JP2012193176A - Milnacipran-containing pharmaceutical composition for percutaneous absorption - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide novel pharmaceutical compositions for percutaneous absorption for enhancing skin permeability of milnacipran or a pharmaceutically acceptable salt thereof and exhibiting superior pharmacological effect, and to provide pharmaceutical preparations containing the same.SOLUTION: The novel pharmaceutical compositions for percutaneous absorption include: milnacipran or a pharmaceutically acceptable salt thereof as an active principle; and menthol, cineole, glyceryl monooleate, or a combination of two or more of them. The pharmaceutical preparations including the pharmaceutical compositions are also provided. The pharmaceutical compositions and the pharmaceutical preparations including milnacipran, as an active principle, which is clinically used widely as a depression therapeutic drug and recognized to be useful as an analgesic for chronic pain and the like, are excellent in efficacy and safety, and highly useful as a percutaneous absorption type antidepressant and analgesic usable for a long period with high compliance.

Description

  The present invention relates to a pharmaceutical composition for percutaneous absorption containing milnacipran or a pharmaceutically acceptable salt thereof as an active ingredient, or a medicine containing this composition.

Depression is a type of mood disorder, including depressed mood (anxiety, agitation, etc.), decreased motivation (such as lethargy, hunger, etc.), decreased mental activity (such as lack of thought), and various physical symptoms (such as insomnia, easy sleep) It is a mental illness that causes fatigue, headache / headache, loss of appetite, etc. Depression is a socially important disease because the number of affected individuals has increased in recent years, and when it becomes severe, it has an impact on daily life and can be life-threatening, such as suicide attempts. Therefore, elucidation of the onset mechanism is desired, but it is thought that psychological factors and neuroscience factors are complicatedly involved in the onset of depression, and it has not been fully elucidated. The treatment of depression is currently carried out by a combination of pharmacotherapy (antidepressants) and psychological care. As antidepressants, tricyclic antidepressants (first generation) such as imipramine and amitriptyline have been first developed and used. However, since tricyclic antidepressants also block histamine H ₁ receptor, acetylcholine muscarinic M ₁ receptor, and adrenergic α ₁ receptor at the postsynaptic side, side effects such as constipation and dysuria due to anticholinergic action There were many. In addition, there is a problem that it becomes fatal in large doses. Therefore, a tetracyclic antidepressant (second generation) with fewer side effects was developed, but the antidepressant effect was insufficient and anticholinergic action still remained. In the 1980s, a serotonin-selective reuptake inhibitor (SSRI) (third generation) with fewer side effects due to anticholinergic activity was developed, but SSRIs are used to induce nausea and vomiting by stimulating serotonin receptors in the brain and intestinal tract. , Caused new side effects such as withdrawal syndrome due to medication interruption. Later, in the 1990s, selective serotonin and noradrenaline reuptake inhibitors (SNRI) were developed and are widely used in clinical settings as drugs that do not have anticholinergic effects although gastrointestinal symptoms still remain.

In drug therapy for depression, it is important to keep the drug concentration in the blood constant at an effective concentration in order to reduce side effects and maximize the therapeutic effect on the patient. However, in the treatment of depression, patients take compliance with oral drugs commonly used to treat depression (drugs prescribed by doctors) because the medication is long-lasting and the symptoms of depression remit and repeat. (Patients should use as directed) It is difficult to take medicine well, which may cause worsening of symptoms due to forgetting to take or side effects due to overdose. In particular, there are preparations that can be taken once a day for SSRI, but milnacipran, which is widely used as SNRI, needs to be taken 2 to 3 times a day, and it is difficult to take medicine with good compliance. .
In contrast to such oral agents, transdermal agents that are administered by transdermally absorbing the drug continuously absorb the drug continuously from the skin. It is possible to maintain. As a result, it is possible to obtain a preparation that can be used only once a day, especially for a drug that has been required to be taken twice or more a day, and compliance can be improved. In addition, in the case of a transdermal agent, since the maximum blood concentration can be reduced, side effects can be easily avoided. In addition, since transdermal administration can avoid the first-pass effect due to drug metabolism in the liver, there is a possibility that an effective blood dose can be maintained with a smaller amount of drug than oral administration. In addition, when a drug is applied to a support substrate to make a patch, not only the patient but also the doctor, nurse, family, etc. can easily confirm that the patient is using the drug. There is also a merit that subsequent drug absorption can be easily stopped by removing the patch. Thus, transdermal agents are very useful for improving patient compliance and quality of life (QOL). However, some drugs are difficult to be transdermally absorbed, and it is often difficult to find a formulation that can be an appropriate transdermally absorbable preparation.

