JP2010248250A - Metastable pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To achieve enhancement of percutaneous absorption by using a volatile medium such as a spray or an aerosol. <P>SOLUTION: A pharmaceutical composition for percutaneous transmittance contains one or more physiologically active agent and a pharmaceutically permissible volatile solvent, wherein the physiologically active agent forms metastable precipitates in evaporation of the volatile solvent. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

FIELD OF THE INVENTION This invention relates to compositions for transdermal delivery of physiologically active agents, to the use of the compositions, and to methods for transdermal delivery of physiologically active agents.

BACKGROUND OF THE INVENTION There is an ongoing need for safe and effective methods of administering physiologically active drugs. For many drugs it is important that the dosage form be as simple and non-invasive as possible to keep patient compliance high. Oral administration is one commonly used dosage form because it is a relatively simple form to follow. However, the route of oral administration is also complex due to the complex circumstances associated with gastrointestinal inflammation and drug metabolism in the liver.

  Administration of physiologically active drugs through the skin (“transdermal drug delivery”) not only provides a relatively simple dosage form, but also compares the release of physiologically active drugs into the systemic circulation. It is also gaining attention as it provides a slow and controlled route. However, transdermal drug delivery is complicated by the fact that the skin functions as a natural barrier and thus the transport of drugs through the skin is a complex mechanism.

  Structurally, the skin consists of two main parts, a relatively thin outermost layer (“epidermis”) and a thicker inner region (“dermis”). The outermost layer of the epidermis (the stratum corneum) consists of flat dead cells filled with keratin. The flat dead cell region of the stratum corneum is filled with lipids that form the lamellar phase responsible for the natural barrier properties of the skin.

  For effective transdermal delivery (“topical application”) of a physiologically active agent applied to the surface of the skin, the agent must first be distributed from the medium to the stratum corneum and then typically It must diffuse into the stratum corneum before being distributed from the stratum corneum to the living epidermis and dermis and then into the bloodstream.

  In order to maximize the concentration of physiologically active agent in the medium (“thermodynamic activity”), it is common for the physiologically active agent to be present as a saturated solution or solid.

  To overcome some of the problems associated with transdermal delivery related to transport through the dermal layer (“transdermal absorption”), physiologically active agents are generally formulated in combination with one or more drug penetration enhancers. Is done. For example, hydrous ethanol is commonly used as a vehicle in topical formulations, and that ethanol can act as a permeation enhancer that can increase the flow of active agents through the skin due to solvent traction effects. It is known (Non-Patent Document 1). Permeation enhancers are known to cause skin irritation in some individuals. In the present invention, since ethanol is applied in small amounts to the skin, it acts as an intermediate solvent that spreads the drug and enhancer onto the skin, so it does not appear to act as a permeation enhancer. The dry time of the composition in question is less than 2 minutes, and in vitro weight loss measurements indicate that ethanol will evaporate within 1 minute on porcine skin with a surface temperature of 32 ° C., and all that remains is a drug. It was confirmed. An exposure time of less than 2 minutes to the skin of ethanol or a similar lipid extraction solvent does not appear to change the barrier function of the skin (2).

  US Pat. No. 6,057,033 combines a specific solvent and dissolved modifier with a skin stabilizer in a transdermal delivery system to form a true solution and minimizes skin irritation. U.S. Patent No. 6,057,051 describes physiologically active non-occlusive delivery through the skin, but this composition relies on permeation enhancers that increase flow. Compositions formulated without the use of permeation enhancers are generally not effective enough to deliver significant amounts of physiologically active molecules through the skin. As can be seen in US Pat. No. 6,057,038 which describes the use of fluoroquinolones in the topical treatment of skin infections and inflammatory conditions, compositions comprising alcohol and acetone vehicles have been used for topical delivery of antibiotics. However, such compositions inherently have a low ability to permeate physiologically active molecules.

  In order to overcome the low permeability capacity, the physiologically active molecule must have maximized thermodynamic activity. According to U.S. Pat. No. 6,047,089, the use of stable shaped particles is particularly well suited for the production of pharmaceutical preparations, where continued free and homogeneous bioavailability is particularly desirable. It has been shown that in order to achieve high permeability through the skin, the dissolved drug concentration may need to be so high that it has a high tendency to crystallize. As a result, transdermal patches are often thermodynamically unstable due to the tendency of the drug to recrystallize during storage (Non-patent Document 3) and (Non-patent Document 4).

