DE102007008231A1 - Use of norethisterone and/or its esters or salts for the treatment of e.g. migraine, stress headaches with or without cervical muscle cramps, sleep disturbances, depressions, panic attacks and fibromyalgia - Google Patents

Abstract

Use of norethisterone and/or its esters or salts for the treatment of migraine, stress headaches with or without cervical muscle cramps, sleep disturbances, depressions, panic attacks, excessive sweating related to progesterone deficiency, fibromyalgia, Parkinson's disease and/or restless leg syndrome. Independent claims are included for: (1) a drug delivery composition for the above mentioned treatment comprising norethisterone ester or its salts (0.25-200 mg); and (2) the preparation of drug delivery composition comprising mixing norethisterone, esters of norethisterone and/or its salts and subsequently forming a dosage form. ACTIVITY : Antimigraine; Analgesic; Tranquilizer; Hypnotic; Antidepressant; Muscular-Gen; Antiparkinsonian. MECHANISM OF ACTION : None given.

Description

The The present invention relates to a pharmaceutical preparation for the treatment of migraine and other diseases based on progesterone deficiency. These include u. a. migraine with or without aura, tension headache with or without neck cramps, sleep disorders, Depression, panic attacks, excessive sweating and related diseases.

Under migraine one understands a chronically recurring, often seizure-like illness, the usually with headache changing strength and Andauer goes along. She occurs more often in women than in men and manifests itself clinically in various forms, for example as a migraine without aura with slowly growing headache or as migraine with aura, which is associated with often neurological deficits, z. B. restricted cognitive perception and light-shyness.

While the Causes of migraine are largely unknown, have been in recent years various Treatment procedure designed to reduce the typical symptoms People like nausea, Vomiting, headache, vascular disorders and others mitigate. For example, in the treatment of acute migraine attacks a combination of a motility-enhancing Antiemetic in combination with a non-opioid analgesic in question, which, however, leads to unwanted side effects leads.

at longer have ongoing migraine attacks the so-called triptans such as Sumatriptan and Rizatriptan proved helpful, but without a longer lasting one Ensure relief of symptoms in all patient groups to be able to.

A Object of the present invention is to provide a more effective and side effect Treatment of migraine and other disorders based on progesterone deficiency enable.

It was surprising found that certain nor-testosterone derivatives are already in low dosage for effective and ongoing treatment and prophylaxis of migraine, Tension headache (with or without neck cramps) and related medical conditions can be used whereas other progestagens do not show this desired activity.

Already For decades, the production of norethisterone has been known See, for example, U.S. Patent 2,744,122 or U.S. Patent 2,849,462.

norethindrone (also called 19-nortesterone or 19-nor-17α-ethynyl-17β-hydroxy-pregn-4-ene; CAS-No. 0000068-22-4) can over the alcohol function in position 17 with common pharmaceutically acceptable acids such as Acetic, oanthanthic, maleic, Fumaric, citric, benzenesulfonic, benzoic, ethanesulfonic, gluconic, Glycolic, lactic, lactobionic, maleic, malic, methanesulfonic, amber, p-toluenesulfonic or tartaric acid be esterified.

Norethindrone acetate as well as its metabolite norethisterone, are so far the first Line for hormonal control of the monthly cycle as well as for Treatment of Mastopathia cystica in sexually mature women used. In the trade z. As tablets containing 1 mg or 5 mg norethisterone acetate and injection solutions for parenteral administration containing 200 mg norethisterone enanthate available in castor oil.

Norethindrone acetate is a synthetic sex hormone and belongs to the group of progestogens (Luteum hormones). These together with the estrogens regulate the monthly cycle the woman as well as the course of a pregnancy. norethindrone is used for years to treat u. a. Menstrual cramps, Mastopathy (benign remodeling of the breast tissue) or endometriosis (growths of the uterine lining).

It was now surprising found that particular norethisterone acetate and norethisterone enanthate (the ester of onan-acid) for the low side-effect treatment of migraine, as well as other diseases, which are based on a progesterone deficiency, z. Migraine with or without aura, tension headache with or without neck cramps, sleep disorders, Depression, panic attacks, excessive sweating and related diseases can be used.

norethindrone, its esters and salts can after prepared in the literature known methods.

