HK1084590B

HK1084590B - Pharmaceutical composition for transdermal or transmucosal administration

Info

Publication number: HK1084590B
Application number: HK06105598.9A
Authority: HK
Inventors: Brigitte Taravella; Valerie Masini-Eteve
Original assignee: Besins Healthcare Luxembourg Sarl
Priority date: 2003-02-20
Filing date: 2004-02-19
Publication date: 2009-06-05

Description

The present invention relates to a novel pharmaceutical composition intended for transdermal or transmucosal administration of at least one active substance, including a fatty acid as a promoter of percutaneous absorption, and a stabilizing agent capable of stabilizing the fatty acid in the pharmaceutical composition, as claimed 1.

It is well known that some active substances are not suitable for oral administration for various reasons, which are inter alia related to either high hepatic metabolism: first-pass effect or high gastrointestinal degradation.

Transdermal or transmucosal formulations have been developed to overcome these disadvantages.

Pharmaceutical formulations intended for transdermal or transmucosal administration have several advantages over oral formulations: elimination of the problem of metabolism of the active substance by the liver, no gastric degradation of the active substance, possible reservoir effect with a continuous release of the active substance over time.

EP-A-0 672 422 discloses a transdermal gel comprising an active substance, lauric acid, a pH 4 buffer, Poloxamer 407, ethanol and propylene glycol.

This is because not all active substances diffuse through the percutaneous barrier in the same way, depending on the chemical and physicochemical characteristics of the molecule.

To facilitate this passage of active substances through the skin, transdermal or transmucosal formulations may include specific molecules called promoter of percutaneous absorption . This designation refers to any molecule that promotes the diffusion of an active substance through the skin or mucous membrane in a reversible manner, and any solubiliser that promotes the sharing of the active substance between the carrier and the corneal layer of the epidermis or mucous membrane.

The applicant has shown, however, that hydroalcoholic compounds containing these fatty acids are not chemically stable, since fatty acid, by virtue of its function acid and in the presence of alcohol, undergoes an esterification reaction according to the laws of organic chemistry, e.g. oleic acid is transformed into ethyl oleate in the presence of ethanol.

However, as medicines are often stored for some time before they are sold, it is essential that their composition is unchanged in order to ensure safety for patients. Therefore, any medicinal product must demonstrate high stability, i.e. its composition must not vary over time. Stability of pharmaceutical composition is a guarantee of consistency in terms of the bioavailability of the active substance, efficacy of the pharmaceutical composition, acceptability and safety of the medicinal product for the patient.

Thus, in a gel or hydro-alcoholic solution, the degradation of the fatty acid, which promotes the absorption of the active substance through the skin, can significantly alter the bioavailability of the active substance and therefore its efficacy.

The applicant company has carried out a great deal of work and research to find a solution to this problem of stability of fatty acids in an alcoholic medium, in order to achieve satisfactory stability.

It thus found that it was possible to stabilise the fatty acid in the pharmaceutical composition by adding small quantities of an ester of the corresponding fatty acid as soon as the pharmaceutical composition was prepared.

The invention therefore concerns a pharmaceutical composition intended for the transdermal or transmucosal administration of at least one active substance, and comprising at least one fatty acid as a promoter of percutaneous absorption, at least one alcoholic vehicle, and at least one stabilizing agent capable of stabilizing the fatty acid in the pharmaceutical composition.

In the context of the present invention, stable means a pharmaceutical composition whose qualitative and quantitative composition and physical, chemical and biological characteristics do not change significantly over time under given temperature and humidity conditions, either for 3 years at 25°C/60% HRC, for 1 year at 30°C/65% HRC and/or for 6 months at 40°C/75% HRC.

significant change any change in quality and/or quantity, and any change in physical, chemical and biological characteristics, which occurs outside the acceptance criteria defined for the analytical method used for each chemical, physical or biological test (numerical limit, interval or other relevant measure).

The promoter (s) of percutaneous absorption in the pharmaceutical composition of the invention are preferably selected from the group of saturated or unsaturated fatty acids.

The preferred group of fatty acids is capric acid (10:0), lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0); oleic acid (18:1), palmitol (16:1), linoleic acid (18:2), and linolenic acid (18:3).