  The use of testosterone in volatile solvents has been previously disclosed (Wester et al., 1976). However, these compositions consisting of testosterone dissolved in acetone that is not divided by water have the property of defatting the skin (removing lipids) under prolonged exposure conditions and are therefore the subject of the present invention. In contrast to certain compositions, it has the disadvantage of causing skin irritation.

  A discussion of the background of the invention is included herein to explain the context of the invention. This is because any of the substances mentioned is published in Australia or any other country on the priority date of any claim, is known, or is part of common general knowledge It should not be taken as an admission that it is.

U.S. Patent No. 6444234 U.S. Pat.No. 6,299,900 U.S. Patent No. 6017912 U.S. Patent No. 6528094

"J. Pharm. Sci" (Berner et al., 78 (5), 402-406, 1989) "J. Invest. Dermatol" (Abrams et al., 101, 609-613, 1993) "Int. J. Pharm." (Xinghang et al., 142 (1), 115-119, 1996) “Eur. J. Pharm. & Biopharm.” (Latsch et al., During printing, proof, 2003)

  The object of the present invention is to achieve enhanced percutaneous absorption using volatile media such as sprays or aerosols.

That is, the gist of the present invention is as follows.
[1] one or more physiologically active agents; and volatile pharmaceutically acceptable solvents;
A pharmaceutical composition for transdermal delivery, wherein the physiologically active agent forms a metastable deposit upon evaporation of the volatile solvent,
[2] One or more physiologically selected from the group consisting of apomorphine, fentanyl, ropinirole, rivastigmine, buspirone, rizatriptan, anticholinergic agent, ethinyl estradiol, or any of the pharmaceutically acceptable salts or derivatives thereof Active compounds; and volatile pharmaceutically acceptable solvents;
A pharmaceutical composition for transdermal delivery, wherein the physiologically active agent forms a metastable deposit upon evaporation of the volatile solvent,
[3] The pharmaceutical composition of [1], wherein the carrier comprises a hydrofluorocarbon high pressure gas, and topical application of the composition as an aerosol provides a metastable deposit upon evaporation of the volatile carrier,
[4] The pharmaceutical composition according to [1] substantially free of a non-volatile permeation enhancer,
[5] The pharmaceutical composition according to [3], wherein the high-pressure gas is HFC-134a,
[6] The pharmaceutical composition according to [3], wherein the hydrofluorocarbon high-pressure gas is 15 to 50% by volume of the whole pharmaceutical composition,
[7] In a chamber of a spray applicator device comprising a valve for delivering the composition from the chamber, a nozzle for dispersing the composition as an aerosol, and means for providing a metered dose of aerosol from the nozzle. A pharmaceutical composition according to [1], which is contained and maintained under pressure in a chamber so as to keep the high-pressure gas in liquid form,
[8] A pharmaceutical composition according to [1], which provides a single-phase solution of a drug in which a volatile solvent and a high-pressure gas are active,
[9] A pharmaceutical composition according to [1], comprising 0.1% to 10% of a physiologically active drug; and 85% to 99.8% by weight of a volatile solvent and high-pressure gas,
[10] The pharmaceutical composition according to [1], wherein the physiologically active drug has a saturation solubility of 0.05% or more in a volatile solvent,
[11] The pharmaceutical composition according to [1], wherein the physiologically active drug component has a molecular weight of less than 600 Daltons and a melting point of less than 200 ° C.
[12] The physiologically active agent comprises one or more compounds selected from the group consisting of apomorphine, fentanyl, ropinirole, rivastigmine, buspirone, rizatriptan, ethinyl estradiol, or a pharmaceutically acceptable salt or derivative thereof, [1] The pharmaceutical composition according to the above,
[13] The pharmaceutical composition according to [1], wherein the physiologically active drug comprises testosterone, MENT (7-methyl-19-testosterone), or a pharmaceutically acceptable salt or derivative thereof,
[14] The pharmaceutical composition according to [1], wherein the volatile solvent has a vapor pressure higher than 35 mmHg at atmospheric pressure and a temperature of 32 ° C.
[15] The pharmaceutical composition according to [1], wherein the volatile solvent contains one or more lower alcohols,
[16] The pharmaceutical composition according to [1], wherein at least 60% by weight of the volatile solvent contains one or more lower alcohols,
[17] The pharmaceutical composition according to [1], wherein the volatile solvent consists essentially of one or more lower alkanols,
[18] The pharmaceutical composition according to [16], wherein the lower alcohol is selected from ethanol and isopropanol,
[19] The pharmaceutical composition according to [1], wherein the thickener is present in an amount of 0.1% to 20% by weight of the whole pharmaceutical composition,
[20] The pharmaceutical composition according to [19], wherein the thickening agent is a cellulose derivative, more preferably hydroxypropylcellulose, hydroxypropyl-methylcellulose, hydroxyethylcellulose, or a mixture thereof.
[21] The pharmaceutical composition according to [19], wherein the thickening agent is CARBOPOL,
[22] Applying a spray of the pharmaceutical composition according to [1] to the skin of a subject to form a metastable deposit of the active agent upon evaporation of the volatile solvent, whereby the stratum corneum The present invention relates to a therapeutic method for providing enhanced osmotic absorption of a physiologically active substance, wherein the distribution of the physiologically active drug from the living epithelium to the living epidermis is enhanced.