To the Use is also physiologically tolerated salts of norethisterone and its esters, being physiologically compatible Salts understood both organic and inorganic salts (see Remington Pharmaceutical Sciences, 17th Edition, p 1414 of 1985).

According to the invention, the active ingredients are preferably used as a pharmaceutical preparation containing norethisterone and / or an ester of norethisterone or one of its salts and at least one physiologically suitable excipient. These components can be mixed and then brought into a suitable form become.

When Acid component in norethisterone esters come physiologically non-interfering acids such as the exemplified above organic acids in question, preferably however, norethisterone acetate or norethisterone enanthate is used.

The inventive preparation is generally administered orally, locally or parenterally.

suitable solid or liquid galenic preparations are, for example, tablets, granules, Powders, dragees, capsules, microcapsules, suppositories, syrups, emulsions, Suspensions, drops or injectable solutions in ampule form as well preparations with protracted drug release such as Transdermal Therapeutic Systems (TTS) and gels for transcutaneous absorption.

at The preparation of the preparation is usually physiological suitable aids such as carrier, Binding, coating, Swelling, Lubricants, Flavorings, Sweeteners or solubilizer for use. As often used carriers and auxiliaries are, for example, magnesium carbonate, titanium oxide, Lactose, mannitol, other sugars, milk protein, gelatin, starch, cellulose and their derivatives, animal and vegetable oils, polyethylene glycols, as well as solvent like water, alcohol, called glycerin.

Preferably the pharmaceutical preparations are prepared in dosage units and administered, each unit as an active ingredient certain dose of norethisterone, norethisterone esters and / or their salts.

at fixed dose units such as capsules or tablets can this dose for example, 0.2 mg to 5 mg, preferably 0.25 mg to 2.5 mg, in particular 0.25 mg to 1.0 mg. The dosage of 0.5 mg of active ingredient per unit has proven itself especially.

Especially in local application forms such as sprays, patches, Transdermal Therapeutic Systems or Implants Can Have One Dosage of, for example, 0.25 to 250 mg, preferably 2.5 to 20 mg are used.

The The daily dose to be administered depends on body weight, sex, age the person and the general or clinical condition of the patient.

The Although administration of the daily dose can be given as a single dose in the form of individual metering unit, it has, however, been advantageous proven, smaller dosing units by multiple use for use bring to.

Especially Advantageously, the use of oral preparations has the award a dose of 0.25 mg to 0.75 mg, preferably 0.4 to 0.6 mg, in particular 0.5 mg of the active ingredient every 3 to 5 hours, especially every 4 Hours proved. For example, through this application scheme a complaint-free night sleep (also without interruptions of Sleep).

The The invention particularly relates to the use of norethisterone and / or norethisterone esters or their salts for the treatment or for the manufacture of a medicament for the treatment of migraine, Tension headache (with or without neck cramps) and related medical conditions. The medicines are usually made by one Norethisterone and / or norethisterone esters or their salts with one or more physiologically suitable excipients in one brings appropriate dosage form.

Also the use of norethisterone and / or norethisterone ester or their salts for the treatment of muscle pain in the back and / or Legs, of sudden severe sweating (eg occurrence of stress-independent hot flashes), sleep disorders (eg. B. falling asleep or staying asleep, to earlier Waking up), excessive anxiety (Panic), and depression is possible.

There it is known from progestins such as progesterone, levonorgestrel and gestodene was that they have a wide range of side effects, such as the generation of nausea, Vomiting and headache, it was particularly surprising to find that the testosterone derivative Norethisterone and in particular its acetate and enanthate to the effective fight of migraine and the progesterone deficiency symptoms can be used.

While Norethisterone and / or the norethisterone esters in particular at Treating women as helpful may be a norethisterone and / or norethisterone ester-containing preparation also in men be used.

diseases like migraine, Tension headache with or without neck cramps, fibromyalgia (cramping of muscles), Parkinson's or restless leg syndrome can be through the use of norethisterone or ester successfully treat.

