Transdermal pharmaceutical formulation for minimizing skin residues

[0001] The present invention relates to a new transdermal or transmucosal pharmaceutical formulation comprising the active ingredient and a solvent system. The solvent system includes monoalkyl ether and glycol in certain ratios as well as a mixture of alcohol and water. The invention also relates to a method of delaying or inhibiting crystallization of an active agent in a transdermal or transmucosal pharmaceutical formulation.

BACKGROUND OF THE INVENTION [0002] It is known that transdermal or mucosal dosage forms conveniently deliver drugs through a localized area of ​​skin or mucosa. One such route of drug delivery through the skin or mucosa is via a non-occlusive transdermal and / or topical dosage form. Some non-limiting examples of non-occlusive transdermal and topical semi-solid dosage forms include creams, ointments, gels, foams, sprays, solutions and lotions (i.e. emulsions or suspensions). Usually, non-occlusive dosage forms are applied to the skin or mucosa and are left uncovered and exposed to free air. Since the non-occlusive dosage form is left uncovered, undesirable transition of the pharmaceutical formulation to the user's clothing or even to other individuals in close proximity to the user is unavoidable. Other disadvantages of the non-occlusive dosage form include evaporation of the formulation, removal of the formulation from skin or mucosa, for example, by bathing or other activities, and non-absorption of the formulation through the skin, as discussed below.

[0003] The inefficiency of drug penetration through skin or mucosal barriers is known. It is also known that the permeation of the drug in a non-occlusive transdermal or transmucosal dosage form may be as low as 1%, and usually not more than 15%. Thus, the vast majority of the active drug remains not absorbed on the surface of the skin or mucosa. Since the vast majority of the drug remains on the skin and does not penetrate the skin or mucosal surfaces, the bioavailability of the drug is not optimal and there is also a high risk of contamination of other individuals in the close vicinity of the user by the undesirable transfer of the pharmaceutical formulation in a non-occlusive dosage form.

[0004] Problems associated with the undesirable transfer of a particular pharmaceutical formulation to others are well documented. For example, Delanoe et al. reported androgenization of female volunteer partners using testerosterone gel during contraceptive testing. (Delanoe, D., Fougeyrollas, B., Meyer, L. & Thonneau, P. (1984): "Androgenisation of female partners of men on medroxyprogesterone acetate / percutaneous testosterone contraception", Lancet 1,276-277). Similarly, Yu et al. reported the masculinization of a two-year-old boy after incidental and unintentional skin exposure to a cream with testeron applied (applied?) to his father's shoulder and back (Yu, YM, Punyasavatsu, N., Elder, D. & D'Ercole, AJ (1999): "Sexual development in a two-year old boy induced by topical exposure to testosterone", Pediatrics, 104, 23).

EP 1670 433 B1 _® [0005] In addition, the patient information booklet for ANDROGEL (1% testerone gel from Unimed Pharmaceuticals Inc.) highlights the possibility of testosterone transfer to other people and / or clothing and the booklet contains safety measures that a subject using a non-occlusive dosage form should take under attention.

[0006] One way to overcome or minimize this contamination issue is to physically secure the transdermal dosage form by covering the skin with the pharmaceutical formulation applied by means of a patch, patch attached, reservoir, application chamber, tape, bandage, bandage, or similar that remain on the skin. at the place of application of the formulation for a long time. Usually this is done with occlusive dosage forms.

[0007] Occlusive dosage forms present some advantages over non-occlusive dosage forms, such as supporting the rate of drug penetration through the skin by keeping the thermodynamic activity of the drug close to its maximum (the thermodynamic activity of the drug in the skin formulation is proportional to the drug concentration and choice of vehicle and according to laws) thermodynamic maximum drug activity refers to the activity of the pure drug crystal). However, occlusive dosage forms also have several significant disadvantages. For example, occlusive dosage forms represent a significant potential for local skin irritation through prolonged skin contact with the drug, volatile components, substrate excipients, and the adhesive used to attach the occlusive element, e.g., a skin patch. In addition, the occlusive nature of certain occlusive dosage forms, such as a patch, also limits the skin's natural ability to "breathe," and thus increases the risk of irritation.

[0008] In addition to the abovementioned disadvantages of the occlusive dosage forms, significant serious hazards have been documented regarding the high drug load that is specific to patches. For example, several cases of abuse with remaining fentanyl in patches with fentanyl have been reported. See, Marquardt KA, Tharratt RS, "Inhalation abuse of fentanyl patch.", J Toxicol Clin. Toxicol. 1994; 32 (1): 75-8 .; Marquardt KA, Tharratt RS, Musallam NA, "Fentanyl remaining in a transdermal system following three days of continuous use.", Ann Pharmacother. 1995 Oct; 29 (10): 969-71 .; Flannagan LM, Butts JD, Anderson WH., "Fentanyl patches left on dead bodies - potential source of drug for abusers.", J Forensic Sci. 1996 Mar; 41 (2): 320-1. Severe cases of accidental intoxication have also been documented. See Hardwick Jr., W, King, W., Palmisano, P., "Respiratory Depression in a Child Unintentionally Exposed to Transdermal Fentanyl Patch", Southern Medical Journal, September 1997.

[0009] Plaster type products typically contain patient information that clearly indicates the risk discussed above. For example, OXYTROL ™ (oxybutynin patch commercialized by WATSON Pharmaceuticals, Inc. USA) contains information for the patient that indicates the following warning: "Since the patch will still contain some oxybutynin, discard it so that it is not accidentally worn or swallowed by another person, especially a child" A high level of active drug residue is therefore a critical disadvantage of patches. Such cases could not occur using gel formulations.

[0010] Although attempts have been made to overcome the disadvantages associated with both occlusive and non-occlusive forms of the drug, such attempts have been in vain. For example, as noted above, one of the disadvantages of non-occlusive dosage forms is that the formulation evaporates that is left open in the atmosphere. The formulation of non-occlusive supersaturated systems could achieve the perfect combination, but transdermal formulations that rely on supersaturation technologies present formulation instability as a major disadvantage, both before and during application to the skin due to solvent evaporation. Davis AF and Hadgraft J - Supersaturated solutions as topical drug delivery systems, Pharmaceutical Skin Penetration Enhancement, Marcel Dekker Inc, New York (1993) 243-267 ISBN 0 8247 9017 0.

[0011] Particularly unique physicochemical changes occur during the evaporation of the solvent system, which results in modifications of the concentration of active agent, which can even lead to precipitation of the drug, thereby changing the driving force of the diffusion of the formulation. See Ma et al., Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 22 (1995). Consequently, transdermal absorption of the active agent can be quite different from that when a solvent is present.

[0012] In addition, controlling crystallization of the drug is of particular interest to non-occlusive transdermal patches. Campbell et al. they resorted to a method of heating the crystalline hydrate to a temperature above the melting point to prevent crystallization of the formulation. See, US Patent No.