  By the present invention, enhanced percutaneous absorption using volatile media such as sprays or aerosols is achieved.

FIG. 1 shows a plot of the cumulative amount of drug that penetrates through the skin from a metastable composition compared to a saturated solution of drug. FIG. 2 shows an example of a base DSC profile before and after evaporation from ethanol. FIG. 3 shows a plot of the melting point of each model drug before evaporation from volatile solvents and after 24 hours. FIG. 4 shows a plot of the diffusion profile of fentanyl through the human epidermis after evaporation from ethanol and isopropyl alcohol.

SUMMARY OF THE INVENTION The present invention is based on the inventors' research on volatile sprays and aerosols, and particularly for limited dosage formulations, where significant enhancement of percutaneous absorption is achieved using volatile media such as sprays or aerosols. Arises from the understanding that it can be obtained from the in situ formation of metastable deposits within.

  Previous studies with these types of pharmaceutical compositions suggest that the rate and extent of distribution into the skin is already sufficiently effective with or without added permeation enhancers ( "J. Pharm. Sci." (Morgan et al., 87 (10), 1213-1218, 1998)). The present invention is, at least in part, able to achieve an increase in the transdermal absorption of a physiologically active drug by careful in situ formation of a metastable drug having a lower melting point than it would otherwise. Arises from the understanding that it can be achieved from various crystalline polymorphs supplied by procedures routinely determined by commercial manufacturers. This decrease in melting point shifts the diffusion of the drug through the epidermis and dermis as well as into the bloodstream. In order to realize the present invention, the inventors have found that some combinations of physiologically active agents and volatile solvents form in situ metastable solids when used topically. It was.

Therefore, the present invention
Provided is a composition comprising one or more physiologically active agents; and a volatile pharmaceutically acceptable solvent, wherein the physiologically active agent is a metastable deposit upon evaporation of the volatile solvent. Form. Lower melting metastable deposits are, at least in part, metastable pseudopolymorphs such as alcohol solvates, metastable polymorphs, metastable amorphous solids, or mixtures thereof. ) From any of the above. The drop in melting point (at atmospheric pressure) typically provided by metastable deposits will be in the range of 1-50 ° C and preferably 2-30 ° C.

  Unlike solid precipitates (e.g., salt derivatives of drugs) or high melting crystalline polymorphs, metastable deposits readily partition to the skin upon evaporation of volatile solvents and diffuse easily through the stratum corneum. . The formation of higher melting crystalline deposits in the skin leads to a higher tendency of skin irritation and reduced transdermal absorption efficiency (because higher energy is required for crystal melting prior to diffusive transport).

  Metastable deposits also have excellent skin feel and feel in cases where it may be desirable to rub the metastable deposits into human skin.

  The compositions of the present invention are essentially free of permeation enhancers. The permeation enhancer has the effect of increasing skin permeability by reversibly damaging or changing the physicochemical properties of the stratum corneum to reduce the diffusion resistance of the stratum corneum. A permeation enhancer is a lipophilic, non-volatile compound with a molecular weight greater than 100 and a vapor pressure less than 10 mm Hg, typically at atmospheric pressure and normal skin temperature of 32 ° C.

