ES2265239B1 - PHARMACEUTICAL COMPOSITION FOR TRANSDERMAL ADMINISTRATION. - Google Patents

Abstract

It comprises a pharmaceutical composition for transdermal administration of alprazolam together with various permeation promoters, as well as a device for transdermal administration in the form of a patch or reservoir. The composition shows improved permeation capacity and tolerability due to an unexpected synergistic effect. It also includes its use in the treatment of psychiatric dysfunctions, fertility and / or Crohn's disease.

Description

Pharmaceutical composition for administration transdermal

This invention is related to the field of human medicine, and specifically with formulations of transdermal administration of drugs that include mixtures of several agents promoting their percutaneous absorption. In particular, it refers to the transdermal administration of alprazolam using skin permeation promoters.

Prior art

Alprazolam is the common denomination international 8-Chloro-1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine of formula (I) and CAS No. 28981-97-7. This compound is a short-acting benzodiazepine anxiolytic, which acts by increasing acid activity gamma-aminobutyric acid (GABA) by facilitating its binding with the GABAergic receptor. It has hypnotic activity, anticonvulsant, sedative, muscle relaxant and amnesic, with specific activity in distress crises, in addition to having antidepressant activity Alprazolam can be used in the anxiety treatment, panic, schizophrenia, anxiety associated with depression, as well as other psychiatric diseases, in fertility problems and for the treatment of disease Crohn.

one

Alprazolam is a triazolobenzodiazepine from moderate lipophilicity Your share coefficient n-octanol / water, expressed as logarithm (logP) is from 1.72 to 2.12. In humans, plasma concentrations Therapeutics are 5 to 50 ng / ml, depending on the indication to try. To reach these therapeutic levels through a transdermal administration flow values of permeation through the skin between 0.25 and 5.50 µg.cm2 / h. In patent application WO 93/03694 it is indicated that values of flow from 1 µm.cm2 / h would already provide quantities of therapeutically effective alprazolam. These flows of permeation will depend on the surface of the formulation and the Permeation promoters used.

The transdermal administration of certain drugs can improve your pharmacokinetic profile, and therefore your clinical efficacy On the other hand, some topical formulations facilitate controlled release of drugs, which allow ensure your dosage for a long period of time and, by therefore, ensure compliance with the prescription by the patient.

Alprazolam is a drug that has some features that make it ideal for administration transdermal, such as its reduced daily dose, clinical need of its use in prolonged treatments and the requirement pharmacokinetics administered in several daily doses that currently requires oral administration.

There are several documents that relate the transdermal administration of alprazolam with the use of promoters of permeation. Most permeation promoters transdermal base their action on the disruption of the structure intercellular lipid temporarily and reversibly, so facilitate permeation of the drug. To be accepted pharmaceutically, a permeation promoter or a combination of these should have the ability to increase the permeability of the skin for the drug, and should not be toxic or irritating to the concentration used

The behavior of the permeation promoter depends on the drug to be penetrated and the transdermal device used. However, it cannot be known a priori which promoters will be most suitable for improving the transdermal flow of a particular drug. In fact, an effective promoter or combination of promoters for a given drug may not be effective with other drugs. Many potential promoters interact adversely with other components of the administration device, one of the main problems being incompatibility with medically acceptable contact adhesives or other components of the device. This incompatibility can lead to adhesive adhesion failures.

Various have been described in the literature examples in which two or more promoters of the permeation that increase the percutaneous absorption of alprazolam showing that they produce a synergistic effect. However in many cases what is produced is an additive effect of the response individual that each component has on its own. So that really produce a synergistic effect, the effect obtained must be greater than the effect of simply adding promoters to permeation

US 4,590,190 describes the use of a combination of at least one monoalcohol and one lactam as promoters of percutaneous permeation of benzodiazepines. Also, in US 4,710,497 the use of an ester is described aliphatic hydroxyalkyl and lactams for the same purpose.