The fatty acid content of the pharmaceutical composition according to the present invention will be preferably between 0.1% and 20%, preferably between 0.2% and 10%, and even more preferably between 0.5% and 5%, these percentages being expressed in terms of weight per 100 g of pharmaceutical composition.

However, it is explicitly stated here that the pharmaceutical composition of the invention may contain other promoters of percutaneous absorption in combination with the fatty acid (s).

The stabilising agent is selected from the group consisting of fatty acid esters corresponding to the fatty acids present in the pharmaceutical composition as promoters of percutaneous absorption.

The buffer (s), when present in the pharmaceutical composition of the invention, makes it possible to maintain the pH of the pharmaceutical composition between 4 and 10, preferably between 5 and 9 and more preferably between 6 and 8.

The buffer content of the pharmaceutical composition of the invention is preferably between 1% and 80%, preferably between 5% and 70% and more preferably between 10% and 50%, these percentages being expressed by weight per 100 g of pharmaceutical composition.

According to a preferred method of manufacture of the pharmaceutical composition according to the invention, the tampons are selected from the group consisting of: alkaline or basic buffers such as a phosphate buffer (e.g. dibasic or monobasic sodium phosphate), a citrate buffer (e.g. sodium citrate or potassium citrate), sodium carbonate, sodium bicarbonate, preferably a mixture of sodium carbonate and sodium bicarbonate, or neutral buffers such as a Tris buffer, preferably a phosphate buffer. The fatty acid esters are therefore preferably selected from the group consisting of ethyl oleate, isopropyl oleate, isopropyl myristate, isopropyl palmitate, ethyl octanoate, ethyl dodecanoate, ethyl linoleate, ethyl linoleate.

The content of fatty acid ester added as a stabilizing agent in the pharmaceutical composition of the invention is preferably between 0.1% and 10%, preferably between 0.2% and 5% and preferably between 0.5% and 2.5%, these percentages being expressed by weight per 100 g of pharmaceutical composition.

The pharmaceutical composition of the invention also contains an alcohol-type non-aqueous vehicle. The alcohol vehicle must be capable of dissolving all the components of the formulation, including the fatty acid and possibly its ester. Preferably, the alcohol vehicle may be selected from ethanol and/or isopropanol. However, ethanol is a preferred vehicle of the invention as it effectively contributes to the transcutaneous passage of the active substance by rapidly evaporating on contact with the skin.

The alcohol content is advantageously between 10% and 90%, preferably between 20% and 80%, and even more preferably between 40% and 70%, these percentages being expressed in terms of weight per 100 g of pharmaceutical composition.

The pharmaceutical composition according to the invention may also include an aqueous vehicle. The aqueous vehicle allows the hydrophilic molecules contained in the formulation to be soluble and also promotes the diffusion of the lipophilic molecules from the formulation to the corneal layer. It forms a binary vehicle with the non-aqueous solvent.

The aqueous vehicle should preferably be water, with a content of between 1% and 80%, preferably between 10% and 70%, and preferably between 20% and 60%, these percentages being expressed by weight per 100 g of pharmaceutical composition.

The pharmaceutical composition of the invention may also contain a co-solvent such as polyols or polyglycols such as glycerol (or glycerin), propylene glycol or polyethylene glycol in a content of between 0.5% and 20%, preferably between 1% and 10%, as these percentages are expressed in terms of weight per 100 g of pharmaceutical composition.

The pharmaceutical composition according to the invention may be in the form of a gel, solution, cream, lotion, milk, ointment, aerosol, or patch.

It is preferably in the form of a gel or solution.

When the pharmaceutical composition according to the invention is in the form of a gel, it also includes a gelling agent.

It is advantageous, depending on the type of gelling agent used, to have a gelling agent content of between 0.2% and 30%, preferably between 0.5% and 10% and even more preferably between 0.3% and 5%, these percentages being expressed in terms of weight per 100 g of pharmaceutical composition.

Carbomeres or polyacrylic acids such as carbopol 980 or 940 NF, 981 or 941 NF, 1382 or 1382 NF, 5984, 2984 or 934 NF, Pemulen TR1 NF or TR2 NF, Ultrez, Synthalen CR, non-pre-neutralized acrylic polymers; cellulosic derivatives such as ethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPMC), carymethyl cellulose (CMC), etc.; polyoxammers or polyetylene-propylene copolymers such as Lutran 68 F127, polyoxammers or other polymers or chemicals, depending on the grade, may be used in the composition of pharmaceutical compounds such as dextromethane or polymers of natural polymers or chemicals.

