EP1185246A1 - Pharmaceutical composition for intranasal use of active substances that are insoluble and/or hardly soluble in water - Google Patents

Pharmaceutical composition for intranasal use of active substances that are insoluble and/or hardly soluble in water

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Publication number
EP1185246A1
EP1185246A1 EP00938686A EP00938686A EP1185246A1 EP 1185246 A1 EP1185246 A1 EP 1185246A1 EP 00938686 A EP00938686 A EP 00938686A EP 00938686 A EP00938686 A EP 00938686A EP 1185246 A1 EP1185246 A1 EP 1185246A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
agents
use according
acid
nasal use
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00938686A
Other languages
German (de)
French (fr)
Inventor
Norbert KLÖCKER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Klocker Norbert Drmed
Original Assignee
Klocker Norbert Drmed
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE1999125290 external-priority patent/DE19925290A1/en
Priority claimed from DE1999136543 external-priority patent/DE19936543A1/en
Application filed by Klocker Norbert Drmed filed Critical Klocker Norbert Drmed
Publication of EP1185246A1 publication Critical patent/EP1185246A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

Definitions

  • the invention relates to a pharmaceutical composition for nasal use, consisting of at least one water-insoluble or sparingly water-soluble active ingredient and neutral oil, it being possible to dispense with the addition of preservatives and propellants.
  • blowing agents are representatives of the fluorine-chlorine hydrocarbons, or fluorine hydrocarbons.
  • the use of these blowing agents is to be avoided today for reasons of environmental protection, since they destroy the ozone layer. From an economic point of view, the use of blowing agents is an additional cost factor.
  • the pump and valve sprays available on the market, which do not require any propellants for application, and nose drops contain active ingredients in aqueous solution. The problem with these aqueous solutions is that sterile manufacture is expensive and difficult. Contamination after opening can hardly be prevented without the addition of a preservative.
  • Preservatives often have a high allergy potential, so allergy sufferers often cannot use these medicines.
  • all common and approved preservatives are cytotoxic and impair the ciliary function and thus the clearance.
  • the addition of preservatives also means that preservation stress tests must be carried out on the pharmaceutical composition in order to achieve a sufficient level To ensure conservation. These tests are lengthy, time-consuming and costly.
  • Aqueous solutions are also relatively problematic in terms of their stability.
  • the strong pH dependence of the nasal absorption of active substances from aqueous solutions represents a further problem.
  • the optimal environment for the cilia of the nasal mucosa is between 7 and 9. However, the maximum absorption takes place at a pH value ⁇ 6. A pH value of 4 leads to the destruction of the cilia.
  • active substances also have an acid instability, so that at the pH value for optimal absorption a large part of the active substance is subject to a change in the chemical structure.
  • This chemically modified active ingredient has no pharmacological activity, so that the bioavailability and the therapeutic activity are greatly reduced.
  • a nasal application of acid-labile active ingredients has thus far hardly been possible.
  • Another possibility for nasal application of active substances is to enclose the active substance in liposomes and to apply this liposome formulation into the nose by means of pump sprays and the like or with the aid of propellants. The preparation of these liposome formulations is complex. The stability is low since the enclosed active ingredient dissolves from these liposomes over time, so that the amount of active ingredient actually applied decreases.
  • sterility can hardly be maintained over a longer period without the addition of preservatives, since a not inconsiderable proportion of water is included in the liposomes. This water inclusion poses a great risk of contamination by bacteria, fungi and viruses. Uptake through the nasal mucosa is also more difficult, since the active ingredient must first be released from the liposome vesicles in order to pass through the mucous membrane. Due to the natural clearance apparatus of the nasal cavity, an active substance applied to the nasal mucosa is transported to the throat within 10 to 20 minutes, from where this active substance is either expectorated or swallowed. Adequate absorption is therefore not always guaranteed with the liposome formulation.
  • the object of the invention is to provide a pharmaceutical composition for nasal use of water-insoluble or poorly water-soluble active ingredients in the form of a solution, the use of propellants and preservatives being unnecessary.
