CA2058817A1 - Pharmaceutical preparation for topical application - Google Patents
Pharmaceutical preparation for topical applicationInfo
- Publication number
- CA2058817A1 CA2058817A1 CA 2058817 CA2058817A CA2058817A1 CA 2058817 A1 CA2058817 A1 CA 2058817A1 CA 2058817 CA2058817 CA 2058817 CA 2058817 A CA2058817 A CA 2058817A CA 2058817 A1 CA2058817 A1 CA 2058817A1
- Authority
- CA
- Canada
- Prior art keywords
- weight
- pharmaceutical preparations
- preparations according
- pharmaceutically acceptable
- contain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 29
- 230000000699 topical effect Effects 0.000 title claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 18
- 239000003974 emollient agent Substances 0.000 claims abstract description 13
- 239000013543 active substance Substances 0.000 claims abstract description 12
- 238000004321 preservation Methods 0.000 claims abstract description 11
- 239000003542 rubefacient Substances 0.000 claims abstract description 10
- 239000000126 substance Substances 0.000 claims abstract description 10
- 206010061218 Inflammation Diseases 0.000 claims abstract description 7
- 241001465754 Metazoa Species 0.000 claims abstract description 7
- 230000004054 inflammatory process Effects 0.000 claims abstract description 7
- 208000002193 Pain Diseases 0.000 claims abstract description 5
- CLOMYZFHNHFSIQ-UHFFFAOYSA-N clonixin Chemical compound CC1=C(Cl)C=CC=C1NC1=NC=CC=C1C(O)=O CLOMYZFHNHFSIQ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001176 L-lysyl group Chemical class [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C([H])([H])C([H])([H])C(N([H])[H])([H])[H] 0.000 claims abstract 4
- 239000006071 cream Substances 0.000 claims description 21
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 20
- 239000000499 gel Substances 0.000 claims description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 11
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical group CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 8
- -1 ketostearyl alcohol Chemical compound 0.000 claims description 8
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 7
- 229940041616 menthol Drugs 0.000 claims description 7
- 229920002125 Sokalan® Polymers 0.000 claims description 6
- 229960001631 carbomer Drugs 0.000 claims description 6
- 239000003607 modifier Substances 0.000 claims description 6
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical group CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 5
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 5
- 239000000872 buffer Substances 0.000 claims description 4
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims 2
- 239000000203 mixture Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229960003763 lysine clonixinate Drugs 0.000 description 6
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 5
- 239000004472 Lysine Substances 0.000 description 5
- CVNFYQCHAWFYQI-ZSCHJXSPSA-N clonixin lysine salt Chemical compound NCCCC[C@H](N)C(O)=O.CC1=C(Cl)C=CC=C1NC1=NC=CC=C1C(O)=O CVNFYQCHAWFYQI-ZSCHJXSPSA-N 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 235000018977 lysine Nutrition 0.000 description 5
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 229960001259 diclofenac Drugs 0.000 description 4
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical class OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 150000008545 L-lysines Chemical class 0.000 description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 description 3
- 239000002260 anti-inflammatory agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 description 3
- 229960003512 nicotinic acid Drugs 0.000 description 3
- 239000011664 nicotinic acid Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 241001535291 Analges Species 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 239000004902 Softening Agent Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 206010006811 Bursitis Diseases 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 206010023204 Joint dislocation Diseases 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000009519 contusion Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940116985 potassium lauryl sulfate Drugs 0.000 description 1
- ONQDVAFWWYYXHM-UHFFFAOYSA-M potassium lauryl sulfate Chemical compound [K+].CCCCCCCCCCCCOS([O-])(=O)=O ONQDVAFWWYYXHM-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- 238000007391 self-medication Methods 0.000 description 1
- 239000003860 topical agent Substances 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
A B S T R A C T
Pharmaceutical preparations containing 1 to 10 % by weight L-lysine salt of the 2-[(3-chloro-2-methylphenyl)amino]-3-pyridine carboxylic acid as active substance, 2 to 15 % by weight pharmaceutically acceptable emulsifiers, 2 to 20 %
by weight pharmaceutically acceptable emollients, 0.01 to 0.2 % by weight pharmaceutically acceptable preservation substances and the remainder water made up to 100 % by weight, and possibly 0.2 to 5 % by weight rubefacients, the water being correspondingly adjusted to a total of 100 % by weight, are suitable for topical application to relieve/alleviate pain and/or inflammation in humans and animals.
