WO2014136717A1

WO2014136717A1 - Transdermally absorbable pharmaceutical composition

Info

Publication number: WO2014136717A1
Application number: PCT/JP2014/055267
Authority: WO
Inventors: 誉子小幡; 高山　幸三
Original assignee: 日本臓器製薬株式会社
Priority date: 2013-03-04
Filing date: 2014-03-03
Publication date: 2014-09-12
Also published as: JP2014169247A; JP5376481B1

Abstract

Provided are: a novel transdermally absorbable pharmaceutical composition which has such characteristic properties that the skin permeability of duloxetine or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition can be increased to exhibit an excellent pharmacological effect of duloxetine or the pharmaceutically acceptable salt thereof and the skin irritancy of the pharmaceutical composition is low; and a medicine comprising the pharmaceutical composition. The present invention relates to: a novel transdermally absorbable pharmaceutical composition which contains duloxetine or a pharmaceutically acceptable salt thereof as an active ingredient and also contains menthol, isopropyl alcohol and isopropyl myristate; and a medicine comprising the pharmaceutical composition. Each of the composition and the medicine according to the present invention contains duloxetine, which has been widely used in clinical practice as a therapeutic agent for depression and is known to be useful as an analgesic agent for chronic pain and the like, as an active ingredient. Therefore, each of the composition and the medicine has excellent efficacy and safety and has extremely high usefulness as a transdermally absorbable anti-depressant agent and a transdermally absorbable analgesic agent which can be used for a long period with good compliance.

Description

Pharmaceutical composition for transdermal absorption

The present invention relates to a pharmaceutical composition for transdermal absorption containing duloxetine 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 people 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. In the treatment of depression, it is considered important to provide psychological care for mild cases, but drug therapy with antidepressants is recommended for moderate and severe cases. 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 effects was developed. Although SSRI is an epoch-making antidepressant, there are problems that cause new side effects such as nausea and vomiting due to stimulating action on serotonin receptors in the brain and intestinal tract, and withdrawal syndrome due to medication interruption. Later, in the 1990s, selective serotonin and noradrenaline reuptake inhibitors (SNRI) were developed, and although gastrointestinal symptoms still remain, they have no anticholinergic effect and are also effective for patients who have been insufficiently treated with SSRI. It is widely used in the clinical field as a certain drug.

Duloxetine [chemical name: (+)-(S) -N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine] is one of the recently developed SNRIs. It is known to exert an antidepressant action by selectively inhibiting reuptake of serotonin and noradrenaline at the intracerebral nerve junction. The active ingredient in capsule preparations sold in various countries including Japan is duloxetine hydrochloride. In the present application, unless otherwise specified, duloxetine hydrochloride may be simply referred to as duloxetine.
Duloxetine does not bind to neurotransmitter receptors like tricyclic or tetracyclic antidepressants, so there are no side effects due to anticholinergic action, and it is not like SSRI, a third-generation antidepressant. There are few side effects of nausea and vomiting by stimulating serotonin receptors in the brain and intestinal tract. Effectively, it inhibits the reuptake of noradrenaline in addition to serotonin, so it does not improve with SSRI that selectively inhibits the reuptake of serotonin. Then it is said. In addition, duloxetine is effective not only for antidepressant action but also for pain. Neuropathic pain including pain associated with diabetic neuropathy, fibromyalgia, pain associated with osteoarthritis, chronic low back pain, etc. Has been reported to have therapeutic effects. In Japan, duloxetine is the only antidepressant and has pain associated with diabetic neuropathy as an indication.

Duloxetine is unstable under acidic conditions. For this reason, it is marketed in various countries as an oral hard capsule filled with granules of enteric-coated duloxetine hydrochloride. A technique relating to the formulation of duloxetine into a capsule is disclosed in Patent Document 1. However, there has been no report on a pharmaceutical composition for transdermal absorption containing duloxetine as an active ingredient.