In patent application WO 94/21262, describes the use of molecules based on C12 aliphatic chains as alprazolam permeation promoters: lauryl lactate with Lauric acid diethanolamide, ethyl laurate with diethanolamide of lauric acid, isostearyl benzoate with diethanolamide lauric acid, lauryl lactate, glyceryl monolaurate, lactate ethyl and lauryl lactate with glyceryl monolaurate.

EP 267.617 describes the effectiveness of a binary combination of short chain monoalcohols and N-cyclic compounds, which favor permeation of lipophilic permeants. However the flow increases Intrinsic drug obtained depend on the drug that is use

Finally, EP 913,158 describes the application of alprazolam in an adhesive matrix that includes C6-C16 aliphatic promoters, whether fatty acids or alcohols, saturated and / or monounsaturated molecules.

Thus, from what is known in the state of the art it follows that it is desirable to have a composition useful to be formulated as a transdermal delivery device of alprazolam that has a permeation rate sufficient to achieve therapeutic plasma concentrations, a acceptable tolerability and satisfactory adhesiveness on the skin.

Explanation of the invention.

The inventors have surprisingly found that the combination of alprazolam, along with the following Permeation promoters: 1-decyl alcohol, diethylene glycol monoethylene ether, 1-dodecyl hexahydro-2-N-azepin-2-one and polyethylene glycol mono-oleyl ether, has a improved permeation capacity and tolerability compared to others known formulations, due to a synergistic effect not expected.

Thus, according to a first aspect of the present invention, a pharmaceutical composition is provided for transdermal administration comprising an amount Therapeutically safe and effective alprazolam, a combination pharmaceutically acceptable 1-decyl alcohol, diethylene glycol monoethylene ether, polyethylene glycol mono-oleyl ether and 1-dodecyl hexahydro-2-N-azepin-2-one  as permeation promoters, optionally with amounts appropriate pharmaceutically acceptable excipients, dispersed in a polymeric support suitable for constituting a formulation transdermal

In a preferred embodiment, alprazolam is in an amount between approximately 0.5% w / w and approximately 15% w / w; 1-decyl alcohol is in an amount between approximately 0.5% w / w and approximately 15% w / w; the diethylene glycol monoethylene ether is in an amount between approximately 0.5% w / w and approximately 15% w / w; polyethylene glycol mono-oleyl ether is in an amount comprised between about 0.05% w / w and about 2% w / w; Y he 1-dodecyl hexahydro-2-N-azepin-2-one is in an amount between approximately 0.5% w / w and approximately 15% w / w. All percentages are given to the whole pharmaceutical composition that includes the alprazolam, the permeation promoters, optionally the possible additional excipients and polymeric support on the that the whole is dispersed. The percentages expressed in the claims are given based on this definition of pharmaceutical composition

According to a more preferred embodiment, the alprazolam is in an amount between approximately 2% w / w and approximately 10% w / w; the 1-decile alcohol is in an amount between approximately 2% w / w and about 10% w / w; diethylene glycol monoethylene ether is in an amount between approximately 2% w / w and approximately 10% w / w; polyethylene glycol mono-oleyl ether is in an amount comprised between about 0.5% w / w and about 1.5% w / w; Y he 1-dodecyl hexahydro-2-N-azepin-2-one is in an amount between approximately 2% w / w and approximately 10% w / w

The most preferred composition comprises the following components in the p / p percentages: alprazolam in a amount of about 5% w / w; 1-decile alcohol in an amount of about 7% w / w; diethylene glycol  monoethylether in an amount of about 7% w / w; polyethylene glycol mono-oleyl ether in an amount of about 1% w / w; Y 1-dodecyl hexahydro-2-N-azepin-2-one in an amount of about 5% w / w.