These gelling agents increase the viscosity of the formulations of the invention but may also act as solubilizing agents.

Carbopol® 980 and/or hydroxypropyl cellulose are particularly preferred in the present invention.

The choice of the gelling agent will be made according to the pH of the composition defined according to the invention and the viscosity desired.

According to another advantageous embodiment of the pharmaceutical composition according to the invention, in the presence of certain types of gelling agents, and in particular non-pre-neutralized acrylic polymers, it may contain a neutralizing agent.

The neutralising agent shall be chosen in such a way that it forms salts soluble in the vehicle in the presence of the polymer.

The neutralizing agent is also chosen in such a way as to achieve optimal polymer chain swelling during charge neutralization and polymer salt formation.

According to the invention, triethanolamine and/or tromethamine (2-Amino 2-Hydroxymethyl-1, 3-propanediol) are used preferably as neutralizing agents in the presence of Carbopol® 980.

Other neutralizing agents such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, arginine, propanol aminomethyl can be used in the pharmaceutical composition according to the invention.

The active substance (s) in the pharmaceutical composition of the invention may be advantageously selected from the group consisting of oestrogens, progestins, androgens, anti-oestrogens, anti-androgens or mixtures thereof.

The active substance content is advantageously between 0.01% and 5%, expressed as a percentage by weight per 100 g of pharmaceutical composition.

Anti-estrogens may be selected from the group consisting of tamoxifen, 4-hydroxycytamoxifen, tamoxifen citrate, toremifen, droloxifen, and raloxifen.

Androgens can be selected from the group consisting of natural androgen, testosterone, and its semi-natural or synthetic derivatives such as methyltestosterone; physiological precursors of testosterone such as dehydroepiandrosterone or DHEA or prasterone and its derivatives such as DHEA sulfate, Δ-4-androstenedione and its derivatives; metabolites of testosterone such as dihydrotestosterone (DHT) obtained after the enzymatic action of 5-α-reductases; or substances having an androgenic-like effect such as tibolone.

Antiandrogens may be selected from the group consisting of steroid compounds such as cyproterone acetate, medroxyprogesterone, or non-steroidal compounds such as flutamide, nilutamide or bicalutamide. Preferably, the active substance in the pharmaceutical composition of the invention is a progestin, an estrogen, or a combination of the two.

The first group includes progesterone-related molecules or progestogen-like progestogens type 1, 2 or 3 (pregnant), e.g. progesterone isomer (retrogesterone), Medrogesterone, norprogesterone derivatives (demegestone or promogestone). The second group may include 17α-hydroxyprogesterone derivatives or progestogen-like progestogens type 2 (PS13.182) or progestogens type 2 (pregestogens), e.g. progestogens or progestogens type 1 (PS1.18). This group also includes the group of norrogestogens, such as C-methyl or norrogestone (3-progestogens) or progestogens or progestogens of the type 19-progestogens (PS13.182) or progestogens of the type 2-progestogens (progestogens). This group includes the examples of the synthetic molecules present in C-methyl or norrogestogens, e.g. methotestosterone or methotestogestogens (3-progestogestogens) or C-methyl or norrogestogestogestogestogestogens (33).

Tibolone, which has both progestin and androgenic activity, can also be advantageously selected in the pharmaceutical composition according to the invention.

The oestrogen (s) used in the pharmaceutical composition according to the invention can be advantageously selected from the group of natural oestrogens: 17-β oestradiol, oestrone, equine conjugated oestrogens, estriol, phytoestrogens; from the semi-natural oestrogens: oestradiol valerate; or from the synthetic oestrogens: ethinyl-estradiol; preferably, 17-β oestradiol.

In an advantageous embodiment of the pharmaceutical composition according to the invention, the progestogen content (s) will be between 0.01% and 5%, preferably between 0.02% and 3%, and more preferably between 0.03% and 1%, these percentages being expressed by weight per 100 g of pharmaceutical composition.