For the therapy of the above-mentioned conditions, the compounds themselves may be used as a compound, but preferably they are with a compatible carrier in the form of a pharmaceutical composition. The carrier must naturally compatible, in the sense that it is compatible with the other ingredients of the composition and is not harmful to the patient. The carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may also be present, including other steroids. The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which consist essentially in that the ingredients are mixed with pharmacologically acceptable carriers and / or excipients.

Inventive pharmaceutical Compositions (preparations) are those intended for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) Administration, although the most suitable route of administration in each individual case of the nature and severity of the treatment Condition and depends on the type of connection used in each case. Also coated formulations and coated slow release formulations belong within the scope of the invention. Preference is given to acid and gastric juice-resistant Formulations. Suitable enteric coatings include Cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

suitable pharmaceutical compounds for oral administration in separate units, such as capsules, cachets, Lozenges or tablets, each containing a certain amount the compound included; as a powder or granules; as a solution to the Suspension in an aqueous or non-aqueous Liquid; or as an oil-in-water or water-in-oil emulsion. These compositions can, As already mentioned, prepared according to any suitable pharmaceutical method, which comprises a step in which the active ingredient and the carrier (the one or more additional ones Constituents can be) brought into contact. In general the compositions become uniform and homogeneous of the active ingredient with a liquid and / or finely divided solid support, after which the Product is molded if necessary. For example, a Be prepared by adding a powder or granules of the tablet Compound is pressed or molded, optionally with a or several additional ones Ingredients. Pressed tablets can be made by tableting Connection in free-flowing Mold, such as a powder or granules, optionally mixed with a binder, lubricant, inert thinner and / or one (several) surface-active / dispersing Means be made in a suitable machine. molded Tablets can by molding the powdery, with an inert liquid thinner moistened connection made in a suitable machine become.

pharmaceutical Compositions for peroral (sublingual) administration Lozenges containing a flavoring compound, usually Sucrose and gum arabic or tragacanth, and lozenges containing the Compound in an inert base such as gelatin and glycerin or Ducrose and gum arabic include.

suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous Preparations of a compound which is preferably isotonic with the blood of the intended recipient are. These preparations are preferably administered intravenously, although the administration is also subcutaneous, intramuscular or intradermal can be done as an injection. These preparations may preferably be prepared be mixed by mixing the compound with water and the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1% to 5% by weight of the active compound.

suitable pharmaceutical compositions for rectal administration are preferably present as single-dose suppositories. These can be made be prepared by adding a compound according to formula I with one or more usual solid straps, For example, cocoa butter, mixes and the resulting mixture in Form brings.

suitable pharmaceutical compositions for topical application the skin are preferably as ointment, cream, lotion, paste, spray, Aerosol or oil in front. As a carrier can Vaseline, lanolin, polyethylene glycols, alcohols and combinations used by two or more of these substances.

Also transdermal administration is possible. Suitable pharmaceutical Compositions for transdermal applications can as single patches exist, which are for a long-term close Contact with the epidermis of the patient are appropriate. Such patches suitably contain the active ingredient in an optional buffered aqueous Solution, solved and / or dispersed in an adhesive or dispersed in one Polymer.

The Above mentioned compounds can also be administered in combination with other active substances.

When further active ingredients for the combination preparations are z. B. suitable: migraine, those in the "Red List 2005 "(German Medicinal Directory) are called. You can with the compounds of the invention especially combined for synergistic effect improvement become. The administration of the drug combination can either by separate administration of the active ingredients to the patient or in the form of combined preparations take place, wherein several active ingredients in a pharmaceutical preparation available.

The The present invention also relates to the preparation of a pharmaceutical Preparation containing norethisterone or its esters, in particular Norethisterone acetate and enantate for the treatment of migraine, as well as other disorders based on progesterone deficiency. For this belong u. a. migraine with or without aura, tension headache with or without neck cramps, sleep disorders, Depression, panic attacks, excessive sweating. Furthermore, the preparations can also be used for the treatment of Fibromyalgia, Parkinson's and / or Restless Leg Syndrome.

