WO1993015716A1 - Levamisole or tetramisole based pour-on formulations - Google Patents
Levamisole or tetramisole based pour-on formulations Download PDFInfo
- Publication number
- WO1993015716A1 WO1993015716A1 PCT/EP1993/000274 EP9300274W WO9315716A1 WO 1993015716 A1 WO1993015716 A1 WO 1993015716A1 EP 9300274 W EP9300274 W EP 9300274W WO 9315716 A1 WO9315716 A1 WO 9315716A1
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- Prior art keywords
- pour
- levamisole
- fatty acid
- glycerin
- formulation according
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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
- A61K9/0017—Non-human animal skin, e.g. pour-on, spot-on
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
Definitions
- the present invention concerns particular levamisole or tetramisole containing pour- on formulations for use in warm-blooded animals.
- the pour-on method offers definite advantages, for example easy and rapid administration and better control of the dose administered.
- Levamisole or tetramisole based pour-on formulations are known, e.g. from US-4,070,476,
- the particular pour-on formulations subject of the present invention show an increased efficacy and little or no irritation.
- the present invention is concerned with pour-on formulations containing isopropanol, glycerin, a fatty acid or fatty acid ester, and as active ingredient an anthelmintically effective amount of levamisole or tetramisole or a pharmaceutically acceptable acid addition salt thereof.
- Levamisole as referred to above and hereinafter is the generic name of the laevo isomer of 2,3,5,6-tetrahydro-6-phenylimidazo[2,l-b]thiazole, tetramisole being the generic designation of the racemate. Both compounds are known from US-3,274,209 and US-3,463,786, and are widely used as anthelmintic agents.
- Levamisole and tetramisole are basic in nature and can form acid-addition salts upon treatment with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric, hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxy- acetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-l,2,3-propanetricarboxylic, ethanesulfonic, ethanesulfonic, benzene- sulfonic, 4-methylbenzenesulfonic, cyclohexa
- levamisole Since the anthelmintic activity of tetramisole is exerted essentially by the laevo isomer, levamisole will preferably be used.
- fatty acid or fatty acid ester refers to any of the naturally occuring fatty acids or esters and the simple synthetic modifications thereof, the latter for example referring to hydrogenated fatty acids or esters.
- Particular acids or esters comprise lauric acid or oleic acid; sorbitan -, glycerin-, sucrose-, glycol-, mono- or, where applicable, di-, tri- or poly-oleates or Cg. i2acid esters.
- Glycol refers to C2-4diols, in particular those with vicinal hydroxy groups, e.g. 1 ,2-ethanediol, 1,2-propanediol and 1,2-butanediol.
- Cg_i2acid esters refers to esters of alkyl carbonic acids having from 8 to 12 carbon atoms, alkyl referring to a hydrocarbon radical, saturated or unsaturated, in the latter instance having one, two or more double bonds.
- esters of Cg, Cio or Cj2 alkyl acids e.g. octanoic, decanoic or lauric acid.
- Preferred fatty acids or esters for use in the pour-on formulations of the present invention are lauric acid, oleic acid, sorbitan monolaurate, glycerin monolaurate, mono-, di-, tri- or polylaurates of sucrose, in particular sucrose monolaurate (e.g.
- aqueous mixture such as Grilloten LSE 65 Soft TM
- sorbitan mono-oleate sorbitan mono-oleate
- triglycerides in particular mixed Cg/Cjo alkanoic acid triglycerides (mixed glycerin decanoates or octanoates)
- C ⁇ -i2acid diesters of C2-4diols in particular propylene glycol dicaprylate/dicaprate (Lexol PG 865 TM).
- the amount of levamisole or tetramisole in the pour-on compositions according to the present invention can range from 5% to 30%, more preferably from 5% to 20% or from 7% to 15%, 10% being of particular interest. As used hereinbefore or hereinafter, all percentages are by weight based on the total weight of the pour-on composition.
- Isopropanol will be present in a quantity of from 30% to about 93%, in particular from about 40% to about 75%, more in particular from about 40% to about 70%, the upper limit evidently not being more than 100% minus the sum of the quantities of the other ingredients.
- Glycerin may be present in a quantity ranging from 1 % to 45% , in particular from 10% to 45%.
- the fatty acids or esters may be present in a quantity ranging from 1% to 30%, in particular from 2% to 25%, more in particular from 4% to 25%. Good results are obtained if the weight by weight ratio of glycerin to the fatty acid or ester is in the range of 10: 1 to 1 :2, and particularly if said ratio ranges from about 7:1 to about 1:1.