According to another particular method of manufacturing the pharmaceutical composition according to the invention, the oestrogen content (s) will be between 0.01% and 5%, preferably between 0.02% and 3%, and more preferably between 0.03% and 2%, these percentages being expressed by weight per 100 g of pharmaceutical composition.

The invention will be better understood by the examples described below.

Comparative example 1 - Instability of ice including oleic acid

A first batch of gels with the compositions given in Table I was tested for stability.

The manufacture of a gel according to the invention is as follows: For example, for 40 kg of a gel manufactured according to the formula E760 containing two active substances, Estradiol (Diosynth) and Progesterone (Xianming):In a Koruma-type mixer, 26000 g of ethanol 95° are introduced under vacuum at 800 mb. Then, from the top of the tank, 2000 g of propylene glycol, 1200 g of oleic acid are successively filled without stirring. The whole is mixed for at least 5 minutes, turbine at 2000 rpm, scraper at 40 rpm.Add 800 g of Progesterone.Then mix for 15 minutes, turbine at 2000 rpm, scraper at 40 rpm.Introduce 400 g of Klucel®HF at 800 mb vacuum, turbine at 1500 rpm.Shake for at least 10 minutes, turbine at 1500 rpm, scraper at 40 rpm.Then load the purified water in sufficient quantity to obtain a total mass of 40000 g, vacuum 800 mb, scraper at 40 rpm.Mix for at least 10 minutes, turbine at 1500 rpm, scraper at 40 rpm.Stop the turbine.Empty the 100 mb for about 2 minutes.Shake slowly for at least 10 minutesThe test shall be carried out at a speed of not more than 10 rpm.

The other formulations are prepared in the same way by changing the amounts of the various components according to Table I.

Oleic acid and ethyl oleate levels were measured by gas chromatography or potentiometry (and potentiometry) after storage at room temperature (25°C) and 60% relative humidity at 0, 1, 2, 3, 6, 10, 12 and 18 months (and 0, 1, 3, 4, 6, 12, 14 and 20 months for placebo), respectively.

The results are given in Tables II and III.

The specifications or standards in the tables correspond to the accepted acceptance criterion which is 5% or more above the initial theoretical value. Any value outside this acceptable range is considered non-compliant and corresponds to a so-called significant variation. These values are shown in grayscale in the tables.



0	2	2	3	3
0	0,06	0,06	0,06	0,06
5	5	5	5	5
2	3	3	2	2
1,5	1	1.5	1	1,5
65	65	65	65	65
Qsp 100g	Qsp 100g	Qsp 100g	Qsp 100g	Qsp 100g

* Hydroxypropylcellulose fabriqué par la société Aqualon.

An accelerated aging test was also performed on the same gels which were stored at 40°C, with a relative humidity of 75% at 0, 1, 2, 3, 4, 5, 6, 10, 11, 12, 18 months. The oleic acid and ethyl oleate levels were then measured as before at the same times.

Significant esterification of oleic acid is observed in all gels during aging.The level of ethyl oleate formed and the rate of esterification are all the higher as the percentage of oleic acid is high at the start and the temperature and humidity conditions are high (difference between 25°C/60% HR and 40°C/75% HR).

This esterification of oleic acid raises two major concerns concerning the integrity of the specialty pharmaceutical: The use of oleic acid in the production of the product is not recommended, as the presence of ethyl oleate is poorly soluble in alcohol, which may lead to unwanted emulsion in the gel.


AO en% de gel	2,9 à 3,2	2,9	3, 1	2,9	2,9	2,8	2,6	2,5	2,6
E formé en% d'AO	0,6	1, 2	2,5	3,0	5,6	12,4	14,8	23, 8
AO en% gel	2,9 à 3,2	2, 8.	3, 1	2,9	2,8	2,8	2,6	2,6	2,6
E formé en% d'AO	0,6	1, 1	2,3	3,0	5,8	12,4	14,4	23,3
AO en% gel	1,9 à 2.,1	2,0	2,1	1,9	2,0	1,8	1,7	1,7	1,8
E formé en% d'AO	0,4	1,0	1, 7	2,6	5,4	10,8	11,8	17,6
AO en% gel	1,9 à 2,1	1, 9	2,0	1, 9	1.9	1,9	1,7	1,7	1,8
E formé en% d'AO	0, 4	0,9	1,6	2,5	4,5	10,1	9,8	16,5


