DE102008050597A1 - Preparation, useful for treating and preventing idiopathic sudden sensorineural hearing loss, comprises pentaerythritol tetra-, pentaerythritol trinitrate, pentaerythritol dinitrate or pentaerythritol mononitrate, and an excipient - Google Patents

Abstract

Preparation comprises pentaerythritol tetranitrate, pentaerythritol trinitrate, pentaerythritol dinitrate or pentaerythritol mononitrate as a drug in an amount of 25-600 mg, and an excipient. ACTIVITY : Auditory. No biological data given. MECHANISM OF ACTION : None given.

Description

Field of application of the invention

The The present invention relates to an acute hearing loss pharmaceutical preparations containing as active ingredient pentaerythrityl tetranitrate (PETN) and its homologues or its metabolites, and these preparations for use in a method of therapeutic and protective treatment of sudden hearing loss.

Known technical background

Of the Idiopathic sudden sensoneurinal hearing loss, abbreviated ISSHL) is an idiopathic sudden occurring, usually unilateral but also bilateral sound sensory disturbance. The severity of the hearing loss, measured by hearing loss, It can be easy or even total deafness pass. It can affect all frequencies or even specific ones Frequency ranges to be limited. The hearing loss is hearing loss by identifiable causes with strict application of the definition delineate. For non-exclusion of other causes for the hearing loss a variety of causes determine.

The hearing loss is treated with a variety of therapies. An overview of the hearing loss related treatment options is in "The sudden deafness", Olaf Michel, Thieme 1994 published.

To In particular, the drug therapies belong Infusion therapies with the aim of improving blood circulation in the Inner ear.

Under the assumption that a hearing loss due to a circulatory disorder of the inner ear is often done in the initial phase mostly the so-called infusion therapy. Patients become during longer periods by infusion circulation-promoting Substances such as hydroxyethyl starch (HES), pentoxifylline or low molecular weight dextrans. Rarely do substances like the piracetam or prostaglandins or prostacyclin as the alprostadil and iloprost are used.

Farther can in addition to the infusion therapies medicinal oral therapies with the aim of improving blood circulation in case of acute hearing loss be used.

Improved blood circulation Substances can be taken orally in tablet or capsule form be administered. The substances in this sense include: Naftidrofuryl, ginkgo biloba extracts, buflomedil and pentoxifylline. Also antihypertensive with vasodilating effect such as nifedipine or nimodipine are for the purpose of circulation improvement used in acute hearing loss.

Further Therapies set systemic-acting. Corticosteroids, in particular also in conjunction with other medications such as pentoxifylline and Dextran or hydroxyethyl starch.

Representing the extremely extensive literature on hearing loss therapy, reference is made to the following works:
(1) Bruce L. Fetterman et al. Prognosis and Treatment of Sudden Sensorineural Hearing Loss, The American Journal of Otology, 17: 529-536, 1996 ; (2) Dt. Ges. F. Otorhinolaryngology, Head and Neck Surgery: Guidelines hearing loss. January 2004. AWMF Guidelines Register No. 017/010 ; (3) Dt. Ges. F. Otorhinolaryngology, Head and Neck Surgery: Guidelines hearing loss. January 2004. AWMF Guidelines Register No. 017/010 ; (4) Ogawa K, Takei S, Inoue Y, Kanzaki J. Effect of prostaglandin E1 on idiopathic sudden sensorineural hearing loss: a double-blinded clinical study. Otol Neurotol 2002; 23 (5): 665-668 ; (5) Michel O, Matthias R: Placebo-controlled double-blind study on acute hearing loss treatment with a stable prostacyclin analogue. Laryngorhinootologie. 1991 May; 70 (5): 255-259 , Linssen O, Schultz-Coulon HJ. Prognostic criteria for sudden hearing loss. ENT 1997; 45 (1): 22-29 ; (6) Suckfüll M. Current therapy for sudden hearing loss. Laryngeal Glandology 2005; 84 (4): 277-282 ; (7) Arellano B, Garcia B, Jr., Gorriz C, Gonzalez FM, Vicente J, Ramirez CR. Protocol de tratamiento de la sordera súbita. Acta Otorrinolaringol Esp 1997; 48 (7): 513-516 ; (8th) Dt. Ges. F. Otorhinolaryngology, Head and Neck Surgery: Guidelines hearing loss. January 2004. AWMF Guidelines Register No. 017/010 ; (9) Wilson WR, Byl FM, Laird N. The efficacy of steroids in the treatment of idiopathic sudden hearing loss. A double-blind clinical study. Arch otolaryngol 1980; 106 (12): 772-776 ,