- the present formulations may comprise, besides the above-mentioned components, other components, e.g. to increase solubility or miscibility.
- the formulations may for example contain other solvents such as water, lower alkanols, e.g. ethanol or n. propanol, or ether alkanols, in particular partially etherified glycols or polyglycols, e.g. butyldioxitol and the like.
- Such other solvents may be present in a quantity ranging from 0 to 30%, in particular from 0 to 20%.
- the instant pour-on compositions can comprise from about 5 to about 15% water, in particular from about 8 to about 10% water.
- the formulations may contain an antioxidant to increase the stability of the active ingredient such as, for example, butylated hydroxy toluene (BHT), hydroquinone, ascorbyl palmitate and the like.
- BHT butylated hydroxy toluene
- hydroquinone ascorbyl palm
- the formulations of the present invention combine good stability, even for longer periods of time, with excellent efficacy and little, acceptably low or no skin-irritation. They show good skin penetration giving rise to high blood levels of the active ingredient, which blood levels are reached rapidly and remain high during the desired period of time for the active ingredient to exert its activity.
- the present pour-on formulations have good penetration properties in cattle- and sheep-skin without causing any appreciable skin-irritation, giving rise to sufficiently high blood levels of the active ingredient
- the formulations of the present invention are readily prepared by intimately mixing the active ingredient with the components that form the carrier, usually at room temperature.
- isopropanol may be mixed with glycerin and the fatty acid or ester, whereupon tetramisole or levamisole is added while stirring until complete dissolution.
- Preferred pour-on formulations for use on wool sheep such as merinos, because of their lack of causing even the least irritation comprise by weight based on the total weight of the composition :
- compositions comprise approximately :
- a preferred pour-on formulation for use on non-wool sheep comprises by weight based on the total weight of the composition : (a) 60% to 75% isopropanol;
- the most preferred such formulation comprises approximately :
- Example 1 675 g of isopropanol is weighed in a stainless steel or glass vessel to which is added
- Example 5 Following the procedure of example 1, a fifth formulation was made comprising :
- the flux of levamisole through sheep-skin is measured and compared with a reference pour-on formulation.
- Sheep skin obtained from anterior dorsal region of a freshly euthanized lamb is placed on a Franz pe ⁇ neation cell and allowed to thermally equilibrate at 36°C ⁇ 0.3°C for 0.5 hours.
- One hundred microliters of a test formulation was placed on the sheep skin and left exposed to air.
- the quantity of levamisole permeating through the tissue into the receptor solution normal saline
- HPLC chromatographically
- the reference formulation consisted of 30 g diisopropyladipate, 10 g levamisole and butyldioxitol to 100 ml.
- the formulations used for oral and intramuscular administration were aqueous solutions of levamisole of levamisole hydrochloride.
Abstract
Anthelmintic levamisole or tetramisole containing pour-on formulations containing isopropanol, glycerin and a fatty acid or ester.
Description
LEVAMISOLE OR TETRAMISOLE BASED POUR-ON FORMULATIONS
Background of the invention The present invention concerns particular levamisole or tetramisole containing pour- on formulations for use in warm-blooded animals.
Compared with other routes for administering levamisole or tetramisole, such as oral administration or injection, the pour-on method offers definite advantages, for example easy and rapid administration and better control of the dose administered. Levamisole or tetramisole based pour-on formulations are known, e.g. from US-4,070,476,
US-3,980,791 and US-4,414, 222, and particular such formulations are now used in the treatment of helminthic infections in farm-raised animals. Although the known formulations in several instances give good results, there still remain a number of disadvantages, such as irritation and unsatisfactory efficacy. Especially with sheep, irritation may be a problem.
The particular pour-on formulations subject of the present invention show an increased efficacy and little or no irritation.
Description of the invention The present invention is concerned with pour-on formulations containing isopropanol, glycerin, a fatty acid or fatty acid ester, and as active ingredient an anthelmintically effective amount of levamisole or tetramisole or a pharmaceutically acceptable acid addition salt thereof.
Levamisole as referred to above and hereinafter is the generic name of the laevo isomer of 2,3,5,6-tetrahydro-6-phenylimidazo[2,l-b]thiazole, tetramisole being the generic designation of the racemate. Both compounds are known from US-3,274,209 and US-3,463,786, and are widely used as anthelmintic agents.
