US3629412A - Topical anti-inflammatory agent - Google Patents
Topical anti-inflammatory agent Download PDFInfo
- Publication number
- US3629412A US3629412A US859591A US3629412DA US3629412A US 3629412 A US3629412 A US 3629412A US 859591 A US859591 A US 859591A US 3629412D A US3629412D A US 3629412DA US 3629412 A US3629412 A US 3629412A
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- US
- United States
- Prior art keywords
- indomethacin
- methylsalicylate
- vehicle
- formulation
- topical
- 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.)
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
Definitions
- This invention is concerned with the topical application CHaO $011200 OH ⁇ N vCH3
- Indomethacins unique chemical structure differentiates it from the salicylates, corticosteroids, phenylbutazonelike compounds and colchicine. Unlike corticosteroids, it has no effect on pituitary or adrenal function and accordingly does not manifest the adverse side effects associated therewith.
- Oral administration of indomethacin has previously been reported as eflective in relieving pain, reducing fever and providing increased mobility in patients with inflammatory disorders including those of a rheumatic nature. When orally administered, the drug behaves as a systemic medicine and passes into the blood stream for general distribution in the body. As is the case with numerous other drugs, not everyone can satisfactorily accept this drug via the oral mode of administration, particularly over extended periods of therapy.
- Another object of this invention is to provide a carrier vehicle for the topical application of indomethacin whereby both local and systemic treatment of inflammation in mammals, including warm-blooded animals, such as mice, rats, horses, dogs, cats, etc., is achieved.
- indomethacin can be administered by applying topically a so lution of the drug in a methylsalicylate vehicle.
- topical application of the indomethacin-methylsalicylate formulation results in systemic treatment of inflammatory disorders. It is believed that the skin, in the presence of the topical formulation, acts 3,629,412 Patented Dec. 21, 1971 as a reservoir absorbing large amounts of the drug and releasing it slowly to other tissues. In this respect it is believed that the skin may act as a depot or reservoir for the indomethacin.
- methylsalicylate in addition to assisting in the solubilization of the drug, also enhances the absorption of indomethacin through the skin and accordingly permits the drug to be employed topically for inflammation of the tendons and joints, etc.
- Methylsalicylate has been widely used for many years, formerly under the name of oil of Wintergreen, for its counter-irritant action in various liniments. Methylsalicylate is produced synthetically or is obtained by maceration from the leaves of Gaultheria procumbeus or from the bark of Betula leuta. It has been reported that it is impolssible to distinguish between the synthetic and natural 01 Although the indomethacin may be advantageously applied topically to the skin with only methylsalicylate as the vehicle carrier, further inclusion in such formulation of non-toxic solvents, surfactants, emollients, etc., which are miscible with the methylsalicylate, may be employed.
- ethanol isopropyl alcohol, 2- 'octyl dodecanol, methyl pyrrolidone, glycerin, squalene, squalone, isopar M (hydroxyphenyldialiphatic amine), isopropyl myristrate, Ceraphyl 230 (diisopropyl adipate), acetulan (acetylated lanolin alcohols), polyethylene glycol, dimethylsulfoxide, diethyl phthalate, dimethylacetamide, polysorbate and diisopropyl adipate.
- Mixtures of the above ingredients may also be combined with the indomethacin-methylsalicylate combination.
- topical anaesthetics and analgesics may be combined with the indomethacin-methylsalicylate formulation.
- Representative members of this class that may be combined with the formulation include alkaloids such as cocaine, benzocaine, procaine, dibucaine, lidocaine, larocaine, cyclomethylcaine, naepine, etc.
- the nontoxic solvents, surfactants, etc., described above may also be included in this formulation.
- the concentration of the indomethacin in the methylsalicylate is not critical and will depend, as one skilled in the art will appreciate, upon a variety of factors including the age, body weight, the severity of the disorder being treated, etc.
- Topical application of a formulation containing from about .1 to 20 mg. of indomethacin per ml. of methylsalicylate vehicle is eflective in the treatment of inflammatory disorders with optimal effects being obtained with topical formulations containing from about 1 to about 10 mg. of indomethacin per ml. of methylsalicylate vehicle.
- the amount applied topically for either local treatment or a systemic response will vary depending upon a number of considerations.