Pharmaceutical preparations containing 1 to 10 % by weight L-lysine salt of the 2-[(3-chloro-2-methylphenyl)amino]-3-pyridine carboxylic acid as active substance, 2 to 15 % by weight pharmaceutically acceptable emulsifiers, 2 to 20 %
by weight pharmaceutically acceptable emollients, 0.01 to 0.2 % by weight pharmaceutically acceptable preservation substances and the remainder water made up to 100 % by weight, and possibly 0.2 to 5 % by weight rubefacients, the water being correspondingly adjusted to a total of 100 % by weight, are suitable for topical application to relieve/alleviate pain and/or inflammation in humans and animals.
Description
ROEMMERS S.A.I.C.F.
. . ~
Pharmaceutical preparation for topical application The invention relate~ to pharmaceutical preparations for to~ical application which are preferably in the form of cream~ or gel~ and contain as active substance the L-ly~ine salt of the 2-[(3-chloro-2-methylphenyl~amino]-3-pyridine carboxylic acid of the formula ~I), hereinafter designated lysine clonixinate.
~ ~o~
~ ~, The pharmaceutical preparations are useful as topical analgesics and anti-inflammatory agents.
Drugs for oral and rectal administration and injectable solutions containing lysine clonixinate as active substance are known from the literature, for example from DE-PS
. . ~
Pharmaceutical preparation for topical application The invention relate~ to pharmaceutical preparations for to~ical application which are preferably in the form of cream~ or gel~ and contain as active substance the L-ly~ine salt of the 2-[(3-chloro-2-methylphenyl~amino]-3-pyridine carboxylic acid of the formula ~I), hereinafter designated lysine clonixinate.
~ ~o~
~ ~, The pharmaceutical preparations are useful as topical analgesics and anti-inflammatory agents.
Drugs for oral and rectal administration and injectable solutions containing lysine clonixinate as active substance are known from the literature, for example from DE-PS
2,253,134 and US-PS 3,973,027 and/or are available on the marXet. These drug~ develop a good analge~ic and anti-inflammatory actlvity. ~owever, there are cases in which they are no~t suitable or appli~able. Thus, when a person . . . : . ,~, .",, suffers from pain in a limited area of the body, for example after a blow or knock or due to a minor accident, in the case of contusions, di~tortions, luxations or arthritis, arthroRis, tenalgia, bursitis, myalgia and sport injuries, a localized topical application of a substance is generally regarded as the mos1; suitable way or the most suitable method for healing. It is also important not to apply an active substance more strongly or more weakly than i9 necessary to relieve or eliminate the pain or inflammation, and thus to avoid unnecessary secondary reactions or habituation to the active substances, ox dependence thereon, or obtaining only slight relief.
Finally, topical Eormulations such as creams or gel~ are less dangerous than tab]ets, in particular for self-medication, as is made possible by freely purchasable remedies. Thus, the making availahle of remedie~ for topical application which develop a mean analgesic and anti-inflammatory activity i8 an important problem in therapeutics~
Topical formulations containing the analgesic/anti-inflammatory agent as active substances are generally known from the literature. For example, NL-OS 8,100,917 (1982), CH-PS 651,4~4 (1985) and US-PS 9,407,824 (1983) relate to the amine salts of diclofenac. In DE-OS 2,935,776 (1981) as well various organic salts of anti-inflammatory medicaments are named which are suitable for topical application.
It has now been found that the L-lysine salt of 2-[(3-chloro-2-methylphenyl)aminol-3-pyridine carboxylic acid is very well suited to the preparation of pharmaceutical compositions for topical application and develops a very good effect on such an application.
~ ' ' ' i The ~ubject of the invention is therefore pharmaceutical preparations for topical application, preferably in the form of cream~ or gels, which with re~pect to the weight contain as active sub~tance 1 to 10 % by weight L-ly~ine salt of the 2- E ( 3-chloro-2-methylphenyl)amino]-3-pyridi.ne carboxylic acid and 2 to 15 % by weight pharmaceutically acceptable emulsifiers, 2 to 20 % by weight pharmaceutically acceptable emollients or ~oftening agents, 0.01 to 0.2 % by weight pharmaceutically acceptable preservation substance~ and water to make up 100 % by weight. Possibly, these agen~s may also contain 0.2 to 5 %
by weight ruhefacients and in the ca~e of creams 3 to 18 %
by weight pharmaceutically acceptable lubricant~ or in the case of gels a . 5 to 5 % by weight pH-value modifiers, the accompanying water always being adjusted to make up 100 %
by weight.