Milnacipran [(±) -cis-2- (aminomethyl) -N, N-diethyl-1-phenylcyclopropanecarboxamide] is one of the typical SNRIs, and it contains serotonin and noradrenaline at the intracerebral nerve junction. It is a fourth generation antidepressant that is known to exert an antidepressant action by selectively inhibiting reuptake. Milnacipran has no side effects due to anticholinergic action because it does not bind to neurotransmitter receptors like tricyclic and tetracyclic antidepressants, and the third-generation antidepressant SSRI Thus, there are few side effects of nausea and vomiting by stimulating serotonin receptors in the brain and intestinal tract. Effectively, it also inhibits the reuptake of noradrenaline in addition to serotonin, so it exerts stronger antidepressant action than SSRI that selectively inhibits the reuptake of serotonin, and it is also effective for willingness that is not particularly effective in SSRI. Have Moreover, milnacipran is effective not only for antidepressive action but also for pain, and has been reported to have therapeutic effects on neuropathic pain, fibromyalgia, tension-type headache and the like.
In the present invention, even when referred to as milnacipran for convenience, milnacipran hydrochloride may be referred to.

  Regarding the transdermal absorption agent of milnacipran, there is a report of Patent Document 1. However, this relates to transmucosal administration of milnacipran, and specifically only discloses a formulation for intranasal administration of milnacipran. The mucosa is a tissue that is relatively easy to permeate drugs, whereas the skin epithelium has a strong drug permeation-preventing function. Therefore, in a preparation for transdermal administration, it is necessary to find a formulation having a stronger absorption promoting action for percutaneously absorbing the drug.

International Publication WO2007 / 086493

  An object of the present invention is to provide a novel pharmaceutical composition for percutaneous absorption for enhancing the skin permeability of milnacipran, which is an active ingredient, or a pharmaceutically acceptable salt thereof, and exhibiting an excellent pharmacological effect. It is in providing the pharmaceutical containing this.

  The present inventors provide a preparation for exerting an excellent pharmacological effect as a transdermal absorbent by improving transdermal absorbability of milnacipran or a pharmaceutically acceptable salt thereof which is difficult to transdermally absorb. We have made an intensive study on the development. As a result, by incorporating menthol, cineol or glycerin fatty acid ester or a combination of two or more thereof as an absorption promoter in milnacipran, the transdermal absorbability of milnacipran is significantly enhanced. The headline and the present invention were completed.

  The pharmaceutical composition of the present invention can exert an effect by transdermal absorption of milnacipran or a pharmaceutically acceptable salt thereof. Therefore, the medicine containing the pharmaceutical composition of the present invention is useful as an external preparation. In particular, when used as a patch, it is extremely useful as a transdermal antidepressant or analgesic that can be used for a long time with good compliance.

1 is a graph showing the cumulative skin permeation amount of milnacipran over time in the in vitro skin permeability test of Example 1. FIG. FIG. 2 is a graph showing the skin permeation rate of milnacipran in the in vitro skin permeability test of Example 1. FIG. 3 is a graph showing the delay time of milnacipran skin permeation in the in vitro skin permeability test of Example 1. 4 is a graph showing the cumulative skin permeation amount of milnacipran (MIL) over time in the in vitro skin permeability test of Example 2. FIG. FIG. 5 is a graph showing the skin permeation rate of milnacipran (MIL) in the in vitro skin permeability test of Example 2. FIG. 6 is a graph showing the effect of the pharmaceutical composition of the present invention on immobility time in the in vivo forced swimming test of Example 3.