4,832,953. Ma et al. they found that PVP added to the matrix acts as an effective crystallization inhibitor for transdermal norethindrone acetate delivery systems. See, Int. J. of Pharm. 142 (1996) p. 115119). DE-A-4210711 confirms that cholesterol and SiO₂ are crystallization inhibitors for the 17-beta-estradiol transdermal delivery system. WWO 95/18603 describes soluble PVP as a crystalline inhibitor for patches and it has been confirmed that soluble PVP increases the solubility of the drug without adversely affecting the tack or drug delivery rate of the pressure-sensitive pressure sensitive adhesive composition.

[0013] Additionally, Biali et al. Reported to inhibit crystallization in transdermal patches. See, US Patent 6,465,005, which describes that the use of a steroid (e.g. estradiol) as an additive in the process of making or storing a transdermal element acts as a crystallization inhibitor during storage of the element.

[0014] Further, transdermal delivery from semi-solid formulations meets conflicting requirements. The drug delivery system should allow the absorption of a significant amount of active drug through the skin in the shortest possible time in order to prevent contamination of individuals, transfer to clothing or accidental removal. The drug delivery system should also provide sustained release of the active drug ideally for 24 hours, so that only once daily application is required. This drug delivery system should also prevent crystallization in the area of ​​the application surface.

[0015] Drug delivery systems having such properties can be achieved by combining different solvents. Volatile solvent can be defined as a solvent that changes easily from solid or liquid to vapor so that it easily evaporates at normal temperatures and pressures. Here are the data for some common solvents where volatility is from 3

EP 1670 433 B1 reflected by molar enthalpy of evaporation Δ_ναρΗ, defined as the change in enthalpy in the conversion of one mole of liquid into gas at a constant temperature. Values ​​are given when available, both at normal boiling point t_b, relative to a pressure of 101.325 kPa (760 mmHg) and at 25 ° C (from "Handbook of Chemistry and Physics, David R. Lide, 79th edition (1998-1999) - Enthalpy of vaporization (6-100 to 6115). Stanislaus et al. (US Patent No. 4,704,406 of October 9, 2001) referred to as a volatile solvent, a solvent whose vapor pressure is above 35 mm Hg when the skin temperature is 32 ° C, and as a non-volatile solvent, a solvent whose vapor pressure is below 10 mm Hg at skin temperature 32 ° C. Examples of non-volatile solvents include, but are not limited to, propylene glycol, glycerin, liquid polyethylene glycols or polyoxyalkylene glycols. Examples of volatile solvents include, but are not limited to, ethanol, propanol or isopropanol.

Table 1 - Enthalpy of evaporation of certain solvents

<td></td><td>tb</td><td>^ ap^{H (vol}b)</td><td>ΔvapH (25 ° C)</td>

<td>Ethanol</td><td> 78,3</td><td> 38,6</td><td> 42,3</td>

<td>Propan-2-ol (isopropanol)</td><td> 82,3</td><td> 39,9</td><td> 45,4</td>

<td>propanol</td><td> 97,2</td><td> 41,4</td><td> 47,5</td>

<td>Butan-2-ol</td><td> 99,5</td><td> 40,8</td><td> 49,7</td>

<td>Butan-1-ol</td><td> 117,7</td><td> 43,3</td><td> 52,4</td>

<td>Ethylene glycol monomethyl ether</td><td> 124,1</td><td> 37,5</td><td> 45,2</td>

<td>Ethylene glycol monoethyl ether</td><td> 135,0</td><td> 39,2</td><td> 48,2</td>

<td>Ethylene glycol monopropyl ether</td><td> 149,8</td><td> 41,4</td><td> 52,1</td>

<td>1,2-propylene glycol</td><td> 187,6</td><td> 52,4</td><td>unavailable</td>

<td>Diethylene glycol monomethyl ether</td><td> 193,0</td><td> 46,6</td><td>unavailable</td>

<td>Diethylene glycol monoethyl ether</td><td> 196,0</td><td> 47,5</td><td>unavailable</td>

<td>1,3-propylene glycol</td><td> 214,4</td><td> 57,9</td><td>unavailable</td>

<td>Glycerine</td><td> 290,0</td><td> 61,0</td><td>unavailable</td>

[0016] Numerous authors have investigated evaporation and transdermal permeation from solvent systems. For example, Spencer et al. (Thomas S. Spencer, "Effect of volatile penetrants on in vitro skin permeability", AAPS workshop took place in Washington DC v. 31 Oct-1, Nov., 1986) determined that the relationship between evaporation and permeation is not absolute and depends on many parameters, such as, for example, tissue hydration or tissue solubility. Stinchcomb et al. reported that the initial uptake of the chemical (hydrocortisone, flurbiprofen) from the volatile solvent system (acetone) is faster than from the non-volatile solvent system (aqueous system). From an aqueous solution, near the saturation solubility of a chemical agent, the uptake driving force remains more or less constant throughout the exposure period. Conversely, for a volatile substrate that begins to evaporate from the moment it is applied, the concentration of the chemical on the surface increases over time to the point where the solvent disappears; the patient then remains with a solid film with a chemical agent from which further uptake into war4

Epidermis may be very slow and dissolution limited. [0017] Special attention should be paid to the risk assessment after dermal exposure to volatile substrates, thus, until the contact between the evaporating solvent and the skin lasts (Audra L. Stinchcomb, Fabrice Pirot , Gilles D. Touraille, Annette L. Bunge, and Richard H. Guy, "Chemical uptake into human stratum corneum in vivo from volatile and non-volatile solvents", Pharmaceutical Research, Vol. 16, No 8, 1999). Kondo et al. studied the percutaneous bioavailability of nifedipine in two-component rats (acetone and propylene glycol PG or isopropyl myristate IPM) or ternary solvent systems (acetonPG-IPM), compared with results from simple PG or IPM drug-saturated solvent systems. (Kondo et al. S, Yamanaka C, Sugimoto I., "Enhancement of transdermal delivery by superfluous thermodynamic potential. III. Percutaneous absorption of nifedipine in rats", J Pharmaco Biodyn. 1987

Grudź.10 (12): 743-9).

[0018] In US Patent 6,299,900 to Reed et al. discloses a non-occlusive transdermal or transdermal drug delivery system having an active agent, a safe and recognized sunscreen agent as an absorption promoter and optionally a volatile liquid. The invention describes a transdermal drug delivery system that includes at least one physiologically active agent or prodrug thereof and at least one low toxicity absorption promoter being a safe, skin-tolerated ester sunscreen. The composition comprises an effective amount of at least one physiologically active agent, at least one non-volatile cutaneous absorption promoter, and at least one volatile liquid.

[0019] US Patent 5,891,462 to Carrara discloses a pharmaceutical formulation in the form of a gel suitable for administering a transdermal active agent from the estrogen class or progestogen class or a mixture of both, comprising lauryl alcohol, diethylene glycol monoethyl ether and propylene glycol as absorption promoters.