The pharmaceutical preparations according to the invention are distinguished by the following advantages:
-- local action, - rapid response~reaction due to rapid absorption, - low toxicity in uninjured or undama~ed tissues or organs.
According to an preferred embodiment the pharmaceutical preparations according to the invention for topical application contain 3 to 7 % by weight L-lysine salt of the 2-[(3-chloro-2-methylphenyl)amino]-3-pyridine carboxylic acid as active substance, 3 to 13 ~ by weight pharmaceutically accep~able emulsifiers, 3 to 10 ~ by weight pharmaceutically acceptable emollients, 0.02 to 0.1 % by weight pharmaceu~ically acceptable preservation substance~ and water as remainder up to 100 %. Possibly, 0.5 to 2 ~ by weight rubefacients may al~o be contained therein ~nd in the ca~e of crea~s 8 to 12 % by weight pharmaceutically acceptable lubricants and in the ca~e of ~.
.
I
- :. .
. . ;, . . ~ :
gels 1 to 3 % by weight modifiers of the pH-value, the accompan~ing water always being made up to a total of 100 %.
Advantageously, the emul~ifiers are selected from the group of the following substances: Glyceryl monostearate, glyceryl monostearate/polyoxyethylene stearate, ketostearyl alcohol/potassium lauryl sulfate ~emulsifier wax) and carbomer.
The softening agent or emollient is preferably selected from propylene glycol, glycerol, sorbite and isopropyl myristate.
As preservative agents or substance, methyl parabene, ethyl parabene and propyl parabene have proved expedient.
Menthol is advantageously used as rubefacient.
As already mentioned, the pharmaceutical preparations according to the invention are preferably brought into the galenic form of a cream or a gel.
If the pharmaceutical preparation according to the invention i5 to be formulated as cream, a~ emulsifier advantageously ketostearyl alcohol/lauryl sulfate ("emul~ifier wax") is used and the lubricants are selected from the group consisting of mineral oil, vaseline and fatty acids.
If the pharmaceutical preparations according to the invention are formulated as gel, advantageously carbomer is used as emulsifier and propylene glycol as softening agent, and the modifiers for the pH-value or buffer are selected from the group consisting of ~odium hydroxide, triethanol i . .
,~ ,'~ ' amine, trlmethamine, (tris~hy~roxymethyl)amino methane) and lysine.
For both creams and gels, isopropyl myristate is very well suited as ~oftening agent or emollient.
Of the preservation agents r methyl parabene and propyl parabene are preferred.
According to the invention, the L-lysine salt of the 2-1(3-chloro-2-methylphenyl)amino~-3-pyridine carboxylic acid can be used for the preparation of a pharmaceutical composition for topical application in order to relieve or at least alleviate pain and/or inflammations in humans and animals.
The following examples serve for more detailed explanation of the invention.
Example 1: Topical pharmaceutical preparation in the form of a cream without rubefacient.
A cream was made having the following composition:
- lysine clonixinate5.0 % by weight - isopropyl myristate9.0 % by weight - methyl parabene0.1 % by weight - emulsifier wax13.0 % by weight - mineral oil 10.0 % by wei~ht - water up to 100.0 % by weight The lubricant, emulsifier and the emollient are melted together at 65 to 70C. The active substance and the preservation agent are di3solved in water. The oily phase is added under constant stirring to the aqueous solution and after cooling to room temperature the desired cream is obtained.
,.
.... .. , , ,, i .- , . ..
. .
:
:
Example 2: Topical pharmaceutical preparation in the form of a cream with a rubefacient.
A cream of the following composition was prepared:
- lysine clonixinate5.0 % by weight - isopropyl myristate10.0 % by weight - methyl parabene0.1 % by weight - propyl parabene0.02 % by weight -"emulsifier wax"10.0 % by weight - vaseline10.0 ~ by weight - menthol 1.0 ~ by weight - water up to100.0 % by weight The lubricant and the emulsifier were melted together at 65-70C. The active substance and the preservation agent were dissolved in water. The oil pha~e is added under constant stirring to the aqueous solution.
Menthol was dissolved up to complete solution in the emollient.
After cooling to 40C the menthol solution in the emollient was added to the emulsion with constant stirring. After cooling to room temperature the desired cream was obtained.
Example 3: I'opical pharmaceutical preparation in the form of a gel without rubefacient.
