Sustained-release topical pharmaceutical composition and related use

专利摘要:
PHARMACEUTICAL COMPOSITIONS OF SUSTAINED RELEASE FOR TOPICAL ADMINISTRATION AND USE OF THE SAME. The present invention relates to compositions and methods for providing sustained release of an active agent through the skin of a subject, wherein a percutaneous pharmaceutical composition comprising at least one fatty acid ester and a therapeutically effective amount of active agent.
公开号:BR112012010083B1
申请号:R112012010083-1
申请日:2010-10-27
公开日:2021-05-18
发明作者:Valérie Masini-Eteve；Denis Canet
申请人:Besins Healthcare Luxembourg Sarl；
IPC主号:

专利说明:

FIELD OF THE INVENTION
The present invention relates to compositions and methods for delivering a therapeutically active agent through the skin of a subject, e.g., for transdermal pharmaceutical compositions. BACKGROUND
It is well known that certain therapeutically active agents are not suitable for oral administration for various reasons associated, inter alia, with either a high level of metabolism in the liver ("first pass effect") or a high level of gastrointestinal degradation. Transdermal or transmucal formulations have been developed in order to overcome these drawbacks. Specifically, pharmaceutical compositions for transdermal or transmucosal administration have several advantages over oral forms, including eliminating the problems associated with metabolism of the therapeutically active agent by the liver and with gastric degradation of the active agent. However, transdermal and transmucosal compositions face problems associated with the kinetics of passage of therapeutically active agents from the surface of the skin into the bloodstream.
Indeed, the skin is a heterogeneous tissue, comprising two layers: the dermis and the outermost layer of epidermis, which can be further divided into the stratum corneum and viable epidermis. These layers provide the skin with barrier capabilities against the entry of foreign substances, such as drugs. The stratum corneum acts as a diffuse physical barrier, while the epidermis and dermis can also provide a biochemical or enzymatic barrier.
Studies concerning the absorption of therapeutically active agents through the skin have focused for the most part on improving the rate of absorption of active agent ingredients through the skin, rather than paying any attention to the fate of the absorbed active agents. For example, the use of permeation enhancers has been proposed in order to increase the initial rate of active agents penetrated through the skin. The term "permeation enhancer" generally refers to any molecule that promotes the reversible diffusion of an active agent through the skin or mucosal membranes, and any solubilizing agent that promotes the breakdown of the active agent between the vehicle and the horny layer of the epidermis or mucous membranes. Most enhancers affect the stratum corneum barrier capabilities, that is, they reversibly alter the stratum corneum structure, thus increasing the diffusivity and solubility of drugs. This fact increases the skin penetration of the active agents, but it can also result in the direct absorption of a large amount of the drug through the tissues, leading to a peak active agent concentration in the blood in the immediate hours after application of the composition. This initial peak is usually followed by a trough in blood concentrations before close application of the composition, which usually occurs many hours later, or once a day. Such a sudden increase in drug concentration in the blood can be dangerous for the patient as it may exceed the dose of drug tolerated by the body. Furthermore, as the total dose of active agent is delivered to the bloodstream and tissues in the first hours after application, the intended effects of the drug cannot withstand until the next application.
There remains a need, therefore, for transdermal pharmaceutical compositions capable of delivering at least a part of their active content in a controlled release manner, for example, through temporary storage in the dermis. SUMMARY
Described here are sustained release transdermal pharmaceutical compositions, and methods of making and using them. According to some embodiments, sustained release pharmaceutical compositions are provided for topical administration to a skin surface comprising: a pharmaceutically active agent comprising one or more steroids, a fatty acid ester, water, a C2-C6 monoalcohol and a fatty acid , wherein the weight:weight ratio of fatty acid ester in the composition to the total active agent in the composition is at least 4: 1 fatty acid ester:active agent, and preferably ranges from about 4: 1 to about 20 : 1.
In some embodiments, the composition additionally comprises a co-solvent, such as propylene glycol. In some embodiments, the co-solvent is present in an amount ranging from 0.01% to 7% by weight of the total weight of the pharmaceutical composition, or in an amount ranging from 3% to 7% by weight of the total weight of the pharmaceutical composition .
In some embodiments, the fatty acid ester is selected from the group consisting of ethyl oleate, isopropyl oleate, isopropyl myristate, isopropyl isostearate, isopropyl palmitate, ethyl octanoate, ethyl dodecanoate, ethyl linoleate , ethyl palmitoleate, ethyl isostearate and ethyl linolenate. In some embodiments, the fatty acid ester is the ester that would result from the reaction of the fatty acid formulated in the composition with an alcohol. In other embodiments, the fatty acid ester is not the ester that would result from the reaction of the fatty acid formulated in the composition with the alcohol formulated in the composition. In some embodiments, the fatty acid ester is present in an amount ranging from 0.01% to 5% by weight of the total weight of the pharmaceutical composition, or an amount ranging from 0.05% to 2.4% by weight of the total weight of the pharmaceutical composition, or in an amount ranging from 0.1% to 2.2% by weight of the total weight of the pharmaceutical composition.
In some embodiments, the fatty acid is a C8C22 fatty acid. In some embodiments, the fatty acid is selected from the group consisting of capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, isostearic acid, palmitoleic acid, linoleic acid, and linolenic acid. In a preferred embodiment, the fatty acid is oleic acid. In some embodiments, the fatty acid is present in an amount ranging from 0.01% to 5% by weight of the total weight of the pharmaceutical composition, or an amount ranging from 0.05% to 3.5% by weight of the weight total pharmaceutical composition, or in an amount ranging from 1.0% to 3.0% by weight of the total weight of the pharmaceutical composition.
In specific embodiments, the compositions comprise 2% ethyl oleate as the fatty acid ester, 2% oleic acid as the fatty acid, and 5% propylene glycol as the co-solvent, all by weight of the total weight of the pharmaceutical composition. . In other specific embodiments, the compositions comprise 0.3% ethyl oleate as the fatty acid ester, 0.3% oleic acid as the fatty acid, and 0.75% propylene glycol as the co-solvent, all by weight of the total weight of the pharmaceutical composition.
In some embodiments, the pharmaceutically active agent is selected from the group consisting of estrogens, antiestrogens or (SERMs), androgens, antiandrogens, progestins, and mixtures thereof. In some embodiments, the pharmaceutically active agent is selected from estradiol and progesterone, and the fatty acid ester is ethyl oleate. In other specific modalities, the pharmaceutically active agent is selected from testosterone and dihydrotestosterone (DHT), and the fatty acid ester is selected from ethyl oleate and isopropyl myristate. In some embodiments, the active agent is present in an amount ranging from 0.01% to 5% by weight of the total weight of the pharmaceutical composition.
In some embodiments, the alcohol is selected from the group consisting of ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, and mixtures thereof. In a preferred embodiment, the alcohol is ethanol. In some embodiments, alcohol is present in an amount ranging from 10% to 90% by weight of the total weight of the pharmaceutical composition, or in an amount ranging from 20% to 80% by weight of the total weight of the pharmaceutical composition, or in an amount ranging from 45% to 75% by weight of the total weight of the pharmaceutical composition.
According to other embodiments there are provided methods of preparing a sustained release pharmaceutical composition for topical administration to a skin surface which comprise a mixture of a pharmaceutically active agent comprising one or more steroids, a fatty acid ester, water, a C2-C6 monoalcohol and a fatty acid, wherein the weight:weight ratio of the fatty acid ester in the composition to the total active agent wherein said composition is at least 4: 1 5 fatty acid ester: active agent, preferably ranging from about 4:1 to about 20:1, Any composition as described above and below can be made by such methods.
According to other embodiments, methods are provided for providing a sustained release of a pharmaceutically active agent through the skin of a subject, comprising topically administering to the skin of the subject a pharmaceutical composition comprising a pharmaceutically active agent comprising one or more steroids, a fatty acid ester, water, a C2-C6 monoalcohol and a fatty acid, wherein the weight:weight ratio of the fatty acid ester in the composition to the total active agent in the composition is at least 4: 1 ester of fatty acid: active agent. Any composition as described above and below can be used in such methods. In specific embodiments, the fatty acid ester is present in the composition in an amount ranging from 0.1% to 20% by weight of the total weight of the pharmaceutical composition.
In some embodiments, sustained release of the pharmaceutically active agent through the skin is observed for at least 24 hours after its administration. In other modalities, sustained release of the pharmaceutically active agent through the skin is observed for at least 36 hours after its administration. In still other modalities, sustained release of the pharmaceutically active agent through the skin is observed at least 48 hours after its administration.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 represents the amount of progesterone delivered through the skin in 48 hours (flow, pg/cm2/h) for the different formulations tested in Example 5. («-Formulation 1; •-Formulation 2 ; A-Progestogel (1% hydroalcoholic progesterone gel) (Besins Healthcare)). Figure 2 represents the amount of estradiol delivered (μg) to-ii across the skin in 48 hours versus drug loading in an exemplary formulation (diamonds) and compared to Estrogel® (0.06% estradiol gel, square) (Ascend Therapeutics). Figure 3 represents the effect of oleic acid, propylene glycol and estradiol concentrations on total estradiol penetration (μg) over 48 hours. Figure 4 represents the effect of oleic acid, propylene glycol and estradiol concentrations on total estradiol penetration (μg) over 48 hours. 10 Figure 5 represents the effect of ethyl oleate and estradiol concentrations on total estradiol penetration (μg) over 48 hours. Figure 6 represents the effect of ethyl oleate and estradiol concentrations on total estradiol penetration (μg) over 48 hours. Figure 7 represents the flow profile (μg/cm2/h) over time for three compositions tested in Example 7. («-Formulation 301; •-Formulation 303; A-Formulation-309) Figure 8 represents the flow profile (μg/cm2/h) over time for three compositions tested in Example 7. («-Formulation 306; •-Formulation 307; A-Formulation-311) 20 Figure 9 represents the flow profile (μg /cm2/h) over time, for five compositions tested in Example 7. («-Formulation 302; «-Formulation 304; A-Formulation 305; ▼ -Formulation-308; ◄-Formulation 310) Figure 10 represents the solubility of ethyl oleate (g Z100g) 25 as a function of the concentration of ethanol (96%) (v/v) in a mixture containing 0.24% estradiol, 5% propylene glycol and 2% oleic acid, in weight, all in total weight of the composition. DETAILED DESCRIPTION
Few studies have investigated whether transdermally administered active agents pass directly through the skin into the bloodstream, or if they are first retained within a compartment within the skin that serves as an active agent storage depot, before being released for circulation. It is known from the article entitled "Skin Levels of Absorbed Material Will Be Systemically Absorbed " (Drugs and Pharmaceutical Science, Vol. 97, 235-239, 1999), that the skin can behave as a storage depot for absorbed materials. For example, a skin storage depot for chemicals has been described by Vickers, Adv. Biol.Skin Vol. 12, 177-89 (1972), to exist in the stratum corneum for topical application of lipophilic chemicals, such as steroids.
However, in accordance with the present invention, it has been found that a dermis storage depot can be more effective than a stratum corneum storage depot, and may provide a better means of regulating the diffusion kinetics of active agents in the tissue and better delivery of the effective drug over time. In fact, der-me constitutes the majority of the skin's mass. It contains dense blood and lymphatic vasculature, and is the drug absorption site for systemic circulation. The dermis, however, has rarely been identified as a site for the administration or deposition of substances, probably due to the difficulty in controlling the skin layer in which the active agent is effectively retained.
Thus, described herein are transdermal pharmaceutical compositions which exhibit advantageous properties and achieve advantageous results with respect to their drug delivery profiles. For example, modalities of the compositions described herein achieve systemic delivery of therapeutically active agent(s) through the outer layers of the skin to the dermis, where a depot is formed from which the active agent is delivered through the bloodstream during an extended period of time, such as over a period of time of at least 12 hours, at least 24 hours, at least 36 hours, or at least 48 hours. This can be seen, for example, when the active agent continues to be released into the bloodstream for up to 24 hours or more after washing the skin.
The compositions of the invention also advantageously achieve a high level of active agent release over a wide range of active agent concentrations. Furthermore, the compositions are formulated to promote the reproducibility of absorption levels between different applications and between different patients.
Thus, according to some embodiments, sustained-release transdermal pharmaceutical compositions are provided for topical administration to a skin surface comprising a pharmaceutically active agent and a fatty acid ester, wherein the weight:weight ratio of the fatty acid ester in the composition for the active agent in the composition is at least 4: 1 fatty acid ester: active agent, preferably ranging from 4: 1 to 20: 1. In some embodiments, the composition additionally comprises water, an alcohol and a fatty acid. In some embodiments, the composition additionally comprises a co-solvent, such as propylene glycol. Other conventional components for transdermal pharmaceutical compositions may also be included, as discussed in more detail below.
In particular, as discussed in more detail in the examples below, the present invention relates to the unexpected discovery that providing a fatty acid ester in at least a four-fold excess over the therapeutically active agent (on a w/w basis) results in a transdermal pharmaceutical composition with advantageous properties including sustained release, consistent delivery profiles across a range of active agent concentrations, and application-to-application and patient-to-patient reproducibility programs. While not wishing to be bound by any theory, this high fatty acid ester/active agent ratio is believed to facilitate the partitioning of the active agent into the dermis and the formation of a deposit within the dermis, resulting in dermis retention. mica of the active agent followed by sustained release into the bloodstream. Thus, the compositions and methods described herein also provide a method for increasing dermal retention of an active agent, and achieving sustained release delivery.
Thus, in accordance with some embodiments, a method is provided for providing a sustained release of a pharmaceutically active agent through the skin of a subject, comprising topically administering to the skin of the subject a pharmaceutical composition comprising a therapeutically effective amount of the active agent and a fatty acid ester, wherein the weight:weight ratio of the fatty acid ester in the composition to the active agent in the composition is at least 4:1 fatty acid ester:active agent. In some embodiments, the composition additionally comprises water, an alcohol and a fatty acid. In some embodiments, the composition additionally comprises a co-solvent, such as propylene glycol. Other conventional components for transdermal pharmaceutical compositions may also be included, as discussed in more detail below.
As used herein, the phrase "sustained" delivery means that the compositions continue to deliver the active agent for a period of time of at least 12 hours, at least 24 hours, at least 36 hours, or at least 48 hours, including a time period of at least 24 hours. For example, sustained release compositions may continue to deliver the active agent after the first 24 hours after application. In some embodiments, the sustained delivery compositions described herein continue to deliver a therapeutically effective amount of the active agent after the first 24 hours after application. Depending on the composition and active agent, this may constitute delivery after the first 24 hours of, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30% or more of the total quantity of active agent delivered. Again, depending on the composition and active agent, this may constitute delivery after the first 24 hours of, for example, at least 2%, at least 3%, at least 4%, at least 5%, or more of the amount total active agent in the applied composition. This can be seen, for example, when the active agent continues to be released into the bloodstream for up to 24 hours or more after application.
In some embodiments, the sustained delivery compositions described herein continue to deliver the active agent after the first 12, 24, 36, or 48 hours after application, at a level that is greater than the amount delivered during the same period of time by a comparable composition that does not include a fatty acid ester. As illustrated in Example 2, this can be seen, for example, by testing a composition as described herein and a comparable composition that does not include a fatty acid ester (e.g., a composition that is identical except for the absence of ester. of fatty acid) in an in vitro assay on Franz cells, where the compositions are applied to a skin sample in the Franz cell, left for 24 hours, then washed, and then drug delivery through the skin after washout (eg after the first 24 hours after application) is determined and compared.
The compositions and methods are described in more detail below, and illustrated in the examples. As used herein, and unless otherwise noted, "the" or "a" means "one or more".
The term "about" and the use of ranges generally, whether or not qualified by the term about, means that the number understood is not limited to the exact number set forth herein, and is intended to refer to ranges substantially within from the range quoted as long as it does not depart from the scope of the invention. As used herein, "about" will be understood by those of ordinary skill in the art and will vary to some extent from the context in which it is used. If there are uses of the term that are not clear to those of ordinary skill in the art, given the context in which it is used, "about" means up to plus or minus 10% of the particular term. Pharmaceutical Compositions As noted above, described herein are compositions which comprise a therapeutically effective amount of a therapeutically active agent and a fatty acid ester, wherein the proportion is weight; weight of fatty acid ester in the composition for the active agent in the composition is at least 4: 1 fatty acid ester; active agent, preferably ranging from 4:1 to 20:1. In particular embodiments, the compositions comprise a pharmaceutically active agent, a fatty acid ester, water, an alcohol and a fatty acid. In other particular embodiments, the composition additionally comprises a co-solvent, such as propylene glycol.
In specific embodiments, the composition comprises about 2% fatty acid (such as oleic acid), about 2% fatty acid ester (such as ethyl oleate), and about 5% co-solvent (such as such as propylene glycol). In other specific embodiments, the composition comprises 2% fatty acid (such as oleic acid), 2% fatty acid ester (such as ethyl oleate), and 5% co-solvent (such as propylene glycol). In other specific embodiments, the composition comprises about 0.3% fatty acid (such as oleic acid), about 0.3% fatty acid ester (such as ethyl oleate), and about 0.75 % co-solvent (such as propylene glycol). In other specific embodiments, the composition comprises 0.3% fatty acid (such as oleic acid), 0.3% fatty acid ester (such as ethyl oleate), and 0.75% co-solvent (such as propylene glycol). As noted above, as used herein, the term "about" encompasses plus or minus 10% of the amounts mentioned.
In some embodiments, the composition comprises the specified components. In some embodiments, the composition consists of the specified components. In other embodiments, the composition consists essentially of the specified components. As used herein, "consists essentially" of the specified components means that the composition includes at least the specified components, and may also include other components which do not materially affect the basic and novel features of the invention.