[0020] Mura et al. describe the combination of diethylene glycol monoethyl ether and propylene glycol as a composition of the transdermal absorption promoter for clonazepam (Mura P., Faucci MT, Bramanti G., Corti P., "Evaluation of transcutol as a clonazepam transdermal permeation enhancer from hydrophilic gel formulations", Eur. J. Pharm. Sci., 2000 Feb; 9 (4): 365-72) [0021] Williams et al. reports the effects of diethylene glycol monoethyl ether (TRANSCUTOL ™) in two-component cosolvent systems with water on the permeability of the model lipophilic drug across the human epidermal membrane and silasitc membrane (AC Williams, NA Megrab and BW Barry, "Permeation of oestradiol through human epidermal and silastic membranes from saturated TRANSCUTOL® / water systems ", in Prediction of Percutaneous Penetration, Vol. 4B, 1996). Many references may also illustrate the effect of TRANSCUTOL ™ as an active intradermal filler depot drug well known to those skilled in the art.

[0022] In US Patent 5,658,587 to Santus et al. disclosed transdermal therapeutic systems for delivering alpha adrenoceptor blocking agents using a solvent boosting system comprising diethylene glycol monoethyl ether and propylene glycol.

[0023] In US Patent 5,662,890 to Punto et al. disclosed alcohol-free skin tanning cosmetic compositions containing a combination of diethylene glycol monoethyl ether and dimethylisosorbide as absorption promoters.

[0024] In US Patent 5,932,243 to Fricker et al. discloses a pharmaceutical emulsion or microemulsion pre-concentrated for oral administration of a macrolide containing a hydrophilic carrier medium consisting of diethylene glycol monoethyl ether, glycofurol, 1,2-propylene glycol or mixtures thereof.

[0025] In US patents 6,267,985 and 6,383,471 to Chen et al. discloses pharmaceutical compositions and methods for improving the solubility of triglycerides and improving the delivery of therapeutic agents containing diethylene glycol monoethyl ether and propylene glycol as hydrophobic ions forming therapeutic agents.

[0026] In US Patent 6,426,078 to Bauer et al. discloses an oil-in-water microemulsion containing diethylene glycol monoethyl ether or propylene glycol as co-emulsifiers for lithophilic vitamins.

[0027] Many research experiments have been performed on diethylene glycol monoethyl ether (sold under the trade mark TRANSCUTOL ™ by Gattefosse) as an intradermal drug depot forming agent. For example, Ritschel, WA, Panchagnula, R., Stemmer, K., Ashraf, M., "Development of an intracutaneous depot for drugs. Binding, drug accumulation and retention studies, and mechanism depot for drugs", Skin Pharmacol, 1991 ; 4: 235-245; Panchagnula, R. and Ritschel, WA, "Development and evaluation of an intracutaneous depot formulation of corticosteroids using TRANSCUTOL® as a cosolvent, in vitro, ex vivo and in-vivo rat studies", J. Pharm. Pharmacology. 1991; 43: 609-614; Yazdanian, M. and Chen, E., "The effect of diethylene glycol monoethyl ether as a vehicle for topical delivery of ivermectin", Veternary Research Com. 1995; 19: 309-319; Pavliv, L., Freebem, K., Wilke, T., Chiang, CC., Shetty, B., Tyle, P., "Topical formulation development of a novel thymidylate synthase inhibitor for the treatment of psoriasis", Int. J Pharm., 1994; 105: 227-233; Ritschel, WA, Hussain, AS, "In vitro skin permeation of griseofulvin in rat and human skin from an ointment dosage form", Arzneimeittelforsch / Drug Res. 1988; 38: 16301632; Touitou, E., Levi-Schaffer, F., Shaco-Ezra, N., Ben-Yossef, R. and Fabin, B., "Enhanced permeation of theophylline through the skin and its effect on fibroblast proliferation", Int. J. Pharm., 1991; 70: 159166; Watkinson, AC, Hadgraft, J. and Bye, A., "Enhanced permeation of prostaglandin E2 through human skin in vitro", Int. J. Pharm., 1991; 74: 229-236; Rojas, J., Falson, F., Courraze, G., Francis, A., and Puisieux, F., "Optimization of binary and ternary solvent systems in the percutaneous absorption of morphine base", STP Pharma Sciences, 1991; 1: 71-75; Ritschel, WA, Barkhaus, JK., "Use of absorption promoters to increase systemic absorption of coumarin from transdermal drug delivery systems", Arzneimeittelforsch / Drug Res. 1988; 38: 1774-1777.

[0028] In US Patent 5, 580, 574 to CR Behl et al. discloses a pharmaceutical composition for transdermal delivery comprising a solvent system made from isopropanol, propylene glycol

EP 1670 433 B1, oleic acid, water and optionally an additional component such as diacetin, caprylic acid or transcutol. The composition may exist as a gel or as a concentrated solution. However, it is limited to transdermal administration of benzodiazepines or benzodiazepine antagonists to a host in need thereof, preferably as a reservoir-type transdermal patch, i.e. as an occlusive formulation.

[0029] Thus, there remains a need to provide a pharmaceutically acceptable transdermal or transmucosal pharmaceutical formulation or drug delivery system that exhibits the benefits of both occlusive systems (high thermodynamic activity) and non-occlusive systems (low irritation and sensitization potential and excellent skin tolerance), while bypassing the disadvantages of these systems. The new transdermal or transmucosal pharmaceutical formulation of the present invention will address this need.

SUMMARY OF THE INVENTION [0030] The transdermal or transmucosal pharmaceutical formulation of the present invention contains as active ingredient testosterone and a solvent system present in an amount sufficient to solubilize at least one active ingredient and inhibit crystallization of at least one active ingredient on the surface of the skin or mucosa of a mammal. Other advantages of the transdermal or transmucosal pharmaceutical formulation of the invention include reducing or preventing transfer of the formulation to clothing or others, reducing contamination of clothing by the formulation, modulating biodistribution of the active agent in different skin layers, and facilitating absorption of the active agent through the skin or mucosal surface, to name a few.

[0031] The new solvent system of the present invention includes monoalkyl ether present in an amount between about 1% and 30% by weight of the solvent system, glycol present in an amount between about 1% and 30% by weight of the solvent system. Monoalkyl ether and glycerol are present in a weight ratio of 1: 4 to 1:10. The solvent system further comprises a mixture of aklohol and water. The mixture is present in an amount between about 40% and 98% of the solvent system, wherein the alcohol is present in an amount of about 5% to 80% of the mixture and the water is present in an amount of about 20% to 95% of the mixture.

[0032] Surprisingly, it has been found that the combined use of diethylene glycol monoethyl ether and glycol in certain ratios, preferably in hydroalcoholic formulations, protects or significantly reduces the transfer of active drug (s) from transdermal semi-solid formulations to clothing or other surfaces. significantly reduces transmission to individuals and also protects or significantly reduces the loss of active drug (s) - and thus the loss of therapeutic efficacy - continuously for accidental removal due to daily activities such as washing, swimming or the like.

[0033] Other advantages of the present invention include the finding that the combination of monoalkyl ether and glycol at certain ratios exhibits synergistic activity and inhibits crystallization of active ingredient (s) in transdermal semi-solid formulations. Furthermore, it has been disclosed that, contrary to the basis of the invention described above, a completely unexpected control of the distribution of active drug (s) in different skin layers is achieved when the range of the monoalkyl ether: glycol ratio described is modified.