- the art further appreciates that in many instances a relatively strong concentration or more frequent application of a weaker concentration may be equally effective. The objective in all cases is to obtain the maximum therapeutic response with minimum dosage.
- topical application daily of from about .5 mg./kg. to 20 mgs./kg. of the formulations described above (based upon the weight of indomethacin) are effective in the treatment of local and systemic inflammation.
- a substance such as ethanol or propanol
- surfactants and solubilization agents other than alcoholic materials may be used in this respect.
- this ingredient may be present in amounts ranging from about 50% to about based upon the total weight of the methylsalicylate-containing vehicle.
- concentration of topical analgesic or anaesthetic may vary from about 5% to about 20% based upon the total weight of the methylsalicylate containing vehicle.
- compositions containing indomethacin and methylsalicylate which include solubilizers, analgesics, anaesthetics, etc.:
- Percent Ethanol Methyl salicylate 10 Squalene 80 containing 2.0 mg. of Indomethacin per ml. of vehicle.
- Methyl salicylate 75 containing 20 mg. of Indomethacin and 10 mg. of benzocaine per ml. of vehicle.
- Percent Methyl salicylate l0 Ethanol containing 5.0 mg. of Indomethacin and 2.0 mg. of benzocaine per ml. of vehicle.
- the formulations of this invention may be prepared employing techniques well known in the art. For example, solutions of up to approximately 10% may be prepared by mixing the indomethacin in methylsalicylate and warming with tap water or in a water bath (approximately 60 C.). The additional ingredients to be included in the formulation may be combined therewith. In addition to solutions, the formulation of the invention may be administered topically as lotions, creams, ointments, salves, etc.
- the anti-inflammatory reaction to the topical administration of indomethacin in a methylsalicylate vehicle is nonspecific and occurs whether the injuring agent or stress be physical or chemical. Moreover, a favorable response is induced by the topical application of the indomethacin-methylsalicylate formulation not merely when the inflammatory reaction is localized but also when the condition is more extensive and the reaction is systemic. Accordingly, it should be noted that topical application of indomethacin in a methylsalicylate formulation provides not merely beneficial effects in the treatment of inflammatory disorders affecting the skin, but relief is obtained in the treatment of diseases involving inflammation of the muscles and joints.
- the indomethacin-methylsalicylate combination may be administered topically to achieve local and/or systemic effect.
- conventional orally administered anti-inflammatory agents which are either ineffected in relieving local disorders when applied topically; or if effective in the treatment of local inflammation, the topical administration of the drug is of negligible significance in the systemic treatment of conditions requiring such therapy.
- the literature reports that the normal, conventional local application of hydrocortisone ointment does not produce an effective systemic response.
- Systemic therapy is of course of preferred when the inflammation involvement is extensive. Topical application of the formulation of this invention provides the unexpected and unobvious advantages of both local and systemic therapy.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
METHODS AND COMPOSITIONS FOR TOPICAL APPLICATION OF AN INDOMETHACIN-METHYLSALICYLATE FORMULATION FOR THE TREATMENT OF INFALMMATION.
Description
United States Patent 3,629,412 TOPICAL ANTI-INFLAMMATORY AGENT Robert H. Silber, Westfield, Kane L. Kelley, Roselle, and Idamae G. Trenner, Westfield, N.J., assignors to Merck & Co., Inc., Rahway, NJ. No Drawing. Filed Sept. 19, 1969, Ser. No. 859,591 Int. Cl. A61k 27/00 US. Cl. 424-232 4 Claims ABSTRACT OF THE DISCLOSURE Methods and compositions for topical application of an 1ndomethacin-methylsalicylate formulation for the treatment of inflammation.
This invention is concerned with the topical application CHaO $011200 OH \N vCH3 Indomethacins unique chemical structure differentiates it from the salicylates, corticosteroids, phenylbutazonelike compounds and colchicine. Unlike corticosteroids, it has no effect on pituitary or adrenal function and accordingly does not manifest the adverse side effects associated therewith. Oral administration of indomethacin has previously been reported as eflective in relieving pain, reducing fever and providing increased mobility in patients with inflammatory disorders including those of a rheumatic nature. When orally administered, the drug behaves as a systemic medicine and passes into the blood stream for general distribution in the body. As is the case with numerous other drugs, not everyone can satisfactorily accept this drug via the oral mode of administration, particularly over extended periods of therapy.