The specific components of the compositions are described in detail below. Active Agents The compositions described herein include at least one therapeutically active agent. The active agent can, for example, be a drug molecule of a generally hydrophobic nature, with a small size such as a molecular weight of less than 500 Daltons. In some modalities, the active agent is selected from steroids, including sex hormones and hormones. The term "sex hormone" refers to natural or synthetic steroid hormones that interact with vertebrate androgens or estrogen receptors, such as estrogens, antiestrogens (or SERMs), androgens, antiandrogens, progesterone, and mixtures thereof.
When the composition comprises more than one steroid, the weight:weight ratio of the fatty acid ester in the composition to the total amount of steroid in the composition is at least 4: 1 fatty acid ester:steroids, preferably ranging from 4 : 1 to 20: 1.
When the composition of the invention comprises one or more steroids and one or more other therapeutically active agents, the weight:weight ratio of the fatty acid ester in the composition to the total amount of active agents in the composition is at least 4: 1 ester of fatty acid: active agents. In other embodiments, the weight:weight ratio of fatty acid ester in the composition to the total amount of active agents in the composition is less than 4: 1 fatty acid ester:active agent, although the weight:weight ratio of acid ester fatty acid composition for the total amount of steroid in the composition is at least 4: 1 fatty acid ester: steroid.
For example, steroid hormones suitable for use in the compositions described herein include various natural and synthetic steroid hormones, including androgens, estrogens, progestins and derivatives thereof, such as, dehydroepiandrosterone (DHEA), androstenedione, androstenediol, dihydrotestosterone, testosterone, progesterone, progestin us, estriol, estradiol. Other suitable steroid hormones include glucocorticoids, thyroid hormone, calciferol, pregnenolone, aldosterone, cortisol and its derivatives. Suitable steroid hormones include especially sex hormones having estrogenic, progestational, androgenic, or anabolic effects, such as estrogen, estradiol and its esters, for example, valerate, benzoate, or undecylate, ethinylestradiol, etc.; progestagens, such as norethisterone acetate, levonorgestrel, chlormadinone acetate, cyproterone acetate, desogestrel, or gestodene, etc.; androgens, such as testosterone and its esters (undecylate, propionate, etc.), etc.; anabolics such as methandrostenolone, nandrolone and their esters. Estrogens
In specific modalities, the one or more estrogens are selected from the group consisting of natural estrogens, such as 17β-estradiol, estrone, conjugated equine estrogens, estriol and phytoestrogens; semi-natural estrogens such as oestradiol valerate; or synthetic estrogens such as ethinyl estradiol.
In some embodiments, the invention provides a pharmaceutical composition for topical administration to the skin surface that comprises water, at least one therapeutically active agent selected from estrogens, an alcohol, and a fatty acid ester. In some embodiments, the invention provides a pharmaceutical composition for topical administration to the skin surface which comprises water, at least one therapeutically active agent being estradiol, an alcohol, and a fatty acid ester. In particular embodiments of such compositions, when the active agent is estradiol, the composition does not further comprise the combination of progesterone, propylene glycol, oleic acid, ethyl oleate, hydroxypropylcellulose, ethanol and purified water. Antiestrogens
Antiestrogens are a class of pharmaceutically active agents now referred to as selective estrogen receptor modulators (SERMs), which were generally understood as compounds capable of blocking the effect of estradiol without exhibiting any estrogenic activity of its own. Such a description is now known to be incomplete, however. The term SERM has been used to describe compounds that, in contrast to pure estrogen agonists or antagonists, have a mixed and selective pattern of estrogen agonist-antagonist activity, which is largely dependent on the target tissue. The pharmacological purpose of these drugs is to produce estrogenic actions on those tissues where these actions are beneficial (such as bone, brain, liver) and to have no antagonist activity or activity in tissues such as breast and endometrium, in which the actions estrogens (cell proliferation) can be deleterious.
In specific embodiments, antiestrogens (SERMs) are selected from the group consisting of endoxifene, droloxifene, clomiphene, raloxifene, tamoxifene, 4-OH tamoxifene, toremifene, danazol, and their pharmaceutically acceptable salts. In a more particular embodiment, the invention provides a pharmaceutical composition for topical administration to the skin surface which comprises water, at least one therapeutically active agent selected from antiestrogens (SERMs) selected from the group consisting of clomiphene, raloxifene , droloxifene, endoxifene or their pharmaceutically acceptable salts, an alcohol, and a fatty acid ester.
In a particular embodiment, the invention provides a pharmaceutical composition for topical administration to the skin surface which comprises water, at least one therapeutically active agent selected from antiestrogens (SERMs), an alcohol, and a fatty acid ester . In some particular embodiments of such compositions, when the active agent is tamoxifen, the fatty acid ester is not isopropyl myristate. In other particular embodiments of such compositions, when the active agent is tamoxifen, the composition additionally comprises a fatty acid. In still other particular embodiments of such compositions, when the active agent is 4-OH tamoxifen, the fatty acid ester is not isopropyl myristate. In other particular embodiments of such compositions, when the active agent is 4-OH tamoxifen, the composition additionally comprises a fatty acid. Androgens
Androgens can be selected from the group consisting of the natural androgen, testosterone, and semi-synthetic or natural derivatives, for example methyltestosterone; physiological testosterone precursors such as dehydroepiandrosterone or DHEA, or alternatively prasterone and its derivatives, for example DHEA sulfate, ,-4-androstenedione and its derivatives; Testosterone metabolites, for example, dihydrotestosterone (DHT), obtained after the enzymatic action of 5-a-reductases; or substances with an androgenic-like effect, such as tibolone.
In a particular embodiment, the invention provides a pharmaceutical composition for topical administration to the skin surface which comprises water, at least one active agent selected from androgens, an alcohol, and a fatty acid ester. In particular embodiments of such compositions, when the active agent is testosterone or dihydrotestosterone (DHT), the composition also comprises a fatty acid as a penetration enhancer. Antiandrogens
Antiandrogens can be selected from the group consisting of steroid compounds, such as cyproterone acetate and medroxyprogesterone, or non-steroid compounds, such as flutamide, nilutamide or bicalutamide compounds.
In a particular embodiment, the invention provides a pharmaceutical composition for topical administration to the skin surface which comprises water, at least one active agent selected from antiandrogens, an alcohol, and a fatty acid ester. progestins
The progestin used in the pharmaceutical composition according to the invention may be selected from the group consisting of natural progestins, progesterone or its ester-type derivatives, and synthetic progestins of type 1, 2 or 3.
The first group comprises progesterone-like molecules or synthetic progestins 1 (SP 1) (pregnanes), for example the gesterone isomer (retrorogesterone), medrogesterone, and its derivatives norprogesterone (demegesterone or promegesterone).
The second group comprises 17α-hydroxyprogesterone derivatives or synthetic progestins 2 (SP2) (pregnanes), for example cyproterone acetate and medroxyprogesterone acetate.
The third group comprises noresteroids or synthetic progestins 3 (SP3), (strane or norandrostanes). These are 19-nortestosterone derivatives, for example norethindrone. This group also comprises gonane-like molecules, which are derived from these norandrostanes or estranes and have a methyl group at C18 and an ethyl group at C13. Examples that may be mentioned include norgestimate, desogestrel (3-ketodesogestrel) or gestodene. Tibolone, which has both progestin and androgenic activity, can also be advantageously selected in the pharmaceutical composition according to the invention.
In a particular embodiment, the invention provides a pharmaceutical composition for topical administration to the skin surface which comprises water, at least one therapeutically active agent selected from progestins, an alcohol, and a fatty acid ester. In particular embodiments of such compositions, when the active agent is progesterone, the composition does not further comprise the combination of estradiol, propylene glycol, oleic acid, ethyl oleate, hydroxypropylcellulose, ethanol and purified water.
In particular embodiments, the therapeutically active agent in the pharmaceutical composition according to the invention is a progestin, an estrogen or a combination of the two.
As noted above, when the composition comprises more than one steroid, the ratio weight:weight of fatty acid ester in the composition to the total amount of steroid active agent in the composition is at least 4: 1 fatty acid ester: active agent such as ranging from 4:1 to 20:1.
The amount of therapeutically active agent present in the composition will generally be influenced by the dose to be delivered for therapeutic effect and formulation considerations. Compositions generally include a therapeutically effective amount of active agent. As used herein, the phrase "therapeutically effective amount" means an amount (dosage) that achieves in an individual the specific pharmacological response for which the drug is administered. It is noteworthy that a "therapeutically effective amount" of a drug that is administered to a particular individual, in a particular case may not always be effective in treating the target conditions and diseases, although such dosage is considered to be a therapeutically effective amount by those of skill in the art. Those skilled in the art will recognize that the "therapeutically effective amount" may vary from patient to patient, or condition to condition, and may determine a "therapeutically effective amount" for a given patient/condition by route.
The therapeutically active agent is advantageously present in the composition in an amount ranging from about 0.01% to about 5%, or from 0.01% to 5%, including from about 0.02% to about 3%, or from 0.02% to 3%, such as from about 0.03% to about 2%), or from 0.03% to 2%, including from about 0.05 % to about 0.5%, or from 0.05% to 0.5%, such as from about 0.2% to about 0.4%, or from 0.2% to 0 .4%, these percentages being expressed by weight, relative to the total weight of the pharmaceutical composition.
According to an advantageous embodiment, when the active agent comprises a progestin, the progestin content ranges from about 0.01% to about 5%, including from about 0.05% to about 3%, such as from about 0.05% to about 3%. about 0.1% to about 1%, these percentages being expressed by weight, relative to the total weight of the pharmaceutical composition. Thus, the progestin content can range from 0.01% to 5%, including from 0.05% to 3%, such as from 0.1% to 1%,
According to another embodiment, when the active agent comprises an estrogen, the estrogen content ranges from about 0.01% to about 5%, including between about 0.02% to about 3%, such as from about 0.03% to about 2%, including from about 0.05% to about 0.50%, such as from about 0.20% to about 0.40%, these percentages being expressed in weight, relative to the total weight of the pharmaceutical composition. Thus, the estrogen content can range from 0.01% to 5%, including from 0.02% to 3%, such as between 0.03% and 2%, including from 0.05% to 0 .50%, such as from 0.20% to 0.40%, including from about 0.30% to 0.40%.
In a more preferred embodiment, when the active agent 5 comprises an estrogen, the estrogen content will range from about 0.30% to 0.40%. Fatty Acid Ester The compositions described herein comprise at least one fatty acid ester.
Suitable fatty acid esters for use herein include long-chain aliphatic fatty acid esters containing from 8 to 22 carbon atoms, such as from 12 to 20 carbon atoms. Fatty acid esters may be those that would result from the reaction of an alcohol with a fatty acid selected, in a non-limiting manner, from the group consisting of capric acid (10:00), lauric acid (12:0 ), myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0), oleic acid (18:1), isostearic acid (18:0), palmitoleic acid (16:1), linoleic acid (18:2) and linolenic acid (18:3).
Thus, for example, the fatty acid ester may optionally be selected from the group consisting of ethyl oleate, isopropyl oleate, isopropyl myristate, isopropyl isostearate, isopropyl palmitate, ethyl octanoate, dodecanoate of ethyl, ethyl linoleate, ethyl palmitoleate, ethyl isostearate and ethyl linolenate. In a particular embodiment, the fatty acid ester is an ester that would result from the reaction of an alcohol with oleic acid.
In one embodiment, the fatty acid ester is an ester that would result from the reaction of the fatty acid formulated in the composition with an alcohol. In other embodiments, the fatty acid ester is not an ester that would result from the reaction of the fatty acid formulated in the composition with an alcohol. In one embodiment, the fatty acid ester is not the ester that would result from the reaction of the fatty acid formulated in the composition with the alcohol formulated in the composition. For example, in the context of the present invention, it is believed that the advantageous results discussed herein, such as sustained delivery are due to the formation of a deposit in the dermis, can be observed without regard to the fatty acid ester formulated in the corresponding composition. to any fatty acid also formulated in the composition.
As noted above, that fatty acid ester is present in the composition in at least a four-fold excess over the therapeutically active agent (on a w/w basis), ie the weight:weight ratio of the fatty acid ester present in the composition for the active agent present in the composition is at least 4:1 fatty acid ester:active agent, preferably ranging from 4:1 to 20:1. In a preferred embodiment, the weight:weight ratio of fatty acid ester present in the composition for the active agent present in the composition is ranging from 4: 1 to 15: 1, preferably between 5:1 to 10: 1, and more preferably between 5:1 to 7: 1. Within these parameters , the fatty acid ester content in the pharmaceutical composition may range from about 0.1% to about 20% by weight, such as from about 0.2% to about 10% by weight, including between about 0 .5% to about 5% by weight, all based on the total weight of the pharmaceutical composition. Thus, the compositions may comprise fatty acid ester in an amount of from 0.1% to 20% by weight, such as from 0.2% to 10% by weight, including from 0.5% to 5% by weight.
In particular embodiments, the fatty acid ester content in the pharmaceutical composition can range from about 0.01% to about 5%, including from about 0.05% to about 2.4%, such as from about 0.1% to about 2.2%, these percentages being expressed in weight, relative to the total weight of the pharmaceutical composition. Thus, the fatty acid ester content can range from 0.01% to 5%, including from 0.05% to 2.4%, such as from 0.1% to 2.2%, Fatty acid
In some embodiments of the present invention, the composition can comprise at least one fatty acid that can be either saturated or unsaturated, such as a fatty acid penetration enhancer. Fatty acids suitable for use in accordance with the invention include long-chain aliphatic fatty acids containing from 8 to 22 carbon atoms, such as from 10 to 18 carbon atoms. Fatty acids can be selected, in a non-limiting manner, from the group consisting of capric acid (10:00), lauric acid (12:0), myristic acid (14:0), palmitic acid (16: 0), stearic acid (18:0); oleic acid (18:1), isostearic acid (18:0), palmitoleic acid (16:1), linoleic acid (18:2) and linolenic acid (18:3). In a particular embodiment, the fatty acid is oleic acid.
In a particular embodiment, the fatty acid formulated in the composition corresponds to the fatty acid ester also formulated in the composition, such as a composition comprising ethyl oleate and oleic acid. Thus, in a particular embodiment, the composition of the invention comprises both oleic acid and at least one of its corresponding esters. In other embodiments, the fatty acid formulated in the composition does not match the fatty acid ester also formulated in the composition.
The fatty acid content in the pharmaceutical composition according to the present invention will advantageously range from about 0.01% to about 5%, including from about 0.05% to about 3.5%, such as from about 1% to about 3%, these percentages being expressed by weight, relative to the total weight of the pharmaceutical composition. Thus, the fatty acid content can range from 0.01% to 5%, including from 0.05% to 3.5%, such as from 1% to 3%, Alcohol
As noted above, the compositions of the invention comprise at least one C2-C6 monoalcohol. As used herein "alcohol" refers to an organic molecule containing at least one carbon atom and only one alcohol group -OH (monoalcohol).
Examples of C2-C6 alcohols may include C2-C4 alcohols, such as ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, or mixtures thereof. Suitable C2-C6 monoalcohols for use in the compositions of the invention are ethanol and isopropanol.
The presence of such a C2-C6 monoalcohol can also accelerate the drying of the composition onto the skin. For that reason, C2-C6 monoalcohols can be chosen that have a boiling point in the range of about 70 to about 130°C, including in the range of about 75 to about 85°C.
Typically, the C2-C6 monoalcohol will be used in an amount ranging from about 10% to about 90%, including between about 20% to about 80%, such as from about 45% to about 75% ), these percentages being expressed by weight, relative to the total weight of the pharmaceutical composition. Thus, the C2-C6 monoalcohol can be present in an amount ranging from 10% to 90%, including from 20% to 80%, such as from 45% to 75%. Co-solvent
The pharmaceutical composition according to the invention may also comprise a co-solvent. Suitable co-solvents for use in pharmaceutical compositions are known in the art, such as polyols or polyglycols, advantageously selected from the group consisting of glycerol, propylene glycol and polyethylene glycol.
The co-solvent may be present in the composition of the invention in an amount ranging from about 0.01% to about 7%, including from about 3% to about 7%, such as from about 4% to about 6%, these percentages being expressed in weight, relative to the total weight of the pharmaceutical composition. Thus, the co-solvent may be present in an amount ranging from 0.01% to 7%, including from 3% to 7%, such as from 4% to 6%.
The co-solvent generally increases the solubility of the therapeutically active agent and in particular may contribute to keeping in solution the therapeutically active agent that remains on the surface of the skin once the alcohol has dried. For that reason, co-solvents can be selected which have a boiling point in the range of about 150°C to about 300°C, such as in the range of about 150°C to about 200°C. Gelling Agents Compositions of the invention may optionally comprise at least one gelling agent.
As used herein, the term "gelling agent" specifies a compound, optionally polymeric in nature, having the ability to form a gel when in contact with a specific solvent, water, for example. Gelling agents (e.g. thickeners) suitable for use in pharmaceutical compositions are known in the art. Gelling agents can act to increase the viscosity of the pharmaceutical compositions of the present invention. For example, a gelling agent can provide the composition with sufficient viscosity to allow easy application of the composition to the skin. Additionally or alternatively, gelling agents can act as solubilizing agents.
Examples of gelling agents include anionic polymers such as acrylic acid-based polymers (including polyacrylic acid polymers, eg Carbopol® by Noveon, Ohio), cellulose derivatives, poloxamers and poloxamines, more precisely, carbomers that are polymeric. 15 mers based on acrylic acid, for example Carbopol® 980 or 940, 981 or 941, 1342 or 1382, 5984, 934 or 934P (Carbopol® are generally acrylic acid polymers crosslinked with allyl sucrose or allylpentaerythritol), Ultrez, Pemulen TR1® or TR2® marketed by Lubrizol (high molecular weight acrylic acid copolymer and 10 C-C30 alkyl acrylate cross-linked with allyl pentaerythritol), Synthalen CR, etc.; cellulose derivatives, such as carboxymethylcelluloses and hydroxypropylcelluloses (Klucel®, for example Klucel HF® or Klucel® HPC sold by Hercules Incorporated), hydroxyethyl (celluloses, ethylcelluloses, hydroxymethylcelluloses, hydroxypropylmethylcelluloses, and the like, and mixtures thereof; poloxamers or polyethylene copolymers) 25 polypropylene such as Lutrol® grade 68 or 127, poloxamines and gelling agents such as chitosan, dextran, pectins and natural gums Any one or more of these gelling agents can be used alone or in combination in pharmaceutical compositions accordingly with the invention. In one aspect, the gelling agent is selected from the group consisting of polyacrylic acids, cellulosic acids, and mixtures thereof. In a preferred embodiment, the compositions of the invention comprise Pemulen® as a gelling agent.