A gel of the following composition was prepared:
- lysine clonixinate5.0 ~ by weight - carbomer 3.0 % by weight - propylene glycol5.0 ~ by weight - isopropyl myristate3.0 % by weight :
- .
- glycerol 3.0 % by weight - methyl parabene 0.1 % by weight - propyl paraben0 0.02 % by weight - - sodium hydroxide 1.5 % by weight - water up to 100.0 % by weight The active substance was diissolved in the mixture of propylene glycol and glycerol (solution A). The preserYation substances were dii~olved in water, the emulsifier wai~ dispersed in the aqueous solution and the buffer (pH-modifier) was added (dispersion B). The solution A was poured over the diispersion B and finally isopropyl myristate was added.
Example 4: Topical pharmaceutical preparation in the form of a gel wi~h rubefacient.
A gel of the following composition was prepared:
- lysine clonixinate 5.0 % by weight ~ carbomer 3.0 ~ by weight - propylene glycol 6.0 ~ by weight - isopropyl myristate 3.5 % by weight : - methyl parabene 0.1 % by weight - sodium hydroxide 2.0 % by weight - menthol 1.0 % by weight water up to 100.0 % by weight The active siubstance was dissolved in the propylene glycol and a third of the total amount of water (solution A). The : preservation substance was dis~olved in the r~maining water and the em~lsifier disperised in isaid aqueoui~ solution;
: thereupon, the buffer IpH-modifier~ was added (dispersion B). Th~ solution A was then poured into the diispersion B
whilst stirring and finally the menthol dissolved in , ~ , ~ , -.. . .. . . .
, isopropyl myri~tate added. The p~l-value was checked and adjusted to ~.2-8.g.
The following examples 5 and 6 will explain the advantageous use of the topical agent according to the invention compared with a conventional analge~ic/anti-inflammatory agent (diclofenac) both as regard~ the alleviation of inflammation~ and the absorption or takeup (through the ~kin).
Example 5 ~.. ~.. ~.. .........................
Anti-inflammatory effect. Paw edema induced by ....... _.. ..~ ~... .................................................................................................................
,,c"",a,rr,,a,~,,,h","e,,e,n,,,i,~n, Carragheenin in 1 % dosage was administered to Wistar rats of both sexes, body weight 175 200 g, that is 0.1 ml into the paw, corresponding to the procedure adopted by Winter et al. ~. Pharmacol. and Exp. Therap. 1949, 96; 99). 30 minutes previously, in each case one of the three groups of six test animals had been treated with the following compositions: lysine clonixinate cream corresponding to example 1, 5 %; 20 mg/kg; sodium diclofenac 5 %, 20 mg/kg;
excipient; in each case on an area of 20 cm3 on the back of the previously shaved animals. The inflammatory edema of the paw was measured with'a Ugo Basile plethysmometer 3 and 5 h after the carragheenin administration. The percentage alleviation or reduction of the inflammation wa~ determined with respect to the control group. The results are eum~arized in tùe following rable l.
i . ~ . .
-:. : : ' T,,a",,b",,,l""""e""""""""",1"
Percentage alleviation of the inflammation by the various compounds tested Pharmaceutical preparation % alleviation 3 h 5 h _ _ . _ .. _ . . . .. . . _ _ .
lysine clonixi:nate 50 48 ~qodium diclofenac 35 30 Exa,m~,le 6 'rran~dermal ab~orption. Com~arative tes$q between a,cre"am a,n,d, ",a""",g"e,,l" ",ea,c"h",",c",o",n"t,,a, i,n",i",n~,",,,ly"si,n,e"""c",l"on,i,xi,n,a,"te,l",,"",w"i,th, corres~ondln~ commercially avail,able productq As teqt animals, Flemish giant rabbits having a body weight of about 3.5 kg were used which had been shaved on their backs over an area of 10 cm3.
~ .
Each group contained three animals which had been treated ;~ with the following formulations and the~following doses:
~:, 1~
a~ Iysine clonixlnate, 5 % cream, 20 mg/kg, prepared according to examp]e l.
b) Lysine clonixinate, 5 % gel, 20 mg/kg, prepared according to example 3.
c) Sodium diclofenac, 5 % cream, 20 mg/kg.
d) Diclofenac diethyl ammonium salt, 5 % gel, 20 mg/kg.
Blood 3amples were taken from the central artery of the ear and the concentration~ of the various active ~ubstance~
determined.