Organic nitric acid esters, also referred to as organic nitrates, such as glycerol trinitrate (GTN) ( Murrel, Lancet: 80, 113, 151 (1879) ), Pentaerythrityl tetranitrate (PETN) ( Risemann et al., Circulation, Vol. XVII, 22 (1958 ) US Patent No. 2370437 ), Isosorbide-5-mononitrate (ISMN) ( DE-OS-2221080 . DE-OS-2751934 . DE-OS-3028873 . DE-PS-2903927 . DE-OS-3102947 . DE-OS-3124410 . EP-A1-045076 . EP-A1-057847 . EP-A1-059664 . EP-A1-064194 . EP-A1-067964 . EP-A1-143507 . US Patent No. 3886186 . US Patent No. 4065488 . US Patent No. 4417065 . US Patent No. 4431829 ), Isosorbide dinitrate (ISDN) ( L. Goldberg, Acta Physiolog. Scand. 15, 173 (1948) ), Propatyl nitrate ( Médard, Mem. Poudres 35: 113 (1953) ), Trol nitrate ( FR-PS 984523 ) or nicorandil ( US Patent No. 4200640 ) And similar compounds are vasodilators, some decades (mainly for the indication angina pectoris or coronary heart disease CHD) breitesten find therapeutic use (Nitrangin ^®, Pentalong ^®, Mono Long ^®, and others).

The known technical background with respect to the organic nitrates and their therapeutic and protective use is particularly to the European patent application 98 961 013.4-2114 ( PCT / DE 98/03030 ), which is incorporated by reference in the relevant for the present invention prior art background.

Presentation of the invention

task The invention is, especially peroral, sublingual and intravenous Applicable, pharmaceutical against acute hearing loss To provide preparations for use in a method for the therapeutic and protective treatment of Hearing loss are suitable.

The The object of the invention is achieved by pharmaceutical anti-hearing loss preparations containing as active ingredient 25 to 600 mg pentaerythrityltetra-, pentaerythrityltri-, pentaerythrityldi- or Pentaerythritylmononitrate and common galenic adjuvants. In this case, the amount of drug at daily and longer continuous single or multiple administration in a wide range without loss of therapeutic efficacy and without occurrence be varied. The ranges are preferred from 25 to 300, 25 to 240 mg, 50 to 150 mg, especially 25 to 150 mg. The proportion of the drug in the preparations may be up to 50% by mass, preferably 10 to 30% by mass.

Another The invention relates to the abovementioned pharmaceutical Preparations for use in a method of therapeutic and protective treatment of sudden hearing loss.

According to one Another feature of the invention, the inventive Task, in particular in the field of application of the preparations characterized solved that used galenic adjuvants retarding or have no retarding effect or a retarding effect Have an effect because they are used in amounts that are not retarding Act. As auxiliaries in the context of this invention are doing Understood substances that make it possible the drugs into the desired preparation forms and the In addition, the properties to be achieved are suitable To achieve drug form and known to improve, especially in terms the effect of the drugs, the regulation of effects, the external Consistency, controllability and durability. substances which are used as adjuvants, must be the following Requirements suffice: atoxicity, therapeutic Indifference, physiological compatibility, adequate Stability and durability, compatibility with the drug u. Ä. Regarding their intended use the auxiliaries are preferably according to the invention from the groups of filling, binding, sliding, mold-separating, Lubricating, disintegrating, moisturizing, adsorbing, retarding, blasting or counter-blasting agents, film formers, absorption accelerators, preservatives, Stabilizers, emulsifiers, solubilizers, salts for influencing osmotic pressure, buffer solutions, color, fragrance, aroma or sweeteners selected. Various Auxiliaries sometimes fulfill several functions.

Corresponding the specific task and the respective substance parameters is the appropriate choice by the pharmaceutical professional Excipients also with regard to the avoidance of drug-excipient incompatibilities hold true. Suitable pharmaceutical excipients are without it limited to celluloses, cellulose derivatives, starches and modified starches lactose, sorbitol, gelatin, PVP, Phosphates, stearic acid and its salts, talc and silica. The respective pharmaceutical preparation is preferably in liquid or solid form. Suitable for this purpose Solutions, in particular for the preparation of drops, injections, Infusions, aerosol sprays or powder inhalers or inhalation sprays, further suspensions, emulsions, syrups, tablets, film-coated tablets, Dragees, capsules, pellets, powders, lozenges, implants, suppositories, Creams, gels, ointments, patches or other transdermal systems.