AO en% gel	1,9 à 2,1	1,8	1,9	1,9	1,9	1,8	1,7	1,7	1,7
OE formé en% d'AO	NE*	3,0	2,9	3,4	5,6	13,5	15,8	22,5

* NE : non effectué


AO en% de gel	2,9 à 3,2	2,9	2,9	12,8	2,7	2,7	2,5	2,5	2,3	2,3	2,7	2,0
OE formé en% d'AO	0,6	3,9	6,1	8,6	11,7	14,7	18,4	34,7	42,3	50,8	69,8
AO en% de gel	2,9 à 3,3	2,8	3,0	2,7	2,7	2,5	2,7	2,5	2,3	2,3	2,3	2,0
OE formé en% d'AO	0,6	3,7	6,3	8,6	11,9	13,3	17,6	31,6	39,8	50,0	65,8
AO en% de gel	1,9 à 2,1	2,0	2,0	11,8	1,9	1,7	1,8	1,8	1,5	1,6	1,6	1,5
OE formé en% d'AO	0,4	2,7	4,5	6,6	19,4	10,6	14,4	27,1	28,9	37,9	49,7
AO en% de gel	1,9 à 2,1	1,9	1,9	1,9	1,8	1,7	1, 7	1,7	1,6	1,6	1,5	1,5
OE formé en% d'AO	0,4	2-, 4	4,3	6,6	8,6	10,3	14,0	24,5	27,5	34,9	47,3

IL FAUDRAIT SUPPRIMER LE GRISE DU LOT E762 à 6,6 %OE .

COMMARATED EXAMPLES 2 - The instability of ice including oleic acid and its stabilization according to the invention

A second set of gels with the compositions given in Table V was tested for stability.

The manufacture of a gel according to the invention is as follows. For example, for 30 kg of a gel manufactured according to the formula E844 containing two active substances, Estradiol (Diosynth) and Progesterone (Xianming):In a Koruma-type mixer, 800 mb 19500 g of 95° ethanol is introduced under vacuum.Then, from the top of the tank, 1500 g of propylene glycol, 1500 g of oleic acid are successively filled without stirring.The whole is mixed for at least 5 minutes, turbine at 2000 rpm, scraper at 40 rpm.We add 18.6 g of Estradiol.Then, we mix for 15 minutes, turbine at 2000 rpm, scraper at 40 rpm.600 g of Progesterone is added.Then, we mix for 15 minutes, turbine at 2000 rpm, scraper at 40 rpm.We introduce 300 g of Klucel®HF at 800 mb vacuum, turbine at 1500 rpm.We shake for at least 10 minutes, turbine at 1500 rpm, scraper at 40 rpm.Then, we load the purified water with enough for 30000.g, under 800 mb vacuum, scraper at 40 rpm.We mix for at least 10 minutes, turbine at 1500 rpm, scraper at 40 rpm.We stop the turbine.We empty at 100 mb for about 2 minutes.We shake slowly for at least 10 minutes, scraper at 10 rpm.

The other formulations E 845 to E 854 were prepared in the same way by modifying the amounts of components introduced according to Table V.

Samples E858 to E865 contain a Carbonate-Bicarbonate buffer pH 10.7 which is loaded in place of the purified water when preparing the gel according to the invention. A solution in purified water of anhydrous Na2CO3 0,2M, i.e.: 21.2 g/l (Solution A) was prepared.A solution in purified water of NaHCO3 0.2M, i.e.: 16.8 g/l (Solution B) was prepared.Then 21.3 ml of solution A were added to 3.8 ml of solution B and water was added to obtain 100 ml.The resulting solution corresponds to the buffer used in tests E858 to E 865.The pH of this buffer solution is 10.7.

The specifications or standards in the tables correspond to the set acceptance criterion which is either 5% or less of the initial theoretical value. Any values outside this acceptable range are considered non-compliant and correspond to a so-called significant variation. These values are shown in grayscale in the tables.

The gels were stored at 25°C and 60% relative humidity and at 40°C and 75% relative humidity (accelerated aging). The oleic acid and ethyl oleate levels were measured as before at 0, 1, 2, 3 and 6 months. The results are given in Table VI (25°C/60%HR) and VII (40°C/75%HR).