  In addition to providing improved transdermal absorption efficiency, the compositions of the present invention are also lower than some other delivery systems, such as benzyl alcohol spray, due to the elimination of irritating permeation enhancers It can also provide irritation. In addition, since the pharmaceutical composition of the present invention exists as a stable single-phase solution, and therefore does not have crystalline properties (or polymorphic stability) during the shelf life of the drug, the composition of the present invention is The problems associated with crystallization and / or supersaturation faced with storage of a type of transdermal patch may be avoided. Another advantage of the present invention is the rapid distribution of these in situ formed metastable compositions into the skin, as a natural crystalline inhibitor for drugs where the skin is physiologically active. It means acting, and also improving the stability of metastable deposits in the skin. This leads to a consistent and reliable delivery profile of the physiologically active agent at the desired dosing interval (typically once every 24 hours).

  The present invention also provides a method for delivering a metastable drug formulation to a host, a method comprising the step of using a topical spray composition comprising one or more physiologically active agents, and a method in which a volatile solvent evaporates and becomes active A pharmaceutically acceptable solvent that is volatile to the skin of the host so as to form a metastable deposit containing the active agent.

The present invention further provides a composition for spray use on a patient's skin for transdermal administration of a physiologically active agent comprising:
(i) a physiologically active agent;
(ii) a volatile pharmaceutically acceptable solvent; and
(iii) high pressure gas, preferably hydrofluorocarbon;
Wherein the composition forms a metastable deposit on the patient's skin when used as a spray on the skin.

  The invention also provides a chamber for maintaining the composition under pressure, a physiologically active agent contained within the chamber, a pharmaceutically acceptable solvent that is volatile when used on the skin, and preferably For the transdermal administration of a physiologically active agent comprising a mixture comprising a high pressure gas maintained at least partially in liquid form under pressure in the chamber, and a valve means for providing delivery of the mixture A spray device for providing a metastable deposit of a physiologically active agent on the skin. The high pressure gas is preferably a hydrofluorocarbon such as HFC-134a or HFC-227. HFC-134a is the most preferred high pressure gas. The hydrofluorocarbon is preferably 15-50% of the total pharmaceutical composition by volume, more preferably 20-40% of the total composition by volume.

  The present invention further provides the use of an active agent for the manufacture of a medicament for the treatment or prevention of a disease in a patient, wherein the composition comprises a physiologically active agent and a volatile carrier, In particular, it is used topically on the patient's skin for transdermal administration, where the volatile solvent evaporates to form a metastable deposit containing the active agent.

  Furthermore, the metastable composition avoids the disadvantages of spray nozzle clogging found in existing film forming sprays or aerosols.

  The present invention also provides a composition contained in a chamber in which the high-pressure gas therein is HFC-134a as described above. The volatile solvent and active molecule will preferably provide a single phase solution of the active molecule.

  As used herein, the phrase “amorphous” means substantially non-crystalline. It will be appreciated that the phrase amorphous includes states that exhibit some degree of crystallinity unless otherwise specified.

  The physiologically active agent and volatile solvent combinations of the present invention are found in a variety of crystalline polymorphs supplied by routine procedures from commercial manufacturers or obtained by crystallization from methanol or chloroform. Functionally limited to those that together form a metastable deposit having a lower melting point than is possible. For this reason, the active agent is preferably relatively non-volatile compared to the volatile solvent so that only the volatile solvent evaporates at physiological temperature when the composition is used on the host skin. .

  In fact, physiologically active drugs are apomorphine, fentanyl, ropinirole, rivastigmine, buspirone, rizatriptan, anticholinergics (such as oxybutynin, tolterodine and darifenacin), testosterone, MENT (7-methyl-19-testosterone) , Ethininyl estradiol, or a pharmaceutically acceptable salt or derivative of any of the foregoing, having a molecular weight of less than 600 Daltons and a melting point of less than 200 ° C. It has been found that a range of physiologically active agents can be selected.

  The drug and solvent generally have the ability to mix thoroughly so that the solvent will interact with the crystal plane of the drug. Thus, the drug will typically have a saturated solubility in the solvent of 0.05% w / w or higher, more preferably 0.1% w / w or higher.

  Preferably, the volatile solvent has a vapor pressure higher than 35 mmHg at atmospheric pressure and normal skin temperature of 32 ° C. The volatile solvent preferably contains a lower alcohol. More preferably, the volatile solvent comprises at least 60% lower alcohol by weight of the total volatile solvent component.

  Most preferably, the volatile solvent component consists essentially of one or more lower alcohols. Preferred lower alcohols are ethanol, isopropanol and mixtures thereof.