The pharmaceutical composition further comprises appropriate amounts of pharmaceutically acceptable excipients to constitute a topical formulation. The composition can understand different types of excipients: spreading agents, agents that increase viscosity, or solubilizers, among others. Optionally, other components can be added to the compositions of this invention in appropriate amounts for improve your pharmaceutical acceptability, as will be obvious to a skilled.

The promoting effect of diethylene glycol monoethylether, a short chain alkanol of formula (II), seems be related to the ability to interact with lipids of the stratum corneum reversibly destructuring them. Dice  which is absorbed very quickly, acts in the initial times of the absorption, and therefore is responsible for the initial absorption from alprazolam.

2

He 1-dodecylhexahydro-2N-azepin-2-one, also known as laurocapram, of formula (III), acts fluidizing the lipid structure of the channels intercellular

3

Mono-Oleyl Polyethylene Glycol ether, Brij 96V, of formula (IV), is a non-phonic surfactant that acts at the level of the stratum corneum interacting at the level of membrane lipids and thus facilitating their permeability.

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 \ melm {\ delm {\ dpara} {\ delm {CH} {\ delm {\ para} {\ delm {(CH2} _ {7}} {\ delm {\ para} {Me}}} }}} {C} {\ uelm {\ para} {\ uelm {(CH2) _ {8}} {\ uelm {\ para} {\ uelm {(CH2} CH2 } O) _ {n}} {\ uelm {\ para} {OH}}}}}} 

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1-decyl alcohol, formula (V), a long chain alkanol is used because its activity as a promoter of absorption it seems to be related to the ability to intercalate between structured lipids of membrane and act as a skin plasticizing agent by increasing thus its permeability.

4

As demonstrated in the examples, the combination in the appropriate proportions indicated above of the permeation promoters together with alprazolam, shows an improved permeation capacity, due to a synergistic effect of their properties.

According to a second aspect of the present invention, a device for administration is provided transdermal alprazolam comprising a matrix deposit polymeric or adhesive base comprising an amount Therapeutically safe and effective composition of the invention; and means to keep the reservoir in contact with the skin.

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In a preferred embodiment, the device is an adhesive base patch containing the components of the defined composition previously dispersed in the adhesive.

In another preferred embodiment, the device allows a permeation flow of alprazolam through the skin of at least 0.5 µg / cm 2 h for a long period of time.

A third aspect of the present invention is refers to the use of the composition described above for the preparation of a medication for the treatment of dysfunctions Psychiatric, fertility and / or Crohn's disease. In a preferred embodiment, the psychiatric dysfunction is selected between the group formed by anxiety, panic, schizophrenia and anxiety associated with depression. In a more preferred embodiment, Psychiatric dysfunction is anxiety associated with depression.

Another aspect of the present invention is also refers to a method of treating a human suffering from a Psychiatric dysfunction, fertility or Crohn's disease. This method comprises the administration to said patient of a composition comprising alprazolam, 1-decyl alcohol, diethylene glycol monoethyl ether, 1-dodecyl hexahydro-2-N-azepin-2-one and polyethylene glycol mono-oleyl ether. The administration is carried out by a device that it comprises a polymer matrix or adhesive base deposit that it comprises a therapeutically safe and effective amount of the composition of the invention; and means to keep the reservoir in  Skin contact.

Throughout the description and the claims, the word "comprises" and its variants do not they intend to exclude other technical characteristics, additives, components or steps. The descriptions in the summary of this Application are incorporated here for reference. For experts in matter, other objects, advantages and characteristics of the invention will come off in part from the description and in part from The practice of the invention.

Brief description of the figures

Fig. 1 is a comparison of average in vitro permeation profiles for formulation 9 of Table 4 (squares) and the baseline permeation profile of the drug (triangles).

The following embodiments will be provided by way of illustration, and are not intended to be Limitations of the present invention.

Detailed statement of embodiments Example 1 In vitro study of the intrinsic permeation of alprazolam

The objective of this study is to determine the baseline ability of the drug alone to spread to through the skin from an aqueous solution at pH physiological.