Levamisole and tetramisole are basic in nature and can form acid-addition salts upon treatment with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric, hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxy- acetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic,
(Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-l,2,3-propanetricarboxylic, ethanesulfonic, ethanesulfonic, benzene- sulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino- 2-hydroxybenzoic and the like acids. Typical examples of such salt forms are e.g. levamisole hydrochloride, hydrobromide or phosphate. Preferably, the base form of levamisole is used in the present pour-on formulations.
Since the anthelmintic activity of tetramisole is exerted essentially by the laevo isomer, levamisole will preferably be used.
The term fatty acid or fatty acid ester refers to any of the naturally occuring fatty acids or esters and the simple synthetic modifications thereof, the latter for example referring to hydrogenated fatty acids or esters. Particular acids or esters comprise lauric acid or oleic acid; sorbitan -, glycerin-, sucrose-, glycol-, mono- or, where applicable, di-, tri- or poly-oleates or Cg. i2acid esters. Glycol refers to C2-4diols, in particular those with vicinal hydroxy groups, e.g. 1 ,2-ethanediol, 1,2-propanediol and 1,2-butanediol. The term Cg_i2acid esters refers to esters of alkyl carbonic acids having from 8 to 12 carbon atoms, alkyl referring to a hydrocarbon radical, saturated or unsaturated, in the latter instance having one, two or more double bonds. Preferred are esters of Cg, Cio or Cj2 alkyl acids, e.g. octanoic, decanoic or lauric acid.
Preferred fatty acids or esters for use in the pour-on formulations of the present invention are lauric acid, oleic acid, sorbitan monolaurate, glycerin monolaurate, mono-, di-, tri- or polylaurates of sucrose, in particular sucrose monolaurate (e.g. in a 60% (w/w) aqueous mixture such as Grilloten LSE 65 Soft ™), sorbitan mono-oleate, triglycerides, in particular mixed Cg/Cjo alkanoic acid triglycerides (mixed glycerin decanoates or octanoates), and Cδ-i2acid diesters of C2-4diols, in particular propylene glycol dicaprylate/dicaprate (Lexol PG 865 ™).
The amount of levamisole or tetramisole in the pour-on compositions according to the present invention can range from 5% to 30%, more preferably from 5% to 20% or from 7% to 15%, 10% being of particular interest. As used hereinbefore or hereinafter, all percentages are by weight based on the total weight of the pour-on composition.
Isopropanol will be present in a quantity of from 30% to about 93%, in particular from about 40% to about 75%, more in particular from about 40% to about 70%, the upper limit evidently not being more than 100% minus the sum of the quantities of the other ingredients. Glycerin may be present in a quantity ranging from 1 % to 45% , in particular from 10% to 45%. The fatty acids or esters may be present in a quantity ranging from 1% to 30%, in particular from 2% to 25%, more in particular from 4% to
25%. Good results are obtained if the weight by weight ratio of glycerin to the fatty acid or ester is in the range of 10: 1 to 1 :2, and particularly if said ratio ranges from about 7:1 to about 1:1.
The present formulations may comprise, besides the above-mentioned components, other components, e.g. to increase solubility or miscibility. The formulations may for example contain other solvents such as water, lower alkanols, e.g. ethanol or n. propanol, or ether alkanols, in particular partially etherified glycols or polyglycols, e.g. butyldioxitol and the like. Such other solvents may be present in a quantity ranging from 0 to 30%, in particular from 0 to 20%. When water-miscible fatty acids or fatty acid esters are employed, the instant pour-on compositions can comprise from about 5 to about 15% water, in particular from about 8 to about 10% water. The formulations may contain an antioxidant to increase the stability of the active ingredient such as, for example, butylated hydroxy toluene (BHT), hydroquinone, ascorbyl palmitate and the like.
The formulations of the present invention combine good stability, even for longer periods of time, with excellent efficacy and little, acceptably low or no skin-irritation. They show good skin penetration giving rise to high blood levels of the active ingredient, which blood levels are reached rapidly and remain high during the desired period of time for the active ingredient to exert its activity.
In particular, the present pour-on formulations have good penetration properties in cattle- and sheep-skin without causing any appreciable skin-irritation, giving rise to sufficiently high blood levels of the active ingredient The formulations of the present invention are readily prepared by intimately mixing the active ingredient with the components that form the carrier, usually at room temperature. For example isopropanol may be mixed with glycerin and the fatty acid or ester, whereupon tetramisole or levamisole is added while stirring until complete dissolution.
