Pharmaceutical composition, blepharospasm treatment agent, hypersensitivity or dystonia treatment agent, and symptom model mouse

Abstract

Provided are: a pharmaceutical composition, a blepharospasm treatment agent, and a hypersensitivity or dystonia treatment agent that have strong effects as treatments for blepharospasm and the like for which treatment has been heretofore difficult or there has been no effective treatment, and that cause little physical burden on patients; and a symptom model mouse having symptoms including blepharospasm, hypersensitivity, and dystonia. The pharmaceutical composition contains tramadol or a salt thereof as an active ingredient and is administered for treatment to a subject showing the symptoms of blepharospasm or hypersensitivity of the eye. The pharmaceutical composition contains 0.01-2.0% w / v of the tramadol or salt thereof. Also provided are a medicine, a blepharospasm treatment agent, and a hypersensitivity or dystonia treatment agent containing the foregoing. The symptom model mouse has symptoms including blepharospasm, hypersensitivity, and dystonia.

Description

Pharmaceutical composition, drug for treating blepharospasm, drug for treating hyperesthesia or dystonia, and symptom model mouse

[0001] The present invention relates to a pharmaceutical composition used for the treatment of blepharospasm and the like, i.e., the treatment, prevention, etc. of blepharospasm and ocular hyperesthesia, eye drops and other therapeutic agents using the same, and a symptomatic mouse model used to verify blepharospasm and ocular hyperesthesia. This application claims priority based on Japanese Patent Application No. 2024-008809, filed January 24, 2024, the contents of which are incorporated herein by reference.

[0002] Blepharospasm (blepharospasm) is a disease presenting with symptoms such as difficulty opening the eyes, feeling better with the eyes closed, sensitivity to light, and eye pain. It is defined as the unintentional, involuntary movement of the eyelids (dystonia; symptoms include being unable to open the eyes despite wanting to, or the eyes closing spontaneously). In addition to the motor symptoms of unintentional, involuntary eyelid movement, hypersensitivity symptoms such as sensitivity to light, eye pain, and dry eyes may also be present, leading to frequent misdiagnosis as dry eye. However, unlike dry eye, treatments and procedures used for dry eye, such as eye drops, are known to be ineffective. In other words, although it exhibits symptoms similar to dry eye, it is a disease that requires a different underlying cause.

[0003] The current standard treatment for blepharospasm involves injecting botulinum toxin into the eyelid skin at approximately 12–16 sites. While some improvement in both motor and sensory hypersensitivity symptoms is observed, only approximately 10% of cases achieve satisfactory subjective and objective improvement. Furthermore, the injection site is the eyelid, and the injection site is more than 10 sites, which can be painful, leading some patients to refuse treatment. The duration of effect is limited to approximately 2–3 months, and satisfactory results are often not achieved. Other treatments include the use of clutch glasses or light-blocking glasses to assist eyelid opening and reduce photophobia. However, no external devices alone have been found to be sufficiently effective. Surgical procedures include frontalis muscle lift, levator palpebrae superioris shortening, eyelid skin resection, or orbicularis oculi muscle resection. However, surgery places a significant physical, time, and financial burden on the patient, and no treatment has been found that is sufficiently effective compared to these burdens. For these reasons, new treatments for blepharospasm are strongly desired.

[0004] Meanwhile, a technology using tramadol, a μ-opioid receptor agonist, has been developed as a general ocular analgesic and eye drop.

[0005] Patent Literature 1 discloses an aqueous composition that can be topically administered to the eyes of humans or animals, characterized by comprising an aqueous solution of at least one water-soluble polymer ophthalmic lubricating medium and an effective amount of at least one water-soluble analgesic composition. More specifically, it discloses a composition for topical administration to the eyes of humans or animals, comprising an aqueous solution of at least one water-soluble polymer ophthalmic lubricating medium and an effective amount of tramadol, for treating pathologies associated with a deficiency of natural tears in the eyes of humans or animals. This technology aims to provide a topically applicable analgesic formulation that is effective for the eyes to reduce pain caused by treatment of pathologies associated with a deficiency of natural tears in the eyes of humans or animals (such as dry eye) using tramadol, a known analgesic, or to reduce pain in eye infections and general pathologies.