  The present invention relates to a novel transdermal absorption containing milnacipran or a pharmaceutically acceptable salt thereof as an active ingredient and containing menthol, cineol or glycerin fatty acid ester or a combination of two or more thereof as an absorption enhancer. The present invention relates to a pharmaceutical composition for use or a medicine containing the same.

  The active ingredient of the pharmaceutical composition or medicament of the present invention is milnacipran or a pharmaceutically acceptable salt thereof. The salt can be used without particular limitation as long as it is a pharmaceutically acceptable acid addition salt. For example, inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, hydrofluoride, hydrobromide, etc. Acid salt, acetic acid, tartrate, lactate, citrate, fumarate, maleate, mesylate, succinate, methanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate And organic acid salts such as camphor sulfonate. Preferably, milnacipran hydrochloride which is commercially available and widely used clinically is used. Moreover, in this application, the hydrate and solvate of a milnacipran are also included by the milnacipran which is an active ingredient of this invention.

  The weight% of milnacipran or a pharmaceutically acceptable salt thereof contained as an active ingredient in the pharmaceutical composition or medicine of the present invention is 0.1 to 10% by weight, preferably 0.2 to 5% by weight. be able to.

  Menthol used in the pharmaceutical composition of the present invention includes l-menthol and dl-menthol which are optical isomers thereof. Mentha oil and mint water mainly composed of menthol are also included in the menthol of the present invention. The amount of menthol used varies depending on the dosage form described below, but can be 0.75 to 10% by weight, preferably 1 to 5% by weight.

  Cineol used in the pharmaceutical composition of the present invention is also called 1,8-cineol, 1,8-epoxy-p-menthane or eucalyptol, and eucalyptus essential oil mainly composed of cineol is also included in the cineol of the present invention. Is done. The amount of cineole used varies depending on the dosage form described below, but can be 0.75 to 10% by weight, preferably 1 to 5% by weight.

  In the pharmaceutical composition of the present invention, the above menthol and cineole can be used in combination, and the amount of menthol and cineole used varies depending on the dosage form and the like described later, but 0.75 to 10% by weight in total, Preferably, it can be 1 to 5% by weight.

  Examples of the glycerin fatty acid ester that can be used in the pharmaceutical composition of the present invention include glycerin fatty acid esters in which the fatty acid has 5 to 25 carbon atoms. More specifically, glyceryl caprylate, glyceryl caprate, glyceryl laurate, glyceryl palmitate, glyceryl oleate, glyceryl stearate, glyceryl dicaprylate, glyceryl tricaprylate, and the like, glycerin oleate is preferred. The amount of glycerin fatty acid ester varies depending on the dosage form described later, but can be 2 to 30% by weight, preferably 5 to 20% by weight.

  Examples of the lower alcohol used in the pharmaceutical composition of the present invention include alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, and 2-butanol. The amount of the lower alcohol used varies depending on the dosage form described below, but can be 5 to 40% by weight, preferably 10 to 30% by weight.

  The specific dosage form of the pharmaceutical containing the pharmaceutical composition for transdermal absorption according to the present invention is not particularly limited, and examples thereof include solutions, creams, ointments, gels, lotions, sprays, patches, It can be formulated as an external preparation such as a tape. In the formulation, additives and bases suitable for each dosage form are used as appropriate, and they can be produced according to the usual methods described in the general rules of formulation of the Japanese Pharmacopoeia. In prescription, it is good also as a compounding agent with another pharmaceutical active ingredient with a milnacipran.