The result~ are ~hown in the following Table 2 and in the diagram attached a~ Fig. l.
T a b 1 ~ 2 Concentration of lysine clonixinate and diclofenac in mg/ml in the various formulations and at various times _ __ Pharmaceuticai time h prep~ation _ _ ______ _ ~ ~ , _ 1 2 3 4 6 2~ 2~
~_..,. ,,., . _. _ .__ _ ~ __ _ ~ . - _ cloni- cream0 56 ~ l2 0 61 ~ 13 ~ 0 14 0 19 ~ 0 ~2 xina~e .- _ ~ _ _ ~ ~ . ~_ 0,54 0,6~ ~ 0,68 0,fiO 0,17 0,~
~l+ 0,I~ ~,1l 0,12 ~ ~,14 ~ 0,1Z + 0,03 ~ 2 __ ~ . . ___--_- _ _~ . ............ , _.
Dicl0,30 0,35 ~o42 0,50 0,30 0,1a 0,10 ~_ cream ~ 0~07 -~,08 ~ 0,Q8 ~ 0010 ~ 0,07 ~ 0,04 + 0,02 ~n~c _ ~ _ _ _ _ ~ _ Cel 0,36 0,40 0,45 V,4B 0,3t 0,16 0,09 ~ ~,a6 ~,08 0,0~ 0,~ ~ Q,0~ ~ 0,03 ~ 0,02 ~ _ ........... , ,- . __ _ _ ~ . ~ __ '. , ,
Finally, topical Eormulations such as creams or gel~ are less dangerous than tab]ets, in particular for self-medication, as is made possible by freely purchasable remedies. Thus, the making availahle of remedie~ for topical application which develop a mean analgesic and anti-inflammatory activity i8 an important problem in therapeutics~
Topical formulations containing the analgesic/anti-inflammatory agent as active substances are generally known from the literature. For example, NL-OS 8,100,917 (1982), CH-PS 651,4~4 (1985) and US-PS 9,407,824 (1983) relate to the amine salts of diclofenac. In DE-OS 2,935,776 (1981) as well various organic salts of anti-inflammatory medicaments are named which are suitable for topical application.
It has now been found that the L-lysine salt of 2-[(3-chloro-2-methylphenyl)aminol-3-pyridine carboxylic acid is very well suited to the preparation of pharmaceutical compositions for topical application and develops a very good effect on such an application.
~ ' ' ' i The ~ubject of the invention is therefore pharmaceutical preparations for topical application, preferably in the form of cream~ or gels, which with re~pect to the weight contain as active sub~tance 1 to 10 % by weight L-ly~ine salt of the 2- E ( 3-chloro-2-methylphenyl)amino]-3-pyridi.ne carboxylic acid and 2 to 15 % by weight pharmaceutically acceptable emulsifiers, 2 to 20 % by weight pharmaceutically acceptable emollients or ~oftening agents, 0.01 to 0.2 % by weight pharmaceutically acceptable preservation substance~ and water to make up 100 % by weight. Possibly, these agen~s may also contain 0.2 to 5 %
by weight ruhefacients and in the ca~e of creams 3 to 18 %
by weight pharmaceutically acceptable lubricant~ or in the case of gels a . 5 to 5 % by weight pH-value modifiers, the accompanying water always being adjusted to make up 100 %
by weight.
The pharmaceutical preparations according to the invention are distinguished by the following advantages:
-- local action, - rapid response~reaction due to rapid absorption, - low toxicity in uninjured or undama~ed tissues or organs.
According to an preferred embodiment the pharmaceutical preparations according to the invention for topical application contain 3 to 7 % by weight L-lysine salt of the 2-[(3-chloro-2-methylphenyl)amino]-3-pyridine carboxylic acid as active substance, 3 to 13 ~ by weight pharmaceutically accep~able emulsifiers, 3 to 10 ~ by weight pharmaceutically acceptable emollients, 0.02 to 0.1 % by weight pharmaceu~ically acceptable preservation substance~ and water as remainder up to 100 %. Possibly, 0.5 to 2 ~ by weight rubefacients may al~o be contained therein ~nd in the ca~e of crea~s 8 to 12 % by weight pharmaceutically acceptable lubricants and in the ca~e of ~.
.
I
- :. .
. . ;, . . ~ :
gels 1 to 3 % by weight modifiers of the pH-value, the accompan~ing water always being made up to a total of 100 %.