The Preparation of the preparations according to the invention is done by usual methods. In addition to oral come for the preparations also the transcutaneous, rectal, intravenous or interarterial as well as the inhalative and sublingual applications in each case also in Liposaomem, microemulsions and microcapsules.

to Preparation of drugs for transcutaneous administration, eg. B. Of transdermal therapeutic applications, the preparations according to the invention in a gel base, Ointment base or liquid base, if necessary with different solubilizers, penetration accelerators and stabilizers are introduced. As primary packaging Sprays, tubes, ampoules and single portions are used. Likewise, when applied to the skin are occlusive dressings suitable. Optionally, the preparations may also with stabilizers and solubilizers on a plaster applied and applied.

Surprisingly, it was found that the achievement of the goal in the sense of this inventions The excipients used exclusively serve as fillers, disintegrants, flow regulators, lubricants and lubricants as well as not as liberating controlling agents. All excipients themselves are indifferent to the active substance. According to the invention, said pharmaceutical preparations are prepared, in particular, in a solid, perorally administrable form. Particularly suitable for this purpose are powders, granules, pellets, tablets, film-coated tablets, capsules and dragees. The provision of pharmaceutical preparations is carried out according to the procedures and rules generally known to the pharmaceutical practitioner, whereby the selection of the technologies to be used and the pharmaceutical excipients used depends primarily on the drug to be processed and the desired absorption site. Here are questions of its chemical-physical properties, the chosen application form, the desired duration of action, the site of action and the avoidance of drug-excipient incompatibilities of particular importance. It is therefore up to the skilled person, using known material and process parameters in a trivial way to select drug form, excipients and manufacturing technology. The preparations according to the invention can be advantageously prepared on the basis of easily applicable technologies in a manner known per se. In the preparation of the pharmaceutical preparations, pentaerythrityltetra-, pentaerythrityltri-, pentaerythrityldi- or pentaerythritylmononitrate in a suitable excipient mixture in defined amounts, so that the finished pharmaceutical preparation contains 25 to 600 mg of the drug, are homogeneously distributed in a mixing system. The resulting powder mixtures can be at a sufficiently high pressure z. B. on a rotary tablet press into tablets. In general, pressures of up to 50 kN will be sufficient. Preference is given to 10 to 30 kN. Furthermore, the powder mixtures can be filled in a capsule filling and sealing machine in hard gelatine cachets or on a bag filling machine in sachets. In addition, it has proved to be useful to first compact, grind and homogenize the powder mixtures mentioned in a conventional manner, before they are then further processed into tablets, hard gelatin capsules or sachets. According to a further feature of the invention, after the introduction and the homogeneous distribution of the drug in excipient mixtures, the powders obtained are also advantageously granulated with binder solutions. The granules can subsequently be filled into capsules or sachets or pressed into tablets. In addition, the produced compacts can be coated in a suitable coating system with a shell, wherein the film tablets or dragees thus obtained in the outer layer also contain only excipients which have no retarding effect or unfold, as non-retarding in the context of the present invention non-enteric coatings to be viewed as. Among other things, the homogeneous distribution of the required amounts of the drug in an excipient mixture is sufficient for obtaining the desired therapeutic goal and for the realization of the task. In particular, the simple filling into capsules, bags, sachets, etc. or the further processing into granules or tablets ensures the range of application and variety of forms of the preparations according to the invention with good bioavailability.

A Another embodiment of the invention is that the respective Pharmaceutical form the total amount of the drug in a unit dose distributed inhomogeneous, especially in discrete subsets.

The pharmaceutical preparations according to the invention can continue to use the single drug, in combination with known cardiovascular therapeutics, for example ACE inhibitors, Antiatherosclerotics, antihypertensives, beta-blockers, cholesterol-lowering drugs, Diuretics, calcium antagonists, coronary dilators, lipid-lowering drugs, peripheral vasodilators, platelet aggregation inhibitors or others, also used as cardiovascular therapeutics substances, contained combined and fed to their clinical use become. Also the administration of the combination in spatially separate dosage forms is possible and is also in Scope of the invention. This includes antioxidants and or phosphodiesterase (PDE) inhibitors, but especially not only PDE-5-type inhibitor.