[0006] JP 2017-141243 A

[0007] As mentioned above, only treatment methods, such as therapies for blepharospasm, have been found that place a heavy burden on patients and are not necessarily sufficiently effective. The technology of Patent Document 1 relates to a composition for eye drop treatment for dry eye, etc. However, although blepharospasm is sometimes misdiagnosed as dry eye, it is a completely different disease from dry eye, and as mentioned above, treatments and procedures for dry eye are ineffective. Furthermore, effective treatments are needed for eye hypersensitivity such as eye strain, peripheral dystonia symptoms, and dystonia symptoms spreading from the eyelids. Furthermore, when investigating the therapeutic effects of these symptoms, there is a need for model animals, such as model mice, that reproduce symptoms such as blepharospasm.

[0008] The present invention has been made in consideration of the above-mentioned circumstances, and its object is to provide a pharmaceutical composition that is highly effective as a treatment for blepharospasm and the like, which have previously been difficult to treat or for which no effective treatment has been available, and that places a low burden on patients, a drug for treating blepharospasm, a drug for treating hyperesthesia or dystonia, and a mouse model of symptoms of blepharospasm, hyperesthesia, dystonia, and the like.

[0009] In order to solve the above problems, the present invention has the following aspects. [1] A pharmaceutical composition containing tramadol or a salt thereof as an active ingredient, for administration to a subject exhibiting symptoms of blepharospasm, or hyperesthesia or dystonia in the face or head and neck. [2] The pharmaceutical composition according to [1], containing 0.01 to 2.0% w / v of tramadol or a salt thereof. [3] The pharmaceutical composition according to [1] or [2], which is an eye drop, an injection, an eye ointment, or an eyelid skin ointment. [4] The pharmaceutical composition according to any one of [1] to [3], which is an eye drop, containing artificial tears, a water-soluble polymer ophthalmic lubricating medium, or a surfactant. [5] A drug for treating blepharospasm, comprising the pharmaceutical composition according to any one of [1] to [4]. [6] A drug for treating hyperesthesia or dystonia in the face or head and neck, comprising the pharmaceutical composition according to any one of [1] to [4]. [7] A symptom model mouse of blepharospasm, hyperesthesia, or dystonia for evaluating the pharmaceutical composition according to any one of [1] to [4] or a treatment using the same, the symptom model mouse being a mouse subjected to stress by a scaffold or airflow. [8] The symptom model mouse according to [7], in which the scaffold stress is imparted by placing the mouse on a swingable scaffold, and the airflow stress is imparted by blowing air in front of and behind the mouse on the scaffold, and the scaffold and airflow stress is imparted for 4 hours or more per day for 14 days or more. [9] The symptom model mouse according to [7] or [8], in which the scaffold stress is imparted by placing water adjacent to the mouse.

[0010] The present invention also has the following aspects. [1A] A medical composition containing tramadol or a salt thereof as an active ingredient, for administration to a subject exhibiting symptoms of blepharospasm, or facial or head and neck hyperesthesia or dystonia. [2A] The medical composition according to [1A], containing 0.01 to 2.0% w / v of tramadol or a salt thereof. [3A] A medicament comprising the medical composition according to [1A] or [2A]. [4A] The medicament according to [3A], which is an eye drop, an injection, an eye ointment, or an eyelid skin ointment. [5A] The eye drop according to [3A], which contains artificial tears, a water-soluble polymer ophthalmic lubricating medium, or a surfactant. [6A] A drug for treating blepharospasm, comprising the medical composition according to [1A] or [2A]. [7A] A drug for treating hyperesthesia or dystonia in the face or head and neck, comprising the medical composition according to [1A] or [2A].

[0011] According to the present invention, it is possible to provide a pharmaceutical composition, a medicine, a drug for treating blepharospasm, a drug for treating hyperesthesia or dystonia, and a model mouse for symptoms of blepharospasm, hyperesthesia, dystonia, etc., which are highly effective as treatments for blepharospasm and the like, which have previously been difficult to treat or for which no effective treatments have been available, and which impose a low burden on patients.

[0012] FIG. 10 is a graph showing the results of the number of blinks when eye drops are administered to symptom model mice.

[0013] The pharmaceutical composition, the drug for treating blepharospasm, and the drug for treating hyperesthesia or dystonia according to the present invention will be described below with reference to embodiments, although the present invention is not limited to the following embodiments.