  • the object is achieved according to the invention by a pharmaceutical composition which contains at least one water-insoluble or poorly soluble active ingredient dissolved in a neutral oil.
  • the composition is essentially anhydrous.
  • Essentially water-free is understood here to mean a water content in the composition which can result from water of hydration, water of crystallization and / or residual moisture in the neutral oil, the active ingredients and / or the auxiliaries.
  • the pharmaceutical composition according to the invention can be applied to the nasal mucosa without the addition of propellants by means of devices which can produce a precisely defined dosage.
  • the preferred devices include common pump and valve sprays and nasal drops.
  • the composition has good absorption, since the solution adheres well to the nasal mucosa, the neutral oil also causes the cells to spread, and the active ingredient is thus very easily absorbed from the solution by the nasal mucosa.
  • the problem of the pH in aqueous solutions with regard to optimal absorption does not arise with the composition according to the invention.
  • Maximum absorption can be achieved without destroying the cilia, restricting their function or causing a change in the chemical structure of the active ingredient.
  • the composition is easy to filter, so that sterile filtration (0.2 ⁇ m pore size) can be used to produce a sterile solution without great effort.
  • the stability is very high, since even in the event of subsequent contamination, it is not possible for human-pathogenic microorganisms such as bacteria, fungi and viruses to multiply and survive in the neutral oil. Due to this fact, no preservative has to be added.
  • Damage to the nasal mucosa and impairment of the ciliary function by preservatives can thus be prevented, especially with long-term treatment, and complex, lengthy preservation stress tests can be dispensed with.
  • the tolerance of the oil solution according to the invention on the nasal mucosa is very good, so that irritation of the mucous membrane caused by the active ingredient and / or the auxiliaries is minimized and patient compliance can thus be increased.
  • neutral oil means medium-chain triglycerides. These can be obtained by esterification of medium-chain fatty acids such as capronic, capric, caprylic, lauric, myristic, linoleic and succinic acid, in particular capric, caprylic, linoleic and succinic acid with glycerol and / or propylene glycol ( Miglyol 810, 812, 818, 840).
  • the viscosity of the neutral oils used is 1-40 mPa s, in particular 5-20 mPa s, a viscosity of 8-15 mPa s is preferred.
  • the preferred neutral oil according to the invention is Miglyol 840.
  • the pharmaceutical composition according to the invention can be water-insoluble or sparingly water-soluble corticoids, androgens, estrogens, progestogens, proton pump inhibitors, 5-HT, antagonists, sympatholytics / sympathomimetics, anticholinergics, tranquillizers / anxiolytics, weaning agents, analgesics, calcium antagonists, hypersensitants, antiemetic agents ; Antiparkinson agents, antihistamines, angiotensin II antagonists, lidocaine and / or nitroglycerin as possible active ingredient components.
  • the pharmaceutical composition according to the invention can be selected from the group of corticoids e.g. B. beclomethasone dipropionate, budesonide base, dexamethasone, hydrocortisone, flunisolide, prednisone, triamcinolone acetonide, methylprednisolone, fluticasone, betamethasone, deflazacort, cortisone, cortisone acetate, prednilyden, cloprednol or undodomolecidanoid or /, Active ingredient component included.
  • corticoids e.g. B. beclomethasone dipropionate, budesonide base, dexamethasone, hydrocortisone, flunisolide, prednisone, triamcinolone acetonide, methylprednisolone, fluticasone, betamethasone, deflazacort, cortisone, cortisone acetate, pred
  • the pharmaceutical composition according to the invention can be selected from the group of androgens e.g. Contain testosterone, testosterone undecanoate, androsterone and / or their derivatives as active ingredient.
  • androgens e.g. Contain testosterone, testosterone undecanoate, androsterone and / or their derivatives as active ingredient.
  • the pharmaceutical composition according to the invention can from the group of estrogens, for example, estradiol, estradiol benzoate, estradiol valerate, estradiol dipropionate, estrone, estriol, diethylstilbestrol, diethylstilbestrol dimethyl ether, diethylstilbestrol diphosphate, diethylstilbestrol dipropionate and / or their derivatives contain active ingredients and / or their derivatives.