Preferred pour-on formulations for use on wool sheep such as merinos, because of their lack of causing even the least irritation, comprise by weight based on the total weight of the composition :
(a) 40 to 50% isopropanol; (a) 40 to 45% isopropanol;
(b) 20 to 25% glycerin; (b) 40 to 45% glycerin;
(c) 10 to 25% Cδ-i2acid ester of sucrose, and (c) 4 to 10% C8-i2acid ester of sucrose, and
(d) about 10% levamisole base. (d) 5 to 10% levamisole base.
The most preferred such compositions comprise approximately :
(a) 45% isopropanol; (a) 42.9% isopropanol;
(b) 22.5% glycerin; (b) 42.9% glycerin;
(c) 13.5% sucrose monolaurate and (c) 4.26% sucrose monolaurate and 9% water, and 2.84% water, and
(d) 10% levamisole base. (d) 7.1% levamisole base.
A preferred pour-on formulation for use on non-wool sheep comprises by weight based on the total weight of the composition : (a) 60% to 75% isopropanol;
(b) 10 to 15% glycerin;
(c) 10 to 15% C8-i2acid di-ester of a C2^diol; and
(d) about 10% levamisole base.
The most preferred such formulation comprises approximately :
(a) 67.5% isopropanol;
(b) 11.25% glycerin;
(c) 11.25% propylene glycol dicaprylate/dicaprate; and
(d) 10% levamisole base.
The invention further is illustrated by the following examples which are not given for the purpose of limiting it thereto.
Example 1 675 g of isopropanol is weighed in a stainless steel or glass vessel to which is added
112.5 g glycerin and 112.5 g of the product which is designated by the trademark "Lexol PG 865" (propylene glycol dicaprylate/dicaprate). The whole is stirred until dissolution whereupon 100 g levamisole base is added. Stirring is continued until complete dissolution. In this way a clear and very slightly yellow solution is obtained with a density at 25°C of 0.8675 g/ml.
Example 2
Following the procedures of example 1, but starting from 765 g of isopropanol, 72 g of glycerin, 72 g of oleic acid and 100 g of levamisole base, there is obtained a pour-on formulation which is clear and coloured very slightly yellow and has a density at 25°C of 0.8467 g/ml.
Example 3
Following the procedures of example 1, a third formulation was made containing
Example 4
Following the procedure of example 1, a fourth formulation was made comprising :
(a) 45% isopropanol;
(b) 22.5% glycerin; (c) 22.5% Grilloten LSE 65 Soft ™ (60% sucrose monolaurate in water), and (d) 10% levamisole base.
Example 5 Following the procedure of example 1, a fifth formulation was made comprising :
(a) 42.9% isopropanol;
(b) 42.9% glycerin;
(c) 7.1% Grilloten LSE 65 Soft ™ (60% sucrose monolaurate in water), and (d) 7.1% levamisole base.
Example 6
The flux of levamisole through sheep-skin is measured and compared with a reference pour-on formulation. Sheep skin obtained from anterior dorsal region of a freshly euthanized lamb is placed on a Franz peπneation cell and allowed to thermally equilibrate at 36°C ± 0.3°C for 0.5 hours. One hundred microliters of a test formulation was placed on the sheep skin and left exposed to air. The quantity of levamisole permeating through the tissue into the receptor solution (normal saline) was determined chromatographically (HPLC) by sampling periodically for 6-7 hours. The cumulative amount of levamisole which permeated through the tissue was plotted vs. time and a flux was calculated from the slope of this plot. The following results were obtained.
The reference formulation consisted of 30 g diisopropyladipate, 10 g levamisole and butyldioxitol to 100 ml.
Reference fluxes were obtained with each experiment. Because of the variations in tissue, this flux varies from experiment to experiment. The enhancement ratios were determined by dividing the flux by the corresponding reference flux. The areas under the curve (AUC) of a plot of plasma concentration versus time were determined graphically for the pour-on formulations of examples 1 and 2 as well as for the reference pour-on, for oral administration and for intramuscular administration. The fraction of the dose absorbed was calculated by dividing the said area under the curve obtained for the pour-on formulations by the AUC obtained for the intramuscular administration. In the same way the fraction of the dose absorbed through oral administration was obtained by dividing the oral AUC by the AUC obtained by intramuscular administration. In these, each AUC is divide by the dose in order to take into account the difference in doses administered.
■ _ AUC p0ur.on/dose pour-on p _ AUC oraj/dose ora]
AUC i.m./dose i.m. AUC i.m./dose i. .
The following results were obtained
The formulations used for oral and intramuscular administration were aqueous solutions of levamisole of levamisole hydrochloride.
From the above results it is concluded that the pour-ons according to the present invention show the same efficacy as aqueous solutions upon oral administration.