In the drug therapy for depression, it is still important to keep the drug concentration in blood constant at an effective concentration in order to reduce side effects and maximize the therapeutic effect on the patient. However, the treatment of depression has peculiarities that it takes time until the effect of an antidepressant appears, the medication is taken for a long period of years, and the depression symptoms are repeatedly remission and exacerbation. As a result, it is often difficult for patients to comply with oral medications commonly used to treat depression (medical prescribed by doctors as directed by patients). It may cause worsening or delay of improvement, or side effects of gastrointestinal disorders. In addition, the existing duloxetine preparations are only hard capsules as described above, but since capsules are larger in size than ordinary tablets, they may be difficult to swallow even in adults. There were aspects that were not suitable for the elderly who declined.
A transdermal agent that is administered by transdermally absorbing the drug to such an oral agent such as a hard capsule is effective in blood compared to the oral agent because the drug is continuously and gradually absorbed from the skin. It is possible to maintain the concentration continuously. In addition, in the case of a transdermal agent, gastrointestinal disorders can be avoided, and the maximum blood concentration does not increase at a stretch, which makes it easier to avoid side effects. 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 dose in blood can be maintained with a smaller amount of drug than oral administration, and duloxetine does not pass through the stomach. It is also possible to avoid being inactivated by. Furthermore, when a medicine is applied to a support substrate to form a patch, not only the patient but also a doctor, nurse, family, etc. can easily confirm that the patient is using the medicine. In addition, the patch has a merit that the subsequent absorption of the drug can be stopped by removing it even when a side effect occurs. Therefore, transdermal agents are very useful from the viewpoints of patient compliance, quality of life (QOL) improvement, safety, and the like. 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.

JP-A-8-40895

An object of the present invention is to provide a novel pharmaceutical composition for percutaneous absorption, which is characterized by excellent skin permeability and low skin irritation of duloxetine, which is an active ingredient, or a pharmaceutically acceptable salt thereof. To provide medicine.

So far, many compounds have been studied as drug skin permeation enhancers. However, when actually used in a preparation, not only the absorption promoting effect but also the safety to the living body is necessary, so many of the compounds (components) used in the research have not been applied clinically. . Therefore, the present inventors have intensively investigated the skin permeability and skin irritation of duloxetine, focusing on the ingredients actually blended in pharmaceuticals and cosmetics. As a result, it was found that when menthol, isopropyl alcohol and isopropyl myristate were used, the percutaneous absorbability of duloxetine was significantly enhanced and the skin irritation was low. In particular, the inventors have found out what amounts and ratios of these components are optimally blended and completed the present invention.

The pharmaceutical composition of the present invention can exert its effect safely by transdermal absorption of duloxetine 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.

FIG. 1 is a graph showing the skin permeation rate of duloxetine of each formulation in the in vitro skin permeability test of Example 1. FIG. 2 is a graph showing the delay time of duloxetine for each formulation in the in vitro skin permeability test of Example 1. FIG. 3 is a graph showing the viable cell ratio of each formulation in the in vitro skin irritation test of Example 1.

The present invention relates to a novel pharmaceutical composition for transdermal absorption containing duloxetine or a pharmaceutically acceptable salt thereof as an active ingredient and menthol, isopropyl alcohol and isopropyl myristate as additives, or a medicine containing the same.

The active ingredient of the pharmaceutical composition or medicine of the present invention is duloxetine 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. Preferred is duloxetine hydrochloride which is commercially available and widely used clinically. Moreover, in this application, the hydrate and solvate of duloxetine are also included in the duloxetine which is an active ingredient of this invention.

The amount of duloxetine or a pharmaceutically acceptable salt thereof contained as an active ingredient in the pharmaceutical composition or medicine of the present invention is 0.5 to 10% by weight, preferably 1 to 5% by weight, more preferably 2 to 4%. % By weight.

The menthol used in the pharmaceutical composition of the present invention includes 1-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. As menthol, l-menthol is particularly preferable. The amount of menthol used varies depending on the dosage form, etc. described later, but is 1 to 5% by weight, preferably 2.3 to 2.9% by weight, more preferably 2.5 to 2.7% by weight. Can do.

The amount of isopropyl alcohol used in the pharmaceutical composition or medicine of the present invention is 10 to 20% by weight, preferably 13.5 to 16.5% by weight, more preferably 14.5 to 15.5% by weight. Can do.

The amount of isopropyl myristate used in the pharmaceutical composition or medicine of the present invention is 5 to 15% by weight, preferably 9.0 to 11.0% by weight, more preferably 9.5 to 10.5% by weight. be able to.

The ratio by weight of isopropyl alcohol to isopropyl myristate is 1: 1 to 4: 1, preferably 1: 1 to 2: 1, more preferably 1.2: 1 to 1.8: 1. it can.

The present invention relates to a pharmaceutical composition for transdermal absorption containing duloxetine or a pharmaceutically acceptable salt thereof as an active ingredient, wherein duloxetine or a pharmaceutically acceptable salt thereof is used with respect to 100% by weight of the pharmaceutical composition. A transdermal pharmaceutical composition containing 0.5 to 10% by weight of the resulting salt, 1 to 5% by weight of menthol, 10 to 20% by weight of isopropyl alcohol, and 5 to 15% by weight of isopropyl myristate.