  • the pharmaceutical composition according to the invention can contain progesterone and / or its derivatives from the group of progestogens as active ingredient.
  • the pharmaceutical composition according to the invention can be selected from the group of proton pump inhibitors e.g. Omeprazole, esomeprazole, lansoprazole, leminoprazole, pantoprazole, rabeprazole, polaprezinc and / or their derivatives, in particular omeprazole as an active ingredient component.
  • proton pump inhibitors e.g. Omeprazole, esomeprazole, lansoprazole, leminoprazole, pantoprazole, rabeprazole, polaprezinc and / or their derivatives, in particular omeprazole as an active ingredient component.
  • the pharmaceutical composition according to the invention can contain from the group of 5-HT r antagonists, for example sumatriptan, rizatriptan, almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, zolmitriptan and / or their derivatives as active ingredient components.
  • 5-HT r antagonists for example sumatriptan, rizatriptan, almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, zolmitriptan and / or their derivatives as active ingredient components.
  • the pharmaceutical composition according to the invention can be selected from the group of sympatholytics / sympathomimetics e.g. Acebutolol, Adimolol, Adrenalin, Albuterol, Micholol, Amosulalol, Arotinolol, Atenolol, Bambuterol, Betaxolol, Bevantolol, Bisoprolol, Bitolterol, Bopindolol, Broxaterol, Bucindolol, Bucumolol, Bufuralol, Buprolololol, Buprololololol, Bofilrololololol, Buprolololol, Bofilrololololol, Buprolololol, Bofilrolololol Celiprolol, Cetamolol, Cicloprolol, Clenbuterol, Cloranolol,
  • the pharmaceutical composition according to the invention can contain from the group of anticholinergics, for example ipratropium, oxitropium, atropine, scopolamine base and / or their derivatives, in particular scopolamine base, as the active ingredient.
  • anticholinergics for example ipratropium, oxitropium, atropine, scopolamine base and / or their derivatives, in particular scopolamine base, as the active ingredient.
  • the pharmaceutical composition according to the invention can be selected from the group of
  • Tranquillizers / anxiolytics e.g. Alprazolam, bentazepam, bromazepam, camazepam,
  • Clorazepate clonazepam, clotiazepam, diazepam, etiracetam, etiolam, fludiazepam,
  • Flunitrazepam flurazepam, flutazolam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, metaclazapam, mexazolam,
  • the pharmaceutical composition according to the invention can be selected from the group of weaning agents e.g. Lobelin and or its derivatives contain as active ingredient.
  • the pharmaceutical composition according to the invention can be selected from the group of analgesics e.g. Acetylsalicylic acid, ibuprofen, ketoprofen, alminoprofen, Bermoprofen, carprofen, dexibuprofen, dexketoprofen, fenoprofen, flobufen, flunoxaprofen, flurbiprofen, loxoprofen, Pelobiprofen, pranoprofen, pentazocine, Tilnoprofen, Ximoprofen, Zaltroprofen, dextropropoxyphene, phenylbutazone, mofebutazone, diclofenac, Aceclofenac, amfenac, Bromfenac, Clidanac, Etodolac, Felbinac, Fentiazac, Lonazolac, Mofezolac, Oxindanac, Tifurac, Indomethacin,
  • the pharmaceutical composition according to the invention can be selected from the group of calcium antagonists e.g. Amlodipine, Arandipine, Azelmidipine, Bamidipine, Benidipine,, Cilnidipine, Efonidipine, Felodipine, Flordipine, Iganidipine, Isradipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilvadipinidine, Nidvadipinidine, Nidvadipinidine, and / or contain their derivatives as active ingredient.