Advantageously, the emul~ifiers are selected from the group of the following substances: Glyceryl monostearate, glyceryl monostearate/polyoxyethylene stearate, ketostearyl alcohol/potassium lauryl sulfate ~emulsifier wax) and carbomer.
The softening agent or emollient is preferably selected from propylene glycol, glycerol, sorbite and isopropyl myristate.
As preservative agents or substance, methyl parabene, ethyl parabene and propyl parabene have proved expedient.
Menthol is advantageously used as rubefacient.
As already mentioned, the pharmaceutical preparations according to the invention are preferably brought into the galenic form of a cream or a gel.
If the pharmaceutical preparation according to the invention i5 to be formulated as cream, a~ emulsifier advantageously ketostearyl alcohol/lauryl sulfate ("emul~ifier wax") is used and the lubricants are selected from the group consisting of mineral oil, vaseline and fatty acids.
If the pharmaceutical preparations according to the invention are formulated as gel, advantageously carbomer is used as emulsifier and propylene glycol as softening agent, and the modifiers for the pH-value or buffer are selected from the group consisting of ~odium hydroxide, triethanol i . .
,~ ,'~ ' amine, trlmethamine, (tris~hy~roxymethyl)amino methane) and lysine.
For both creams and gels, isopropyl myristate is very well suited as ~oftening agent or emollient.
Of the preservation agents r methyl parabene and propyl parabene are preferred.
According to the invention, the L-lysine salt of the 2-1(3-chloro-2-methylphenyl)amino~-3-pyridine carboxylic acid can be used for the preparation of a pharmaceutical composition for topical application in order to relieve or at least alleviate pain and/or inflammations in humans and animals.
The following examples serve for more detailed explanation of the invention.
Example 1: Topical pharmaceutical preparation in the form of a cream without rubefacient.
A cream was made having the following composition:
- lysine clonixinate5.0 % by weight - isopropyl myristate9.0 % by weight - methyl parabene0.1 % by weight - emulsifier wax13.0 % by weight - mineral oil 10.0 % by wei~ht - water up to 100.0 % by weight The lubricant, emulsifier and the emollient are melted together at 65 to 70C. The active substance and the preservation agent are di3solved in water. The oily phase is added under constant stirring to the aqueous solution and after cooling to room temperature the desired cream is obtained.
,.
.... .. , , ,, i .- , . ..
. .
:
:
Example 2: Topical pharmaceutical preparation in the form of a cream with a rubefacient.
A cream of the following composition was prepared:
- lysine clonixinate5.0 % by weight - isopropyl myristate10.0 % by weight - methyl parabene0.1 % by weight - propyl parabene0.02 % by weight -"emulsifier wax"10.0 % by weight - vaseline10.0 ~ by weight - menthol 1.0 ~ by weight - water up to100.0 % by weight The lubricant and the emulsifier were melted together at 65-70C. The active substance and the preservation agent were dissolved in water. The oil pha~e is added under constant stirring to the aqueous solution.
Menthol was dissolved up to complete solution in the emollient.
After cooling to 40C the menthol solution in the emollient was added to the emulsion with constant stirring. After cooling to room temperature the desired cream was obtained.
Example 3: I'opical pharmaceutical preparation in the form of a gel without rubefacient.
A gel of the following composition was prepared:
- lysine clonixinate5.0 ~ by weight - carbomer 3.0 % by weight - propylene glycol5.0 ~ by weight - isopropyl myristate3.0 % by weight :
- .
- glycerol 3.0 % by weight - methyl parabene 0.1 % by weight - propyl paraben0 0.02 % by weight - - sodium hydroxide 1.5 % by weight - water up to 100.0 % by weight The active substance was diissolved in the mixture of propylene glycol and glycerol (solution A). The preserYation substances were dii~olved in water, the emulsifier wai~ dispersed in the aqueous solution and the buffer (pH-modifier) was added (dispersion B). The solution A was poured over the diispersion B and finally isopropyl myristate was added.
Example 4: Topical pharmaceutical preparation in the form of a gel wi~h rubefacient.
A gel of the following composition was prepared:
- lysine clonixinate 5.0 % by weight ~ carbomer 3.0 ~ by weight - propylene glycol 6.0 ~ by weight - isopropyl myristate 3.5 % by weight : - methyl parabene 0.1 % by weight - sodium hydroxide 2.0 % by weight - menthol 1.0 % by weight water up to 100.0 % by weight The active siubstance was dissolved in the propylene glycol and a third of the total amount of water (solution A). The : preservation substance was dis~olved in the r~maining water and the em~lsifier disperised in isaid aqueoui~ solution;
: thereupon, the buffer IpH-modifier~ was added (dispersion B). Th~ solution A was then poured into the diispersion B
whilst stirring and finally the menthol dissolved in , ~ , ~ , -.. . .. . . .