From Parkinson's disease is previously thought to be due to a degeneration of the dopaminergic neurons is caused. This leads to an imbalance of neurotransmitters, especially acetylcholine and dopamine. Parkinson's disease manifests itself u. a. through symptoms like tremor, bradykinesia, disorders in the course and speech disorders.

In usually the disease occurs in men and women alike middle age up. Since the previous therapeutic approaches with Levo-Dopa causes serious side effects and an ever-increasing dosage to lead can, there is a big one Need for novel treatments with fewer side effects.

It was now surprising found that norethisterone acetate or enantate to the effective Therapy and prophylaxis of Parkinson's is suitable.

Also a treatment of Restless Leg Syndrome (RLS) by application a preparation containing norethisterone acetate or norethisterone enanthate is possible. RLS is a neurological disease, in particular with a discomfort in the legs and a strong urge to move accompanied. These symptoms can be similar a migraine to a severe impairment to lead the night sleep. By Use of norethisterone acetate, for example, several times a day in Low dose applied, can relieve the symptoms of RLS treat it effectively.

The The present invention also relates to a preparation for the transdermal Application, in particular a Transdermal Therapeutic System (TTS) for the administration of norethisterone or its esters the skin over a longer one Period. Such a TTS usually consists of a fixation aid and a matrix containing the active ingredient.

The TTS offers the advantage of continuous drug delivery bypassing the gastrointestinal tract. For cost reasons and for a better one Patient compliance provides a provision of a norethisterone patch for several days Use on. As it is used in the treatment of migraine or tension headache with or without neck cramps and other diseases caused by progesterone deficiency, by means of Norethisterone / acetate on one as possible constant feed less Quantities of No rethisterone or norethisterone acetate arrives, recommends the use of a modern transdermal therapeutic system, for example, a TTS (eg consisting of a methacrylate polymer matrix, containing the active substance, one or more cover layers and a durable fixation). In this case, it is preferable to use a TTS that lasts for one or more days a dosage of 0.5 to 8 mg of the active ingredient, in particular 1.5 to 3 mg per day, with this release in particular with almost constant delivery rate.

The present examples are intended to explain the invention in more detail, without departing from the invention in any way limit.

example 1

It A tablet is made in addition to 1 mg norethisterone acetate the common ones Additives and auxiliary substances such as lactose, magnesium stearate, talc, caboxymethylcellulose Contains sodium type H, gelatin and potato starch.

A 37 year old Patient who has been suffering from persistent headache for several weeks as well as touch pain the left breast complains, receives norethisterone acetate as tablet in the dosage 1 mg per day cyclically, d. H. from the 12th Cycle day until the 22nd cycle day. The patient is already behind 2 days of administration of 1 mg norethisterone acetate as a tablet completely symptom-free.

After discontinuation of norethisterone acetate (once daily, 1 mg each as a tablet) after the 22nd cycle day, the symptoms begin again and will not disappear until the next intake of 1 mg norethisterone acetate on the 12th day of the next month cycle.

First after use of 1 mg norethisterone acetate daily without interruptions the patient is complete symptom-free. Even after a long time Duration of daily income 1 mg norethisterone acetate shows no evidence of side effects.

During the Therapy of migraine and tension headache is also found to be muscle pain in back and legs as well as insomnia with subsequent depression completely disappear. The described problems are often accompanied by a drop of course occurring progesterone levels in the organism. The shown effectiveness of norethisterone acetate in insomnia and depression suggests on the regulatory ability in the area of the central nervous system.

At the Man finds the production of progesterone and estrogens in the Testes take place. Since norethisterone has androgenic activity is the employment also with the man absolutely possible. Field of application is too here, for example, the migraine and tension headache with or without neck cramps.

Example 2:

It A tablet is made containing 0.5 mg norethisterone acetate the common ones Additives and auxiliaries, such as. Lactose, magnesium stearate, talc, Carboxymethylcellulose contains sodium type H, gelatin and potato starch.

at a 50 year old Patient with over 10 years Years ago tension headache with neck bouts, muscle pain in back and Legs, insomnia with subsequent depression, tachycardia and panic attacks are tested various commercial progestogen monopreparation, without relief of the symptoms can be achieved.