In the present invention simultaneously, but independently of the above-mentioned crystallization inhibiting effect.

[0034] In addition, glycol has been found to act as a modulator of the ability of the monoalkyl ether to build a drug depot in various skin layers. Also, a significant reduction in the non-absorbed active drug (s) remaining on the surface of the application results from the simultaneous, although independent, inhibition of crystallization and transdermal penetration of the drug, increased or not by the additional absorption promoter (s).

BRIEF DESCRIPTION OF THE DRAWINGS [0035]

Figure 1 is a schematic illustration of a diffusion cell used in a vertical diffusion cell used to test transdermal oxybutynin formulations in vitro;

Figure 2 is a graph illustrating the 24-hour in-vitro testosterone biodistribution of selected formulation examples disclosed herein;

Figure 3 is the in-vitro kinetic testosterone permeation profile of selected formulation examples disclosed herein;

Figure 4 is a graph of in-vitro 24-hour biodistribution of testosterone from selected formulation examples shown in Figure 4;

Figures 5A to 5H illustrate the results of crystallization kinetic studies of prior art compositions compared to the formulations of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [0036] The present invention relates to a new transdermal or mucosal pharmaceutical formulation. The transdermal or transmucosal non-occlusive pharmaceutical formulation includes as active ingredient testosterone and a solvent system present in an amount sufficient to solubilize the active ingredient and characterized in that it comprises: (i) a pharmaceutically acceptable diethylene glycol monoalkyl ether present in an amount between about 1% and 30% by weight solvent system; (ii) a pharmaceutically acceptable glycol present in an amount between about 1% and 30% by weight of the solvent system with diethylene glycol monoalkyl ether and glycol present in a weight ratio of 1: 4 to 1:10; (iii) a mixture of C2 to C4 alcohol and water, which mixture is present in an amount between about 40% and 98% of the solvent system, wherein the C2 to C4 alcohol is present in an amount of about 5% to 80% of the mixture and water is present in an amount of about 20% to 95% of the mixture; and (iv) wherein diethylene glycol monoethyl ether and glycol in combination are present in an amount of at least 15% and not more than 60% of the formulation, so that, compared to formulations containing the same ingredients, but in different amounts and ratios, the current system solvent (a) inhibits the crystallization of at least one active ingredient on the surface of the mammal's skin or mucosa, (b) reduces or prevents the transfer of the formulation to clothing or subsequent individuals, (c) modulates the biodistribution of at least one active ingredient in different skin layers, (d) facilitates the absorption of at least one active ingredient through the skin or mucosal surface of a mammal, or (e) provides a combination of one or more from (a) up to (d). In accordance with the present invention, a formulation for

Transdermal or transmucosal drug delivery is in the form of a semi-solid formulation, gel, cream, or ointment, lotion (i.e., emulsion or dispersion), solution, foam or spray. Although alternatives are also within the scope of the claims.

[0037] The expression "semi-solid" formulation means a heterogeneous system in which one solid phase is dispersed in the other liquid phase.

[0038] The expression "transdermal" delivery applicants intend to include both transdermal (or "transdermal") and transmucosal administration, i.e. delivery via drug passage through the skin or mucosal tissue into the blood stream.

[0039] The phrase "pharmaceutically active" or "physiologically active" to describe a "component" or "agent" as used herein means any chemical material or compound suitable for transdermal or transmucosal administration that induces the desired systemic effect.

[0040] The expression "therapeutically effective" amount of a pharmaceutically active agent means a non-toxic but sufficient amount of a compound to provide the desired therapeutic effect.

[0041] The expression "non-occlusive" system, as used herein, means a system that does not trap or separate the skin from the atmosphere by, for example, a patch system, attached reservoir, application chamber, tape, bandage, adhesive patch, or similar that remain on the skin at the application site for a long time.

[0042] The expression "pollution" or "transfer", as used herein, means the unintended presence of harmful substances in individuals or on surfaces by direct contact between individuals, between surfaces or between individuals and surfaces (and vice versa).

[0043] The expression "synergy", "synergism", "synergistic effect" or "synergistic effect" as used herein means the effect of the interaction or action of two factors, such that the result of the combined action is greater than expected as a simple combined combination of two factors operating separately.

[0044] The expression "modulate", "regulate" or "control" as used herein means to adapt or maintain with respect to the desired rate, degree or condition, how to adjust the permeation rate, crystallization rate, division of a pharmaceutically active ingredient in skin layers .

[0045] The expression "effective" or "suitable" absorption promoter or combination, as used herein, means an absorption promoter or combination that will provide the desired increase in skin permeability and, accordingly, the desired depth of penetration, rate of administration, and amount of drug administered.

[0046] The expression "diethylene glycol monoalkylene ether" means a chemical compound having the general formula C₄H₁₀ABOUT₃(C_nH_2n+₁), in which n = 1-4. Further, the term "glycol" includes a wide range of chemical compounds including, but not limited to, propylene glycol, dipropylene glycol, butylene glycol and

Polyethylene glycols having the general formula HOCH₂(CH₂OH)_nCH₂OH in which n (number of oxyethylene groups) = 4-200.

[0047] The expression "thermodynamic activity" of a substance means the form of energy involved in the penetration of this substance through the skin. The chemical potential of a substance is defined in thermodynamics as the partial molar free energy of a substance. The difference between the chemical potential of the drug outside and inside the skin is a source of energy for the processes of penetration through the skin.

[0048] The expression "absorption promoter" as used herein means an agent that improves the transdermal transport speed of active agents through the skin or the use and delivery of active agents to organisms such as animals, for topical application or topical application, or for systemic delivery.

[0049] The expression "stratum corneum" as used herein means the outer layer of the skin, which includes about 15 layers of terminally differentiated keranocytes, mainly made of the protein-like keratin material, patterned as "bricks and mortar" with a mortar composed of a lipid matrix produced mainly from cholesterol, ceramides and long chain fatty acids. The stratum corneum forms a barrier that limits the rate of diffusion of the active agent through the skin.

[0050] The expression "depot in the skin" as used herein means a reservoir or bed of active agent and cutaneous absorption promoter in the stratum corneum, either intracellularly (in keranocytes) or intercellularly.

As stated above, the present invention relates to transdermal or transmucosal drug delivery formulations. The invention more particularly relates to a non-occlusive transdermal or transmucosal formulation, preferably in the form of a gel, for use in delivering at least one pharmaceutically active ingredient to a warm-blooded animal. The formulations of the present invention can be used for topical or systemic delivery.

[0052] The formulation may include an absorption promoter, gelling agent, preservative, antioxidant, buffer, humectant, complexing agent, moisturizing agent, surfactant, emollient or any combination thereof. The active agent is testosterone.

[0053] In one embodiment, the pharmaceutical formulation includes testosterone as the active agent and diethylene glycol monoalkyl ether and glycol in a 1: 4 weight ratio to 1:10.