[0014] (Pharmaceutical Composition) The pharmaceutical composition according to this embodiment contains tramadol or a salt thereof as an active ingredient and is intended to be administered to treat a subject exhibiting symptoms of blepharospasm, or facial or head and neck hyperesthesia or dystonia. Pharmaceutical compositions broadly include not only so-called medicines but also compositions used for medical purposes (medical compositions).

[0015] Tramadol (C １６ H ２５ NO ２ , CAS number: 27203-92-5) is known as one of the opioid analgesics, and has been reported to act as a partial agonist of the μ-opioid receptor and to inhibit the reuptake of serotonin and noradrenaline.

[0016] The salt of tramadol can be appropriately selected from pharmaceutically acceptable salts, and various derivatives of tramadol can be selected as long as they are within the pharmaceutically and physiologically acceptable range and do not reduce the pharmacological effect.

[0017] The pharmaceutical composition of this embodiment is a pharmaceutical composition for administration to treat a subject exhibiting symptoms such as blepharospasm. Blepharospasm (blepharospasm) is a disease accompanied by unintended, involuntary eyelid movements (dystonia). Dystonia in the eyes and eyelids includes symptoms such as being unable to open the eyes despite wanting to, or the eyes spontaneously closing. Specific examples of involuntary movements include difficulty opening the eyes and feeling more comfortable with the eyes closed. Symptoms such as sensitivity to light and eye pain may also occur. As a result, symptoms similar to those of dry eye may occur, such as dryness and pain. Therefore, the condition may be misdiagnosed as dry eye or other eye diseases exhibiting these symptoms. In this embodiment, blepharospasm refers to a disease accompanied by unintended, involuntary eyelid movements. In other words, blepharospasm in this embodiment does not refer to symptoms of dry eye alone, symptoms of a pathological condition accompanied by a deficiency of natural tears alone, or symptoms accompanied by only dryness and pain in the eyes without involuntary movements, for example.

[0018] The pharmaceutical composition of this embodiment is also effective against ocular hyperesthesia symptoms. The pharmaceutical composition of this embodiment is also effective against head and neck dystonia and hyperesthesia symptoms around the eyes. It is also expected to be effective when the disease spreads from the eyelids to the face, leading to head and neck dystonia. Examples of these symptoms include eye strain. More specifically, examples include eye strain associated with close-up tasks such as reading. In this specification, blepharospasm and other diseases targeted by this embodiment, such as facial or head and neck hyperesthesia or dystonia, are sometimes collectively referred to as "blepharospasm, etc."

[0019] The subject of this embodiment, who exhibits symptoms of blepharospasm, hyperesthesia, or dystonia, can be selected from humans and other animals as appropriate. Other animals include primarily mammals. Specific examples of mammals include livestock animals (pigs, sheep, goats, cows, horses, etc.), pet animals (dogs, cats, etc.), laboratory animals (mice, guinea pigs, hamsters, rats, other rodents, rabbits, etc.), and other animals (marmosets, chimpanzees, other monkeys). In this specification, the term "patient" primarily refers to a human subject, but is not limited to this.

[0020] The pharmaceutical composition of this embodiment is administered to a patient suffering from blepharospasm or the like for the purpose of treatment, and the purpose of treatment broadly includes medical treatment such as cure, prevention, and prevention of recurrence after treatment. As described below, treatments include, but are not limited to, eye drops.

[0021] The pharmaceutical composition of this embodiment preferably contains 0.01 to 2.0% w / v of the tramadol or its salt, more preferably 0.5 to 1.5% w / v of the tramadol or its salt, and even more preferably 0.8 to 1.2% w / v of the tramadol or its salt. The dosage, administration interval, administration method, and administration route are not particularly limited and can be selected appropriately depending on the conditions of the subject to be treated, such as age, body weight, symptoms, and target site.

[0022] The pharmaceutical composition may be in the form of a medicine containing the above-mentioned ingredients. The medicine is preferably in a form to be administered to the eye or the area around the eye for treatment. Specifically, the medicine may be in the form of eye drops, injections, eye ointments, or eyelid skin ointments.

[0023] (Eye Drops) The pharmaceutical composition of this embodiment may be an eye drop. It is preferably a solution containing the pharmaceutical composition in a form suitable for eye drops, more preferably an aqueous solution. The concentration can be appropriately selected based on the concentration of the pharmaceutical composition. In addition to the pharmaceutical composition, the eye drop of this embodiment may contain pharmaceutically acceptable optional components within a range that does not impair the effects of the configuration of this embodiment. Examples of optional components include thickeners, preservatives, tonicity agents, dispersants (such as polysaccharides), buffers, and pH adjusters.