With Norethisterone acetate in a dosage of 0.5 mg every 4 hours taken orally, it is possible to achieve a lasting freedom of the patient.

The The dosage described does not show any clinically relevant side effects. Also, virilization phenomena occur even with prolonged treatment not up. The use of 1 mg / day or 4 × 0.5 mg every 4 hours proves Compared to other progestogen monopreparations as very effective with low side effect profile.

Especially at the dose of 4 × 0.5 mg Norethisterone acetate / day, water retention in the tissue are minimal. Virilization can not be observed. Altered laboratory parameters will be even after a longer one Treatment period not observed.

Example 3:

at a 40 year old Patient who repeatedly for several weeks of persistent headache and other migraine symptoms suffers, norethisterone enanthate is used.

to Norethisterone Enanthate 200 mg (equivalent to 145,353 mg norethisterone) as commercial Pre-filled syringe (three-month syringe). The patient turns after a short time Time to realize that her migraine, which has been around for years, has completely disappeared. The Effect holds for several weeks.

Of the Use of norethisterone acetate or norethisterone enanthate as Depot is useful in the sense of a long-term gentle hormone replacement therapy. There are no more migraine symptoms and no headaches. The menstrual period also does not occur more.

Of the Use of norethisterone esters over sustained-release formulations on, for example, over a TTS containing the drug in a slow-release polymer matrix contains. It leaves so a targeted release of z. From 0.5 mg to 8 mg per day achieve good patient compliance.

Claims (12)

Use of norethisterone, norethisterone esters and / or their physiologically acceptable salts for treatment from migraine, Tension headaches with or without neck bouts, sleep disorders, Depression, panic attacks, excessive sweating based on a progesterone deficiency, fibromyalgia, Parkinson's and / or restless leg syndrome. Use of norethisterone, norethisterone esters and / or their physiologically acceptable salts as claimed 1, characterized in that the active ingredient as a medicament for an oral Formulation is formulated, the 0.25 mg to 2.5 mg of the active ingredient contains. Use of norethisterone, norethisterone esters and / or their physiologically acceptable salts as claimed 1 or 2, characterized in that the active ingredient as locally or parenterally administrable formulation containing 0.25 mg to 200 mg of the active ingredient. Use of norethisterone, norethisterone esters and / or their physiologically acceptable salts according to one the claims 1 to 3, characterized in that a transdermal therapeutic System containing 2.5 mg to 20 mg of the active ingredient is used. Use of norethisterone, norethisterone esters and / or their physiologically acceptable salts according to one the claims 1 to 4, characterized in that as the active substance norethisterone acetate and / or norethisterone enanthate is used. Pharmaceutical preparation for the treatment of migraine, tension headache with or without neck bouts, Sleep disorders, Depression, panic attacks, excessive sweating based on a progesterone deficiency, fibromyalgia, Parkinson's and / or Restless leg syndrome containing 0.25 mg to 200 mg of a norethisterone ester or a physiologically tolerable Salt. Pharmaceutical preparation according to claim 6, characterized that they contain 0.25 to 0.75 mg norethisterone acetate and / or norethisterone enanthate contains. Pharmaceutical preparation according to one of claims 6 or 7, characterized in that they are for the treatment of migraine and / or tension headache with or without neck crunches is used and the preparation 0.4 mg to 0.6 mg of a norethisterone acetate contains. Pharmaceutical preparation according to one of claims 6 to 8, characterized in that it is an oral preparation is. Pharmaceutical preparation according to one of claims 6 to 8, characterized in that it is a preparation for a transdermal Application is. Pharmaceutical preparation according to one of claims 6 to 9, characterized in that the preparation is a Transdermal Therapeutic System Acts. Process for the preparation of a pharmaceutical Preparation according to one the claims 6 to 11, characterized in that norethisterone and / or a Ester of norethisterone or one of its salts and at least mixed a physiologically suitable excipient and then in be brought to a suitable shape.