  • calcium antagonists e.g. Amlodipine, Arandipine, Azelmidipine, Bamidipine, Benidipine,, Cilnidipine, Efonidipine, Felodipine, Flordipine, Iganidipine, Isradipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilva
  • the pharmaceutical composition according to the invention can be selected from the group of antiemetics, for example alizapride, azasetron, batanopride, clebopride, dazopride, dolasetron, domperidone, granisetron, itasetron, levosulpiride, metoclopramide, nabilone, ondansetron, Contain pancoprid, ramosetron, tropisetron, zatosetron and / or their derivatives as active ingredient.
  • antiemetics for example alizapride, azasetron, batanopride, clebopride, dazopride, dolasetron, domperidone, granisetron, itasetron, levosulpiride, metoclopramide, nabilone, ondansetron, Contain pancoprid, ramosetron, tropisetron, zatosetron and / or their derivatives as active ingredient
  • the pharmaceutical composition according to the invention can be selected from the group of the pituitary / hypothalamic hormones e.g. Contain tetracosactide, desmopressin, nafarelin, leuprorelin, buserelin, deslorelin, goserelin, triptorelin and / or their derivatives as active ingredient.
  • the pituitary / hypothalamic hormones e.g. Contain tetracosactide, desmopressin, nafarelin, leuprorelin, buserelin, deslorelin, goserelin, triptorelin and / or their derivatives as active ingredient.
  • the pharmaceutical composition according to the invention can be selected from the group of anti-Parkinson agents e.g. Aptiganel, Budipin, Cabergolin, Droxidopa, Etacapon, Idazoxan, Lazabemid, Milacemid, Mofegilin, Pergolid, Pramipexol, Quineloran, Rasagelin, Remacemid, Ropinorol, Selegilin, Talipexol, Tolcapon and / or contain derivatives as active ingredient.
  • anti-Parkinson agents e.g. Aptiganel, Budipin, Cabergolin, Droxidopa, Etacapon, Idazoxan, Lazabemid, Milacemid, Mofegilin, Pergolid, Pramipexol, Quineloran, Rasagelin, Remacemid, Ropinorol, Selegilin, Talipexol, Tolcapon and / or contain derivatives as active ingredient.
  • the pharmaceutical composition according to the invention can be selected from the group of antihistamines e.g. Acrivastine, asremizole, desloratadine, ebestin, emedastine, epinastine, fexofenadine, levocabastine, loratadine, mequitazine, misoprostol, mizolastine, nafamostat, norastemizole, olopatidine, oxatomide, rupatadine, tazifylxidine, faminastinidine, teminate Contain roxatidine and / or their derivatives as active ingredient.
  • antihistamines e.g. Acrivastine, asremizole, desloratadine, ebestin, emedastine, epinastine, fexofenadine, levocabastine, loratadine, mequitazine, mis
  • the pharmaceutical composition according to the invention can be selected from the group of angiotensin II antagonists e.g. Contain candesartan, candesartan-cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, valsartan and / or their derivatives as active ingredient.
  • angiotensin II antagonists e.g. Contain candesartan, candesartan-cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, valsartan and / or their derivatives as active ingredient.
  • the pharmaceutical composition according to the invention can have an active substance content of 0.01-15% by weight, in particular 0.08-5% by weight, preferably 0.1, 0.2, 0.5 and 1% by weight.
  • the percentages relate to the total amount of the pharmaceutical composition.
  • the pharmaceutical composition according to the invention can optionally also contain antioxidants such as, for example, ⁇ -tocopherol, ⁇ -tocopherol esters, ascorbic acid, ascorbic acid esters (myristate, palmitate and stearate), ß-carotene, cysteine, acetylcysteine, folic acid (vitamin B 2 group), phytic acid, ice and / or trans-urocanoic acid, carnosine (N-ß-alanine-L- Histidine), histidine, flavones, flavonoids, lycopene, tyrosine, glutation, glutation ester, -liponic acid, ubiquinone, nordihydroguaiaretic acid (NDGA), gallic acid ester (ethyl, propyl, octyl, dodecyl gallate), phosphoric acid derivatives (monophate phosphate), polyphosphol BHT), butylated hydroxyanisole (BHA
  • the content of the optionally added antioxidants can be 0.001-1% by weight, based on the total amount of the pharmaceutical composition.
