US 4,849,418 AGrant
Transdermally Absorbable Water-Containing Preparations of Arylpropionic Acid Derivatives and Process for Preparing Same
Issue Date:1989-07-18
•16 Claims
•1 Drawing Sheets
Abstract
Transdermally absorbable water-containing preparations of therapeutically active arylpropionic acid derivatives comprises 1 to 15% by weight of such active ingredient, from 10 to 40% by weight of polyoxyethylene polyoxypropylene copolymers, from 10 to 50% by weight of one or more physiologically acceptable organic solvents, optionally up to 1% by weight of preservatives, colorants and/or perfumes, and at least 10% by weight of water. From polyoxyethylene polyoxypropylene copolymers having a relative molecular weight of more than 6,000 there may also be prepared gels, if certain ratios of amounts are chosen.
Metadata
Assignee
- Dolorgiet Beteiligungs-GmbH
Inventors
- Manfred Lohner
- Hans H. Wagener
Application Information
Application Number:US 101532&
Filing Date:1987-11-16
Priority Date:1985-09-12
Art Unit:125
Classifications
IPC:
A61K 3119A61K 3161
Field of Search:
514570;163
Patent Drawings (1 sheets)
Description
Typical preparations according to the present invention and especially preparations obtained in the form of gels, are illustrated in detail hereinbelow.
Example 1
20.0 kg of ibuprofen
64.0 kg of isopropanol
40.0 kg of dimethylisosorbide
64.0 kg of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
211.7 kg of water
are thoroughly mixed for 10 minutes. The mixture is then heated at 85.degree. C. with stirring and under slightly elevated pressure (by 0.3 bar) and maintained at this temperature for 15 minutes. Then it is allowed to cool to 65.degree. C. and admixed with aroma materials (0.1 kg of lavender oil and 0.2 kg of neroli oil). The solution is cooled to room temperature with stirring. During the cooling phase the solution begins to gel at a temperature of about 45.degree. C. to form a clear gel. The gel contains 5% of ibuprofen.
Example 2
7.500 g of ibuprofen
15.925 g of isopropanol
10.000 g of dimethylisosorbide
16.000 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
50.500 g of water
0.025 g of lavender oil
0.050 g of neroli oil
are processed as described in Example 1. The gel contains 7.5% of ibuprofen.
Example 3
10.000 g of ibuprofen
15.925 g of isopropanol
12.000 g of dimethylisosorbide
18.000 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
44.000 g of water
0.025 g of lavender oil
0.050 g of neroli oil
are processed as described in Example 1. The gel contains 10% of ibuprofen.
Example 4
5.00 g of ibuprofen
16.00 g of isopropanol
10.00 g of glycerol
16.00 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
53.00 g of water
are thoroughly mixed for 10 minutes. The mixture is then heated at 85.degree. C. with stirring and under slightly elevated pressure (by 0.3 bar) and maintained at this temperature for 15 minutes. The solution is cooled to room temperature with stirring. During the cooling phase the solution begins to gel at a temperature of about 45.degree. C. to form a clear gel. The gel contains 5% of ibuprofen.
Example 5
5.00 g of ibuprofen
16.00 g of isopropanol
10.00 g of dimethylsulfoxide
16.00 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. 127, Wyandotte Chemicals Corp.)
53.00 g of water
are processed as described in Example 4. The gel contains 5% of ibuprofen.
Example 6
5.00 g of ibuprofen
17.90 g of isopropanol
17.90 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127. Wyandotte Chemicals Corp.)
59.20 g of water
are processed as described in Example 4. The gel contains 5% of ibuprofen.
Example 7
5.00 g of ibuprofen
31.00 g of dimethylisosorbide
15.50 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
48.50 g of water
are processed in Example 4. The gel contains 5% of ibuprofen.
Example 8
5.00 g of ibuprofen
35.00 g of dimethylsulfoxide
15.50 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
44.50 g of water
are processed in Example 4. The gel contains 5% of ibuprofen.
Example 9
5.00 g of ibuprofen
14.00 g of isopropanol
10.00 g of dimethylisosorbide
30.00 g of polyoxyethylene-polyoxypropylene copolymer 6500 (Pluronic.RTM. F 105, Wyandotte Chemicals Corp.)
41.00 g of water
are processed in Example 4. The gel contains 5% of ibuprofen.