Preferably, the present invention is a pharmaceutical composition for transdermal absorption containing duloxetine or a pharmaceutically acceptable salt thereof as an active ingredient, wherein duloxetine or a pharmaceutical composition thereof is used with respect to 100% by weight of the pharmaceutical composition. 1 to 5% by weight of pharmaceutically acceptable salt, 2.3 to 2.9% by weight of menthol, 13.5 to 16.5% by weight of isopropyl alcohol, and 9.0 to 11.0% by weight of isopropyl myristate % Is a pharmaceutical composition for transdermal absorption.

More preferably, the present invention relates to a pharmaceutical composition for transdermal absorption containing duloxetine or a pharmaceutically acceptable salt thereof as an active ingredient, wherein duloxetine or a pharmaceutical composition thereof is used with respect to 100% by weight of the pharmaceutical composition. 2 to 4% by weight of a pharmaceutically acceptable salt, 2.5 to 2.7% by weight of menthol, 14.5 to 15.5% by weight of isopropyl alcohol, 9.5 to 10.5 of isopropyl myristate It is a pharmaceutical composition for transdermal absorption containing% 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 duloxetine.

An example of a patch is that it is formulated into a patch (patch) in the form of a hydrogel. The hydrogel can be produced by using a conventional method of using a viscous agent such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, etc. and swollen with water as a base. In order to uniformly mix certain duloxetine and the above-mentioned additives into the preparation, it can be formulated using an appropriate solvent such as isopropanol or ethanol.

The pharmaceutical composition and medicine for percutaneous absorption according to the present invention can be used for patients who have conventionally been administered oral duloxetine for depression or chronic pain. As analgesics, in addition to or included in chronic pain such as chronic low back pain, neuropathic pain such as pain associated with diabetic neuropathy, headache, migraine, tension headache, chronic pelvic pain, muscle It can be used to treat various pains such as pain, joint pain, low back pain, fibromyalgia. In addition, for example, it can be used for treatment of diseases such as generalized anxiety disorder and stress urinary incontinence for which the effect of duloxetine is reported.

Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited to these examples.

Example 1. Examination of optimal formulation (1) Preparation of duloxetine-containing hydrogel Based on the Box-Benken Design, 27 types of formulations were assigned by assigning concentrations of l-menthol, isopropyl alcohol and isopropyl myristate as shown in Table 1. The designed and duloxetine-containing hydrogel was prepared by the following method. In the following examples, duloxetine 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 allowed to stand for 12 hours to swell the base. Thereafter, duloxetine, l-menthol, isopropyl alcohol and isopropyl myristate were added in the proportions shown in Table 1, and the mixture was stirred with a magnetic stirrer for 12 hours to obtain 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.

(2) In vitro skin permeability test 7-week-old male Hos: HR-1 hairless mouse isolated skin (registered trademark: Labskin, 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 is on the receiver side. The receiver cell was filled with 16 mL of phosphate buffered saline (PBS) having a pH of 7.4 and heated in a warm bath at 32 ° C. After 30 minutes from the start of heating, 1.0 g of the hydrogel was applied to the donor cell. 20 μL of the solution was taken from the receiver cell every hour, and duloxetine was quantified by high performance liquid chromatography (HPLC). Immediately after the separation, 20 μL of PBS was supplemented to the receiver cell. HPLC is mobile phase acetonitrile: potassium dihydrogen phosphate buffer = 40: 60, column is YCM-Pack ODS-A (150 mm × 4.6 mm ID), wavelength is 229 nm, flow rate is 1.0 mL / min, The column temperature was room temperature and the injection volume was 20 μL. In addition, each test was done 3 times and the average value +/- standard deviation was calculated | required. From the results of measuring the cumulative skin permeation amount of duloxetine per unit area in each prescription (cumulative permeation amount-time curve graph), the skin permeation rate of duloxetine (μg / cm ² / hour) [the skin permeation rate is cumulative FIG. 1 shows the results of calculating the slope of the regression line obtained by linear regression of the transmission amount-time curve plot. Furthermore, the delay time obtained from this regression line [time until the skin permeation rate reaches a steady state] is shown in FIG.

(3) In vitro skin irritation test FIG. 2 shows the results of evaluating the skin irritation by calculating the viable cell ratio by applying the hydrogel to human three-dimensional cultured skin. The human three-dimensional cultured skin uses a human three-dimensional cultured epidermis kit (registered trademark: LabCyte EPI-MODEL24) manufactured by Japan Tissue Engineering Co., Ltd., according to the instruction manual attached to the kit. Irritation was evaluated.