[0024] Thickeners adjust the viscosity (form) of drugs. Examples of thickeners include cellulose-based thickeners such as methylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose; vinyl-based thickeners such as carboxyvinyl polymer, polyvinyl alcohol (fully or partially saponified), and polyvinylpyrrolidone; sodium alginate, sodium chondroitin sulfate, and macrogol. Preservatives improve the shelf life of drugs. Examples of preservatives include cationic soaps such as benzalkonium chloride, benzethonium chloride, and chlorhexidine gluconate; parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben; and alcohols such as chlorobutanol, phenylethyl alcohol, and benzyl alcohol. Isotonicity agents, in drugs such as eye drops, reduce eye irritation. Examples of isotonicity agents include sugars such as glucose; polyhydric alcohols such as propylene glycol, glycerin, mannitol, sorbitol, and xylitol; and inorganic salts such as sodium chloride and potassium chloride. Dispersants suppress aggregation of components contained in pharmaceuticals. Examples of dispersants include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and derivatives thereof. pH adjusters adjust the pH of pharmaceuticals. Examples of pH adjusters include dilute hydrochloric acid and sodium hydroxide. Buffers stabilize the pH of pharmaceuticals. Examples of buffers include sodium citrate hydrate, sodium acetate hydrate, sodium bicarbonate, trometamol, boric acid, borax, sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate.

[0025] The eye drops of this embodiment may contain artificial tears, a water-soluble polymer ophthalmic lubricating medium, or a surfactant. Artificial tears include those conventionally known as components that promote good lubrication of the eye, also known as ophthalmic lubricant compositions. For example, artificial tears include lubricating formulations containing sodium hyaluronate, hypromellose, or carbomer gel. The water-soluble polymer ophthalmic lubricating medium may contain a water-soluble polymer as a component that promotes lubrication of the eye. Examples of such water-soluble polymers include polyvinyl alcohol (PVA), polyethylene glycol (PEG), carbomer, and polyvinylpyrrolidone (PVP). Surfactants can reduce the surface tension of the tear composition, thereby improving wetting of the eye surface. Surfactants may include nonionic surfactants and ionic surfactants. Examples of nonionic surfactants that can be used include polysorbates, poloxamers, and tetrafunctional block copolymers. These components can be used within a pharmaceutically acceptable range.

[0026] The eye drops of the present embodiment may contain no preservatives, and may further contain no ingredients other than the solvent (water) and tramadol or its salt as the active ingredient. Because tramadol or its salt is stable in the solvent for a long period of time, it can be used as an eye drop even if it does not contain any other ingredients.

[0027] (Other Medications) The pharmaceutical composition may be an injection or an eye ointment. These may contain the same ingredients as the eye drops. The pharmaceutical composition may be an eyelid skin ointment. In addition to the above, these may contain the same ingredients as common skin ointments. These ointments may be in the form of a liquid ointment, lotion, emulsion, spray, cream, gel, or the like. They may also be in the form contained in other external products such as lotions and serums.

[0028] (Drug for treating blepharospasm, and drug for treating hyperesthesia or dystonia) The drug for treating blepharospasm and drug for treating hyperesthesia or dystonia of this embodiment include the pharmaceutical composition. The drug for treating blepharospasm, etc. of this embodiment can take any conventionally known form. The drug for treating blepharospasm, etc. of this embodiment is preferably in the form of eye drops. When the drug for treating blepharospasm, etc. of this embodiment takes the form of eye drops, it may have the same configuration (composition, etc.) as the eye drops. As for the form of the formulation, any formulation form conventionally used for each administration form can be used without particular limitation.

[0029] The administration conditions for the drug for treating blepharospasm and the like of this embodiment may be appropriately selected depending on the form of the drug, and the patient's symptoms, weight, age, sex, and the like. For example, when the drug is in the form of the above-mentioned eye drops, the administration conditions may be selected from those for conventionally known eye drops. For example, the drug may be administered 1 to 6 times a day, preferably 2 to 4 times a day, for one week or more, preferably one month or more.

[0030] The drug for treating blepharospasm and the like of this embodiment can be widely used for the above-mentioned purposes, such as administering it to a subject showing symptoms of blepharospasm and the like to treat the subject.