Example 10
5.00 g of ibuprofen
18.46 g of ethanol
11.54 g of 1,2-propanediol
15.50 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
49.50 g of water
are processed as described in Example 4. The gel contains 5% of ibuprofen.
Example 11
5.00 g of ibuprofen
10.00 g of ethanol
18.00 g of isosorbide
15.50 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
51.50 g of water
are processed as described in Example 4. The gel contains 5% of ibuprofen.
Example 12
5.00 g of flurbiprofen
17.00 g of isopropanol
10.00 g of dimethylisosorbide
16.00 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
52.00 g of water
are processed as described in Example 4. The gel contains 5% of flurbiprofen.
Example 13
4.00 g of ketoprofen
15.00 g of isopropanol
7.50 g of dimethylisosorbide
23.50 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
50.00 g of water
are processed as described in Example 4. The gel contains 4% of ketoprofen.
Example 14
4.00 g of naproxen
12.00 g of isopropanol
30.00 g of dimethylsulfoxide
22.00 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
32.00 g of water
are processed as described in Example 4. The gel contains 4% of naproxen.
Example 15
4.00 g of naproxen
10.00 g of ethanol
30.00 g of dimethylsulfoxide
24.00 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
32.00 g of water
are processed as described in Example 4. The gel contains 4% of naproxen.
Example 16
5.00 g of ibuprofen
19.00 g of isopropanol
10.00 g of dimethylisosorbide
10.00 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
56.00 g of water
are stirred and heated at 50.degree. C., and stirring is continued until a clear solution has been formed. Then the composition is cooled to room temperature while the stirrer is operating. The lotion contains 5% of ibuprofen.
Example 17
15.00 g of ibuprofen
35.00 g of isopropanol
15.00 g of dimethylisosorbide
25.00 g of polyoxyethylene-polyoxypropylene copolymer 1900 (Pluronic.RTM. L 35, Wyandotte Chemicals Corp.)
10.00 g of water
are processed at 40.degree. C. as described in Example 16. The lotion contains 15% of ibuprofen.
Example 18
15.00 g of ibuprofen
30.00 g of isopropanol
15.00 g of dimethylisosorbide
25.00 g of polyoxyethylene-polyoxypropylene copolymer 1900 (Pluronic.RTM. L 35, Wyandotte Chemicals Corp.)
15.00 g of water
are processed at 40.degree. C. as described in Example 16. The lotion contains 15% of ibuprofen.
Example 19
5.00 g of ketoprofen
17.00 g of isopropanol
10.00 g of dimethylisosorbide
16.00 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
52.00 g of water
are processed as described in Example 16. The lotion contains 5% of ketoprofen.
Example 20
4.00 g of naproxen
17.00 g of isopropanol
15.00 g of dimethylisosorbide
30.00 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
34.00 g of water
are processed as described in Example 16. The Lotion contains 4% of naproxen.
Example 21
10.000 g of ibuprofen
18.000 g of isopropanol
10.000 g of dimethylisosorbide
2.000 g of polyoxypropylene-(15)-stearylether
19.000 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
40.925 g of water
0.025 g of lavender oil
0.050 g of neroli oil
are processed as described in Example 1. The gel contains 10% of ibuprofen.
Example 22
5.00 g of ibuprofen
16.00 g of isopropanol
10.00 g of dimethylisosorbide
1.00 g of polyoxyethylene-(4)-laurylether
16.00 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. 127, Wyandotte Chemicals Corp.)
52.00 g of water
are processed as described in Example 4. The gel contains 5% of ibuprofen.
Example 23
0.400 kg of ibuprofen
1.200 kg of isopropanol
0.800 kg of dimethylisosorbide
1.280 kg of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
4.234 kg of water
are thoroughly mixed for 10 minutes. The mixture is then heated at 85.degree. C. with stirring and under slightly elevated pressure (0.3 bar) and maintained at this temperature for 15 minutes. Then it is allowed to cool to 65.degree. C. and admixed with benzyl nicotinate (0.080 kg) and aroma materials (2 g of lavender oil and 4 g of neroli oil). The solution is cooled to room temperature with stirring. During the cooling phase the solution begins to gel at a temperature of about 45.degree. C. to form a clear gel. The gel contains 5% of ibuprofen.