Typically, the gelling agent will be used in an amount ranging from about 0.05% to about 5% by weight, including about 0.1% to about 3%, such as about 1.5. % to about 2.5% by weight, these percentages being expressed by weight, relative to the total weight of the pharmaceutical composition. Thus, the gelling agent may be present in an amount ranging from 0.05% to 5% by weight, including 0.1% to 3%, such as 1.5% to 2.5% by weight. Moisturizers
Compositions of the invention may optionally comprise at least one moisturizer. As used herein, "moisturizer" specifies an agent that hydrates the skin. Moisturizers suitable for use in pharmaceutical compositions are known in the art. Moisturizers can be used alone or in combination, for example a combination of two or three (or more) different moisturizers can be used. In some modalities, moisturizers are selected from emollients and/or humectants. As used herein, "emollients" specify substances that soften the skin and tend to improve skin hydration. Emollients suitable for use in pharmaceutical compositions are well known in the art, and include mineral oil, petrolatum, polydecene and isohexadecane, fatty acids and alcohols of 10 to 30 carbon atoms; pelargonic, lauric, myristic, palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachidic, behenic, euric and alcohol acids; triglyceride esters, castor oil, cocoa butter, safflower oil, sunflower oil, jojoba oil, cottonseed oil, corn oil, olive oil, cod liver oil, almond oil, avocado oil, palm oil, sesame oil, squalene, Kikui oil, soybean oil, acetoglyceride esters, ethoxylated glycerides, ethoxylated glyceryl monostearate, fatty acid alkyl esters having 10 to 20 carbon atoms, hexyl laurate, laurate isohexyl, isohexyl palmitate, isopropyl palmitate, decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stearate, diisopropyl adipate, diisohexyl adipate, diisopropyl sebacate, lauryl lactate myristyl lactate, acetyl lactate; alkenyl esters of fatty acids having 10 to 20 carbon atoms, oleyl myristate, oleyl stearate, oleyl oleate, fatty acid esters of ethoxylated fatty alcohols, polyhydric alcohol esters, mono and di-5 esters of ethylene glycol fatty acids, diethylene glycol mono- and di-fatty acid esters, polyethylene glycol, wax esters, beeswax, spermaceti, myristyl myristate, stearyl stearate, silicone oils, dimethicones, cyclomethicones. In some embodiments, the composition comprises one or more emollients that are liquid at room temperature.
As used herein, "humectants" specify hygroscopic substances that absorb water from the air. Suitable humectants for use in the invention include propylene glycol, glycerin, glyceryl triacetate, a polyol, sorbitol, maltitol, a polymeric polyol, polydextrose, quillaia, lactic acid, and urea.
Suitable moisturizers for use in the present invention can comprise amines, alcohols, glycols, amides, sulfoxides, and pyrrolidones. In one aspect, the moisturizer is selected from the group consisting of lactic acid, glycerin, propylene glycol, and urea.
In one embodiment of the invention, the moisturizer is used in an amount ranging from about 0.01% to about 30% by weight, including from about 0.05% to about 20% by weight, such as about from 0.1% to about 10% by weight, including from about 0.5% to about 5% by weight, these percentages being expressed by weight relative to the total weight of the pharmaceutical composition. Thus, for example, a moisturizer can be used in an amount ranging from 0.01% to 30% by weight, including from 0.05% to 20% by weight, such as from 0.1% to 10% by weight, including from 0.5% to 5% by weight.
In one embodiment, the composition comprises glycerin in an amount ranging from about 0.01% to about 30% by weight, including from about 0.05% to about 20% by weight, such as from from about 0.1% to about 10% by weight, including from about 0.5% to about 5% by weight, these percentages being expressed by weight, relative to the total weight of the pharmaceutical composition. Thus, a composition may comprise glycerin in an amount ranging from 0.01% to 30% by weight, including from 0.05% to 20% by weight, such as from 0.1% to 10% by weight, including from 0.5% to 5% by weight. Aqueous Vehicle
As noted above, the composition of the invention comprises an aqueous vehicle, and thus includes water. Suitable aqueous vehicles for pharmaceutical compositions are known in the art.
According to one aspect of the invention, the aqueous vehicle comprises, in addition to water, ingredients useful in adjusting the pH, for example at least one buffering agent, which advantageously makes it possible to maintain the pH of the composition between about 4 and about 10, such as between about 5 and about 9, or between about 6 and about 8, including 4 to 10, 5 to 9 and 6 to 8.
According to a particular embodiment of the pharmaceutical composition according to the invention, buffers are selected from the group consisting of: basification or basic buffers, such as a phosphate buffer (e.g. monobasic or dibasic sodium phosphate ), a citrate buffer (eg, sodium citrate or potassium citrate), sodium carbonate, sodium bicarbonate, including a mixture of sodium carbonate and sodium bicarbonate, or neutral buffers such as a Tris buffer ( for example, tris maleate), or a phosphate buffer. In a preferred embodiment, the compositions of the invention comprise a mixture of sodium carbonate and sodium bicarbonate.
The buffer can be introduced into the composition, directly, for example, added in a powder form, or diluted with water, for example, at a concentration ranging from 1 to 500 mM. Thus, the liquid buffer solution can be introduced into the composition.
One skilled in the art would understand how to adjust the amount of buffer to obtain the desired buffering effect, depending on the chemical nature of the buffer used, its form (either powdered or diluted in water) and the desired starting pH of the composition.
Without being limited to these values, it can reasonably be estimated that when the buffers used in the composition are a mixture of sodium carbonate and sodium bicarbonate introduced in a powder form (see example 8 of the present invention), the carbonate of sodium can be introduced in an amount ranging from about 0.01 to 0.1%, and sodium bicarbonate can be introduced in an amount ranging from about 0.001 to 0.01%, these percentages being expressed by weight , with respect to the total weight of the pharmaceutical composition.
Without being limited to these values, it can reasonably be estimated that when the buffer used in the composition is a 60mM solution of carbonate buffer with a pH = 10.7 (see examples 1 to 3 of the present invention), the solution of 60mM buffer can be introduced in an amount ranging from about 1% to about 80%, including from about 5% to about 70%, such as from about 10% to about 50%, these percentages being expressed by weight, relative to the total weight of the pharmaceutical composition.
However, the amount of buffer in the composition may still vary depending on the composition of the formula into which it is introduced, in accordance with standard buffer techniques.
In another aspect, the pharmaceutical composition of the invention further comprises a base. Advantageously, the base is, for example, pharmaceutically acceptable, and is typically selected from the group consisting of triethanolamine, sodium hydroxide, ammonium hydroxide, potassium hydroxide, arginine, aminomethylpropanol or tromethamine, and mixtures thereof. When the pH of the pharmaceutical composition is not optimized for transdermal administration, for example, where the gelling agent comprises at least one polymer based on acrylic acid, resulting in a more acidic pH than desired for the product Finally, the use of a base can contribute to the neutralization of the pharmaceutical composition. Furthermore, the use of the base (neutralizer) can improve or optimize the swelling of polymer chains during charge neutralization and the formation of polymer salts. In embodiments where the gelling agent comprises a polymer-based acrylic acid, the base may comprise triethanolamine. The use of a base can also improve or optimize viscosity.
The person skilled in the art will know how to choose a suitable amount of base to use in the composition, and can select the base based on the nature of the gelling agent present therein, and the alcohol content of the composition. For example, with carbomers and/or a high alcohol content, tromethamine and/or NaOH can be selected as a base, in amounts chosen so as to reach the desired final pH in the composition. Other Optional Components
The pharmaceutical compositions of the invention may optionally comprise other usual pharmaceutical additives, including salt(s), stabilizer(s), antimicrobial(s) such as paraben compounds, fragrance(s), and/or propellant(s).
It may, for example, be advantageous to include a stabilizer such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and ascorbic acid. BHA, however, can color the compositions of the invention in yellow. Therefore, in a more preferred embodiment, the composition of the invention does not comprise BHA.
Depending on the nature of the selected ingredients, it may be advantageous to include a surfactant. Suitable surfactants for use in pharmaceutical compositions are known in the art, and the skilled person can select suitable surfactants for use in the present invention, such as surfactants which are dermatologically and/or cosmetically acceptable. Examples of these include non-ionic surfactants, for example: esters such as: polyethylene glycol esters with fatty acids, including Labra-30 sol®, which is a mixture of mono-, di- and triglycerides and polyethylene glycol mono- and diesters with acids fatty; sucrose esters with fatty acids such as sucrose laurate with HLB16; sucrose palmitate with HLB 16; polyoxyethylene sorbitan esters such as Tween® compounds including Tween® 20, 60 and/or 80; alkylene oxide copolymers, such as ethylene oxide and propylene oxide copolymers, for example Pluronics®.
Other examples include anionic surfactants such as SDS (sodium dodecyl sulfate), and the like and cationic surfactants such as cetrimide (alkyltrimethylammonium bromide) and the like.
Typically, surfactants will be used in the compositions of the invention in an amount ranging from about 0.01% to about 5% by weight, including about 0.05% to about 3% by weight, these percentages being expressed in weight, relative to the total weight of the pharmaceutical composition. Thus, a surfactant can be used in the compositions in an amount ranging from 0.01% to 5% by weight, including 0.05% to 3% by weight.
The pharmaceutical composition according to the invention may be in the form of a solution, a gel, a cream, a lotion, a milk, an ointment, an aerosol or a patch.
In a particular embodiment, the composition of the invention is in the form of a gel or a solution. Exemplary Composition and Uses Exemplary, non-limiting compositions are provided below. As mentioned above, percentages (%) refer to amounts by weight based on the total weight of the composition (w/w). The sum of the different composition components adds up to 100% (w/w) of the total composition. In one aspect, the present invention relates to a pharmaceutical composition for topical administration to a skin surface wherein the composition comprises: (i) 0.01 to 2.5% (w/w) of a pharmaceutically active agent comprising one or more steroids, (ii) 10 to 90% (w/w) of at least one C2-C6 monoalcohol, such as ethanol or isopropanol, (iii) 0.04 to 10% (w/w) of a fatty acid ester, (iv) 0% to 10 (w/w) of a fatty acid (v) 0 to 5% (w/w) of at least one gelling agent, (vi) qsf 100% (w/w) water, wherein the weight:weight ratio of the fatty acid ester in the composition to the total active agent wherein said composition is at least 4: 1 fatty acid ester:active agent.
In a preferred embodiment, the present invention relates to a pharmaceutical composition for topical administration to a skin surface wherein the composition comprises: (i) 0.01 to 1.25% (w/w), preferably 0 .30 to 0.50% (w/w) of a pharmaceutically active agent chosen from among estrogens, preferably estradiol, (ii) 20 to 80% (w/w) of at least one C2-C6 monoalcohol, such as such as ethanol or isopropanol, (iii) 0.04 to 5% (w/w) of a fatty acid ester, preferably ethyl oleate, (iv) 0.01 to 5% (w/w) of a fatty acid, preferably oleic acid, (v) 0.05% to 5% (w/w) of at least one gelling agent, preferably a high molecular weight copolymer of acrylic acid and C10-C30 alkyl acrylate cross-linked with allyl pentaerythritol, eg Pemu-len® TR-1, (vi) qsf 100% (w/w) water, wherein the ratio weight: weight of fatty acid ester in the composition to the total active agent wherein said composition is at least 4: 1 fatty acid ester: active agent, of preference ranging between 4: 1 and 7: 1.
Depending on the active agent used, the pharmaceutical compositions of the invention may be useful for various treatments. For example, the compositions can be used in any methods where delivery of a pharmaceutically active agent is desired, and can be particularly useful where sustained, systemic delivery of the pharmaceutically active agent is desired. When the composition comprises one or more steroids, it can be used in any method where delivery of the steroid(s) is desired, and can be particularly useful where sustained, systemic delivery of the steroid(s) is desired. For example, the compositions can be used in methods of treating a patient suffering from or at risk of developing any condition that can be treated, ameliorated or prevented by systemic administration of one or more steroids. Exemplary, non-limiting therapeutic methods include: - When the active agent is an antiestrogen (SERM), the compositions of the invention are useful for the treatment of a patient suffering from or at risk of developing a breast disorder, such as: - Conditions that involve dense breast tissue, such as high-density breast tissue that is a predictor of breast cancer risk and/or that compromises mammographic sensitivity; - Benign breast diseases, such as adenosis, cysts, ductal ectasia, fibroadenoma, fibrosis, hyperplasia, metaplasia and other fibrocystic changes; gynecomastia; breast cancer, including non-invasive breast cancer; malignant melanoma; breast tenderness; - cancer and/or localized tumors, such as lung tumors, and other therapies that involve the systemic administration of an antiestrogen. - When the active agent is an estrogen such as estradiol, an antiestrogen (SERM), an androgen such as testosterone or DHT, the compositions of the invention are useful for the treatment of an osteoporosis-related bone disorder such as osteoporosis , menopause-associated osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormal bone resorption, bone cancer, bone loss (generalized bone loss and/or localized bone loss), bone metastasis (with or without hypercalcemia), myeloma multiple and other conditions that present bone fragility. - When the active agent is an estrogen, such as estradiol, the compositions of the invention are useful for: preventing cardiovascular disease or improving cognitive functions; - manage menopausal symptoms such as hot flashes, 10 night sweats, trouble sleeping (insomnia), dryness, vaginal fatigue and itching and burning, loss of sex drive, irregular menstrual periods, bladder and mood problems; - Prostate cancer, and other therapies that involve the systemic administration of an estrogen. - When the active agent is a progestogen, such as progesterone, the compositions described herein are useful for the treatment of: benign breast disease, mastodynia, mastopathy, cyclic breast pain, and to prevent cysts and benign tumor recurrence. - Premenstrual syndrome, menstrual irregularities due to ovulation or anovulation disorders, benign mastopathy, premenopause, concomitant use with postmenopausal estrogen, prevention of endometrial hyperplasia in non-hysterectomized postmenopausal women who are receiving estrogen therapy, infertility due to luteal phase defect, threatened abortion, premature and threatened birth, progesterone support during ovarian failure or complete ovarian failure, in women with no ovarian function (egg donation), to support the luteal phase during in vitro fertilization cycles, to support the luteal phase during spontaneous or induced cycles, in primary or secondary infertility or subfertility in particular due to deovulation; and other therapies that involve the systemic administration of a progestin.
When the active agent is an androgen such as testosterone or DHT, the compositions of the invention are useful for the treatment of: hypogonadism; depressive disorder, type 2 diabetes, to increase glycemic control, erectile dysfunction, metabolic syndrome, frailty, angina pectoris, congestive heart failure, osteopenia and osteoporosis, and other therapies that involve the systemic administration of an androgen.
Although the above examples have been provided, one of skill in the art will readily appreciate that the compositions described herein are useful in any context where systemic delivery of a pharmaceutically active agent, such as one or more steroids, is desired. Furthermore, for any and all uses, one skilled in the art will be able to determine the appropriate amounts of gel to apply daily to achieve a goal at the in vivo delivery level using a given gel with a given concentration of active agent as using permeation data as shown in figure 2. Modes of Administration Specimens
As noted above, the compositions described herein are suitable for transdermal administration. For example, the compositions can be directly applied to a skin surface, for direct non-occlusive transdermal/transcutaneous application. As used herein, the terms "directly" and "non-occlusive" reflect that the compositions do not require a matrix or membrane to effect administration and, therefore, are not required to be dispensed through an adhesive, patch or tape system, or the like. However, the compositions can optionally be dispensed through an adhesive, plaster or tape system, or the like.
The compositions can be administered by any effective means to apply the composition to a skin surface. For example, the compositions can be applied manually, directly using the hand or with an applicator such as a dropper or pipette, an applicator such as a swab, brush, cloth, pad, sponge, or with any other applicator such as as a solid support comprising paper, cardboard or a laminated material, including material comprising flocked, glued or otherwise attached fibers. Alternatively, the compositions can be applied as an aerosol or non-aerosol spray from a pressurized or non-pressurized container. In some embodiments, the compositions are administered in metered doses, such as from a metered dose applicator or from an applicator that comprises a single dose of the composition.
In some embodiments, the composition is administered to a skin surface over a defined surface area. The administration of a defined, finite amount of the composition to a defined surface area allows the control of the amount of active substance that is applied to a given surface area, ie, controlling the local concentration. By controlling (eg limiting) local concentration, local side effects, such as local androgenic effects (including, but not limited to: acne, oily skin), can be minimized.
In some embodiments, the amount of composition administered is a defined finite amount that provides a therapeutically effective amount (e.g., a single dose) of active agent. Composition Preparation Methods
The invention also provides methods for preparing the pharmaceutical compositions of the present invention. Those skilled in the art can prepare the pharmaceutical compositions of the invention by any suitable means, based on common general knowledge. For example, the pharmaceutically active agent(s) can be dissolved in the alcohol and mixed with the aqueous vehicle (eg, water, and other optional components discussed above) and co-solvent, if used, followed by the addition of other ex- excipients, such as moisturizer if used, and additional mixing. A gelling agent, if used, can be introduced under agitation. A neutralizer, if used, is usually added at or near the end of the method, as otherwise in the final composition. For example, if the composition comprises Carbopol®, NaOH or triethanolamine it can be used to neutralize the composition. Other optional components can be added to other stages of the method in accordance with known procedures. For example, a preservative, if used, can be added in an appropriate solvent at any suitable time in the process.
For example, in a particular modality, components can be added and mixed in the following order. 1. Add alcohol and co-solvent and mix until uniform. 2. Slowly add therapeutically active agent and mix until completely dissolved. 3. Add fatty acid and mix until uniform. 4. Add fatty acid ester and mix until uniform. 5. Slowly add gelling agent, if used, and mix well until completely hydrated. 6. Slowly add a buffer solution, if used, and mix until uniform.
The following specific examples are included as illustrative of the compositions described herein. These examples are in no way intended to limit the scope of the invention. Other aspects of the invention will be apparent to those skilled in the art to which the invention pertains. Examples Example 1: In Vitro Absorption of Estradiol in the Dermis A. Chemistry and Formulations Tritiated [3H] estradiol is used in the preparation of pharmaceutical compositions as follows.