[0031] (Symptom Model Mouse) The symptom model mouse of this embodiment is a symptom model mouse for evaluating a pharmaceutical composition or a treatment using the same. That is, the symptom model mouse of this embodiment is a model mouse of the symptom of a subject exhibiting the above-mentioned symptoms, blepharospasm, or symptoms of hyperesthesia or dystonia in the face or head and neck, and is used to verify the symptom and to evaluate the effect of treatment for the symptom, particularly treatment using a pharmaceutical composition. Examples of the pharmaceutical composition include a pharmaceutical composition containing tramadol or a salt thereof as the above-mentioned active ingredient.

[0032] The symptom model mouse of this embodiment is a symptom model mouse that has been subjected to stress by a scaffold or airflow, i.e., the symptom model mouse of this embodiment is caused to exhibit the above-mentioned symptoms of blepharospasm, or hyperesthesia or dystonia in the face or head and neck by applying a certain amount of stress to the mouse for a certain period of time.

[0033] The scaffold stress can be applied by providing an unstable scaffold. For example, it can be applied by placing the mouse on a swingable scaffold. An example of a swingable scaffold is one that is not fixed, such as a scaffold suspended by a string. It is also preferable that the scaffold itself is difficult to maintain its position. For example, a rod or long scaffold whose width is equal to or less than the width of the mouse's body can be used.

[0034] The stress caused by the scaffolding may be mental stress (psychological stress) in addition to the instability of the scaffolding. For example, the scaffolding may be provided at a high place.

[0035] For example, the stress caused by the scaffold may be imparted by placing water adjacent to the mouse. Placing water adjacent to the mouse refers to placing the water close enough for the mouse to easily come into contact with the water. For example, placing the water near the unstable scaffold is preferable. Furthermore, for example, placing the water at a lower position than the swingable scaffold is even more preferable. A specific example of such a scaffold may be a rod-shaped scaffold suspended by a string in a swingable state above a water tank. By placing the water so that the mouse can easily fall off the scaffold and come into contact with the water, it is possible to impart strong mental stress to the mouse and strongly impart one of the risk factors for blepharospasm. Here, water broadly refers to an aqueous solution in which water accounts for the majority of the mass of its components, regardless of purity.

[0036] The stress caused by the air blowing not only causes stress to the mouse's eyes, but also increases the stress caused by the instability of the platform. Air blowing causes dry eyes and prolonged staring (inhibition of blinking), which can be a significant risk factor for blepharospasm. The stress caused by air blowing is caused by blowing air to the front or back of the mouse on the platform. The means and strength of the air blowing may be selected appropriately depending on the conditions under which the various symptoms appear. In this embodiment, air blowers are used to blow air to the mouse on the platform from both the front and back.

[0037] The conditions such as the time and frequency of applying the stress may be appropriately selected depending on the conditions under which the various symptoms appear, but as a guideline, by applying the stress of the scaffold and the scaffold and the air blow for 4 hours or more per day for 14 days or more, the symptoms of blepharospasm, or hyperesthesia or dystonia in the face or head and neck can be confirmed. In particular, by applying the stress for 4 hours per day for 18 days or more, the symptoms of blepharospasm can be confirmed.

[0038] Furthermore, the model mice may be subjected to other conditions such as stress that correspond to risk factors for blepharospasm. Three risk factors for blepharospasm are predicted: sex hormone changes, prolonged blink suppression, and mental stress. For example, symptom model mice may be aged mice subjected to the above stresses. Aged mice are considered to be significantly affected by sex hormone changes. Furthermore, mice that have undergone sex hormone changes, such as removal or inactivation of organs related to hormone secretion, such as the ovaries, may be used.

[0039] To evaluate a pharmaceutical composition or a treatment using the same using the symptom model mouse of this embodiment, the evaluation can be performed by comparing a control mouse that has not been subjected to the stress, or a mouse that has not been treated with the pharmaceutical composition or the pharmaceutical composition, with a mouse that has been treated.

[0040] (Effects of this embodiment) According to this embodiment, it is possible to provide a pharmaceutical composition, a drug for treating blepharospasm, a drug for treating hyperesthesia or dystonia, and a symptom model mouse that are highly effective as treatments for blepharospasm and the like, which have traditionally been difficult to treat or for which no effective treatments have been available, and which impose a low burden on patients.