1.1. Method of permeation through the skin

For the in vitro study of transdermal permeation vertical diffusion cells connected to an automatic sampling apparatus (Microette, Hanson Research) were used that allowed samples of the receptor solution to be obtained at predetermined times.

Abdominal human skin was used as a membrane of permeation This skin was frozen at -20ºC and before its utilization was thawed and cut to a thickness of 250 µm which includes the epidermal stratum corneum, which is the histological layer permeation limitation. This membrane was placed in the cells of diffusion through a fixing system.

The donor solution was an aqueous solution at saturation of alprazolam. The receiving solution used consisted of in a phosphate regulatory solution pH 7.0, diethylene glycol monoetileter and ethanol in a ratio of 80/15/5. The study is performed at a constant temperature of 32 ° C through a circuit that thermostatizes the shirts of the diffusion cells.

The samples obtained were evaluated by HPLC-UV. The chromatographic conditions used were: methanol: water (60:40), column C18-RP (eg: Kromasil 100, 15 x 0.4 cm), flow of 1 ml / min, quantification at 222 nm. From each series of results of permeated amounts versus the time obtained with each cell, in vitro transdermal flow values were estimated from the slope of the linear permeation phase.

1.2. Results

Next, Table 1 shows the intrinsic permeation parameters of alprazolam obtained from the solution maintained at saturation. It indicates the flow values (J), amounts permeated at 24 hours (Q 24H) as well as the plasma concentrations (Cee) that can be predicted with these values in vitro .

TABLE 1 Intrinsic permeation of alprazolam

Parameter / units Half J mug / cm 2 h 1 0.14 Q_ {24H} \ mug 3.26 EEC ng / ml 0.4

Example 2 Synergistic effect of transdermal permeation promoters of the present invention

Table 2 lists three of the promoters Permeation used:

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TABLE 2 Nature of three of the promoters used

Substance Denomination 1-dodecyl hexahydro-2-N-azepin-2-one Amide cyclic Laurocapram, Azona® 1-decyl alcohol Chain alcohol long 1-decyl alcohol diethylene glycol monoethylene ether Alcohol chain short Transcutol®

A solution of alprazolam was prepared in a binary solvent formed by ethanol-dichloromethane 1: 1 by magnetic stirring for about 10 minutes. The amount of alprazolam was used to obtain end of the procedure a wealth in the formulation of 5% of drug. Once dissolved, the laurocapram was incorporated to reach a final concentration of 5%. It stirred about 2 minutes and Durotack acrylate-vinyl acetate base was added 87-2051 in sufficient quantity that completes 100% of the final composition. It was stirred for about 15 minutes until observe a completely transparent solution; later the resulting solution was spread on a polyester sheet coated (Scotchpak 1022, 3M) and laminated to a thickness of 250 \ mum. Then, the solvents were evaporated to a temperature of 60 ° C for 30 minutes, all through an oven discontinuous laminator (Labcoater, Mathis AG). Finally I know completed the formulation by depositing a polyester sheet (Scotchpack 1109, 3M).

2.2: Composition of 5% alprazolam + 5% laurocapram + 5% 1-decyl alcohol

An amount of alprazolam was dispersed in ethanol by magnetic stirring for about 40 min, after which promoters were incorporated: 1-decyl alcohol and laurocapram. The added amounts of these three components were necessary to obtain a concentration 5% final for each of them. It stirred for about 5 minutes and a base of Durotack acrylate-vinyl acetate 87-2051 in sufficient quantity that completes 100% of the final composition. After an hour of agitation a completely homogeneous and transparent dispersion. Later the resulting solution was spread on a polyester sheet coated (Scotchpak 1022, 3M) and laminated to a thickness of 250 µm and the solvents were evaporated at a temperature of 60 ° C for 30 minutes, all through a rolling oven discontinuous (Labcoater, Mathis AG). Finally the formulation by depositing a polyester sheet (Scotchpack 1109, 3M).