The alcohol content is adapted to solubilize lipophilic ingredients. B. Methods 1. Principle of the method Percutaneous absorption in vitro is studied quantitatively with human skin biopsies placed on Franz diffusion cells (Franz TJ, "Percutaneous absorption on the relevance of in vitro data", J Invest Dermatol. 1975 Mar, 64 (3): 190-5) that allow the contact of a receiving fluid with the dermis in which the absorbed substance is measured. 2. Description of cells
A skin biopsy is held horizontally between two parts of the Franz cell, delimiting two separate compartments referred to as epidermal and dermal. The epidermal compartment consists of a specific surface area (1.77cm2) glass cell cap placed on the upper side of the skin. The dermal compartment, on the underside of skin biopsies, comprises a fixed volume reservoir (~6.5 ml) equipped with a lateral retractable port. The two elements are held in place with a clamp.
The dermal compartment is filled with a receptor fluid consisting of a 9 g/l sodium chloride solution and 15 g/l bovine serum albumin. This fluid is completely removed periodically during the test and replaced with fresh recipient fluid using the retractable side port.
A double-circulating water jacket, containing 37°C water, surrounds the bottom of the cell in order to mimic physiological skin temperature. To ensure homogeneity of temperature and content in the receiving fluid, a stirring rod is placed in the dermal compartment and each cell is placed on a magnetic stirrer.
The upper part, or epidermis compartment, is opened at the outer end, exposing the surface of the skin to ambient laboratory air. 3. Preparation of skin biopsies
The human abdominal skins used for the experiments are taken from donors after plastic surgery procedures. Skins are stored at -20°C. One day before the application of radioactive formulations, after thawing, subcutaneous fats are removed (unless already done before freezing), and the skins are removed from the dermis at about 350 µm. The skins are mounted on the cells the day before the radioactive formulation is applied. 4. Operating Procedures
Ten microliters (» 1 μCi) of the preparations are applied to the surface of the epidermis delimited by the glass cell cap. During the experiment, the recipient fluid is completely removed at 2, 4, 6, 8 and 24 hours through the retractable side port. The dermal compartment is then refilled with fresh solution.
At the end of the test (24 hours), the residual drug remaining on the skin surface is removed by surface washing. The epidermis is separated from the dermis by gentle scraping with a scalpel. 5. Sample treatment and measurement of radioactivity
The radioactivity contained in the samples obtained as described above is measured using a scintillating liquid beta counter equipped with dedicated software. 6. Expression of the results obtained for the dermis:
The amount of estradiol that is found in the dermis is expressed as equivalent amounts ng or as percentages of the administered dose. Each result represents the mean value of (n) experimental determinations and is associated with its standard deviation. 7. Results and discussion
*performed on the % of Estradiol recovered in the dermis in 24-hour data
These results show that at both concentrations of estradiol tested, the addition of ethyl oleate induces a significant increase (at least 1.5-fold) in dermis retention of estradiol (p < 0.01). (Compare results with Formulation 2 vs. 1 and 4 vs. 3). Example 2: In Vitro Absorption of Testosterone in the Dermis A. Chemistry and Formulations Tritiated [3H] Testosterone is used in the preparation of pharmaceutical compositions as follows.