  As an example of the patch, it can be formulated into a patch (patch) in the form of a hydrogel. Hydrogels can be made using a commonly used method that uses a viscous agent such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, etc., and swells with water as a base. In order to uniformly mix a certain milnacipran and the above absorption enhancer into the preparation, it can be formulated using an appropriate solvent such as isopropanol or ethanol.

  The percutaneous absorption pharmaceutical composition and medicament of the present invention can be used for patients who have been conventionally administered oral milnacipran due to depression or chronic pain. As analgesics, in addition to or included in chronic pain, various types of pain such as neuropathic pain, headache, migraine, tension headache, chronic pelvic pain, muscle pain, joint pain, low back pain, fibromyalgia, etc. Can be used to treat pain. In addition, for example, it can be used for treatment of diseases such as stress urinary incontinence for which the effect of milnacipran has been reported.

  EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Example 1. Examination of absorption accelerator (1) Preparation of milnacipran-containing hydrogels Milnacipran-containing hydrogels having different absorption accelerators were prepared by the following method. In the following examples, milnacipran hydrochloride is used, and the indicated weight% of each composition component is based on the final total amount (100 weight%).
Hydroxyethyl cellulose and hydroxypropyl cellulose were each added to water so as to be 1% by weight, and milnacipran hydrochloride was further added so as to be 2% by weight, and left overnight to swell the base. Thereafter, 2% by weight of 1-menthol, 2% by weight of d-limonene, 2% by weight of 1,8-cineole, 1% by weight of 1-menthol and 1% by weight of 1,8-cineole as absorption promoters. In combination, 10% by weight of N-methylpyrrolidone or 10% by weight of glyceryl monooleate was added, and further 20% by weight of isopropyl alcohol was added and allowed to stand overnight to form a uniform hydrogel. In addition, the amount of water to be used was adjusted in accordance with the increase / decrease in the amount of the components so that the total amount became 100% by weight. Furthermore, as a control, a milnacipran-containing hydrogel without the addition of an absorption enhancer was similarly prepared.

(2) In vitro skin permeability test 7-week-old male Hos; HR-1 hairless mouse isolated skin (registered trademark: Labo Skin, Hoshino Laboratory Animal Breeding) vertical diffusion cell (effective diffusion area) : 2.01 cm ² , receiver cell volume 16.0 mL) so that the skin stratum corneum is on the donor side and the skin basement membrane side is on the receiver side. 1.0 g of the above hydrogel was applied in the donor cell and the receiver cell was filled with phosphate buffered saline (PBS) at pH 7.4. A 0.2 mL solution was taken from the receiver cell every hour, and milnacipran was quantified by high performance liquid chromatography (HPLC). Immediately after the separation, 0.2 mL of PBS was replenished to the receiver cell. For HPLC, the mobile phase was potassium dihydrogen phosphate-potassium hydroxide buffer (pH 5.5, ionic strength 59 mM): methanol = 60: 40, the column was YCM-Pack ODS-A (150 mm × 44.6 mm), wavelength Was 222 nm, the flow rate was 1.0 mL / min, the column temperature was room temperature, and the injection volume was 90 μL. Each test was performed three times, and the average value ± standard deviation was obtained.

(3) Results of milnacipran skin permeability test As a result of the above in vitro skin permeability test, the cumulative skin permeation amount per unit area of milnacipran from the milnacipran-containing hydrogel added with each absorption enhancer was measured over time. FIG. 1 shows the results of the measurement (cumulative permeation amount-time curve graph). Further, the skin permeation rate (μg / cm ² / h) of milnacipran determined from the above measured values [the skin permeation rate is the slope of the regression line obtained by linear regression of the cumulative permeation amount-time curve plot. 2 is shown in FIG. Furthermore, the delay time obtained from this regression line [time until the skin permeation speed reaches a steady state] is shown in FIG.