[0054] In another aspect of the invention, there is provided a method of delaying or inhibiting crystallization of an active agent in a transdermal or transmucosal formulation. It has surprisingly been found that the present invention delays or inhibits the crystallization of the active agent on the surface of the skin or mucosa for a significant period. One problem with the crystallization of the drug on the skin is that the crystals have difficulty passing through the skin or mucosal barrier. Thus, the active factor stays on after 10

EP 1670 433 B1 for an extended period of time. In fact, there is an increase in the likelihood that the active agent will transfer to clothing or contaminate another individual who comes in contact with the user of the pharmaceutical formulation. The present invention has at least three advantages by inhibiting or delaying crystallization of the active agent. Delaying or inhibiting the active agent will increase the absorption of the drug through the skin or mucosal barrier. Accordingly, the transfer of the pharmaceutical formulation to clothing is reduced. In addition, contamination of other active agents is reduced.

[0055] In accordance with the present invention, the transdermal or transmucosal pharmaceutical formulation is a drug delivery formulation comprising the active ingredient and a solvent system. The solvent system of the invention includes a pharmaceutically acceptable monoalkyl ether, a pharmaceutically acceptable glycol, and a mixture of alcohol and water.

[0056] For example, the monoalkyl ether is diethylene glycol monomethyl ether, diethylene glycol monoethyl ether or a mixture thereof. Also, for example, glycol is propylene glycol, dipropylene glycol or a mixture thereof. Monoalkyl ether and glycol are present in an amount between about 1% and 30% w / w. each and are present in a ratio from 1: 4 to 1:10. In a preferred embodiment, the pharmaceutically acceptable monoalkyl ether is diethylene glycol monoethyl ether and the glycol is propylene glycol.

[0057] Preferably, the solvent system comprises a combination of volatile and non-volatile solvents. Examples of non-volatile solvents include, but are not limited to, propylene glycol, glycerin, liquid polyethylene glycols or polyoxyalkylene glycols. Examples of volatile solvents include, but are not limited to, ethanol, propanol or isopropanol. Preferably the volatile solvent is alcohol C₂-C₄. For example, alcohol C.₂-C₄ preferably ethanol, isopropanol or a mixture thereof. Alcohol C.₂-C₄ is present in an amount between about 5 and 80% w / w and preferably between 15 and 65%, and more preferably between 20 and 50%.

[0058] It is to be understood that "active agent" is intended to mean a single active agent or a combination of more than one active agent. The amount of systemically and / or locally active agent contained in the formulation depends on the extent to which an increase in permeation is achieved.

[0059] Also in accordance with the invention, absorption promoters may be additionally incorporated into the pharmaceutical formulation. Absorption promoters include, but are not limited to, sulfoxides such as dimethyl sulfoxide and decyl methyl sulfoxide; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, poloxamer (231, 182, 184), tween (20, 40, 60, 80) and lecithin; 1-substituted azacycloheptan-2-ones, especially 1-n-dodecylcycloazacycloheptan-2-one; fatty alcohols such as lauric alcohol, myristyl alcohol, oleyl alcohol and the like; fatty acids such as lauric acid, oleic acid and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, methyl propionate and ethyl oleate; polyols and their esters such as propylene glycol, ethylene glycol, glycerol, butanediol, polyethylene glycol, and polyethylene glycol monolaurate, amides and other nitrogen compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1 -methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine, terpenes; alkanones and acids

Organic compounds, especially salicylic acid and salicylates, citric acid and succinic acid. As noted earlier, "Percutaneous Penetration Enhancers", ed. Smith et al. (CRC Press, 1995) provides an excellent overview of the field and further information regarding possible secondary promoters to be used in conjunction with the present invention. More absorption promoters suitable for use with the present invention may be known to those skilled in the art. The absorption promoter is present in an amount of from about 0.1 to about 30.0% w / w. depending on the type of relationship. Preferably, the absorption promoters are fatty alcohols and fatty acids, and more preferably fatty alcohols. Preferably the fatty alcohols have the formula CH₃(CH₂) N (CH)_mCH₂OH in which n is in the range of (8-m) to (16-m), m = 0-2.

[0060] The pharmaceutical formulation of the invention may further comprise a gelling agent or thickening agent, e.g. carbomer, carboxyethylene or polyacrylic acid such as carbomer 980 or 940 NF, 981 or 941 NF, 1382 or 1342 NF, 5984 or 934 NF, ETD 2020, 2050, 934P NF, 971P NF, 974P NF and carbomer derivatives; cellulose derivatives such as ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), ethyl hydroxyethyl cellulose (EHEC), carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), etc .; natural gums such as gum arabic, xanthan gum, guar gums, alginates, etc. poly (vinylpyrrolidone) derivatives; poly (oxyethylene-oxypropylene) copolymers, etc .; others (chitosan, polyvinyl alcohols), pectins, various types of veegum and the like. Other suitable gelling agents for using the present invention include, but are not limited to, carbomers. Alternatively, other gelling agents or a viscosifying agent known to those skilled in the art may also be used. The gelling agent or thickener is present in an amount of from about 0.2 to about 30% w / w. depending on the type of polymer as known to a person skilled in the art.

[0061] The transdermal and transmucosal pharmaceutical formulation may further contain preservatives such as benzalkonium chloride and derivatives, benzoic acid, benzyl alcohol and derivatives, bronopol, parabens, centrimide, chlorhexidine, cresol and derivatives, imidourea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric salts, thimerosal, sorbic acid and derivatives. The preservative is present in an amount of from about 0.01 to about 10% w / w. depending on the type of relationship.

[0062] The transdermal and transmucosal pharmaceutical formulation may further contain an antioxidant such as, but not limited to, tocopherol and derivatives, ascorbic acid and derivatives, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, malic acid, propyl gallate, disulfates and derivatives. The antioxidant is present from about 0.001 to about 5.0% w / w. Depending on the type of relationship.

[0063] Also in accordance with the invention, the formulation may further contain buffers such as carbonate buffers, citrate buffers, phosphate buffers, acetate buffers, hydrochloric acid, lactic acid, tartaric acid, diethylamine, triethylamine, diisopropylamine, and aminomethylamine. Although other buffers, such as those known in the art, may also be included. The buffer can replace up to 100% of the amount of water in the formulation.

[0064] In one embodiment, the transdermal or transmucosal pharmaceutical formulation further comprises a humectant such as glycerin, propylene glycol, sorbitol, triacetin. The humectant is present in an amount from

About 1 to 10% w / w depending on the type of relationship.

[0065] The present formulation may further contain a complexing agent such as edetic acid. The complexing agent is present from about 0.001 to about 5% w / w. depending on the type of relationship.

[0066] Also in accordance with the invention, the formulation comprises a moisturizing agent such as sodium docusate, polyoxyethylene alkyl ethers, polyoxyethylated castor oil derivatives, polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate. The moisturizing agent is added in an amount of from about 1.0 to about 5% w / w. depending on the type of relationship.

