responsive solution, and method of use therefor |
-
1983
- 1983-12-23 CA CA000444225A patent/CA1208134A/en not_active Expired
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11826704B2 (en) | 2016-10-04 | 2023-11-28 | Aquafortus Technologies Limited | Thermo-responsive solution, and method of use therefor |
| WO2019070134A3 (en) * | 2017-10-03 | 2020-01-02 | Aquafortus Technologies Limited | A salt recovery solution and processes of use thereof |
| US11987506B2 (en) | 2017-10-03 | 2024-05-21 | Aquafortus Technologies Limited | Salt recovery solution and processes of use thereof |
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