These analyses show that the use of the Carbonate-Bicarbonate buffer at pH 10.7 significantly reduces the esterification of oleic acid into ethyl oleate.

E844 à 865


2	0,06	5	5	1	65	0	Eau
2	0,06	5	5	1	65	0	Eau
3	0,06	5	5	1	65	0	Eau
3	0,06	5	5	1	65	0	Eau
3	0,06	5	5	1,5	65	0	Eau
3	0,06	5	5	1,5	65	0	Eau
3	0,06	5	2	1	65	0	Eau
3	0,06	5	2	1	65	0	Eau
2	0,06	5	5	1,5	65	0	Eau
2	0,06	5	5	1,5	65	0	Eau
3	0,06	5	2	1,5	65	0	Eau
3	0,06	5	2	1,5	65	0	Eau
2	0,06	5	5	1	65	0	Tampon
2	0,06	5	5	1	65	0	Tampon
3	0,06	5	2	1	65	0	Tampon
3	0,06	5	2	1	65	0	Tampon
3	0,06	5	5	1	65	0	Tampon
3	0,06	5	5	1	65	0	Tampon
5	0,06	5	3	1	30	35	Tampon

E844 à 865


Acide oléique en g/100 g gel	4,8 à 5,3	4,9	4,8	4,7	4,6
Oléate d'Et formé en g/100 g AO	2,3	8,4	11,9	16,2
Acide oléique en g/100 g gel	4,8 à 5,3	5,0	4,8	4,7	4,6
Oléate d'Et formé en g/100 g AO	2,06	8,1	11,4	15,8
Acide oléique en g/100 g gel	4,8 à 5,3	5,0	4,8	4,7	4,6
Oléate d'Et formé en g/100 g AO	2,0	7,8	10,5	14,7
Acide oléique en g/100 g gel	4,8 à 5,3	5,0	4,8	4,7	4,6
Oléate d'Et formé en g/100 g AO	1,8	7,5	10,5	14,9
Acide oléique en g/100 g gel	4,8 à 5,3	5,0	4,9	4,8	4,6
Oléate d'Et formé en g/100 g AO	1,8	7,0	9,9	13,8
Acide oléique en g/100 g gel	4,8 à 5,3	5,0	5,00	4,8	4,7
Oléate d'Et formé en g/100 g AO	1,60	6,7	9,9	13,7
Acide oléique en g/100 g gel	1,9 à 2,1	2,0	2,0	2,0	2,0
Oléate d'Et formé en g/100 g AO	0,8	4,3	5,6	6,6
Acide oléique en g/100 g gel	1,9 à 2,1	2,0	2,0	2,0	2,0
Oléate d'Et formé en g/100 g AO	0,50	4,3	5,4	6,7
Acide oléique en g/100 g gel	4,8 à 5,3	4,9	4,8	4,7	4,7
Oléate d'Et formé en g/100 g AO	1,8	7,6	10,2	14,6
Acide oléique en g/100 g gel	4,8 à 5,3	5,0	4,8	4,7	4,6
Oléate d'Et formé en g/100 g AO	1,6	7,2	10,2	14,9
Acide oléique en g/100 g gel	1,9 à 2,1	2,0	2,0	1,9	2,0
Oléate d'Et formé en g/100 g AO	0,63	3,9	4,9	6,0
Acide oléique en g/100 g gel	1,9 à 2,1	2,0	2,0	2,0	2,0
Oléate d'Et formé en g/100 g AO	0,50	4,0	4,6	6,1