(4) Analysis of optimal prescription The optimal prescription was analyzed using analysis software (registered trademark: dataNESIA) manufactured by Azbil Corporation. This analysis software can create a response phase from experimental data by double harmonic spline interpolation and search for the optimum value (Savemation Review 2003 Vol. 21 32-39: http://www.azbil.com/ jp / library / review / pdf / 2003_8_05.pdf). Based on the concentrations of l-menthol, isopropyl alcohol and isopropyl myristate, the skin permeation rate and delay time of duloxetine obtained by the above in vitro skin permeability test and the viable cell rate obtained by the above in vitro skin irritation test The response phase was created by this analysis software with the characteristic value. The size of the preparation is 25 cm ² , the maximum blood concentration described in the interview form of the existing duloxetine preparation is set as the target value, the number of living cells is set as 80%, and the skin permeation from the above response phase is set. We searched for an optimal formulation with high speed and short delay time. As a result, l-menthol was about 2.6% by weight (optimal solution 2.5667%), isopropyl alcohol was about 15% by weight (idle 14.764%), and isopropyl myristate was about 10% by weight (same as 10.049%). %), The absorption rate was calculated to be about 3000 μg / cm ² / hour, the delay time was about 4 hours, and the cell viability was about 80%. In addition, about the description amount which attached "about" in this application, the range of the +/- 10% is accept | permitted as a preferable amount (refer the general rule 35 of 16th revision Japanese Pharmacopoeia).

As is apparent from the results of the above pharmacological tests, by containing menthol, isopropyl alcohol and isopropyl myristate, it was possible to promote the transdermal absorbability of duloxetine and develop a remarkable pharmacological effect. Furthermore, an optimal formulation was found in which the transdermal absorbability of duloxetine was significantly enhanced and the skin irritation was low. The medicament containing the pharmaceutical composition of the present invention comprises duloxetine, which is widely used clinically as a therapeutic drug for depression and has been recognized as useful as an analgesic, and has excellent transdermal absorbability. It is very useful as a transdermal antidepressant and analgesic that can be used for a long time with good compliance.

Claims

A pharmaceutical composition for transdermal absorption comprising duloxetine or a pharmaceutically acceptable salt thereof as an active ingredient and containing menthol, isopropyl alcohol and isopropyl myristate.
The content of menthol, isopropyl alcohol and isopropyl myristate is 1 to 5% by weight, 10 to 20% by weight and 5 to 15% by weight, respectively, with respect to 100% by weight of the pharmaceutical composition for transdermal absorption. A pharmaceutical composition for transdermal absorption.
The content of menthol, isopropyl alcohol and isopropyl myristate is 2.3 to 2.9% by weight, 13.5 to 16.5% by weight and 9.0 to 11% with respect to 100% by weight of the pharmaceutical composition for transdermal absorption, respectively. The pharmaceutical composition for transdermal absorption according to claim 1, which is 0.0% by weight.
The pharmaceutical composition for transdermal absorption according to claim 2 or 3, wherein the ratio of isopropyl alcohol to isopropyl myristate in weight percent is 1: 1 to 4: 1.
The pharmaceutical composition for percutaneous absorption according to claim 2 or 3, wherein the ratio of isopropyl alcohol to isopropyl myristate in weight percent is 1: 1 to 2: 1.
The pharmaceutical composition for transdermal absorption according to any one of claims 1 to 5, wherein the content of duloxetine or a pharmaceutically acceptable salt thereof is 0.5 to 10% by weight with respect to 100% by weight of the composition. .
The pharmaceutical composition for transdermal absorption according to any one of claims 1 to 5, wherein the content of duloxetine or a pharmaceutically acceptable salt thereof is 1 to 5% by weight with respect to 100% by weight of the composition.
The pharmaceutical composition for transdermal absorption according to any one of claims 1 to 7, wherein duloxetine or a pharmaceutically acceptable salt thereof is duloxetine hydrochloride.
The pharmaceutical composition for transdermal absorption according to any one of claims 1 to 8, wherein the menthol is l-menthol.
The pharmaceutical composition for transdermal absorption according to any one of claims 1 to 9, which is in the form of a hydrogel.
The pharmaceutical containing the composition as described in any one of Claims 1 thru | or 10.
The medicament according to claim 11, which is an antidepressant.
The medicament according to claim 11, which is an analgesic.
The medicament according to claim 13, 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 medicament according to claim 13, wherein the analgesic is a therapeutic or prophylactic agent for chronic pain, neuropathic pain or fibromyalgia.
The medicament according to claim 13, wherein the analgesic is a therapeutic or prophylactic agent for neuropathic pain or fibromyalgia.
The medicament according to claim 13, wherein the analgesic is an agent for treating or preventing pain associated with diabetic neuropathy.
The medicine according to any one of claims 11 to 17, which is in the form of a patch.