  As is clear from FIGS. 1 and 2, the milnacipran-containing composition to which no absorption enhancer was added (control) showed almost no skin permeability, but 1-menthol (2% by weight) or 1, The composition containing 8-cineole (2% by weight) significantly promotes the skin permeability of milnacipran, and the composition containing glyceryl monooleate (10% by weight) also has a skin permeability of milnacipran. Was shown to be promoted. However, the composition containing d-limonene or N-methylpyrrolidone did not promote skin permeability. In particular, d-limonene belongs to monoterpenes like l-menthol and 1,8-cineole, and although the chemical structure is similar, the absorption promoting action of milnacipran was not recognized. This indicates that a combination of a drug called milnacipran and an absorption enhancer suitable for it is important for promoting transdermal absorption.

  Further, in the composition containing 1% by weight of 1-menthol and 1,8-cineole, milnacipran penetrates the skin in the same manner as the composition containing 1% by weight of l-menthol or 2,8-cineole. Sex was promoted (FIG. 2). As is apparent from FIG. 3, the composition containing 1% by weight of l-menthol and 1,8-cineole each is more than the composition containing 2% by weight of l-menthol or 1,8-cineole. The effect of milnacipran on shortening the skin permeation delay time was recognized. The shorter the delay time, the faster the time until the drug effect appears, which can be a favorable property for the composition.

Example 2 Dose study of milnacipran (1) Preparation of milnacipran-containing hydrogel A hydrogel having the formulation shown in Table 1 was prepared by the following method. That is, water was added to milnacipran, hydroxypropylcellulose, and hydroxyethylcellulose and allowed to stand overnight to swell the base. Thereafter, isopropyl alcohol (and 1-menthol) was added and allowed to stand overnight to form a uniform hydrogel. In addition, the amount of water to be used was adjusted according to the increase / decrease in the blending amount of milnacipran and other components so that the total amount became 100% by weight.

(2) Results of milnacipran skin permeability test When the amount of milnacipran added is set to 1, 2 or 3 wt% when the weight of all compositions is 100 wt%, and l-menthol is not added And milnacipran skin permeability when 2% by weight of 1-menthol was added. Similar to the in vitro skin permeability test of Example 1, FIG. 4 shows a graph of a cumulative permeation amount-time curve in which the cumulative skin permeation amount of milnacipran per unit area was measured over time. Further, the skin permeation rate (μg / cm ² / h) of milnacipran determined from the above measured values is shown in FIG. As apparent from FIGS. 4 and 5, milnacipran hardly permeated through the skin in the formulation containing no l-menthol regardless of the concentration (dose) of milnacipran. On the other hand, in the composition containing l-menthol, an increase in the skin permeation amount of milnacipran was observed with time (FIG. 4). Further, as shown in FIG. 5, when compared with compositions having the same milnacipran content (1%, 2% and 3%), the skin permeability of milnacipran was significantly promoted by the addition of l-menthol. (N = 3, *** P <0.001). Furthermore, each composition containing 2% by weight l-menthol was promoted linearly (n = 3) depending on the concentration (dose) of milnacipran when compared to 1% by weight milnacipran. , ** P <0.01, *** P <0.001). Thus, it was shown that the skin absorption rate can be adjusted by adjusting the content of milnacipran.

Example 3 In vivo forced swimming test In order to confirm that milnacipran is delivered into the living body through the skin and exerts a pharmacological effect, the following forced swimming test was performed. Each test was performed 5 times, and the average value ± standard error was obtained.

A glass cylinder having a diameter of 9.5 cm was filled with an appropriate amount of water and kept warm in a 25 ° C. water bath. After that, a 7-week-old male C57BL / 6J mouse (Tokyo Experimental Animal Co., Ltd.) was subjected to stress loading by forced swimming for 10 minutes in a glass cylinder. After 12 hours of stress loading, the milnacipran-containing hydrogel of Example 1 was applied to the back hair of the mouse for 12 hours (effective diffusion area; 0.16 cm ² ). After 12 hours, the hydrogel was removed from the back of the mouse, and forced swimming was performed again in a glass cylinder for 6 minutes. At this time, the immobility time of the mouse for the last 5 minutes was measured, and the decrease in the immobility time was evaluated as an antidepressant action of milnacipran. Further, as a positive control, the same test was carried out in mice administered milnacipran 60 mg / kg intraperitoneally (ip).