It is one object of this invention to provide a method of administering indomethacin which avoids the disadvantages of oral administration.
Another object of this invention is to provide a carrier vehicle for the topical application of indomethacin whereby both local and systemic treatment of inflammation in mammals, including warm-blooded animals, such as mice, rats, horses, dogs, cats, etc., is achieved.
In accordince with this invention it is found that indomethacin can be administered by applying topically a so lution of the drug in a methylsalicylate vehicle. In addition to providing highly effective relief with respect to local inflammation, topical application of the indomethacin-methylsalicylate formulation results in systemic treatment of inflammatory disorders. It is believed that the skin, in the presence of the topical formulation, acts 3,629,412 Patented Dec. 21, 1971 as a reservoir absorbing large amounts of the drug and releasing it slowly to other tissues. In this respect it is believed that the skin may act as a depot or reservoir for the indomethacin. It is theorized that the methylsalicylate, in addition to assisting in the solubilization of the drug, also enhances the absorption of indomethacin through the skin and accordingly permits the drug to be employed topically for inflammation of the tendons and joints, etc.
Methylsalicylate has been widely used for many years, formerly under the name of oil of Wintergreen, for its counter-irritant action in various liniments. Methylsalicylate is produced synthetically or is obtained by maceration from the leaves of Gaultheria procumbeus or from the bark of Betula leuta. It has been reported that it is impolssible to distinguish between the synthetic and natural 01 Although the indomethacin may be advantageously applied topically to the skin with only methylsalicylate as the vehicle carrier, further inclusion in such formulation of non-toxic solvents, surfactants, emollients, etc., which are miscible with the methylsalicylate, may be employed. Included among the materials suitable for this purpose are the following: ethanol, isopropyl alcohol, 2- 'octyl dodecanol, methyl pyrrolidone, glycerin, squalene, squalone, isopar M (hydroxyphenyldialiphatic amine), isopropyl myristrate, Ceraphyl 230 (diisopropyl adipate), acetulan (acetylated lanolin alcohols), polyethylene glycol, dimethylsulfoxide, diethyl phthalate, dimethylacetamide, polysorbate and diisopropyl adipate.
Mixtures of the above ingredients may also be combined with the indomethacin-methylsalicylate combination.
In addition, one may combine topical anaesthetics and analgesics with the indomethacin-methylsalicylate formulation. Representative members of this class that may be combined with the formulation include alkaloids such as cocaine, benzocaine, procaine, dibucaine, lidocaine, larocaine, cyclomethylcaine, naepine, etc. If desired, the nontoxic solvents, surfactants, etc., described above may also be included in this formulation.
The concentration of the indomethacin in the methylsalicylate is not critical and will depend, as one skilled in the art will appreciate, upon a variety of factors including the age, body weight, the severity of the disorder being treated, etc.
Topical application of a formulation containing from about .1 to 20 mg. of indomethacin per ml. of methylsalicylate vehicle is eflective in the treatment of inflammatory disorders with optimal effects being obtained with topical formulations containing from about 1 to about 10 mg. of indomethacin per ml. of methylsalicylate vehicle.
As indicated above, the amount applied topically for either local treatment or a systemic response will vary depending upon a number of considerations. In this regard, the art further appreciates that in many instances a relatively strong concentration or more frequent application of a weaker concentration may be equally effective. The objective in all cases is to obtain the maximum therapeutic response with minimum dosage.
For example, topical application daily of from about .5 mg./kg. to 20 mgs./kg. of the formulations described above (based upon the weight of indomethacin) are effective in the treatment of local and systemic inflammation.
As indicated above, it is highly desirable to add a substance such as ethanol or propanol to the indomethacinmethylsalicylate to assist in the solubilization of the drug. It will be appreciated that surfactants and solubilization agents other than alcoholic materials may be used in this respect. Where it is found desirable to add an agent of this nature, this ingredient may be present in amounts ranging from about 50% to about based upon the total weight of the methylsalicylate-containing vehicle. The concentration of topical analgesic or anaesthetic may vary from about 5% to about 20% based upon the total weight of the methylsalicylate containing vehicle.