The alcohol content is adapted to solubilize lipophilic ingredients. B. Methods and Results The operating procedures described in Example 1 are followed with the two testosterone formulations described above. After 24 hours, residual drug remaining on the skin surface is removed by cell-by-cell washing of the skin surface immediately prior to filling the dermal compartment with fresh receptor fluid. Cells are then monitored for another 24h. After 48 hours, the recipient fluid is collected and the epidermis is separated from the dermis by gentle scraping with a scalpel. The dermis is separated from the bottom of the cell. The epidermis and dermis are digested for a few hours at 60°C for radioactivity extraction in 1 ml (epidermis) or 3 ml (dermis) of Soluene 350® (Packard). a) Retention in the dermis within 48 hours:
*performed on the % of testosterone in the dermis in 48h data
These results show that the addition of ethyl oleate induces a significant increase (at least 1.5-fold) in dermis retention (p<0.05), even when measured 2 days after application and 1 day after skin washing. b) Release in the reservoir between 24h and 48h:

These results also show a significant impact of ethyl oleate on penetration absorption 24 hours after skin washing.
These results clearly show that the compositions and methods of the invention provide a sustained release of active testosterone agent from the skin during 24 hours after washing the skin. 10 Example 3: In Vitro Absorption of Testosterone in Dermis A. Chemistry and Formulations Tritiated [3H] testosterone is used in the preparation of pharmaceutical compositions as below.
The alcohol content is adapted to solubilize lipophilic ingredients, B. Methods and results
The operating procedures described in Example 1 are followed with the two testosterone formulations described above.
* Performed on % testosterone recovered in the dermis in 24h data These results show that at the tested testosterone concentration 5, the addition of isopropyl myristate induces a significant (at least 2.5-fold) increase in dermal retention after 24 hours ( p<0.01). Example 4: In Vitro Absorption of Dihydrotestosterone in the Dermis A. Chemistry and Formulations Tritiated [3H] dihydrotestosterone, is used in the preparation of pharmaceutical compositions as below.
B. Methods and Results The operating procedures described in Example 1 are followed with the two DHT formulations described above.
* Performed on the % of DHT recovered in the dermis in 24h data
These results show that an increase in the percentage of IPM in the gel induces a significant (p<0.05) dermal retention of Dihydrotestosterone (at least twice) after 24 hours. Example 5: Evaluation of Percutaneous Progesterone Absorption Using Franz Finite Dose Human Skin Model A. Introduction
The Franz finite-dose human skin in vitro model has proven to be a valuable tool for studying percutaneous absorption and for determining the pharmacokinetics of topically applied drugs. The model utilizes ex vivo human cadaver or surgical skin mounted in specially designed diffusion chambers allowing the skin to be maintained at a temperature and humidity that match typical in vivo conditions (Franz, TJ, "Percutaneous absorption; on the reevance of in vitro data", J Invest Derm 1975, 64; 190-195). A finite dose (eg 4-7 mg/cm2) of formulation is applied to the outer surface of the skin and drug absorption is measured by monitoring its rate of appearance in the reservoir solution bathed in the inner surface of the skin. Data defining total absorption, absorption rate as well as skin content can be accurately determined in this model. The method has historical precedent for accurately predicting in vivo percutaneous absorption kinetics (Franz TJ, "The finite dose technique as a valid in vitro model for the study of percutaneous absorption in man" In: Skin: Drug Application and Evaluation of Environmental Hazards , Current Problems in Dermatology, vol 7, G. Simon, Z. Paster, M. Klingberg, M. Kaye (Eds), Basel, Switzerland, S. Karger, 1978, pp 58-68). C. Study Project
The pharmacokinetics of percutaneous absorption of progesterone from two tests and reference formulations was studied using the in vitro finite dose model on human skin using a single open-label center within the donor study of three (3) formulations of topical gels containing progesterone. Each formulation was tested in triplicate on three different skin donors using the finite dose in vitro Franz skin model. D. Study Products and Dosage Reference Product: Commercial Progestogel (1% hydroalcoholic progesterone gel) (Besins Healthcare). Test Product(s): New Formulation #1: Progesterone Ethanol (USP 190 Proof) Propylene Glycol Oleic Acid 1% 72% 5% 2% Ethyl Oleate 2% Pemulen TR-1 2% Carbonate Buffer (pH 10.8 ) QSF New Formulation #2: 100% Progesterone Ethanol (USP 190 Proof) Propylene Glycol Oleic Acid 3% 72% 5% 2% Ethyl Oleate Pemulen TR-1 2% 2% Carbonate Buffer (pH 10.8) QSF 100 % (Carbon Buffer was prepared from 16.91 parts of water, 0.070 part of sodium carbonate and 0.007 part of sodium bicarbonate). Dosage 5 μl of formulation/cm2/ skin section (dosed by pipette and rubbed using a glass rod). The glass rod is kept for analysis as part of mass balance accounting and for applied dose correction. E. Study Procedures 1. Reagents and Source of Standards All reagents used in this study are of analytical reagent grade or better. 2. Reservoir Medium For the skin integrity test, the support base consists of a phosphate-buffered saline solution (pH 7.4 ± 0.1). For all additional study conducts, the base medium consists of 0.1 x PBS with 0.1% Volpo (a non-ionic surfactant; Volpo (oleth-20) is a non-ionic surfactant known to increase solubility Aqueous compounds sparingly soluble in water. Volpo in the reservoir solution will ensure diffusion immersion conditions during percutaneous absorption, and is known not to affect the barrier properties of the test skin). 3. Cell Diffusion and Skin Preparation
Ex vivo, human trunk skin without obvious signs of skin disease is used in this study. It was peeled, cryopreserved, sealed in a watertight plastic bag, and stored at ~ -70°C until the day of the experiment. Before use it is thawed in ~37°C of water, then rinsed in tap water to remove any blood or other adhering material from the surface.
Skin from a single donor is cut into several smaller sections large enough to fit 1.0 cm2 of nominal Franz diffusion cells. The dermal chamber is filled to capacity with a reservoir solution of isotonic phosphate buffered saline (PBS), pH 7.4 ± 0.1, and the epidermal chamber is left open for the laboratory environment.
The cells are then placed in a diffusion apparatus in which the dermal reservoir solution is magnetically stirred at ~600 RPM and its temperature maintained to achieve a skin surface temperature of 32.0±1.0°C.
To ensure the integrity of each skin section, its permeability to tritiated water is determined prior to application of the test products (Franz TJ, Lehman PA: the use of water permeability as a means of validation for skin integrity in in vitro percutaneous absorption studies Abst. J Invest Dermatol 1990, 94:525). After a brief equilibration period (0.5-1 hour), 3H2O (NEN, Boston, MA, sp. Lei. ~ 0.5 μCi/mL) is layered on top of the skin by dropper of so that the entire exposed surface is covered (approximately 200-500 µL). After 5 minutes, the aqueous 3H2O layer is removed. At 30 minutes, the reservoir solution is collected and analyzed for radioactive content by liquid scintillation counting. Skin samples where the absorption of 3H2O is less than 1.56 are considered acceptable. 4. Dose Administration and Sample Collection
Prior to administration of the topical test formulations to the skin sections, a pre-dose sample is collected and the stock solution is replaced with a fresh 0.1 x PBS solution with 0.1% Volpo.
Subsequently, each test product is applied to triplicate skin sections from the same donor. Dosing is performed using a positive displacement pipette set to deliver 5 µL of formulation/cm2 with the applied dose rubbed onto the skin using a glass rod. The glass rod is held for analysis as part of mass balance accounting.
At pre-selected times after dosing (4, 8, 12, 24, 32, and 48 hours), the reservoir solution is removed in its entirety, replaced by a fresh reservoir solution, and a predetermined volume aliquot saved for subsequent analysis.
After the last sample is collected, the surface is washed twice with 50:50 methanol:water (0.5 ml volume each time) to collect unabsorbed formulation from the skin surface. After washing, the intact skin is then removed from the chamber and extracted in 50:50 methanol/water. 5. Analytical Laboratory
Quantification of progesterone is performed by High Performance Liquid Chromatography (HPLC). Briefly, HPLC is conducted on a Hewlett-Packard 1100 series HPLC system with a diode array UV detector and, if necessary, a mass spectroscopy (MS) using the standard laboratory method. Peak areas are quantified for concentration using an external standard curve prepared daily from the pure standard. Samples not tested on the day of collection are stored at or below -20°C. F. Analyzes and Reports 1. Study Parameters
The following parameters are calculated: a) total absorption (sum of all sample reservoir solutions from one chamber) b) rate and extent of penetration over the study period. c) washing the surface and skin contents. 2. Data evaluation a) If any sample is <LLD (lower limit of detection), then that sample can be treated as a different data value. At the investigator's discretion, all <LLQ (lower limit of quantification) values may be declared as zero values or an actual measured value for purposes of calculating key parameters. b) A suspected outlier is confirmed with the Dean and Dixon Outlier test. At the investigator's discretion, values declared as extreme values may be removed from the overall sum of data (but will be noted as such in text or data tables). c) Within a chamber, if a given time-point value has been declared a different data value, or is absent due to other reasons, the time-point value can be replaced by an interpolated value to calculate the parameters relevant. The interpolated value will be calculated on a line connecting the adjacent values as follows: Given 3 points: (T1, A), (T2, B) and (T3, C) with (B) missing, where T = time and AC = measured data values Estimated B = A - [((AC)/| T1-T3 ]) x (| T1-T2 |)] 3. Statistical Evaluation
Repeats within donors are taken from the mean and standard deviation is calculated for each key parameter. Within donor mean are then collected and the mean of the donor population with standard deviation is calculated. Differences between test articles are assessed using Student's t-test. G. Results Results are in μg/cm2
The 1% progesterone formulation achieves a 4 times greater delivery of active ingredient into the reservoir compartment as does the commercial Progestogel formulation with the same concentration of active ingredient (1% progesterone).
The 3% progesterone formulation delivers less active to the reservoir than the 1% formulation over a 48 hour period, but carries a much higher amount of drug to the skin (31.7 vs 3.9 μg) , thus predicting a release of the active from the skin into the reservoir over a longer period of time. Figure 1 illustrates the penetration profiles for the three formulations tested. Example 6: Evaluation of Percutaneous Estradiol Absorption Using Franz Finite Dose Human Skin Model The same protocol as described in Example 5 is followed, with differences noted below.
Four different gel formulations containing 0.36% estradiol were tested, each with 2% oleic acid, 2% ethyl oleate, and 5% propylene glycol. Formulation variables (eg, buffer, and gelling agent) are given in Table 6-1. Cumulative drug penetration after 48 hours ranged from 1.03 to 1.77 μg, with maximum delivery occurring between 8 to 20 hours (see Table 6-3). The results are compared in Table 6-3 below with the results from two batches of 0.06% estra-diol gel (one batch prepared for these experiments and a sample of the commercial product, see Table 6-2 for the composition of the 0.06% estradiol gel formulation), where the cumulative drug penetration after 48 hours was about 0.07 µg, with maximum delivery occurring after eight hours. Thus, a six-fold increase in estradiol concentration (from 0.06% to 0.36%) resulted in between a 15- and 25-fold increase in cumulative drug delivery. From this it can be concluded that the increase in penetration cannot be based solely on the increased concentration, but must also have been influenced by the formulation design. Table 6-1: 0.36% of Estradiol Formulations