[0067] In addition, the formulation may contain anionic, nonionic or cationic surfactants. The surfactant is present in an amount of from about 0.1 to about 30% w / w. depending on the type of relationship.

[0068] Also in accordance with the present invention, the formulation contains emollients such as, but not limited to, cetyl stearyl alcohol, synthetic olbrot, cholesterol, glycerin, glycerol fatty esters, isopropyl myristate, isopropyl palmitate, lecithin, light mineral oil, mineral oil, petroleum jelly, lanolin and their combinations. The emollient is present in an amount from about 1.0 to about 30.0% w / w. depending on the type of relationship.

[0069] In another aspect of the present invention there is provided a method of delaying or inhibiting crystallization of an active agent in a transdermal or transmucosal pharmaceutical formulation. The method comprises preparing a formulation comprising at least one active agent and a solvent system that includes a pharmaceutically acceptable diethylene glycol monoalkyl ether and glycerol present in a weight ratio of 1: 4 to 1:10.

[0070] Preferably, diethylene glycol monoalkyl ether and glycol in combination are present in an amount of at least 15% and not more than 60% of the formulation.

[0071] Preferably, the method reduces or inhibits crystallization of the active agent, such that it facilitates or increases absorption and penetration through the skin or mucosal surface to which it is applied. Preferably, the formulation comprises an absorption promoter to increase the permeability of the active agent through the surface of the skin or mucosa. For example, the formulation may further contain lauryl alcohol or myristyl alcohol in an amount between 0.5 to 2% by weight of the total formulation.

EXAMPLES [0072] The following examples are illustrative and should not be construed as limiting the invention.

Example 1 [0073] A gel containing 1.00% by weight (w / w) of testosterone, 5.00% (w / w) of monoethyl ether

EP 1670 433 B1 diethylene glycol, 6.00% (w / w) propylene glycol, 46.28% (w / w) ethanol, 38.11% (w / w) purified water, 1.20% (w / w) carbomer (CARBOPOL ™ 980 NF), 0.35% (w / w) triethanolamine, 0.06% (w / w) edetate disodium salt (EDTA), 2.00% (w / w) lauryl alcohol was prepared by dissolving the active ingredient (if not soluble in water) in a mixture of ethanol / propylene glycol / diethylene glycol monoethyl ether / lauryl alcohol. Then EDTA solution was added and the carbomer was completely dispersed in a hydroalcoholic solution with mechanical stirring at room temperature at an appropriate speed ensuring good homogenization of the formulation, avoiding clumping and air entrapment. Finally, triethanolamine was added with stirring to form a gel.

Example 2 [0074] In accordance with the production techniques described in Example 1, a gel consisting of 1.00% by weight (w / w) testosterone, 5.00% (w / w) diethylene glycol monoethyl ether was prepared, 30.0 % (w / w) propylene glycol, 34.31% (w / w) ethanol, 28.07% (w / w) purified water, 1.20% (w / w) carbomer (CARBOPOL ™ 980 NF), 0.35% (w / w) triethanolamine,

0.06% (w / w) EDTA disodium salt.

Example 3 [0075] Gel composed of 1.00% by weight (w / w) testosterone, 0.10% (w / w) estradiol, 5.00% (w / w) diethylene glycol monoethyl ether (TRANSCUTOL ™ P), 30.0% (w / w) propylene glycol, 38.00% (w / w), ethanol, 25.40% (w / w) purified water, 0.50% (w / w) hydroxypropyl cellulose (KLUCEL ™ MF Pharm) was prepared by dissolving the active ingredient (if not soluble in water) in a mixture of ethanol / propylene glycol / diethylene glycol monoethyl ether / lauryl alcohol. Then purified water was added and hydroxypropyl cellulose was completely dispersed in an aqueous-alcoholic solution with mechanical stirring at room temperature at a suitable speed ensuring good homogenization of the formulation, avoiding clumping and entrapment of air until complete swelling.

COMPARATIVE EXAMPLES OF THE BIODYSTRIBUTION AND DRUG TRANSFER

- IN VITRO

Example 4 [0076] In vitro biodistribution and drug permeability experiments through pig ear skin were made using a diffusion chamber, which is schematically shown in Figure 1 (Franz Vertical Diffusion Chamber). In vitro studies of skin penetration through human skin are limited due to the lack of human skin availability. It is widely described in the literature that pig ear skin can be used as the closest model of human skin when assessing percutaneous absorption of chemical products.

[0077] Fresh skin from a pig's corpse ear obtained from a slaughterhouse was processed according to standard operating procedures. Ears were assessed for their integrity (without bites, scratches or eras14)

EP 1670 433 B1) and condition. The skin was cut out of the ears using scalpels avoiding perforation or any damage.

The excised skin samples were washed with PBS solution and placed on the surface for successive punching of skin discs. Pieces of skin discs were embedded between sections of a vertical diffusion chamber₂

1.77 cm surface area, with the epidermis layer from above. 50 mg of transdermal patches previously illustrated were applied to the epidermal layer, while the skin layer was in contact with the acceptor solution: 2.0% by weight / volume polyoxyethylene (20) oleyl ether (Oleth 20), with a 10 mM solution of PBS phosphate buffer, pH 7, 4. The acceptor chamber was kept at 35 ° C and the tests were carried out under non-occlusive conditions and at a mixing speed of 600 rpm. At the given time points, samples from the acceptor solution were taken and the acceptor chamber was immediately refilled with fresh solution. All samples taken from the acceptor solution (permeating drug) were analyzed using high-performance liquid chromatography (HPLC). After completing the permeability study and using the appropriate solvent formulation, all pieces of skin discs were examined for drug distribution in the skin layers: dermis, epidermis, and stratum corneum. The non-absorbed formulation was also tested. A mass balance was then carried out to assess the complete recovery / distribution of the drug over a period of time after administration / application of the medicinal product, taking into account the unadulterated formulation, the amount of drug in the stratum corneum and the amount of drug in the deepest layers of the skin (epidermis, dermis and acceptor solution). circulating blood). Various compartments were tested using the high performance liquid chromatography (HPLC) method.

Determination of cumulative drug that has permeated and drug flow (in vitro permeation study) ₂ [0078] For each study, the total amount of drug that permeated (mcg / cm) during the duration was determined ₂ transdermal examination and flow (mcg / cm / h).

Biodistribution study [0079] After completion of the in vitro permeability study, the distribution of the active compound in the various compartments was assessed as previously explained. To demonstrate an improvement in permeability using the invention disclosed herein, as well as an improvement in reducing the amount of drug that can potentially be transferred to clothing or partners, in vitro permeation studies and drug biodistribution studies of the examples using the agents of the invention were compared with examples made without The purpose of the invention was to present the results obtained using the invention disclosed herein, by conducting in vitro biodistribution studies and by estimating the amount of drug remaining on the skin surface that could potentially be transferred or transferred to other surfaces or partners when the formulation is used "in vivo".

Example 5 - Comparison between the formulation of the present invention and the prior art formulation [0080] Reference to "Examples" above for qualitative-quantitative formulations of the examples cited below.