Example 24
5.00 g of ibuprofen
16.00 g of isopropanol
10.00 g of dimethylisosorbide
16.00 g of polyoxyethylene-polyoxypropylene-copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
52.00 g of water
are thoroughly mixed for 10 minutes. The mixture is then heated at 85.degree. C. with stirring and under slightly elevated pressure (0.3 bar) and maintained at this temperature for 15 minutes. Then it is allowed to cool to 65.degree. C. and admixed with methyl salicylate and further treated as described in Example 23. The gel contains 5% of ibuprofen.
Example 25
75.000 g ibuprofen
195.000 g isopropanol
253.875 g 2,2,-dimethyl-4-hydroxymethyl-1,3-dioxolane
217.500 g polyoxyethylene-polyoxypropylene-copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
757.500 g water
are intensively mixed for 10 minutes. The mixture is then heated with stirring under light pressure (0.3 bar) to 85.degree. C. and left at that temperature for 15 minutes. The mixture is then cooled to 65.degree. C. and treated with aromatic substances (0.375 g lavender oil and 0.750 g neroli oil). The solution is cooled to room temperature with constant mechanical stirring. During the cooling phase, the solution then starts to gel and at a temperature of about 45.degree. C. forms a clear gel. The gel contains 5% ibuprofen.
Example 26
5.000 g ibuprofen
15.925 g isopropanol
10.000 g .alpha.-tetrahydrofurfuryl-107 -hydroxypoly(oxyethylene)
16.000 g polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic.RTM. F 127, Wyandotte Chemicals Corp.)
53.000 g water
mixed intensively for 10 minutes. The mixture is then heated to 85.degree. C. with stirring under light pressure (0.3 bar) and left at that temperature for 15 minutes. Then, it is cooled to 65.degree. C. and treated with aromatic substances (0.025 g lavender oil and 0.050 g neroli oil). The solution is cooled with constant stirring to room temperature.
During the cooling phase, the solution gels at a temperature of about 45.degree. C. to a clear gel. The gel contains 5% ibuprofen.
The preparations according to the invention are applied depending on the type of disease to be treated. Preferably, the inflamed or painful region is anointed 3 to 6 times per day with a strand of gel 5 to 10 cm in length or the corresponding amount of liquid liniment so that 100 to 500 mg of arylpropionic acid derivative are administered. As indications there are considered degenerative and inflammatory articular diseases, soft tissue rheumatism, lumbago, myogeloses and traumatic states following sport injuries and accidents.
The bioavailability of a gel according to the present invention (Example 1) was investigated in comparison to a commercially available cream according to German Pat. No. DE-PS 32 05 504 and a gel according to European Application EP-OS 0 127 840 (Example 4) in eight test persons. On the upper part of the back of the test persons a skin area 20 cm x 20 cm in size was color-marked. On this area an amount of the test preparations corresponding to 300 mg of ibuprofen was applied. The preparations were anointed by an assistant whose hand was protected by a rubber glove. Prior to anointing and 0.25, 0.5, 1, 2, 4 and 6 hours after the application blood samples were taken. From the blood the plasma was recovered by centrifuging after addition of ethylenediaminetetraacetic acid, wherein the ibuprofen was determined by a HPLC separation using an electrochemical detector. The average values of the analytical results are shown as a curve in FIG. 1.
The bioavailability of a drug substance from a preparation is understood to mean the velocity and extent with which said drug substance is passed into the circulating blood. (E. Mutschler, Arzneimittel-Wirkungen, Wissenschaftl. Verlagsgesellschaft mbH, Stuttgart 1981).
According to F.H. Dost (Grundlagen der Pharmakokinetik, Georg Thieme Verlag, Stuttgart 1968) the area included by the blood level curve and the time axis (AUC=area under the curve) conforms to the amount of substance in the organism. This permits the comparison of the bioavailability of one substance from various application forms. From the course of the plasma levels as shown in FIG. 1 the AUC values were calculated, and the relative bioavailability of ibuprofen was determined (Table 1).
From Table 1 it is apparent that with the gel preparation according to the present invention on the bioavailability of the active ingredient over a previously described gel preparation and a commercially available cream, respectively, has been improved by 145% and 38%, respectively.
Moreover, as is apparent from the comparison of the slopes of the plasma level curves of the two gel preparations, with the gel of the invention a more rapid supply of the active substance takes place than with the previously known gel. Thus, due to the more rapid release and higher bioavailability of the arylpropionic acid derivatives from the gel preparations according to the invention, better and more rapidly effective transdermally applicable medicaments are available than heretofore.