  The results are shown in FIG. The immobility time of the positive control in which milnacipran was intraperitoneally administered relative to the onset control was significantly reduced (n = 5, ** P <0.01). When a hydrogel containing no l-menthol was applied, no significant effect with milnacipran was observed. On the other hand, in each composition to which 2% by weight of 1-menthol was added, in the case of the composition of the present invention to which 2 or 3% by weight of milnacipran was added, mil The dose-dependent decrease in immobility time by the plan was significantly observed, and an antidepressant effect equivalent to that of the positive control was observed (n = 5, ** P <0.01). Moreover, in the composition to which 2% by weight of 1-menthol was added, the pharmaceutical composition of the present invention to which 2 or 3% by weight of milnacipran was added was significantly different from the composition to which milnacipran was not added. A decrease in the immobility time was observed (n = 5, * P <0.05), and this decrease in the immobility time was shown to be a manifestation of the medicinal effect due to skin penetration of milnacipran.

  As is apparent from the results of the above pharmacological test, by incorporating an appropriate absorption enhancer, it became possible to promote transdermal absorbability of milnacipran and develop a remarkable pharmacological effect. As the absorption enhancer, menthol, cineol, glycerin fatty acid ester or a combination of two or more thereof can be used, and a combination of menthol and cineol is preferable. In addition, in the pharmaceutical composition of the present invention, a pharmaceutical preparation having better percutaneous absorption can be obtained by further adding a lower alcohol such as isopropanol or ethanol. The pharmaceutical composition containing the pharmaceutical composition of the present invention comprises milnacipran, which is widely used clinically as a therapeutic drug for depression and has been recognized as being useful as an analgesic, and has a transdermal absorbability. It is highly useful as a transdermal absorption type antidepressant and analgesic that is excellent and can be used for a long time with good compliance.

Claims (20)

A pharmaceutical composition for transdermal absorption comprising milnacipran or a pharmaceutically acceptable salt thereof as an active ingredient and containing menthol, cineol, glycerin fatty acid ester or a combination of two or more thereof as an absorption enhancer. The composition according to claim 1, wherein the absorption enhancer is menthol. The composition according to claim 2, wherein the absorption enhancer is l-menthol. The composition according to claim 1, wherein the absorption enhancer is cineol. The composition of claim 1, wherein the absorption enhancer is a combination of menthol and cineole. The composition according to claim 5, wherein the absorption enhancer is 1-menthol and 1,8-cineole. The composition according to any one of claims 1 to 6, wherein the content of the absorption accelerator is 0.75 to 10% by weight. The composition according to claim 1, wherein the absorption accelerator is a glycerin fatty acid ester. The composition according to claim 8, wherein the absorption enhancer is glyceryl monooleate. The composition according to claim 8 or 9, wherein the content of the absorption accelerator is 2 to 30% by weight. The composition according to any one of claims 1 to 10, wherein the active ingredient is milnacipran hydrochloride. The composition according to any one of claims 1 to 11, further comprising a lower alcohol. The composition according to claim 12, wherein the lower alcohol is isopropanol. The composition according to claim 12 or 13, wherein the content of the lower alcohol is 5 to 40% by weight. 15. A composition according to any one of the preceding claims in the form of a hydrogel. The pharmaceutical containing the composition as described in any one of Claims 1 thru | or 14. The medicament according to claim 16, which is an antidepressant. The medicament according to claim 16, which is an analgesic. 19. The medicament according to claim 18, wherein the analgesic is a therapeutic or preventive agent for chronic pain, neuropathic pain, headache, migraine, tension headache, chronic pelvic pain, muscle pain, joint pain, low back pain or fibromyalgia. The medicine according to any one of claims 16 to 19, which is in the form of a patch.

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