EP 1670 433 B1

24-hour biodistribution of testosterone

Normalized recovery (% of total relative recovery) [0081]

Table I: 24-hour in vitro biodistribution of testosterone

<td rowspan="2">compartments</td><td colspan="3">(control)</td><td colspan="3">Example2 (TC: PG ratio 1: 6)</td><td colspan="3">(StosunekTC: PG 5: 1)</td>

<td>Average %</td><td>SD %</td><td>N</td><td>Average %</td><td>SD%</td><td>N</td><td>Average %</td><td>SD%</td><td>N</td>

<td>Non-absorbed formulation</td><td> 92,5</td><td> 20,1</td><td> 4</td><td> 66,5</td><td> 32,2</td><td> 4</td><td> 82,4</td><td> 15,9</td><td> 4</td>

<td>Stratum corneum</td><td> 5,7</td><td> 3,0</td><td> 4</td><td> 12,6</td><td> 8,3</td><td> 4</td><td> 6,6</td><td> 4,0</td><td> 4</td>

<td>Cutaneous acceptor</td><td> 1,8</td><td> 0,5</td><td> 4</td><td> 20,9</td><td> 4,8</td><td> 4</td><td> 11,1</td><td> 5,5</td><td> 4</td>

<td>TOTAL</td><td> 100,0</td><td></td><td></td><td> 100,0</td><td></td><td> 100,0</td><td> 100,0</td><td></td><td></td>

[0082] Table 1 above clearly shows a significant reduction in the amount of drug that is not absorbed when the transdermal or transmucosal formulation of the present invention is used compared to a transdermal or transmucosal formulation that does not contain a new ratio of monoalkyl ester and glycol. As shown, after 24 hours, a large amount of testosterone (92.5%) remained unabsorbed from the control composition that did not include the novelty of the present invention, on the contrary, Example 2 of the present invention had a significantly less non-absorbed drug, 66.5%. Figure 2 illustrates these results in graphic form.

[0083] Table 1 above and Figure 2 show that in the stratum corneum in Example 2, where the invention is present in a ratio of 1: 6, a higher amount of testosterone (12.6% versus 6, 6%) is present. This result shows that the accumulation of active drug in the outermost layer of skin or mucosa results from the combination of diethylene glycol monoethyl ether: propylene glycol in different ratios and does not depend only on the concentration of diethylene glycol monoethyl ether as expected in the previously described basis of the invention.

[0084] This biodistribution study demonstrates the usefulness of the present invention (i.e. the combination of diethylene glycol monoethyl ether and propylene glycol tested in this case at two extreme ratios: 1: 6 and 5: 1) and that the present invention significantly reduces formulation residues on the skin .

EP 1670 433 B1

Example 6 — Comparison between the formulation comprising the invention described herein in various ratios [0085] Three different formulations were prepared, each containing a constant concentration of diethylene glycol monoethyl ether (5% w / w) and a variable concentration of propylene glycol (6, 15 or 30% w / w) and drug permeability and biodistribution after 24 hours were compared; Examples 3, 5 and 9 above. The results of the permeability study are provided in Table III below.

24-hour penetration of testosterone in vitro [0086]

Table III: 24-hour permeation of testosterone in vitro

<td rowspan="2">Cza (hours)</td><td colspan="3">Accumulated testosterone - 24 hours ^ g / cm²) Average ± SD</td>

<td>Control</td><td>Example 1</td><td>Example 2</td>

<td> 0</td><td>H</td><td> 0</td><td> 0</td>

<td> 6</td><td> 3,9 ± 3,1</td><td> 2,1 ± 1,7</td><td> 1,5 ± 1,0</td>

<td> 12</td><td> 10,9 ± 6,1</td><td> 9,9 ± 8,3</td><td> 7,2 ± 5,6</td>

<td> 18</td><td> 16,9 ± 6,5</td><td> 21,4 ± 13,4</td><td> 18,1 ± 12,0</td>

<td> 24</td><td> 20,7 ± 6,7</td><td> 31,0 ± 14,5</td><td> 29,5 ± 14,6</td>

[0087] Table III shows that three different compositions, each having different ratios ranging from 1: 1.2 to 1: 6 diethylene glycol: propylene glycol monoethyl ether, result in significantly similar cumulative amounts of permeated testosterone. Figure 3 illustrates the relative kinetic profile of each of these three compositions.

[0088] Changes in the amount of formulations do not result in any significant change in permeation.

24-hour biodistribution of testosterone [0089] Normalized recovery (% of total relative recovery)

EP 1670 433 B1

Table IV: 24-hour biodistribution of testosterone

<td rowspan="3">compartments</td><td colspan="3">(control)</td><td colspan="3">Example</td><td colspan="3">(TC: PG ratio 5: 1)</td>

<td></td><td></td><td></td><td colspan="3">2 (TC: PG ratio 1: 6)</td><td></td><td></td><td></td>

<td>Dia. %</td><td>SD%</td><td>N</td><td>Dia. %</td><td>SD%</td><td>N</td><td>Dia. %</td><td>SD%</td><td>N</td>

<td>Non-absorbed formulation</td><td> 88,6</td><td> 4,1</td><td> 4</td><td> 79,0</td><td> 18,5</td><td> 4</td><td> 75,1</td><td> 16,0</td><td> 4</td>

<td>Stratum corneum</td><td> 2,6</td><td> 1,5</td><td> 4</td><td> 4,8</td><td> 2,2</td><td> 4</td><td> 8,1</td><td> 3,1</td><td> 4</td>

<td>Cutaneous epidermal acceptor</td><td> 8,8</td><td> 2,3</td><td> 4</td><td> 16,2</td><td> 4,8</td><td> 4</td><td> 16,8</td><td> 3,5</td><td> 4</td>

<td>TOTAL</td><td> 100,0</td><td></td><td></td><td> 100,0</td><td></td><td></td><td> 100,0</td><td></td><td></td>

[0090] As shown in Table IV above and in Figure 4, increasing the ratio of the present formulation from 1: 3 (5% w / w diethylene glycol monoethyl ether / 15% w / w propylene glycol) to 1: 6 in Example 2 (5% w / w diethylene glycol monoethyl ether / 30% w / w propylene glycol) gave only a 5% reduction in non-absorbed drug, but gave about 66% increase in drug distributed in the stratum corneum (stratum corneum). The drug, which is deeper in the skin layers, can be considered unchanged. This study shows that it is possible to modify the distribution of the active drug in the outermost layers of the skin or mucosa, while at the same time it does not significantly affect the distribution of the drug in the deepest layers of the skin or mucosa.

[0091] This direction of in vitro permeation and biodistribution studies clearly demonstrates that drug distribution is modulated by the formulation ratio. These in vitro permeation and biodistribution studies also clearly demonstrate that changes in the ratio in which the new formulation results in significantly different permeation. In addition, these in vitro permeation and biodistribution studies clearly show that the new formulation has independent effects.