Table 6-2: Estrogel® Composition
Table 6-3: Total absorption among skin donors
Percutaneous Absorption of Estradiol Through Intact Human Corpse Skin For 48 Hours From A Single Application. Mean ± 5 SE as Percent of Applied Dose and Total Mass (g/cm2).

These results show that formulation C gave maximum delivery, about 25 times greater than formulation Estrogel®. Formulation C was subsequently studied at lower concentrations of estradiol to determine a dose-response. The results show (figure 2) that the amount of drug administered increased with increasing concentration of applied estradiol. The results obtained at the highest concentration (0.36%) agree well with the data obtained in this example (Table 6-3 Formulation C). Furthermore, the values obtained for Estrogel® (0.06% estradiol) are in close agreement between the two studies, further supporting its reliability.
The results presented in Figure 2 also show that, even at roughly equivalent estradiol concentrations (0.07% vs. 0.06%), the new formulation (C) delivered about 10 times more drug than the Estrogel formulation ®. Thus, the compositions described herein make it possible to deliver an equivalent dose to the existing commercial transdermal gel product with 10 times less of the volume applied, as with Formulation C containing 0.07% estradiol. This represents a significant advantage, including safety advantages, regulation advantages and cost savings due to product need, so that much less product provides an equivalent dose. For example, regulatory agencies often encourage the development of products that contain the minimum amount of active agent necessary for therapeutic efficacy. Example 7: Assessing Formulation Influences on Percutaneous Estradiol Absorption Using Franz Finite Dose Human Skin Model
In order to study the influence of penetration promoters and co-solvent on the percutaneous absorption of the active substance in the new gel formulations of the invention, a statistically designed 2-phase experiment was carried out.
In the first phase, the influence of varying concentrations of oleic acid and co-solvent (propylene glycol), together with the concentration of estradiol, on the total amount of active substance delivered was studied.
In the second phase, the influence of varying concentrations of ethyl oleate and estradiol on the amount of active delivered and on the delivery time profile was studied.
The "Design-Expert" statistical software (available from StateEase at www.stateease.com) was used to generate the experimental data points used in the study.
The same protocol as described in Example 5 is followed, with differences noted below. A. First Phase of Study For the first phase, a D-ideal design combined with oleic acid and propylene glycol as blend components and with estradiol as the numerical (process) factor is used. The concentrations of oleic acid and propylene glycol are varied so that the total of their two concentrations remained constant and equal to 7%, thus minimizing potential differences in solubility between the formulations.
The table below summarizes the formulations that are prepared and tested in triplicate on samples from two different donors. Each formulation also contained: 72% ethanol, 2% ethyl oleate and 2% Pemulen TR-1.


In addition, the following steps are performed: Potency Assessment The potency of Estradiol from the final formulations can be determined in triplicate by HPLC/UV. Potency can be calculated as (w/v) to calculate the amount of mass of estradiol in the applied dose, so that the absorbed percentage of the applied dose can be calculated. Potency can also be calculated by correcting for density, such as (w/w), to compare with the target potency of the prepared formulations indicated in the table above. The potency of estradiol must be within ± 5.0% to be acceptable for this study. In analyzing the data, the actual concentrations of estradiol from each formulation are used. Formulation Preparation: 1. Add ethanol and propylene glycol and mix until uniform. 2. Slowly add estradiol and mix until completely dissolved. 3. Add oleic acid and mix until uniform. 4. Add ethyl oleate and mix until uniform. 5. Slowly add Pemulen TR-1 and mix well until completely hydrated. 6. Slowly add the carbonate buffer solution to the above gel matrix and mix until uniform. B. Second phase of the study
For the second phase, a response surface design with a central composite structure is used. The formulations to be studied are shown in the table below, with the addition of: 72% ethanol, 2% Pemulen TR-1, 2% oleic acid, and 5% propylene glycol.
The rest of the experimental procedure is like the one in the first phase of the study. C. Results of the First Phase of the Study
As described in Section A. above in the "Potency Assessment" paragraph, each formulation is labeled for its actual estradiol concentration. The measured values are shown in the Table below, and are used in data analysis.