  • the pharmaceutical composition according to the invention can optionally also provide solubilizers such as e.g. Contain lysophosphatidylcholine, lysophosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol (ol) e and / or spingophospholipids.
  • solubilizers such as e.g. Contain lysophosphatidylcholine, lysophosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol (ol) e and / or spingophospholipids.
  • composition according to the invention may optionally also contain detergents (surfactants) such as e.g. Genapol®, sodium dodecyl sulfate,,
  • Sorbitan trioleate Sorbitan trioleate, sorbitan tristearate, sorbitan monolaurate, polysorbate 20, polysorbate 60,
  • the detergents can prevent, among other things, any adsorption compound of the active ingredient from occurring with the wall of the container (deposit).
  • the administered drug concentration can thus be kept constant and easy transport can be guaranteed.
  • the pharmaceutical composition according to the invention may optionally also contain absorption enhancers such as, for example, dimethyl- ⁇ -cyclodextrin, permethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, randomized methylated ⁇ -cyclodextrin, carboxymethyl- ⁇ -cyclodextrin, maltosyl- ⁇ -cycodextrin, ⁇ -cyclodextrin, Contain sodium taurofusidate, sodium glycocholate, Laureth-9 and / or ⁇ -lecithin.
  • absorption enhancers such as, for example, dimethyl- ⁇ -cyclodextrin, permethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, randomized methylated ⁇ -cyclodextrin, carboxymethyl- ⁇ -cyclodextrin, maltosyl- ⁇ -cycodextrin, ⁇ -cyclodextrin, Conta
  • scopolamine a scopolamine dissolved in 100 ml of Miglyol 840.
  • This oil solution is sterile filtered through a 0.2 ⁇ m Pall Fluorodyne II grade DFL pharmaceutical grade filter and filled into a pump spray (S4 pump) with a dose volume of 100 or 50 ⁇ l.
  • the active substance concentration is 36.4 ⁇ g scopolamine (0.00692%) with a 50 ⁇ l spray and 69.2 ⁇ g scopolamine with a 100 ⁇ l spray. This dosage is particularly suitable for pediatric use.
  • scopolamine 138.4 mg scopolamine are dissolved in 100 ml Miglyol 840.
  • This oil solution is sterile filtered through a 0.2 ⁇ m Pall Fluorodyne II grade DFL pharmaceutical grade filter and filled into a pump spray (S4 pump) with a dose volume of 100 or 50 ⁇ l.
  • the active substance concentration is 72.8 ⁇ g scopolamine with a 50 ⁇ l spray and 138.4 ⁇ g scopolamine with a 100 ⁇ l spray. This dosage is suitable for use in adults.
  • budenoside 71.42 mg budenoside are dissolved in 100 ml Miglyol 840.
  • This oil solution is sterile filtered through a 0.2 ⁇ m Pall Fluorodyne II grade DFL pharmaceutical grade filter and filled into a pump spray (3K pump; filling volume: 14 ml) with a dose volume of 140 ⁇ l.
  • the active substance concentration is 100 ⁇ g budenoside with a 140 ⁇ l spray.
  • Example 4 Example 4:

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Abstract

The invention relates to a pharmaceutical composition for the intranasal use. Said composition consists of at least one active substance dissolved in neutral oil which is insoluble or hardly soluble in water. The inventive pharmaceutical composition can be applied on the nasal mucosa by means of devices that provide an exactly defined dose and requires no propellants and preservatives.

Description

PHARMAZEUTISCHE ZUSAMMENSETZUNG ZUR NASALEN ANWENDUNG VON WASSERUNLÖSLICHEN UND/ODER SCHWER WASSERLÖSLICHEN WIRKSTOFFEN PHARMACEUTICAL COMPOSITION FOR THE NASAL USE OF WATER-INSOLUBLE AND / OR HEAVY WATER-SOLUBLE ACTIVE SUBSTANCES
Die Erfindung betrifft eine pharmazeutische Zusammensetzung zur nasalen Anwendung, bestehend aus mindestens einem wasserunlöslichen oder schwer wasserlöslichen Wirkstoff und Neutralöl, wobei auf einen Zusatz von Konservierungs- und Treibmitteln verzichtet werden kann.The invention relates to a pharmaceutical composition for nasal use, consisting of at least one water-insoluble or sparingly water-soluble active ingredient and neutral oil, it being possible to dispense with the addition of preservatives and propellants.