Claims
1. A pour-on formulation comprising isopropanol, glycerin, a fatty acid or fatty acid ester and as active ingredient tetramisole or levamisole, or a salt thereof.
2. A pour-on formulation according to claim 1 wherein the active ingredient is levamisole.
3. A pour-on formulation according to claim 2 wherein the fatty acid or fatty acid ester is lauric acid, oleic acid, sorbitan monolaurate, glycerin monolaurate, a mono-, di-, tri- or polylaurate of sucrose, sorbitan mono-oleate, a triglyceride or a C8-i2acid diester of C2-4diol.
4. A pour-on formulation according to claim 3 wherein the fatty acid or fatty acid ester is sucrose monolaurate or propylene glycol dicaprylate/dicaprate.
5. A pour-on formulation according to claim 3 comprising by weight based on the total weight of the formulation from 5 to 20% of the active ingredient tetramisole or levamisole, from 1 to 30% of a fatty acid or fatty acid ester, from 1 to 45% of glycerin, and from 30 to 93% of isopropanol, the maximum amount of each of the components being selected so that the total amount never exceeds 100%.
6. A pour-on formulation according to claim 3 comprising from 7 to 15% of levamisole, from 4 to 25% of the said fatty acid or ester, from 10 to 45% of glycerin and from 40 to 70% of isopropanol.
7. A pour-on formulation according to claim 6 wherein the weight-by-weight ratio of glycerin to the fatty acid or fatty acid ester ranges from about 10:1 to about 1:2.
8. A pour-on formulation according to claim 1 comprising by weight based on the total weight of the formulation approximately 42.9% isopropanol; 42.9% glycerin; 4.26% sucrose monolaurate and 2.84% water, and 7.1% levamisole base.
9. A pour-on formulation according to claim 1 comprising by weight based on the total weight of the formulation approximately 67.5% isopropanol; 11.25% glycerin;
11.25% propylene glycol dicaprylate/dicaprate; and 10% levamisole base.
10. A process of preparing a pour-on formulation according to any one of claim 1 to 9 characterized in that the active ingredient is intimately mixed with the components that form the carrier.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP92200367 | 1992-02-11 | ||
EP92200367.8 | 1992-02-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993015716A1 true WO1993015716A1 (en) | 1993-08-19 |
Family
ID=8210411
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1993/000274 WO1993015716A1 (en) | 1992-02-11 | 1993-02-04 | Levamisole or tetramisole based pour-on formulations |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU3453693A (en) |
WO (1) | WO1993015716A1 (en) |
ZA (1) | ZA93926B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2468792C1 (en) * | 2011-03-21 | 2012-12-10 | Государственное научное учреждение Краснодарский научно-исследовательский ветеринарный институт (ГНУ КНИВИ) | Medication for prevention and treatment of associated helminthiasis in ruminants |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2233985A1 (en) * | 1973-06-22 | 1975-01-17 | Bayer Ag | |
FR2347052A1 (en) * | 1976-04-06 | 1977-11-04 | Bayer Ag | NEW ANTHELMINTHIC FORMULATIONS FOR EXTERNAL APPLICATION |
EP0147883A2 (en) * | 1983-12-21 | 1985-07-10 | Janssen Pharmaceutica N.V. | Aqueous non-aggressive anthelmintic pour-on formulations |
-
1993
- 1993-02-04 AU AU34536/93A patent/AU3453693A/en not_active Abandoned
- 1993-02-04 WO PCT/EP1993/000274 patent/WO1993015716A1/en active Application Filing
- 1993-02-10 ZA ZA93926A patent/ZA93926B/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2233985A1 (en) * | 1973-06-22 | 1975-01-17 | Bayer Ag | |
FR2347052A1 (en) * | 1976-04-06 | 1977-11-04 | Bayer Ag | NEW ANTHELMINTHIC FORMULATIONS FOR EXTERNAL APPLICATION |
EP0147883A2 (en) * | 1983-12-21 | 1985-07-10 | Janssen Pharmaceutica N.V. | Aqueous non-aggressive anthelmintic pour-on formulations |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2468792C1 (en) * | 2011-03-21 | 2012-12-10 | Государственное научное учреждение Краснодарский научно-исследовательский ветеринарный институт (ГНУ КНИВИ) | Medication for prevention and treatment of associated helminthiasis in ruminants |
Also Published As
Publication number | Publication date |
---|---|
AU3453693A (en) | 1993-09-03 |
ZA93926B (en) | 1994-08-10 |
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