[0041] The present inventors have discovered that the use of tramadol hydrochloride, a μ-opioid receptor agonist, as an eye drop improves the symptoms of blepharospasm. Because μ-opioid receptor agonists are expected to have analgesic effects, it is conceivable that they may improve hypersensitivity symptoms such as pain and dryness in patients with blepharospasm. However, when tramadol hydrochloride eye drops were actually administered to patients with blepharospasm, eyelid motor symptoms improved independently of the improvement of hypersensitivity symptoms. Furthermore, the composition of this embodiment was also effective against symptoms of ocular hypersensitivity, such as eye strain. Similarly, it is believed to be effective against similar symptoms in other areas that are affected by blepharospasm, such as the face, head, neck, and upper body.

[0042] Conventionally, the therapeutic effects of tramadol have been widely known as its analgesic effect, and it has also been known to have some effect on dry eye. However, its effect on improving other hypersensitivity and motor symptoms has not been known. Unlike a simple analgesic effect, this embodiment has been shown to have an ameliorative effect on motor symptoms, and topical administration of tramadol hydrochloride to the eye can improve the motor symptoms of patients with blepharospasm. Furthermore, this embodiment can obtain a symptom model mouse that reproduces symptoms corresponding to ocular hypersensitivity symptoms such as blepharospasm or eye strain, and can be used to verify these diseases, symptoms, and treatments.

[0043] (Other Aspects of the Present Embodiment) This embodiment also includes the following aspects as other aspects. Another aspect of this embodiment is a method for producing a medicament for treating blepharospasm using the pharmaceutical composition. Another aspect of this embodiment is use of the pharmaceutical composition for producing a medicament for treating blepharospasm. Another aspect of this embodiment is use of the pharmaceutical composition for treating blepharospasm and the like. Another aspect of this embodiment is use of the pharmaceutical composition for use in treating blepharospasm and the like. Another aspect of this embodiment is a method for treating blepharospasm and the like using the pharmaceutical composition.

[0044] Although the embodiment of the present invention has been described above, the present invention is not limited to the above embodiment and various modifications can be made.

[0045] The effects of the present invention will be made clearer by the following examples and comparative examples. Note that the present invention is not limited to the following examples, and can be practiced by making appropriate changes within the scope of the present invention.

[0046] (Test Example 1) A 5-fold dilution solution was prepared from a commercially approved tramadol injection solution (Tramadol Hydrochloride OD Tablets 25 mg "KO", Kotobuki Pharmaceutical Co., Ltd.), the dilution solution was sterilized by suction filtration, dispensed into eye dropper bottles, filled, and stored in a refrigerator. As a quality test, a sample was extracted for quality inspection, and the drug quantity, properties, pH, osmotic pressure ratio, sterility, insoluble foreign matter, and fine particles were inspected. The sample was transported and stored to prepare a pharmaceutical composition in the form of an eye drop containing 1% tramadol, which was used in the following administration test.

[0047] Nine patients with blepharospasm were administered the 1% tramadol eye drops four times a day for one month. Subjective symptoms were evaluated before and after administration using a visual analog scale (VAS) and multiple questionnaires.

[0048] The results of administration were as follows: 5 / 9 cases: both sensory hypersensitivity and motor symptoms improved 2 / 9 cases: only sensory hypersensitivity improved 1 / 9 cases: only motor symptoms improved 1 / 9 cases: neither sensory hypersensitivity nor motor symptoms improved The average for the 9 cases was: Sensory hypersensitivity VAS Before treatment: 56.9 ± 18.9 After treatment: 36.9 ± 21.4 (p = 0.003) Motor symptoms Total score Before treatment: 3.4 ± 1.4 After treatment: 1.8 ± 1.2 (p = 0.02)

[0049] Of nine patients with blepharospasm, five showed improvement in both motor and hypersensitivity symptoms. Two showed improvement in hypersensitivity symptoms only, and one showed improvement in motor symptoms only. One patient showed no improvement in either motor or hypersensitivity symptoms. That is, by administering 1% tramadol eye drops, both motor and hypersensitivity symptoms improved in more than half of the patients with blepharospasm. Furthermore, the results showed that most patients showed improvement in either motor or hypersensitivity symptoms. Prior art has not found a technology that can provide a high level of improvement, such as a reliable subjective symptom, for blepharospasm symptoms, or a treatment method that can achieve a high rate of improvement in a variety of patients. However, it is believed that using the pharmaceutical composition of this embodiment as an eye drop or therapeutic agent will provide an effective treatment for blepharospasm.