With The presented invention will thus be improved and considerably opened up extended therapeutic possibilities, in addition to hearing loss pathological situations such as heart and Vascular diseases, in particular coronary heart disease, Vascular stenoses and circulatory disorders peripheral arteries, hypertension, micro- and macroangiopathies in the context of diabetes mellitus, stress conditions in vessels and tissues such as atherosclerosis, as well as the resulting folic diseases erectile dysfunction, increased intraocular pressure, dysmenorrhea, dysfunctional uterine bleeding, dysfunctions of uterine contractility like premature onset of labor, menopausal symptoms or incontinence using the described pharmaceutical To treat preparations.

The The following examples are intended to illustrate the invention in terms of its Essence and its execution especially for oral Explain application forms in more detail, but without them to be limited in scope.

embodiments

example 1

In a suitable mixer is 160 g of pentaerythrityl tetranitrate (PETN), 300 g lactose, 80 g microcrystalline cellulose, 76 g corn starch, 20 g of talc, 20 g of silica and 4 g of magnesium stearate homogeneous mixed. The mix is at a bounce of 10-30 kN into tablets with a nominal mass of 600 mg pressed.

Example 2

350 g PETN, 1000 g lactose, 323 g microcrystalline cellulose and 273 g potato starch are in a fluidized bed granulator mixed, with 1050 ml of a 4% aqueous solution of starch granulated, then dried, sieved and with 60 g talc, 20 g of magnesium stearate and 32 g of silica homogeneous mixed. The granules are added on a rotary tablet press a bounce force of 10-30 kN to tablets with a target mass of 1050 mg pressed.

Example 3

In a suitable mixer is 900 g of lactose, 300 g of corn starch, 30 g silica and 300 g PETN to homogeneity mixed. The mixture is packed in Sachets (bag) with 1530 mg filling weight bottled.

Example 4

In a fluidized bed granulator is mixed with 450 g of PETN, 1350 g of lactose, 300 g of microcrystalline cellulose and 400 g of potato starch mixed. 36 g of gelatin and 18 g of sorbitol dissolved in 350 g of water, are sprayed onto the mixture. The resulting granules is dried and sieved. 80 g talc, 25 g magnesium stearate and 41 g of silica are added to the raw granules and until the Homogeneity mixed. Be on a rotary tablet press Compresses with a pressing force of 10-30 kN a target mass of 900 mg produced.

Example 5

In PETN and galenic auxiliaries are defined in a mixer Quantities mixed homogeneously. The mix is added to a tablet press Compressed processed.

Example 6

The Substances PETN and in defined amounts galenic excipients mixed to homogeneity in a mixer and then (A) filled in sachets and (B) in capsules.

Example 7

In A mixer becomes PETN and a defined amount more galenic Excipients mixed. This is followed by compaction. The compresses are combined with a screening machine to a uniform Homogenized particle size. The screenings will (A) filled in sachets and (B) in capsules.

Example 8

In A fluidized bed granulator is PETN and defined quantities mixed galenic adjuvants and then with a granulated aqueous binder solution. The dried granules are sieved and mixed with galenical flow-regulating, lubricating and lubricants mixed. On a tablet press are compressed prepared (A). The compressed products thus obtained are (B) in one Coating plant filmed.

Example 9

• a) der typische Nitratkopfschmerz, nicht zu beobachten sind ( Jähnchen et al., Pentaerythrityltetranitrat-Strukturchemische, zellbiologische und klinische Perspektiven, Dr. Dietrich Steinkopff Verlag, Darmstadt, 1997 );
• b) außerdem die unter PETN und in Dosen größer 80 mg ausbleibende Wirkabschwächung (Nitrattoleranz) nicht auftritt ( Schneider, Pentaerythrityltetranitrat-Beiträge zum klinischen und pharmakologischen Status, Dr. Dietrich Steinkopff Verlag, Darmstadt, 1995 ).

Clinical studies with dosages of PETN greater than 80 mg prove that the side effects otherwise associated with nitrates, in particular

• a) the typical nitrate headache can not be observed ( Jähnchen et al., Pentaerythrityl tetranitrate structural mixtures, cell biology and clinical perspectives. Dietrich Steinkopff Verlag, Darmstadt, 1997 );
• b) In addition, the effect attenuation (nitrate tolerance) absent under PETN and in doses greater than 80 mg does not occur ( Schneider, pentaerythrityl tetranitrate contributions to clinical and pharmacological status, dr. Dietrich Steinkopff Verlag, Darmstadt, 1995 ).