In addition to compositions containing indomethacin and methylsalicylate, the following are representative examples of vehicle formulations which include solubilizers, analgesics, anaesthetics, etc.:
Percent Ethanol 54 Ceraphy1-230 36 Methyl salicylate 10 containing 2.5 mg. Indomethacin per ml. of vehicle.
Percent Ethanol 50 Methyl salicylate l Polysorbate 80 15 Ceraphyl-23O Water 20 containing 2.0 mg. of Indomethacin per ml. of vehicle.
Percent Ethanol Methyl salicylate 10 Squalene 80 containing 2.0 mg. of Indomethacin per ml. of vehicle.
Percent Ethanol 17 Squalene 68 Methyl salicylate containing 2.0 mg. of Indomethacin per ml. of vehicle Percent Ethanol 5 Methyl salicylate 5 'Squalane 90 containing 10.0 mg. of Indomethacin per ml. of vehicle.
Percent Ethanol 10 Methyl salicylate 30 Squalane 60 containing 2.5 mg. of Indomethacin per ml. of vehicle.
Percent Isopropyl alcohol 28.34 Methyl salicylate 1.66 Isopar M 70 containing 3.2 mg. of Indomethacin per ml. of vehicle.
Percent Isopropyl alcohol 25 Methyl salicylate 5 Isopar M 70 containing 6.2 mg. of Indomethacin per ml. of vehicle.
Percent Isopropyl Alcohol 15 Methyl Salicylate 15 Isopar M 70 containing 2.0 mg. of Indomethacin per ml. of vehicle.
Percent Ethanol 25 Methyl salicylate 75 containing 20 mg. of Indomethacin and 10 mg. of benzocaine per ml. of vehicle.
Percent Methyl salicylate l0 Ethanol containing 5.0 mg. of Indomethacin and 2.0 mg. of benzocaine per ml. of vehicle.
The formulations of this invention may be prepared employing techniques well known in the art. For example, solutions of up to approximately 10% may be prepared by mixing the indomethacin in methylsalicylate and warming with tap water or in a water bath (approximately 60 C.). The additional ingredients to be included in the formulation may be combined therewith. In addition to solutions, the formulation of the invention may be administered topically as lotions, creams, ointments, salves, etc.
The anti-inflammatory reaction to the topical administration of indomethacin in a methylsalicylate vehicle is nonspecific and occurs whether the injuring agent or stress be physical or chemical. Moreover, a favorable response is induced by the topical application of the indomethacin-methylsalicylate formulation not merely when the inflammatory reaction is localized but also when the condition is more extensive and the reaction is systemic. Accordingly, it should be noted that topical application of indomethacin in a methylsalicylate formulation provides not merely beneficial effects in the treatment of inflammatory disorders affecting the skin, but relief is obtained in the treatment of diseases involving inflammation of the muscles and joints.
As indicated previously, the indomethacin-methylsalicylate combination may be administered topically to achieve local and/or systemic effect. This is in sharp distinction with conventional orally administered anti-inflammatory agents which are either ineffected in relieving local disorders when applied topically; or if effective in the treatment of local inflammation, the topical administration of the drug is of negligible significance in the systemic treatment of conditions requiring such therapy. For example, the literature reports that the normal, conventional local application of hydrocortisone ointment does not produce an effective systemic response. Systemic therapy is of course of preferred when the inflammation involvement is extensive. Topical application of the formulation of this invention provides the unexpected and unobvious advantages of both local and systemic therapy.
What is claimed is:
1. The method of administering indomethacin to a patient afilicted with inflammation which comprises the topical application of a formulation comprising an effective amount of indomethacin in methylsalicylate.
2. The method of claim 1 wherein the formulation contains a solubilizer.
3. The method of claim 2 wherein the solubilizer is an alcohol.
4. The method of claim 3 which further contains an anaesthetic or analgesic.
Merck Index, 7th ed. (1960), p. 683. Chem. Absts., vol. 67 (1967), 81065H.