[0050] (Test Example 2) A mouse model reproducing symptoms corresponding to blepharospasm was created, and the eye drops containing tramadol were administered to the mouse model to examine the effect of the pharmaceutical composition on symptom alleviation. It was confirmed in a separate preliminary study that when mice were subjected to stress (risk factors) due to scaffolding and airflow, a blepharospasm-like phenotype developed compared to mice not exposed to these stresses (not shown). Furthermore, when the number of blinks was compared between a tramadol eye drop administration group and a saline eye drop administration group after instillation once daily for three days in unstressed mice (n = 4 eyes each), no significant difference in the number of blinks was observed between the two groups, and no other significant differences were observed in the eyes or the whole body. It was also confirmed that tramadol had no other effects on mice without symptoms corresponding to blepharospasm (not shown).

[0051] Six 38-week-old female C57BL / 6JJcl mice were stressed with a scaffold and airflow to create a symptomatic mouse model exhibiting symptoms equivalent to blepharospasm. An unstable suspension bridge scaffold consisting of rod-shaped components suspended by strings was placed above a cage filled with water. Stress from the scaffold and airflow was applied by placing the mice on the scaffold and blowing air from the front and back using a fan. Stress was applied for four hours per day (excluding weekends) for approximately three weeks.

[0052] In parallel with the stress environment, three of these symptom model mice were administered eye drops containing tramadol, as in Test Example 1. The other three mice in the group received only saline. On day 18, the administration of tramadol was stopped, and on day 21, the number of blinks was measured. The number of blinks per minute was measured by holding the awake mice still.

[0053] Figure 1 is a graph showing the results of the number of blinks in symptom model mice administered with eye drops. In the figure, Saline indicates mice administered with saline only, and Tramadol indicates mice administered with eye drops. Administration of the eye drops significantly reduced the number of blinks.

[0054] These results demonstrate that administration of eye drops containing tramadol to model mice with blepharospasm alleviates the symptoms.

[0055] Although the embodiments of the present invention have been described above, these embodiments are presented as examples and are not intended to limit the scope of the invention. These embodiments can be embodied in various other forms, and various omissions, substitutions, and modifications can be made without departing from the spirit of the invention. These embodiments and their modifications are included within the scope and spirit of the invention, as well as within the scope of the invention and its equivalents as defined in the claims.

[0056] According to the present invention, it is possible to provide a pharmaceutical composition, a drug for treating blepharospasm, a drug for treating hyperesthesia or dystonia, and a symptom model mouse that are highly effective as treatments for blepharospasm and the like, which have previously been difficult to treat or for which no effective treatments have been available, and which impose a low burden on patients.

Claims

1. A pharmaceutical composition for administration and treatment to a subject showing symptoms of eyelid myoclonia, or hypersensitivity or dystonia in the face or head and neck, containing tramadol or a salt thereof as an active ingredient.

2. The pharmaceutical composition according to claim 1, containing 0.01 to 2.0% w / v of the tramadol or a salt thereof.

3. The pharmaceutical composition according to claim 1 or 2, which is an eye drop, an injection, an eye ointment or a topical agent for eyelid skin.

4. The pharmaceutical composition according to claim 3, which is an eye drop containing artificial tears, a water-soluble polymer ophthalmic lubricating medium or a surfactant.

5. A medicament for treating eyelid myoclonia, containing the pharmaceutical composition according to claim 1 or 2.

6. A medicament for treating hypersensitivity or dystonia in the face or head and neck, containing the pharmaceutical composition according to claim 1 or 2.

7. A symptom model mouse for eyelid myoclonia, hypersensitivity or dystonia for evaluating the pharmaceutical composition of claim 1 or a treatment using the same, which is a mouse stressed by a scaffold or air blowing.

8. The stress by the scaffold is applied by placing the mouse on a swingable scaffold, the stress by the air blowing is applied by blowing air to the front and rear of the mouse on the scaffold, and the stress of the scaffold and the air blowing is applied for 4 hours or more per day for 14 days or more. The symptom model mouse according to claim 7.

9. The symptom model mouse according to claim 7 or 8, wherein the stress by the scaffold is applied by placing water adjacent to the mouse.

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