Regarding This therapy success criteria does not show up in the application Disadvantage compared to conventional dosage regimes.

In pending or planned extended multicenter, Randomized studies show the effectiveness of the invention Preparations against hearing loss or will this effectiveness still checked.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - US 2370437 [0010]
• DE 2221080A [0010]
• DE 2751934 A [0010]
• - DE 3028873A [0010]
• - DE 2903927 [0010]
• - DE 3102947 A [0010]
• - DE 3124410 A [0010]
• EP 045076 A1 [0010]
• EP 057847 A1 [0010]
• - EP 059664 A1 [0010]
• EP 064194 A1 [0010]
• EP 067964 A1 [0010]
• - EP 143507 A1 [0010]
• US 3886186 [0010]
• - US 4065488 [0010]
• US 4417065 [0010]
• US 4431829 [0010]
• FR 984523 [0010]
• - US 4200640 [0010]
• - EP 98961013 [0011]
• - DE 98/03030 [0011]

Cited non-patent literature

• - "The sudden deafness", Olaf Michel, Thieme 1994 [0003]
• Bruce L. Fetterman et al. Prognosis and Treatment of Sudden Sensorineural Hearing Loss, The American Journal of Otology, 17: 529-536, 1996 [0009]
• - Dt. Ges. F. Otorhinolaryngology, Head and Neck Surgery: Guidelines hearing loss. January 2004. AWMF Guidelines Register No. 017/010 [0009]
• - Dt. Ges. F. Otorhinolaryngology, Head and Neck Surgery: Guidelines hearing loss. January 2004. AWMF Guidelines Register No. 017/010 [0009]
• - Ogawa K, Takei S, Inoue Y, Kanzaki J. Effect of prostaglandin E1 on idiopathic sudden sensorineural hearing loss: a double-blinded clinical study. Otol Neurotol 2002; 23 (5): 665-668 [0009]
• - Michel O, Matthias R: Placebo-controlled double-blind study on acute hearing loss treatment with a stable prostacyclin analogue. Laryngorhinootologie. 1991 May; 70 (5): 255-259 [0009]
• - Linssen O, Schultz-Coulon HJ. Prognostic criteria for sudden hearing loss. ENT 1997; 45 (1): 22-29 [0009]
• - Suckfüll M. Current therapy for sudden hearing loss. Laryngeal Glandology 2005; 84 (4): 277-282 [0009]
• - Arellano B, Garcia B, Jr., Gorriz C, Gonzalez FM, Vicente J, Ramirez CR. Protocol de tratamiento de la sordera súbita. Acta Otorrinolaringol Esp 1997; 48 (7): 513-516 [0009]
• - Dt. Ges. F. Otorhinolaryngology, Head and Neck Surgery: Guidelines hearing loss. January 2004. AWMF Guidelines Register No. 017/010 [0009]
• - Wilson WR, Byl FM, Laird N. The efficacy of steroids in the treatment of idiopathic sudden hearing loss. A double-blind clinical study. Arch otolaryngol 1980; 106 (12): 772-776 [0009]
• - Murrel, Lancet: 80, 113, 151 (1879) [0010]
• - Risemann et al., Circulation, Vol. XVII, 22 (1958 [0010]
• - L. Goldberg, Acta Physiolog. Scand. 15, 173 (1948) [0010]
• - Médard, Mem. Poudres 35: 113 (1953) [0010]
• - Jähnchen et al., Pentaerythrityl tetranitrate structural mixtures, cell biology and clinical perspectives, Dietrich Steinkopff Verlag, Darmstadt, 1997 [0032]
• - Schneider, pentaerythrityl tetranitrate contributions to clinical and pharmacological status, dr. Dietrich Steinkopff Verlag, Darmstadt, 1995 [0032]

Claims (2)

Pharmaceutical preparations for preventing acute hearing loss, characterized in that they contain a) as medicament pentaerythrityltetra-, pentaerythrityltri-, pentaerythrityldi- or pentaerythritylmononitrate, b) in an amount of 25 to 600 mg and c) conventional galenic adjuvants. Pharmaceutical compositions according to claim 1 for Application in a method of therapeutic and protective Treatment of hearing loss.