Acide oléique en g/100 g gel	4,3 à 5,7	4,5	4,5	4,4	4,5
Oléate d'Et formé en g/100 g AO	0,31	2,3	2,5	4,3
Acide oléique en g/100 g gel	4,3 à 5,7	4,6	4,5	4,4	4,4
Oléate d'Et formé en g/100 g AO	0,4	2,5	2,6	4,3
Acide oléique en g/100 g gel	1,4 à 1,6	1,5	1,5	1,4	1,4
Oléate d'Et formé en g/100 g AO	0	1,3	traces	traces
Acide oléique en g/100 g gel	1,4 à 1,6	1,5	1,5	1,4	1,4
Oléate d'Et formé en g/100 g AO	0	1,3	0,1	traces
Acide oléique en g/100 g gel	4,3 à 5,7	4,4	4,5	4,4	4,5
Oléate d'Et formé en g/100 g AO	0,2	2,5	2,5	3,8
Acide oléique en g/100 g gel	4,3 à 5,7	4,4	4,5	4,5	4,5
Oléate d'Et formé en g/100 g AO	0,3	2,2	2,4	3,8
Acide oléique en g/100 g gel	2,4 à 2,6	2,5	2,6	2,5	2,5
Oléate d'Et formé en g/100 g AO	0	0,9	traces	traces


Acide oléique en g/100 g gel	4,8 à 5,3	5,0	4,5	3,9	4,0
Oléate d'Et formé en g/100 g AO	2,3	14,4	25,9	37,2
Acide oléique en g/100 g gel	4,8 à 5,3	5,0	4,6	4	4,0
Oléate d'Et formé en g/100 g AO	2,06	13,5	22,2	35,5
Acide oléique en g/100 g gel	4,8 à 5,3	5,0	4,1	4,3	4,0
Oléate d'Et formé en g/100 g AO	2,0	14,1	21,6	34,7
Acide oléique en g/100 g gel	4,8 à 5,3	5,0	4,6	4,3	4,1
Oléate d'Et formé en g/100 g AO	1,81	12,4	20,5	34,5
Acide oléique en g/100 g gel	4,8 à 5,3	5,0	4,6	4,3	4,1
Oléate d'Et formé en g/100 g AO	1,8	11,6	19,2	33,7
Acide oléique en g/100 g gel	4,8 à 5,3	5,0	4,6	4,0	4,1
Oléate d'Et formé en g/100 g AO	1,6	11,4	20,9	33,9
Acide oléique en g/100 g gel	1,9 à 2,1	2,0	2,0	1,9	1,8
Oléate d'Et formé en g/100 g AO	0,8	7,3	11,1	19,0
Acide oléique en g/100 g gel	1,9 à 2,1	2,0	1,9	1,9	1,8
Oléate d'Et formé en g/100 g AO	0,50	7,5	11,2	8,5
Acide oléique en g/100 g gel	4,8 à 5,3	4,9	4,5	4,3	4,0
Oléate d'Et formé en g/100 g AO	1,8	12,5	20,7	34,6
Acide oléique en g/100 g gel	4,8 à 5,3	5,0	4,6	4,3	4,1
Oléate d'Et formé en g/100 g AO	1,6	13,0	19,8	35,6
Acide oléique en g/100 g gel	1,9 à 2,1	2,0	2,0	2,0	1,8
Oléate d'Et formé en g/100 g AO	0,63	6,3	9,8	17,1
Acide oléique en g/100 g gel	1,9 à 2,1	2,0	1,9	1,8	1,8.
Oléate d'Et formé en g/100 g AO		0,5	7,0	10,3	17,0


Acide oléique en g/100 g gel	4,3 à 5,7	4,5	4,4	4,3	4,3
Oléate d'Et formé en g/100 g AO	0,31	4,0	5,9	11,5
Acide oléique en g/100 g gel	4,3 à 5,7	4,6	4,5	4,3	4,2
Oléate d'Et formé en g/100 g AO	0,4	4,3	6,1	12,2
Acide oléique en g/100 g gel	1,4 à 1,6	1,5	1,5	1,4	1,5
Oléate d'Et formé en g/100 g AO	0	1,9	1,1	1,4
Acide oléique en g/100 g gel	1,4 à 1,6	1,5	1,4	1,4	1,4
Oléate d'Et formé en g/100 g AO	0	2,0	1,2	1,4
Acide oléique en g/100 g gel	4,3 à 5,7	4,4	4,5	4,3	4,4
Oléate d'Et formé en g/100 g AO	0,2	4,3	5,9	11,3
Acide oléique en g/100 g gel	4,3 à 5,7	4,4	4,5	4,4	4,3
Oléate d'Et formé en g/100 g AO	0,3	4,2	6,2	11,2
Acide oléique en g/100 g gel	2,4 à 2,6	2,5	2,5	2,5	2,5
Oléate d'Et formé en g/100 g AO	0	1,3	0,3	1,2