  Conveniently, the composition is a topical spray composition comprising a physiologically active agent and a volatile solvent, and the method comprises spraying the composition onto the skin of the host to provide a physiologically active substance. Forming a metastable deposit comprising:

  In each of the above cases, metastable deposits are preferably formed in the host skin.

DETAILED DESCRIPTION OF THE INVENTION An advantage of the present invention is that the composition is stable, which means it is less saturated or crystallized during the shelf life of the drug. This can be in good contrast to transdermal patches where crystallization of the active agent involved has been problematic in the past. Thus, the compositions of the present invention can be stored in primary containers for the shelf life without facing the shelf life issues of prior art transdermal patches.

  The compositions of the present invention may comprise from about 0.1% to about 10% physiologically active agent and from about 85% to about 99.8% volatile solvent.

  Optionally, the vehicle can have additional pharmaceutical excipients, such as gels such as CARBOPOL and cellulose derivatives.

  The invention will now be described with reference to the following examples. It should be understood that the examples are provided by way of illustration of the invention and that they in no way limit the scope of the invention.

Example 1
In Situ Formation of Metastable Drug Deposits Formation of metastable deposits of drug within the stratum corneum results in simple diffusion of a solid drug in a saturated solution of the drug or on the skin surface, as shown in Figure 1 (level not detected) It can be expected that drug penetration through the skin will increase.

Example 2
Melting point reduction of various active drugs mixed with volatile solvents As shown in Figures 2 and 3, the ability to form metastable deposits of drugs after evaporation of volatile solvents was achieved 24 hours after solvent evaporation It can be determined by lowering the melting point.
Raw material Fentanyl buspirone Testosterone Ethinyl estradiol (EE2)
95% EtOH
Isopropyl alcohol (IPA)
Chloroform Acetone As shown in the table below, the selected active agents exhibited various ranges of physicochemical properties.

Selected drug-physicochemical properties

Methods Various% w / v mixtures of active drug and volatile solvent were prepared: 10 microliters of aluminum micro-DSC pan was then placed in 50 microliters of aluminum DSC pan and 5 microliters of each formulation Aliquots were pipetted into 10 microliter DSC pans. The volatile solvent was evaporated and another aliquot was poured again until enough residue remained.

  The pan was maintained at ambient temperature and 33% relative humidity for 24 hours. After this, the pan was covered and sealed. Next, DSC was performed in a nitrogen flow at 10 ° C./min within a temperature range depending on the drug.

Results Melting point changes were caused by evaporation of each solvent (Fig. 2). DSC analysis of buspirone after solvent evaporation showed a more stable melting point reduction (Figure 3). In contrast, fentanyl, testosterone and EE2 showed a solvent-dependent melting point decrease. Isopropyl alcohol showed the most significant difference in melting point change when compared to the compound base in each case. What we have found is that the lower melting point suggests that the composition will have an increase in percutaneous absorption. Furthermore, the stratum corneum prevents crystallization, so that a metastable solid deposited in the solvent can form in the stratum corneum.

Example 3 Effect of Metastable Composition on Percutaneous Permeation The selection of the solvent used in the composition allows the percutaneous penetration (one example is shown in FIG. 4) to achieve the desired pharmacological effect. May be selected based on the desired transdermal delivery profile as measured by.
The above examples are not meant to be limiting, and combinations of volatile solvents could also be used to obtain the desired pharmacological effect, eg, on a weight basis;
Ethanol: IPA 20-80: 20-80
Ethanol: Acetone or IPA or chloroform 60-90: 10-40
Or its mixture
It is.

Diffusion studies Diffusion studies were performed to determine the delivery profile of metastable compositions through the skin.

Formulation Fentanyl (1 mol) in ethanol
Fentanyl (1 mol) in isopropyl alcohol
All formulations were prepared by accurately weighing an appropriate amount of physiologically active molecules in a volumetric flask and volumed with an appropriate volatile solvent.

Methods In vitro diffusion experiments were performed using a stainless steel flow-through diffusion cell with a human epidermis maintained at 32 ° C. The receiving solution consisted of either 10% EtOH in 0.002% NaN3 or 20% EtOH in 0.002% NaN3. Eight cells for each condition were treated with 5 μl of the appropriate donor phase, each with a limited dose depending on the formulation. Samples were collected at appropriate time points and analyzed by high performance liquid chromatography (HPLC).

Table 1. HPLC conditions for receiving solution analysis

Results Diffusion experiments after evaporation of ethanol and isopropyl alcohol were conducted using fentanyl as a model compound.