Example 7 - Crystallization study [0092] Drug crystallization kinetics studies of the present invention were also conducted in which the new formulation of the present invention was compared with formulations having no new specific ratio. The aim was to establish a correlation between the crystallization kinetics of the new formulations of the present invention ("slow" or "fast" crystallization rate) with in vitro permeation and biodistribution results, and thus to determine the partner / surface transfer potential ("low" or "high" potential ).

[0093] Various active compounds have been evaluated in formulations containing the invention disclosed herein as compared to formulations not comprising the invention. The invention relates to the use of a certain combination of carriers that enhances or promotes the uptake of the drug from the skin while minimizing the amount of residue on the skin after application of the medicinal product to the skin.

[0094] Microscopic examination was carried out on individual gel formulations containing the invention described herein and the active compound compared to formulations that do not contain the invention and the same active compound. A placebo formulation was also used for the blind comparison.

[0095] Androgen compound, testosterone (octanol: water partition coefficient or Log P was about 3.3) and minoxidil (Log P about 1.2, therefore less lipophilic than testosterone) were used as drug models to illustrate the invention.

[0096] A sample (1 ml) of the formulations tested was placed on a glass plate and immediately spread with a coverslip to form a homogeneous gel layer. The glass plates with the sample were in all cases exposed to evaporation at a controlled room temperature (25 ° C) and observations and photos were made at different exposure times.

[0097] The photo illustrated here as Figures 5a to 5h were taken under the same conditions, i.e. the same time points (usually less than 5 minutes; 30 minutes; 2 hours for fast crystallizing formulations or 4 hours for slow crystallizing formulations; more than 8 hours in a certain case), at the same magnification (total X 6.5), in the same positions: the glass plate was set at the beginning of the test, and then it was not moved until the end of the test. Some slight differences in contrast or texture are attributed to solvent evaporation.

[0098] Figures 5a to 5h show the crystallization state of some formulations not containing the present invention 30 minutes after spreading the formulation on a glass plate.

Crystallization of testosterone formulations [0099] A comparative study focused on the crystallization rate of the testosterone formulation was undertaken in which the crystallization rate of the testosterone formulation of the present invention was compared with other testosterone formulations not containing the present invention. In this regard, the formulations (solutions or semi-solids) were spread on a slide and observed under a microscope for the appearance of crystal formation.

In the first study, the gel formulation of Example A was compared with the gel formulation of Example B in terms of crystallization rate. Example A was ANDROGEL®, and a 1% testosterone gel sold in the US for male hypogonadism. The composition of ANDROGEL® is as follows:

<td>Ingredient</td><td>Wt.% / Wt.</td>

<td>testosterone</td><td> 1,00</td>

<td>Carbomer C980 NF</td><td> 0,90</td>

<td>Isopropyl myristate</td><td> 0,50</td>

<td>Ethanol 96%</td><td> 71,4</td>

<td>Sodium hydroxide</td><td> 4,72</td>

<td>Purified Water</td><td>qs</td>

EP 1670 433 B1

Example A: Composition of ANDROGEL® [0100] Androgel® (Example A), which does not include the present invention, was compared with Example B, which also did not contain the present invention. As noted below, Example B is a testosterone gel containing diethylene glycol monoethyl ether and propylene glycol in a weight ratio (TC: PG) of 1: 1.2. Example A does not contain diethylene glycol monoethyl ether or propylene glycol.

<td>Ingredient</td><td>% w / w</td>

<td>testosterone</td><td> 1.00</td>

<td>Carbomer C980 NF</td><td> 1.20</td>

<td>Diethylene glycol monoethyl ether (TRANSCUTOL®, "TC")</td><td> 5,00</td>

<td>Propylene glycol ("PG")</td><td> 6.00</td>

<td>Edetate Disodium</td><td> 0.06</td>

<td>Ethanol 96%</td><td> 47,5</td>

<td>triethanolamine</td><td> 0,35</td>

<td>Purified Water</td><td>qs</td>

Results from Example A compared to Example B [0101] In Example A, crystallization was observed 10 minutes after applying the gel formulation to the cover slide. Similarly, crystallization was also observed in Example B after 10 minutes. Thus, no significant difference in crystallization rate was observed between Example A, ANDROGEL®, and the gel formulation of Example B, which includes diethylene glycol monoethyl ether and propylene glycol in a 1: 1.2 weight ratio.

[0102] A comparative study was also undertaken for the formulations in the solutions of Examples C and D below

Example C [0103]

<td>Ingredient</td><td>% w / w</td>

<td>testosterone</td><td> 1,00</td>

<td>Isopropyl myristate</td><td> 0,50</td>

<td>Ethanol 96%</td><td> 71,4</td>

<td>Purified Water</td><td>qs</td>

EP 1670 433 B1

Example D [0104]

<td>Ingredient</td><td>% w / w</td>

<td>testosterone</td><td> 1,00</td>

<td>Diethylene glycol monoethyl ether (TRANSCUTOL®, "TC")</td><td> 5,00</td>

<td>Propylene glycol ("PG")</td><td> 6,00</td>

<td>Edetate Disodium</td><td> 0,06</td>

<td>Ethanol 96%</td><td> 47,5</td>

<td>Purified Water</td><td>qs</td>

[0105] In Example C, crystallization was observed after one minute and in Example D after four minutes. Thus, formulations containing diethylene glycol monoethyl ether and propylene glycol in a 1: 1.2 weight ratio do not differ significantly from Reference Example A, neither as a gel formulation nor as a solution formulation. A third comparative study was undertaken in which propylene glycol was increased from 6.00% w / w up to 20% w / w in Examples E and F. (Viscosity was adjusted to ANDROGEL®; around 8000cP).

<td>EXAMPLE E</td><td></td>

<td>Ingredient</td><td>% w / w</td>

<td>testosterone</td><td> 1.00</td>

<td>Carbomer C980 NF</td><td> 0,60</td>

<td>Diethylene glycol monoethyl ether (TRANSCUTOL®, "TC")</td><td> 5,00</td>

<td>Propylene glycol ("PG")</td><td> 20,0</td>

<td>Edetate Disodium</td><td> 0,06</td>

<td>Ethanol 96%</td><td> 47,5</td>

<td>triethanolamine</td><td> 0,35</td>

<td>Purified Water</td><td>qs</td>

<td>EXAMPLE F: Solution</td><td></td>

<td>Ingredient</td><td>% w / w</td>

<td>testosterone</td><td> 1,00</td>

<td>Diethylene glycol monoethyl ether (TRANSCUTOL®, "TC")</td><td> 5,00</td>

<td>Propylene glycol ("PG")</td><td> 20,0</td>

<td>Edetate Disodium</td><td> 0,06</td>

<td>Ethanol 96%</td><td> 47,5</td>

<td>Purified Water</td><td>qs</td>

[0106] No crystallization was observed in Example E four hours after applying the formulation to the glass surface. Crystallization was observed after 30 minutes in Example F. Thus, when both the gel formulation and the formulation in solution contains diethylene glycol monoethyl ether and propylene glycol in a ratio of 1: 4, the crystallization rate of both formulations was significantly reduced compared with other tested examples.