, isopropyl myri~tate added. The p~l-value was checked and adjusted to ~.2-8.g.
The following examples 5 and 6 will explain the advantageous use of the topical agent according to the invention compared with a conventional analge~ic/anti-inflammatory agent (diclofenac) both as regard~ the alleviation of inflammation~ and the absorption or takeup (through the ~kin).
Example 5 ~.. ~.. ~.. .........................
Anti-inflammatory effect. Paw edema induced by ....... _.. ..~ ~... .................................................................................................................
,,c"",a,rr,,a,~,,,h","e,,e,n,,,i,~n, Carragheenin in 1 % dosage was administered to Wistar rats of both sexes, body weight 175 200 g, that is 0.1 ml into the paw, corresponding to the procedure adopted by Winter et al. ~. Pharmacol. and Exp. Therap. 1949, 96; 99). 30 minutes previously, in each case one of the three groups of six test animals had been treated with the following compositions: lysine clonixinate cream corresponding to example 1, 5 %; 20 mg/kg; sodium diclofenac 5 %, 20 mg/kg;
excipient; in each case on an area of 20 cm3 on the back of the previously shaved animals. The inflammatory edema of the paw was measured with'a Ugo Basile plethysmometer 3 and 5 h after the carragheenin administration. The percentage alleviation or reduction of the inflammation wa~ determined with respect to the control group. The results are eum~arized in tùe following rable l.
i . ~ . .
-:. : : ' T,,a",,b",,,l""""e""""""""",1"
Percentage alleviation of the inflammation by the various compounds tested Pharmaceutical preparation % alleviation 3 h 5 h _ _ . _ .. _ . . . .. . . _ _ .
lysine clonixi:nate 50 48 ~qodium diclofenac 35 30 Exa,m~,le 6 'rran~dermal ab~orption. Com~arative tes$q between a,cre"am a,n,d, ",a""",g"e,,l" ",ea,c"h",",c",o",n"t,,a, i,n",i",n~,",,,ly"si,n,e"""c",l"on,i,xi,n,a,"te,l",,"",w"i,th, corres~ondln~ commercially avail,able productq As teqt animals, Flemish giant rabbits having a body weight of about 3.5 kg were used which had been shaved on their backs over an area of 10 cm3.
~ .
Each group contained three animals which had been treated ;~ with the following formulations and the~following doses:
~:, 1~
a~ Iysine clonixlnate, 5 % cream, 20 mg/kg, prepared according to examp]e l.
b) Lysine clonixinate, 5 % gel, 20 mg/kg, prepared according to example 3.
c) Sodium diclofenac, 5 % cream, 20 mg/kg.
d) Diclofenac diethyl ammonium salt, 5 % gel, 20 mg/kg.
Blood 3amples were taken from the central artery of the ear and the concentration~ of the various active ~ubstance~
determined.
The result~ are ~hown in the following Table 2 and in the diagram attached a~ Fig. l.
T a b 1 ~ 2 Concentration of lysine clonixinate and diclofenac in mg/ml in the various formulations and at various times _ __ Pharmaceuticai time h prep~ation _ _ ______ _ ~ ~ , _ 1 2 3 4 6 2~ 2~
~_..,. ,,., . _. _ .__ _ ~ __ _ ~ . - _ cloni- cream0 56 ~ l2 0 61 ~ 13 ~ 0 14 0 19 ~ 0 ~2 xina~e .- _ ~ _ _ ~ ~ . ~_ 0,54 0,6~ ~ 0,68 0,fiO 0,17 0,~
~l+ 0,I~ ~,1l 0,12 ~ ~,14 ~ 0,1Z + 0,03 ~ 2 __ ~ . . ___--_- _ _~ . ............ , _.