  The fentanyl diffusion profile by the human epidermis shows a change in the delivery profile that is solvent dependent (FIG. 5). After evaporation from ethanol, fentanyl exhibits a sigmoidal, first order diffusion profile, indicating that the initial burst through the skin is limited. However, after evaporation from isopropyl alcohol, fentanyl exhibits a zero order release rate profile. Therefore, the leaving tendency can be corrected by changing the volatile solvent vehicle.

Claims (22)

One or more physiologically active agents; and a volatile pharmaceutically acceptable solvent;
A pharmaceutical composition for transdermal delivery, wherein the physiologically active agent forms a metastable deposit upon evaporation of the volatile solvent. One or more physiologically active selected from the group consisting of apomorphine, fentanyl, ropinirole, rivastigmine, buspirone, rizatriptan, anticholinergics, ethinyl estradiol or any of the pharmaceutically acceptable salts or derivatives thereof A compound; and a volatile pharmaceutically acceptable solvent;
A pharmaceutical composition for transdermal delivery, wherein the physiologically active agent forms a metastable deposit upon evaporation of the volatile solvent.   The pharmaceutical composition of claim 1, wherein the carrier comprises a hydrofluorocarbon high pressure gas and topical application of the composition as an aerosol provides a metastable deposit upon evaporation of the volatile carrier.   The pharmaceutical composition according to claim 1, which is substantially free of non-volatile permeation enhancers.   The pharmaceutical composition according to claim 3, wherein the high-pressure gas is HFC-134a.   The pharmaceutical composition according to claim 3, wherein the hydrofluorocarbon high-pressure gas is 15 to 50% by volume of the whole pharmaceutical composition.   Contained in a chamber of a spray applicator device comprising a valve for delivering the composition from the chamber, a nozzle for dispersing the composition as an aerosol, and means for providing a metered dose of aerosol from the nozzle; The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is maintained under pressure in the chamber to keep the high pressure gas in liquid form.   The pharmaceutical composition of claim 1 wherein the volatile solvent and the high pressure gas provide a single phase solution of the active agent.   The pharmaceutical composition of claim 1 comprising 0.1% to 10% physiologically active agent; and 85% to 99.8% by weight volatile solvent and high pressure gas.   The pharmaceutical composition according to claim 1, wherein the physiologically active drug has a saturation solubility of 0.05% or more in the volatile solvent.   The pharmaceutical composition of claim 1, wherein the physiologically active pharmaceutical ingredient has a molecular weight of less than 600 Daltons and a melting point of less than 200 ° C.   2. The physiologically active agent comprises one or more compounds selected from the group consisting of apomorphine, fentanyl, ropinirole, rivastigmine, buspirone, rizatriptan, ethinyl estradiol, or a pharmaceutically acceptable salt or derivative thereof. The pharmaceutical composition as described.   The pharmaceutical composition according to claim 1, wherein the physiologically active agent comprises testosterone, MENT (7-methyl-19-testosterone), or a pharmaceutically acceptable salt or derivative thereof.   The pharmaceutical composition according to claim 1, wherein the volatile solvent has a vapor pressure higher than 35 mmHg at atmospheric pressure and a temperature of 32 ° C.   The pharmaceutical composition according to claim 1, wherein the volatile solvent comprises one or more lower alcohols.   The pharmaceutical composition according to claim 1, wherein at least 60% by weight of the volatile solvent comprises one or more lower alcohols.   The pharmaceutical composition of claim 1, wherein the volatile solvent consists essentially of one or more lower alkanols.   The pharmaceutical composition according to claim 16, wherein the lower alcohol is selected from ethanol and isopropanol.   The pharmaceutical composition according to claim 1, wherein the thickening agent is present in an amount of 0.1% to 20% by weight of the total pharmaceutical composition.   20. The pharmaceutical composition according to claim 19, wherein the thickening agent is a cellulose derivative, more preferably hydroxypropylcellulose, hydroxypropyl-methylcellulose, hydroxyethylcellulose, or a mixture thereof.   The pharmaceutical composition according to claim 19, wherein the thickening agent is CARBOPOL.   Applying a spray of the pharmaceutical composition according to claim 1 to the skin of a subject to form a metastable deposit of the active agent upon evaporation of the volatile solvent, whereby the living epidermis from the stratum corneum A therapeutic method for providing enhanced osmotic absorption of a physiologically active substance, wherein the distribution of the physiologically active agent to the physiological substance is enhanced.

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