Claims

Pharmaceutical composition for transdermal or transmucous administration of at least one active substance having an active substance content of between 0.01% and 5%, and comprising at least one fatty acid as percutaneous absorption promoter, at least one alcoholic vehicle, and also at least one stabilizer capable of stabilizing the fatty acid in said pharmaceutical composition, wherein said fatty acid is an aliphatic fatty acid with long chains containing 10 to 18 carbon atoms, wherein the stabilizer is the ester of said fatty acid resulting from the reaction between said fatty acid and said alcoholic vehicle.
Pharmaceutical composition according to Claim 1, wherein the fatty acid(s) is (are) selected from the group consisting of capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, palmitoleic acid, linoleic acid and linolenic acid.
Pharmaceutical composition according to any one of claims 1 and 2, having a fatty acid content of between 0.1% and 20%, preferably between 0.2% and 10% and even more preferably between 0.5% and 5%, these percentages being expressed on a weight basis relative to 100 g of pharmaceutical composition.
Pharmaceutical composition according to any one of claims 1 to 3, wherein the fatty acid esters are selected from the group consisting of ethyl oleate, isopropyl oleate, isopropyl myristate, isopropyl palmitate, ethyl octanoate, ethyl dodecanoate, ethyl linoleate and ethyl linolenate.
Pharmaceutical composition according to claim 4, having a fatty acid ester content of between 0.1% and 10%, preferably between 0.2% and 5% and even more preferably between 0.5% and 2.5%, these percentages being expressed on a weight basis relative to 100 g of pharmaceutical composition.
Pharmaceutical composition according to any one of claims 1 to 5, wherein the alcoholic vehicle(s) is (are) selected from the group consisting of ethanol and/or isopropanol, preferably ethanol.
Pharmaceutical composition according to claim 6, having an alcoholic vehicle content of between 10% and 90%, preferably between 20% and 80% and even more preferably between 40% and 70%, these percentages being expressed on a weight basis relative to 100 g of pharmaceutical composition.
Pharmaceutical composition according to any one of claims 1 to 7, further comprising a co-solvent preferably selected from the group consisting of glycerol (or glycerine), propylene glycol and polyethylene glycol, and mixtures thereof.
Pharmaceutical composition according to claim 8, having a co-solvent content of between 0.5 and 20% and preferably between 1% and 10%, these percentages being expressed on a weight basis relative to 100 g of pharmaceutical composition.
Pharmaceutical composition according to any one of claims 1 to 9, being in the form of a gel, a solution, a cream, a lotion, a milk, an ointment, an aerosol or a patch, preferably a gel or a solution.
Pharmaceutical composition according to any one of claims 1 to 10, being in the form of a gel, and having a content of between 0.2% and 30% of a gelling agent, preferably between 0.5% and 10% and even more preferably between 0.3% and 5%, these percentages being expressed on a weight basis relative to 100 g of formulation.
Pharmaceutical composition according to claim 11, wherein the gelling agent is selected from the group consisting of carbomers, non-preneutralized acrylic polymers, cellulose derivatives, poloxamers, poloxamines, chitosan, dextran, pectins, natural gums, and mixtures thereof, preferably carbomers and/or cellulose derivatives, and even more preferably Carbopol® 980 and/or hydroxypropylcellulose.
Pharmaceutical composition according to any one of claims 1 to 12, further comprising a neutralizer.
Pharmaceutical composition according to claim 13, wherein the neutralizer is selected from the group consisting of triethanolamine, sodium hydroxide, ammonium hydroxide, potassium hydroxide, arginine, aminomethylpropanol and tromethamine, and mixtures thereof, preferably triethanolamine and/or tromethamine.
Pharmaceutical composition according to any one of claims 13 and 14, wherein the neutralizer/gelling agent ratio is between 10/1 and 0.1/1, preferably between 7/1 and 0.5/1 and even more preferably between 4/1 and 1/1.
Pharmaceutical composition according to any one of claims 1 to 15, wherein the active substance(s) is (are) selected from the group consisting of oestrogens, progestins, androgens, anti-oestrogens and anti-androgens, or mixtures thereof.