Dicl0,30 0,35 ~o42 0,50 0,30 0,1a 0,10 ~_ cream ~ 0~07 -~,08 ~ 0,Q8 ~ 0010 ~ 0,07 ~ 0,04 + 0,02 ~n~c _ ~ _ _ _ _ ~ _ Cel 0,36 0,40 0,45 V,4B 0,3t 0,16 0,09 ~ ~,a6 ~,08 0,0~ 0,~ ~ Q,0~ ~ 0,03 ~ 0,02 ~ _ ........... , ,- . __ _ _ ~ . ~ __ '. , ,
Claims (13)
1. Pharmaceutical preparations for topical application containing 1 to 10 % by weight L-lysine salt of the 2-[(3-chloro-2-methylphenyl)amino]-3-pyridine carboxylic acid as active substance, 2 to 15 % by weight pharmaceutically acceptable emulsifiers, 2 to 20 % by weight pharmaceutically acceptable emollients, 0.01 to 0.2 % by weight pharmaceutically acceptable preservation substances and the remainder water made up to 100 % by weight, and possibly 0.2 to 5 % by weight rubefacients, the water being correspondingly adjusted to a total of 100 % by weight.
2. Pharmaceutical preparations according to claim 1, characterized in that they are present in the form of a cream or gel and in the case of a cream additionally contain 3 to 18 % by weight pharmaceutically acceptable lubricants and in the case of a gel 0.5 to 5 % by weight pH-value modifiers (buffers), the water content being correspondingly adjusted to 100 % by weight.
3. Pharmaceutical preparations according to claim 1 or 2, characterized in that they contain 3 to 7 % by weight of the L-lysine salt of the 2-[(3-chloro-2-methylphenyl)amino]-3-pyridine carboxylic acid as active substance, 3 to 13 % by weight pharmaceutically acceptable emulsifiers, 3 to 10 % by weight pharmaceutically acceptable emollients, 0.02 to 0.1 % by weight pharmaceutical preservation substances, and the remainder water corresponding to 100 % by weight, possibly additionally 0.5 to 2 % by weight rubefacients, and in the case of creams 8 to 12 % by weight pharmaceutically acceptable lubricants and in the case of gels 1 to 3 % by weight pH-value modifiers, the proportion of accompanying water having been correspondingly adjusted to 100 %.
4. Pharmaceutical preparations according to any one of claims 1 to 3, characterized in that the emulsifier is selected from the group consisting of glyceryl monostearate, glyceryl monostearate/polyoxyethylene stearate, ketostearyl alcohol/
sodium lauryl sulfate ("emulsifier wax") and carbomer.
sodium lauryl sulfate ("emulsifier wax") and carbomer.
5. Pharmaceutical preparations according to any one of claims 1 to 4, characterized in that the emollient is selected from the group consisting of propylene glycol, glycerol, sorbite and isopropyl myristate.
6. Pharmaceutical preparations according to any one of claims 1 to 5, characterized in that the preservation agent is selected from the group consisting of methyl parabene, ethyl parabene and propyl parabene.
7. Pharmaceutical preparations according to any one of claims 1 to 6, characterized in that the rubefacient is menthol.
8. Pharmaceutical preparations according to any one of claims 2 to 7, characterized in that in the case of a cream they contain as emulsifier ketostearyl alcohol/sodium lauryl sulfate ("emulsifier wax").
9. Pharmaceutical preparations according to any one of claims 2 to 7, characterized in that in the case of a gel they contain carbomer as emulsifier.
10. Pharmaceutical preparations according to any one of claims 2 to 7 and 9, characterized in that they contain propylene glycol as emollient.
11. Pharmaceutical preparations according to any one of claims 2 to 10, characterized in that they contain isopropyl myristate as emollient.
12. Pharmaceutical preparations according to any one of claims 2 to 11, characterized in that they contain as preservation agent methyl parabene or propyl parabene.
13. Use of the L-lysine salt of the 2-[(3-chloro-2-methylphenyl)amino]-3-pyridine carboxylic acid for producing a pharmaceutical preparation for topical application which relieves/alleviates pain and/or inflammation in humans and animals.
;
;
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2058817 CA2058817A1 (en) | 1992-01-06 | 1992-01-06 | Pharmaceutical preparation for topical application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2058817 CA2058817A1 (en) | 1992-01-06 | 1992-01-06 | Pharmaceutical preparation for topical application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2058817A1 true CA2058817A1 (en) | 1993-07-07 |
Family
ID=4149034
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2058817 Abandoned CA2058817A1 (en) | 1992-01-06 | 1992-01-06 | Pharmaceutical preparation for topical application |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2058817A1 (en) |
-
1992
- 1992-01-06 CA CA 2058817 patent/CA2058817A1/en not_active Abandoned
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