Following the same procedure as in the previous examples, other compositions at 5% of alprazolam with different combinations of the promoters mentioned in Table 2.

Table 3 summarizes the formulations. made with 5% alprazolam together with the respective results of transdermal flow (mug / cm 2 h), concentrations predicted plasma (ng / ml) and increased flow compared to baseline value (Δ).

TABLE 3 Alprazolam 5% formulations with different promoters

N ° Formulation Flow (\ mug.cm2 / h) Cee (ng / ml) \Delta one 5% laurocapram 0.26 2.4 1.9 2 5% transcutol 0.20 1.8 1.4 3 5% 1-decile alcohol 0.30 2.7 2.1 4 5% laurocapram + 5% transcutol 0.41 3.4 2.9 5 5% laurocapram + 5% 1-decile alcohol 0.33 2.9 2.4 6 5% laurocapram + 5% 1-decil alcohol + 5% transcutol 0.93 8.5 6.6

Table 3 shows that with formulation 6, composed of a mixture of the three promoters, you get a increase in permeation flow 6.6 times higher than the baseline, and this combination of promoters has a synergy in the promoter effect greater than the sum of the flow increases individual.

Example 3 Synergistic effect of the incorporation of a surfactant into the formulation 6 of Example 1 3.1: Composition of 5% alprazolam + 7% 1-decyl alcohol + 7% laurocapram + 5% transcutol + 1% Brij 96V

The necessary amount of alprazolam was dissolved in binary solvent ethanol-dichloromethane ratio 1: 1 by magnetic stirring for about 10 minutes for a final concentration of 5%. Once dissolved they were incorporated adequate amounts of 1-decyl alcohol, laurocapram, transcutol and polyethylene glycol mono-oleyl ether (for example, Brij 96V) for reach at the end concentrations of 7%, 5%, 7% and 1% respectively, and stirred for 10 minutes until dissolution of all components. Once dissolved, a base of Durotack acrylate-vinyl acetate 87-2051 and Durotack 87-2196, in one 70/30 proportion in sufficient quantity that completes 100% of the final composition, stirred about 15 minutes until a completely homogeneous and transparent solution. Subsequently spread the resulting solution on a polyester sheet coated (Scotchpak 1022, 3M) and laminated to a thickness of 250 µm and the solvents were evaporated at a temperature of 60 ° C for 30 minutes, all through a rolling oven discontinuous (Labcoater, Mathis AG). Finally completed depositing a polyester sheet (Scotchpack 1109, 3M).

Table 4 shows the results of in vitro transdermal flow values (mug.cm2 / h), flow rate ratios with respect to formulation 7 ("Ratio"), predicted plasma concentrations and the increase in flow obtained with respect to the baseline value (Δ) of different formulations made at 5% alprazolam.

TABLE 4 Permeation results with formulations of 5% alprazolam with different promoters

N ° Formulation Flow Ratio EEC \Delta (\ mug.cm2 / h) (ng / ml) 7 1% Brij 96V 0.4 - 3.3 2.8 8 7% 1-decyl alcohol + 1% Brij V96 1.5 1.6 13.2 10.7 9 5% laurocapram + 7% 1-decyl alcohol + 7% transcutol + 2.8 3.0 25.4 20.0 one% Brij 96V

The results in Table 4 indicate that with the formulation 9, an increase in the permeation flow of almost 20 times higher than the basal alprazolam. In actually, the permeate amounts of drug are of the order of 200 times higher than baseline values.

Example 4 Study of potential tolerability of formulations rehearsed

Tolerability of the formulations tested 6 and 9 was studied. An albino rabbit irritation test was performed following the methodology of Draize (Draize et al. , J. Pharmacol. Exp. Therap. 1944, vol. 82, pp. 377- 90).