Claims
What is claimed is:
1. A transdermally absorbable water-containing analgesic, antirheumatic, antiinflammatory, gel preparation comprising from 5 to 10% of ibuprofen, from 10 to 40% by weight of polyoxyethylene polyoxypropylene copolymers, from 10 to 50% by weight of one or more physiologically acceptable organic solvents, optionally up to 1% by weight of preservatives, colorants and/or perfumes, and at least 10% by weight of water, said gel being free of neutralizing bases.
2. A preparation according to claim 1, which comprises from 15 to 32% by weight of polyoxyethylene polyoxypropylene copolymers, and from 17 to 44% by weight of one or more physiologically acceptable organic solvents.
3. A preparation according to claim 1, wherein the polyoxyethylene polyoxypropylene copolymers have relative molecular weights of from 1,000 to 13,000.
4. A preparation according to claim 1, characterized in that the polyoxyethylene polyoxypropylene copolymers have relative molecular weights of from 6,000 to 13,000.
5. A preparation according to claim 1, characterized in that as the physiologically acceptable organic solvents there are used dimethyl sulfoxide or mono-, di- or tri-hydroxy straight-chain, branched or cyclic alcohols having from 2 to 6 carbon atoms in the carbon backbone into which 0 to 2 oxygen atoms have been inserted, or polyoxyalkylene fatty alcohol ethers or mixtures thereof.
6. A preparation according to claim 5, characterized in that there are used as solvents ethanol, isopropanol, 1,2-propanediol, glycerol, isosorbide, dimethylisosorbide, polyoxyethylene-(4)-lauryl ether, polyoxypropylene-(15)-stearyl ether or mixtures thereof.
7. A preparation according to claim 1, characterized in that it further comprises up to 2% by weight of a blood circulation-promoting or rubefacient substance selected from the group consisting of benzyl nicotinate and a salicylate.
8. A preparation according to claim 7, characterized in that the blood circulation-promoting or rubefacient substance is benzyl nicotinate.
9. A preparation according to claim 7, characterized in that the blood circulation-promoting or rubefacient substance is a salicylate.
10. A process for making a transdermally absorbable water-containing antirheumatic, anti-inflammatory, analgesic gel characterized in that a mixture comprising from 5 to 10% by weight of ibuprofen as an active ingredient, from 10 to 40% by weight of polyoxyethylene polyoxypropylene copolymers, from 10 to 50% by weight of one or more physiologically acceptable organic solvents, optionally up to 1% by weight of preservatives, colorants and/or perfumes, and at least 10% by weight of water are heated with stirring at from 40.degree. C. to 90.degree. C. in the absence of neutralizing bases then cooled.
11. The process for making a gel according to claim 10, characterized in that from 15 to 32% by weight of polyoxyethylene polyoxypropylene copolymers and from 17 to 44% by weight of one or more physiologically acceptable organic solvents are heated at from 80.degree. C. to 90.degree. C. in the absence of neutralizing bases and then cooled.
12. The process according to claim 10, characterized in that, as the physiologically acceptable organic solvents there are used dimethyl sulfoxide or mono-, di- or trihydroxy straight-chain, branched or cyclic alcohols having from 2 to 6 carbon atoms and 0 to 2 oxygen atoms in the carbon backbone or polyoxyalkylene fatty alcohol ethers or mixtures thereof.
13. The process according to claim 12, characterized in that there are used as solvents ethanol, isopropanol, 1,2-propanediol, glycerol, isosorbide, dimethylisosorbide, polyoxyethylene-(4)-lauryl ether, polyoxypropylene-(15)-stearyl ether or mixtures thereof.
14. The process according to claim 10, characterized in that the mixture further comprises up to 2% by weight of a blood circulation-promoting or rubefacient substance selected from the group consisting of a benzyl nicotinate and a salicylate.
15. The process according to claim 14, characterized in that the blood circulation-promoting or rubefacient substance is benzyl nicotinate.
16. The process according to claim 14, characterized in that the blood circulation-promoting or rubefacient substance is a salicylate.
Patent Citations (9)
Non-Patent Literature (3)
- "Rote Liste 1985", Herausgeber: Bundesverband der Pharmazeutischen Industrie e. V., 6000 Frankfurt Germany, 9/9/1985.
- Chemical Abstracts, vol. 104, p. 392, May 13, 1986.
- Chemical Abstracts, vol. 10, No. 178, (C-355)[2234] 6/21/1986, European Search Report.