STANLEY I. FRIEDMAN, Primary Examiner US. Cl. X.R.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US85959169A | 1969-09-19 | 1969-09-19 |
Publications (1)
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US3629412A true US3629412A (en) | 1971-12-21 |
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US859591A Expired - Lifetime US3629412A (en) | 1969-09-19 | 1969-09-19 | Topical anti-inflammatory agent |
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5636411A (en) * | 1979-08-31 | 1981-04-09 | Sumitomo Chem Co Ltd | Liquid agent for external use |
EP0055029A2 (en) * | 1980-12-09 | 1982-06-30 | Kowa Company, Ltd. | Preparations for the treatment of dermatoses |
EP0072462A2 (en) * | 1981-08-14 | 1983-02-23 | Toko Yakuhin Industry Co., Ltd. | Pharmaceutical preparations |
DE3336047A1 (en) * | 1982-10-07 | 1984-04-12 | CIBA-GEIGY AG, 4002 Basel | NEW TOPICALLY APPLICABLE PHARMACEUTICAL COMPOSITIONS |
US4525347A (en) * | 1978-06-17 | 1985-06-25 | Kowa Company Limited | Antiinflammatory analgesic gelled ointment |
DE19641259A1 (en) * | 1996-10-07 | 1998-04-16 | Kade Pharma Fab Gmbh | Medicines based on diclofenac |
US20050032877A1 (en) * | 2003-08-07 | 2005-02-10 | Dittrich Wayne V. | Method and composition for treating burned skin |
NL2003419C2 (en) * | 2009-09-01 | 2011-03-02 | Shieldmark Zacco | Composition for tropical application, uses thereof, applicator device and kit of parts. |
-
1969
- 1969-09-19 US US859591A patent/US3629412A/en not_active Expired - Lifetime
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4525347A (en) * | 1978-06-17 | 1985-06-25 | Kowa Company Limited | Antiinflammatory analgesic gelled ointment |
JPS5636411A (en) * | 1979-08-31 | 1981-04-09 | Sumitomo Chem Co Ltd | Liquid agent for external use |
EP0055029A2 (en) * | 1980-12-09 | 1982-06-30 | Kowa Company, Ltd. | Preparations for the treatment of dermatoses |
EP0055029A3 (en) * | 1980-12-09 | 1982-09-15 | Kowa Company, Ltd. | Preparations for the treatment of dermatoses |
US4545992A (en) * | 1981-08-14 | 1985-10-08 | Toko Yakuhin Industry Co., Ltd. | Pharmaceutical preparations |
EP0072462A3 (en) * | 1981-08-14 | 1983-11-30 | Toko Yakuhin Industry Co., Ltd. | Pharmaceutical preparations |
EP0072462A2 (en) * | 1981-08-14 | 1983-02-23 | Toko Yakuhin Industry Co., Ltd. | Pharmaceutical preparations |
DE3336047A1 (en) * | 1982-10-07 | 1984-04-12 | CIBA-GEIGY AG, 4002 Basel | NEW TOPICALLY APPLICABLE PHARMACEUTICAL COMPOSITIONS |
FR2540726A1 (en) * | 1982-10-07 | 1984-08-17 | Ciba Geigy Ag | ANTI-INFLAMMATORY PHARMACEUTICAL COMPOSITIONS FOR TOPICAL USE, PREPARATION THEREOF AND USES THEREOF |
US4917886A (en) * | 1982-10-07 | 1990-04-17 | Ciba-Geigy Corporation | Novel topically administrable pharmaceutical compositions |
DE19641259A1 (en) * | 1996-10-07 | 1998-04-16 | Kade Pharma Fab Gmbh | Medicines based on diclofenac |
US20050032877A1 (en) * | 2003-08-07 | 2005-02-10 | Dittrich Wayne V. | Method and composition for treating burned skin |
US20050031555A1 (en) * | 2003-08-07 | 2005-02-10 | Wayne Dittrich | Method and composition for treating sunburned skin |
US7705032B2 (en) | 2003-08-07 | 2010-04-27 | Lil Brat Pharmaceuticals Of Marlette, Mi | Method and composition for treating burned skin |
US7714015B2 (en) | 2003-08-07 | 2010-05-11 | Lil Brat Pharmaceuticals Of Marlette, Mi | Method and composition for treating sunburned skin |
NL2003419C2 (en) * | 2009-09-01 | 2011-03-02 | Shieldmark Zacco | Composition for tropical application, uses thereof, applicator device and kit of parts. |
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