The total penetration data (amount of active having penetrated into the reservoir compartment after 48 hours) was of sufficient quality to allow analysis in a statistically significant way with the quadratic models for the project mixture and process parts. Figure 3 illustrates the response surface obtained. As propylene glycol (front of graph) is gradually replaced by oleic acid (back of graph), absorption variation as a function of estradiol concentration goes from a bell-shaped curve to a flat, constant curve.
The bell-shaped curve results from a strong dependence of absorption on the concentration of therapeutically active agent in the formulation, as is the case, for example, for formulations with high propylene glycol and low concentrations of oleic acid.
This dependence on therapeutically active agent concentration is not desirable, as compositions capable of achieving efficient delivery over longer ranges of active agent concentrations are generally preferable from a regulatory and commercial standpoint.
At the other end of the oleic acid/propylene glycol axis i.e. in the high oleic acid/low propylene glycol region, the dependence of absorption on estradiol concentration was not observed, and total absorption reaches higher absolute levels, probably due to to the efficiency of fatty acid as a penetration enhancer. The reproducibility of the experimental data points is not good, however, as seen in figure 3 for the replicates conducted at 0.26 and 0.5% estradiol. This lack of reproducibility is confirmed by looking at the standard error plot for the same data set (not shown - error increases with increasing oleic acid concentration), and also with the individual data for each experimental point, which consisted of 3 replicates in two different donors. Such a spread in absorption from one donor sample to another, and even between repetitions on the same donor sample indicates instability in the system. In fact, some experiments deliver large amounts of assets while other experiments, despite all experimental parameters being held constant, deliver significantly less assets. This type of behavior is not desirable in a pharmaceutical composition, because, when translated in the clinic, these formulations can give large patient-to-patient variations or even within patient-to-patient variations from application to application. For these reasons, it may be advantageous to select ranges of fatty acid and co-solvent concentrations that do not cover the higher and lower concentrations of propylene glycol/oleic acid studied here.
Furthermore, to illustrate this point, Figure 4 is a top-down view of the three-dimensional data illustrated in Figure 3. The middle region, centered around 2% oleic acid and 5% propylene glycol, appears to be the most desirable for a composition that exhibits absorption with minimal dependence on active agent concentration (the problem seen with higher concentrations of propylene glycol), while achieving strong reproducibility between data points (contrary to data obtained with higher concentrations of oleic acid), even if it does not provide the highest delivery of the active.
In specific modalities, therefore, the fatty acid permeation enhancer is present in an amount of 0.01% to 5%, including from 0.05% to 3.5%, such as from 1% to 3 % by weight, based on the total weight of the composition.
Furthermore, in specific embodiments, the co-solvent (such as propylene glycol) is present in an amount of from 0.01% to 7%, including from 3% to 7%, such as from 4% to 6% by weight with based on the total weight of the composition. D. Results of the Second Phase of the Study Figures 5 and 6 illustrate the influence of the concentration of ethyl oleate and estradiol on total absorption over 48 hours. The variation in estradiol concentration affects absorption in a bell-shaped manner, as already illustrated in the first phase of the study, in the corresponding concentrations of oleic acid and propylene glycol. The addition of ethyl oleate has the effect of increasing the total amount of absorption and also of shifting the optimal estradiol concentration (ie, the estradiol concentration corresponding to the maximum absorption) to higher values. This phenomenon is more clearly visible in figure 6.
The main effect of the ester (ethyl oleate), however, as already described in examples 1 to 4, is to modify the delivery profile over time, providing a sustained release effect. To illustrate this phenomenon, the graphs representing the time courses of absorption flows for the 11 tested compositions were grouped into 3 categories, illustrated in figures 7 to 9, Figure 7 shows the flow profiles for a first group that triggers after about 20 hours an increase in flow, leading to a profile in which the dose increases with time. This is not desirable for a product where strong delivery within hours of application is required followed by a steady drug release plateau. The three data points illustrated in figure 7 belong to the corner "low ethyl oleate" - "high estra-diol" in the graph of figure 6. Figure 8 shows flow profiles of a second group, where the flux decreases rapidly after the peak occurring at 6 hours after administration. This profile is typical of several prior art compositions, which achieve fast and efficient delivery within the first few hours post administration, but which lack constant release over a long term, ie 24 or even 48 hours. The three data points illustrated in Figure 8 are along the Y = X line in the graph in Figure 6.
Finally, Figure 9 shows the experimental data point profiles with a rapid, onset rise in flux, followed by a steady flux level for 2 days, ie a sustained release, storage depot effect. This type of flux is desirable in many therapies, where both rapid realization of therapeutic blood concentrations and sustained blood drug concentrations is desired. Compositions that achieve this type of profile are compositions according to the present invention in the middle of the "high ethyl oleate" - "low estradiol" graph of figure 6 (in other words, above the X = Y line).
This qualitative analysis of the flow profiles over time demonstrates that a sustained release of active agent is satisfactorily achieved when the fatty acid ester is present in a greater amount than the active agent, such as the fatty acid ester. of being present in an amount at least four times that of the active agent, on a weight: weight basis.
In particular, it appears that the more ester is present in the composition, the better the storage depot effect is. This factor suggests that it should be claimed to include as much fatty acid ester in the composition as possible. An upper limit is imposed, however, by the solubility of the fatty acid ester in the composition. As an example, Figure 10 illustrates the amount of ethyl oleate that can be dissolved, at room temperature, as a function of ethanol concentration (96% v/v) in a formulation prepared with: 0.24% estradiol; 5% propylene glycol; and 2% oleic acid Qsf Water.
From figure 10 and the table below, it is evident that, in a formulation comprising 72% ethanol, a maximum of 2.2% ethyl oleate can be dissolved.
Example 8: Skin Sensitization Studies
Previous studies have reported skin irritation problems with transdermal compositions comprising high amounts of co-solvents, such as propylene glycol, in amounts used in some embodiments described herein, such as at about 5% (w/w). To determine whether the compositions described herein are irritating, and thus possibly not suitable for general clinical use, skin sensitization studies are conducted in guinea pigs and rabbits, using the following formulations: Active K36:


These studies are performed to assess the potential of the test positions, Active K36 and Active P36, to cause or provoke skin sensitivity reactions (allergic contact dermatitis) through topical application of adhesives in animal models.
Guinea Pigs: Compositions are applied by closed topical adhesive and application of Hilltop Chamber for Cri: HA Guinea Pigs (Albino Hartley). During the induction phase, three treatment groups of five animals/sex/group were given Placebo K36, Placebo P36, or the positive control, Hexylcinnamic Aldehyde (HCA 100%), while the remaining two treatment groups were ten animals/sex/group are administered with the test compositions, Active K36 or Active P36. During the challenge phase, each placebo group is administered with the respective test composition, and the positive control receives 50% HCA in mineral oil (10 50% HCA). In both phases, all groups are administered with placebos, positive control, or test compositions by dermal application at 0.4 mL/dose. During the induction phase, placebos, positive control and test compositions are administered once a week for 3 weeks on days 1, 8, and 15, followed by a 2-week interval period, while during the induction phase. the challenge phase, positive control and test articles are administered once on day 29.
For the duration of the study, observations of mortality, morbidity, injury, and availability of food and water are conducted twice daily for all animals. In addition, body weights for all animals are measured and recorded before randomization (Day -7), before each administration of the test compositions (with the exception of Day 15, body weights were recorded at approximately 6 hours after dose, after splitting), and the day before termination (day 31). During the single challenge phase, skin irritation score for skin sensitization is conducted at approximately 24 and 48 hours after patch removal (post-dose). At the end of the study, animals are sacrificed by carbon dioxide inhalation.
Skin irritation scores recorded at 24 and 48 hours post-administration during the challenge phase indicated that sensitization did not occur after administration of induction doses and subsequent two-week washout period. Irritation scores in the Active K36 and Active P36 groups were generally equivalent to or less than scores recorded for the Placebo K36 and Placebo P36 groups. Furthermore, reduced body weight gain was observed in Active K36 and Active P36 when compared to the respective placebo groups. These lower body weight gains were considered to be a related but not adverse test article.
Rabbits: This study is conducted to assess the potential skin irritation and/or corrosive effects of the test compositions. A treatment group of three female New Zealand White Hra: (NZW) SPF albinos rabbits is administered with Active K36 and P36 formulations, and their respective placebos, at one of four dorsal sites at a dose level of 0.5 mUlocal. Placebos and test articles are administered to the respective test sites of each animal by dermal application once daily for 3 consecutive days.
Observations for morbidity, mortality, injury, and availability of food and water are performed twice daily for all animals. Body weight is measured and recorded pre-dose. Dermal irritation scores are scored within 30-60 minutes, and at 4 and 24 hours after dosing, on days 1 and 2. On Day 3, test sites are scored within 30-60 minutes, and at 4, 24, 48 and 72 hours post-dose. Additional irritation scores are taken on days 8 and 15 to fully assess the reversibility or irreversibility of the observed effects. At the end of the study, all animals are sacrificed, and the carcasses are discarded without further evaluation.
Minimal mild erythema and edema were observed for both Placebos K36 and P36 and Active formulations. Placebo P36 and Active P36 appeared to cause slightly more irritation than Palcebo K36 and Active K36, but these differences were minimal. A slight decrease in body weight was observed for all three animals and was considered a related, but not adverse, test article.
These studies demonstrate that the compositions described herein, comprising about 5% propylene glycol, are non-irritating, and do not give rise to significant sensitizing effects on the skin. Thus, these factors do not limit its clinical use. Example 9: 21-day Rabbit Dermal Toxicity Study
This study is carried out to evaluate the potential toxicity of the two formulations of the test compositions described above, Active K36 and 5 Atvio P36 and their respective placebos, when administered once a day through dermal application for 21 consecutive days to two treatment groups of 10 males and 10 females New Zealand White Hra: (NZW) SPF albinos.
Both Active K36 and Active P36 are formulated with an active concentration of 0.36% estradiol. Test articles are administered at a dose volume of about 0.85-1.11 ml. Two other groups of ten animals/sex will serve as controls and will receive placebos, Placebo K36 and Placebo P36.
Observations for morbidity, mortality, injury, and availability of food and water are performed twice daily for all animals. Clinical observations are conducted weekly. Test sites are evaluated for erythema and edema daily during the first week of dosing, and weekly thereafter. Body weight is measured and recorded weekly.
Food consumption is measured and recorded daily. Blood and urine samples for clinical pathology evaluations are collected from all animals pre-test and prior to terminal necropsy. At the end of the study, necropsy examinations are performed and organ weights are recorded. Selected tissues are analyzed microscopically for animals that received Active P36 and Placebo. Tissues from the other two study groups are kept for possible future reference.
There were no test composition-related changes in body weight and no clinical findings related to test composition evident. Possible clinical findings related to test composition 30 included inappetence, aggressive behavior, and vocalization. These findings were limited to one animal per sex per group treated with either Active K36 or Active P36, and were not observed in either placebo group.
Very mild (almost unnoticeable) erythema was observed sporadically throughout the study with less or similar frequency of Active K36 and Active P36 than in the respective placebo groups. These findings were considered to be primarily vehicle related and not related to the test composition.
Decreases in food consumption related to test composition, but not adverse, were observed in both Active K36 and Active p36 groups when compared to the respective placebo groups. Male food consumption was more severely affected (18.4% - 19.2%) and frequent and statistically significant, whereas female food consumption was moderately affected (6.5% -11.1%) and only occasional and statistically significant.
Test composition-related changes in haematological parameters included moderate reductions in erythrocytes, hemoglobin, hematocrit, reticulocytes, platelets and in both Active K36 and Active P36 dose groups. Total leukocytes and lymphocytes were also reduced in these groups.
Changes related to test composition in clinical chemistry parameters included decreased aspartate aminotransferase (AST), alanine aminotransferase (ALT), y-glutamyltransferase (GGT), sorbitol dehydrogenase (SDH), urea nitrogen, and creatinine , decreased triglycerides in both Active K36 and Active P36 groups. Increases in liver enzymes tended to be slightly greater in males who received P36 than in those who received K36. Increases in urea nitrogen and creatinine were minimal and may have been secondary. There were no test composition-related changes in coagulation parameters or urinalysis.
There were no macroscopic findings related to test composition in males in this study. Macroscopic observations related to test composition in females in the Active P36 group included oviduct cysts in three animals and an abdominal cavity adhesion in which the uterus and cervix were adhered to the abdominal wall in one animal. A likely macroscopic observation related to the test composition of red discoloration of the uterine horn and body was made in a female rabbit in the Active K36 group. Although microscopic analysis 5 was not performed, it is likely that this observation was correlated with lesions similar to those observed in Active P36 female rabbits.
Statistically significant changes related to test composition in organ weights occurred in spleen, liver and thymus weights of males and females, from both Active P36 and Active K36 groups, and in uterus with cervix weights of females of both Active P36 and Active K36 groups.
Microscopic changes related to test composition occurred within liver, spleen and thymus of males and females, prostate and seminal vesicles in males, and in oviducts, uterus with cervix and vagina of females.
Within the liver, there was a diffuse depletion of intrahepatocellular glycogen stores. In addition, there was minimal mild bile duct hyperplasia. Biliary hyperplasia was possibly a direct effect of the test article, just as estrogens have been shown to stimulate cholangiocyte proliferation (LeSage, G, S. Glaser and G. Alpini "Regulation od Cholangiocyte Proliferation". Liver 21 (2001) :. 73-80).
Within the spleen, there was minimal to moderate hyperplasia of reticuloendothelial macrophages that was occasionally accompanied by increased erythrophagocytosis, an increase in pigmented macrophages (hemosiderin-laden), and rarely by dilation of the splenic red pulp sinusoids. In addition, there was minimal to moderate depletion of the splenic lymphoid population in treated animals. These changes could be either direct effects of test composition or estrogens have been shown in rats to stimulate spleen reticuloendothelial cells, resulting in increased phagocytosis (Steven, WM and T. Snook. "The Stimulatory Effects of Diethylstilbesterol and Diethylstilbesterol Diphosphate on the
Reticuloendothelial Cells of the Rats Spleen." American Journal of Anatomy 144.3 (1975): 339-359), and also, elevated levels of estrogens have been shown to cause decreases in both T- and B- cell populations in the spleen of rats (Burns-Naas, LA, BJ Meade and AE Munson "Toxic 5 Response of the Immune System". Cassarett & Doull's Toxicology: The Basic Science of Poisons. Ed Curtis D. Klaassen New York: McGraw-Hill, 2001 419 - 470).
Thymic changes consisted of mild to severe generalized lymphoid depletion. Estrogens have been shown to cause thymic depletion 10 (Burns-Naas, supra).
Microscopic changes within the prostate gland and the seminal vesicles of treated animals included smooth muscle hypertrophy associated with both of these glands, and occasional animals increased fibroplasia with the subepithelial stroma resulting in thickening of intraglandular septa in the prostate gland. In addition to these stromal changes, there was a dysmaturity or regression of the glandular epithelium, meaning that the epithelium was of decreased maturity (increased immaturity) compared to other characteristics of the gland such as increased luminal diameter.
In treated females, there was mild to severe mucification of the vaginal epithelium and mild to moderate hypertrophy of the vaginal smooth muscle. A similar finding was present in the epithelium of the cervical region of the uterus. A decidual reaction (Zook, BC, OA Janne, AA Abraham, and HA Nash “The Development and Regression of Deciduosarcomas and other estrogen and progesterone injuries in rabbits.” Toxicological Pathology 29.4 (2001): 411-416 ; Jaane, OA, BC Zook, AK Didolkar, K. Sundaram, and HA Nash “The Roles of Estrogen and Progesterone in Producing Deciduosarcoma and Other Lesions in the Rabbit.” Toxicological Pathology 29.4 (2001): 417-421) , a common response to estrogenic compounds, has been observed to
minus one minimum grade in all uterus and two spleen samples from females in the Active P36 group. The deciduous reaction occurs both within the subendometrial stroma as well as in the blood vessels within the uterus.
In rabbits with severely affected vessels, it was not associated with ischemic necrosis of the adjacent uterine tissue due to interrupted blood supply. This necrosis was occasionally transmural, and in one rabbit, it resulted in fibrosis on the abdominal surface of the uterus and adhesion to the parietal surface of the abdominal cavity.
Also in females, three of the animals in the Active P36 group had oviduct cysts. Cysts are not uncommon in several female reproductive organs, so it is possible that these cysts could represent developmental anomalies, however, the presence of these cysts in three females of the Active P36 group and without any control animals suggests that this change may be related to the administration of the test article. There were no significant differences between the activity of the Atico K36 and Active P36 treatment groups.
In general, these findings are commonly associated with the administration of the estrogen-containing test composition, and thus do not impair the potential clinical utility of the specific formulations described herein. Example 10: Dose-Aggravation Study in 12 Healthy Male Subjects
A multiple-dose, open-label, dose escalation study was designed in which 12 healthy male subjects were scheduled to receive 1 of 2 treatments once daily for 3 days with an 11-day lag period between doses.
The objective of this Phase 1 study was to evaluate the safety and pharmacokinetic (PK) profile of multiple dose administration of 0.25 g and 1.00 g of a 0.07% estradiol transdermal gel in healthy volunteers male. The transdermal gel used had the following formulation:


Twelve (12) healthy individuals were selected and participated in two open-label treatment periods. Subjects who successfully completed the screening process checked for the research site on Day 1, approximately 1 to 2 hours prior to drawing blood prior to each treatment period. For Treatment Period A, 0.25 g of the 0.07% gel was to be administered once daily for three days. During Treatment Period B, 1.0 g of the 0.07% gel was to be administered once daily for three days. Dosing days should be separated by an interval period of at least 10-11 days.
Diagnosis and Main Criteria for Inclusion: Healthy adult male volunteers, 18-45 years of age, with a body mass index (BMI) between 18 and 30 kg/m2, inclusive, and a minimum weight of 50 kg (110 pounds) .
Conclusion:
Mean baseline estradiol concentrations ranged from 14.3 pg/ml to 21.7 pg/ml After administration of 0.25 g of gel, estradiol concentrations increased slightly above baseline (mean plasma concentration highest = 25.6 pg/ml). After administration of 1.00 g of gel, estradiol concentrations increased approximately 2-3 fold (highest mean plasma concentration = 54.3 pg/ml). In general, estradiol concentrations returned to baseline levels by approximately 12 h post-dose for the 0.25 g gel; for the 1.00 g gel, estradiol concentrations returned to baseline levels within approximately 96 hours.
In general, Tmax of estradiol after 1.00 g was lower than that after 0.25 g. Estradiol Tmax was observed between about 3 h (0.25 g, third dosing interval) and 13 h (0.25 g, first dosing interval) after gel administration.
Within each dose group, the mean AUC estimates for each 24-h dosing interval (AUC0-24) were comparable, indicating that there is no significant accumulation of estradiol. There was a less proportional increase in estradiol exposure with an increase in gel dose.
The increase in peak and global systemic exposure to estradiol after a 4.00-fold increase in gel dose was 1.95-fold based on Cmax 0-120 and 1.26-fold based on AUC0-120.
The ratios (0.25 g: 1.00 g) (90% confidence intervals) for estradiol CmaxO-120 and AUCO-120 were 47.89% (40.17%, 57.10%.) and 80 .01% (70.45%, 90.88%), respectively. Example 11: Dose-Aggravation Study in 12 Healthy Male Subjects
The primary objective of this Phase 1 study was to compare the pharmacokinetic (PK) profiles of two different transdermal gel estradiol formulations in healthy male volunteers. The secondary objective of this study was to assess the incidence and severity of adverse events.
This was a two-treatment, open-label, multiple-dose study was performed in two parts to assess the pharmacokinetics of estradiol after transdermal administration of two different formulations to healthy male volunteers. 12 healthy adult male subjects participated in 2 randomized clinical periods. During each treatment period, 1.25 g of 0.06% EstroGel® (estradiol gel) or 1.0 g of a 0.07% estradiol gel according to the invention (the formulation in the Table below) were administered once a day in the subject's upper arm for five days. Patients were randomized to receive treatment code A or B during the first treatment period and the opposite treatment code during the second treatment period. Treatment periods 1 and 2 were separated by a 3-day break period.
Subjects remained confined to the research center for blood draw for at least 24 hours after the last study gel application in each treatment period, and returned to the research center for blood draw and other study procedures on days 7 and 8 .
Dose = 1.25 gx 0.6 mg/g = 0.75 mg estradiol Topical, once daily for five days 24 hours between dose applications Application site: upper arm Plasma target level: about 80 pg/mL Treatment Code Treatment Intervention B: Drugs: 0.07% estradiol test gel Dose = 1.0 gx 0.7 mg/g = 0.7 mg estradiol Topical, once daily for five days 24 hours between dose applications Application site: upper arm Plasma target level: about 80 pg/mL
During each treatment period, blood samples were collected for measurement of estradiol before each dose and after each dose, at selected times within 72 hours post-dose. Up to 102 blood samples (-510 mL of whole blood) were obtained from each subject for pharmacokinetic assessments, excluding screenings and post-treatment safety assessments. During periods 1 and 2, all blood samples were collected from the contralateral arm where the study gel is being administered, to avoid sample contamination.
Before progression to the next treatment period, safety data (adverse events, clinical laboratory tests) will be reviewed before administering the substance.
For all treatment periods, subjects were required to shower/void approximately 1 hour prior to each application of the study gel. Bathing/voiding privileges were suspended until one hour before the next application of the study gel. Each dose was applied topically to the designated application site. After administration, no food was allowed until two hours after dosing. Water was retained for one hour post-dose and then left ad lib for the remainder of the confinement period. Subjects were served meals at approximately the same time in relation to the dose for each treatment period, the same menu options were available in all treatment periods. Bathing/voiding privileges were suspended for one hour after administration. Results: A summary of pharmacokinetic parameters for estradiol after topical application of the test gel at 0.7 mg QD x 5 days and EstroGel 0.75 mg QD x 5 days to healthy male volunteers is provided. in the table below. EstroGel Gel Test
* Arithmetic Mean ± standard deviation (N), except Tmax for which the median (N) [Range] is reported. Absolute Cmax and Tmax with all doses. +AUC from first to last dose.
Both Examples 10 and 11, where the gels disclosed herein were tested in human clinical trials, demonstrated that the formulations are safe and effective in systematically delivering the drug of interest to patients.

权利要求:
Claims (20)
[0001]
1. Sustained-release pharmaceutical composition for topical administration to a skin surface characterized in that it comprises: a pharmaceutically active agent comprising one or more steroids, 0.01% to 5% by weight of the total weight of the pharmaceutical composition of an ester of fatty acid, water, a C2-C6 monoalcohol, a fatty acid, and 0.05% to 5% by weight of a gelling agent, wherein the weight:weight ratio of the fatty acid ester in the composition to the total active agent in said composition is at least 4: 1 fatty acid ester: active agent, preferably ranging from 4: 1 to 20: 1.
[0002]
2. Composition according to claim 1, characterized in that it additionally comprises a co-solvent, preferably propylene glycol.
[0003]
3. Composition according to claim 1 or 2, characterized in that the co-solvent is present in an amount ranging from 0.01 to 7% by weight of the total weight of the pharmaceutical composition, preferably from 3% to 7% by weight.
[0004]
4. Composition according to any one of claims 1 to 3, characterized in that the fatty acid ester is selected from the group consisting of ethyl oleate, isopropyl oleate, isopropyl myristate, isopropyl isostearate, palmitate of isopropyl, ethyl octanoate, ethyl dodecanoate, ethyl linoleate, ethyl palmitoleate, ethyl isostearate and ethyl linolenate.
[0005]
5. Composition according to any one of claims 1 to 4, characterized in that the fatty acid ester is isopropyl myristate.
[0006]
6. Composition according to any one of claims 1 to 4, characterized in that the fatty acid ester is ethyl oleate.
[0007]
7. Composition according to any one of claims 1 to 6, characterized in that the fatty acid ester is the ester that would result from the reaction of the fatty acid formulated in the composition with an alcohol.
[0008]
8. Composition according to any one of claims 1 to 6, characterized in that the fatty acid ester is different from the ester that would result from the reaction of the fatty acid formulated in the composition with the alcohol formulated in the composition.
[0009]
9. Composition according to any one of claims 1 to 8, characterized in that the fatty acid ester is present in an amount ranging from 0.01% to 5% by weight of the total weight of the pharmaceutical composition, of preferably from 0.05% to 2.4% by weight and more preferably from 0.1% to 2.2% by weight.
[0010]
10. Composition according to any one of claims 1 to 9, characterized in that the fatty acid is a C8-C22 fatty acid, preferably selected from the group consisting of capric acid, lauric acid, myristic acid, acid palmitic acid, stearic acid, oleic acid, isostearic acid, palmitoleic acid, linoleic acid and linolenic acid, and most preferably the fatty acid is oleic acid.
[0011]
11. Composition according to any one of claims 1 to 10, characterized in that the fatty acid is present in an amount ranging from 0.01% to 5% by weight of the total weight of the pharmaceutical composition, preferably 0.05% to 3.5% by weight, and more preferably from 1.0% to 3.0% by weight.
[0012]
12. Composition according to any one of claims 1 to 4 and 6 to 11, characterized in that it comprises 0.3% ethyl oleate as the fatty acid ester, 0.3% oleic acid as the fatty acid , and 0.75% propylene glycol as the co-solvent, all by weight of the total weight of the pharmaceutical composition.
[0013]
13. Composition according to any one of claims 1 to 12, characterized in that the pharmaceutically active agent is selected from one or more of estradiol and progesterone, and the fatty acid ester is ethyl oleate.
[0014]
14. Composition according to any one of claims 1 to 12, characterized in that the pharmaceutically active agent is selected from one or more of testosterone and dihydrotestosterone (DHT), and the fatty acid ester is selected from of ethyl oleate and isopropyl myristate.
[0015]
15. Composition according to claim 14, characterized in that the pharmaceutically active agent is dihydrotestosterone (DHT).
[0016]
16. Composition according to any one of claims 1 to 15, characterized in that the active agent is present in an amount of at least 0.01% by weight of the total weight of the pharmaceutical composition.
[0017]
17. Composition according to any one of claims 1 to 16, characterized in that the C2-C6 monoalcohol is selected from the group consisting of ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, and mixtures thereof, preferably the C2-C6 monoalcohol being ethanol.
[0018]
18. Composition according to any one of claims 1 to 17, characterized in that the C2-C6 monoalcohol is present in an amount ranging from 10% to 90% by weight of the total weight of the pharmaceutical composition, preferably 20% to 80% by weight, and more preferably 45% to 75% by weight.
[0019]
19. Use of a composition as defined in any one of claims 1 to 18, characterized in that it is in the preparation of a sustained release pharmaceutical composition prepared for topical administration to a skin surface.
[0020]
20. Use according to claim 19, characterized in that the sustained release of the pharmaceutically active agent through the skin is observed at least 24 hours after administration, preferably at least 36 hours after administration, and more preferably at least 48 hours after administration.

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法律状态:
2020-11-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-11-10| B25G| Requested change of headquarter approved|Owner name: BESINS HEALTHCARE LUXEMBOURG SARL (LU) |

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2020-11-17| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-12-29| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2021-01-05| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-04-20| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-05-18| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 27/10/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |

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2021-08-31| B16C| Correction of notification of the grant [chapter 16.3 patent gazette]|Free format text: REF. RPI 2628 DE 18/05/2021 QUANTO A QUALIFICACAO. |

优先权:

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申请号 | 申请日 | 专利标题

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US25524109P| true| 2009-10-27|2009-10-27|

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US61/255,241|2009-10-27|

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EP09178762|2009-12-10|

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EP091787862.2|2009-12-10|

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PCT/EP2010/066283|WO2011051354A2|2009-10-27|2010-10-27|Transdermal pharmaceutical compositions comprising active agents|

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