Prior to the application of the patch in the loin area, the area under study was shaved, reserving a part for the baseline evaluation. The patch was applied over a period of 48 h, after which it was removed with caution. After 30 minutes, 1 hour and 2 hours after removing the patch, the most characteristic signs of irritation that appeared on the animal's skin were visually evaluated. A scale of assessment of the degree of erythema and edema was used in accordance with those commonly used in this type of study (Skin irritation and sensitization testing of generic transdermal drug products. FDA Guidance for industry 1999).

When comparing the series of results for each formulation no significant differences were observed between they. This result is remarkable and surprising since the formulation 9 additionally contains a surfactant in its composition and surfactants are substances widely described in the scientific literature as potentially irritants (Kydonieus AF, WiIIe JJ. Biochemical Modulation of skin reactions. CRC Press, Washington 2000).

Claims (11)

1. Pharmaceutical composition for transdermal administration characterized in that it comprises a therapeutically safe and effective amount of alprazolam and a pharmaceutically acceptable combination of 1-decyl alcohol, diethylene glycol monoethyl ether, polyethylene glycol mono-oleyl ether and 1-dodecyl hexahydro-2-N-azepin-2- one as promoters of permeation. 2. Pharmaceutical composition according to claim 1, characterized in that the alprazolam is in an amount between about 0.5% w / w and about 15% w / w; 1-decyl alcohol is in an amount between about 0.5% w / w and about 15% w / w; diethylene glycol monoethylether is in an amount between about 0.5% w / w and about 15% w / w; the polyethylene glycol mono-oleyl ether is in an amount between about 0.05% w / w and about 2% w / w; and 1-dodecyl hexahydro-2-N-azepin-2-one is in an amount between about 0.5% w / w and about 15% w / w, optionally with appropriate amounts of pharmaceutically acceptable excipients, dispersed in a polymeric support suitable. 3. Pharmaceutical composition according to claim 2, characterized in that alprazolam is in an amount between about 2% w / w and about 10% w / w; 1-decyl alcohol is in an amount between about 2% w / w and about 10% w / w; diethylene glycol monoethylether is in an amount between about 2% w / w and about 10% w / w; the polyethylene glycol mono-oleyl ether is in an amount between about 0.5% w / w and about 1.5% w / w; and 1-dodecyl hexahydro-2-N-azepin-2-one is in an amount between about 2% w / w and about 10% w / w. 4. Pharmaceutical composition according to claim 3, characterized in that the alprazolam is in an amount of approximately 5% w / w; 1-decyl alcohol is in an amount of approximately 7% w / w; diethylene glycol monoethylene ether is in an amount of approximately 7% w / w; the polyethylene glycol mono-oleyl ether is in an amount of about 1% w / w; and 1-dodecyl hexahydro-2-N-azepin-2-one is in an amount of approximately 5% w / w. 5. Pharmaceutical composition according to any of claims 1-4, characterized in that it further comprises appropriate amounts of pharmaceutically acceptable excipients to constitute a topical application formulation. 6. Device for the transdermal administration of alprazolam in the form of a patch or reservoir, characterized in that it comprises: a) a deposit of polymer matrix or base adhesive comprising a therapeutically safe amount and Effective composition according to any of the claims 1 to 5; Y b) means to keep the deposit in contact with the skin. 7. Device according to claim 6, characterized in that the device is an adhesive base patch containing the components of the composition defined in claims 1-5 dispersed in the adhesive. Device according to any one of the preceding claims 6 to 7, characterized in that the alprazolam is administered through the skin with a permeation flow of at least 0.5 µg / cm 2 h for a long period of time. . 9. Use of a composition according to any of the preceding claims 1 to 5 for the preparation of a medication for the treatment of psychiatric dysfunctions, Fertility and / or Crohn's disease. 10. Use according to claim 9, characterized in that the psychiatric dysfunction is selected from the group consisting of anxiety, panic, schizophrenia and anxiety associated with depression. 11. Use according to claim 10, characterized in that the psychiatric dysfunction is anxiety.