Die bisher zur nasalen Anwendung von Wirkstoffen verwendeten pharmazeutischen Zusammensetzungen benötigen häufig Treibmittel, um eine entsprechende Applikation zu gewährleisten. Übliche Treibmittel sind Vertreter der Fluor-Chlor-Kohlenwasserstoffe, oder Fluor-Kohlenwasserstoffe. Die Verwendung von diesen Treibmitteln ist in der heutigen Zeit aus Gründen des Umweltschutzes zu vermeiden, da sie die Ozonschicht zerstören. Zudem ist aus wirtschaftlicher Sicht die Verwendung von Treibmitteln ein zusätzlicher Kostenfaktor. Die auf dem Markt erhältlichen Pump- und Ventilsprays, welche keine Treibmittel zur Applikation benötigen, sowie Nasentropfen beinhalten Wirkstoffe in wäßriger Lösung. Das Problem dieser wäßrigen Lösungen ist, daß eine sterile Herstellung kostenintensiv und schwierig ist. Eine Kontamination nach dem Öffnen kann kaum verhindert werden, ohne daß ein Konservierungsmittel zugesetzt wird. Mit Konservierungsmitteln ist häufig ein hohes Allergiepotential verbunden, so daß Allergiker oft diese Arzneimittel nicht verwenden können. Zudem sind alle gebräuchlichen und zugelassenen Konservierungsmittel zytotoxisch und beeinträchtigen die Ziliarfunktion und damit die Clearance. Der Zusatz von Konservierungsmitteln hat außerdem zur Folge, daß Konservierungsbelastungstests mit der pharmazeutischen Zusammensetzung durchgeführt werden müssen, um eine ausreichende Konservierung zu gewährleisten. Diese Tests sind langwierig, aufwendig und kostenintensiv. Wäßrige Lösungen sind außerdem hinsichtlich ihrer Stabilität relativ problematisch. Die starke pH- Wert-Abhängigkeit der nasalen Resorption von Wirkstoffen aus wäßrigen Lösungen stellt ein weiteres Problem dar. Das optimale Milieu für die Zilien der Nasenschleimhaut liegt bei einem pH- Wert zwischen 7 und 9. Allerdings erfolgt die maximale Resorption bei einem pH- Wert < 6. Ein pH- Wert von 4 fuhrt zur Zerstörung der Zilien. Auch weisen viele Wirkstoffe eine Säurelabilität auf, so daß bei dem pH- Wert für eine optimale Resorption ein Großteil des Wirkstoffes einer Veränderung der chemischen Struktur unterliegt. Dieser chemisch veränderte Wirkstoff weist keine pharmakologische Wirksamkeit auf, so daß die Bioverfügbarkeit und die therapeutische Wirksamkeit stark reduziert wird. Eine nasale Anwendung von säurelabilen Wirkstoffen ist somit bisher kaum möglich. Eine weitere Möglichkeit zur nasalen Applikation von Wirkstoffen besteht darin, den Wirkstoff in Liposomen einzuschließen und diese Liposomenformulierung mittels Pumpsprays und dergleichen oder mit Hilfe von Treibmitteln in die Nase zu applizieren. Die Herstellung dieser Liposomenformulierungen ist aufwendig. Die Stabilität ist gering, da der eingeschlossene Wirkstoff sich im Laufe der Zeit aus diesen Liposomen herauslöst, so daß die tatsächlich applizierte Wirkstoffmenge sinkt. Die Sterilität kann genauso wie bei wäßrigen Lösungen kaum über einen längeren Zeitraum ohne Zusatz von Konservierungsmitteln aufrecht erhalten werden, da in den Liposomen ein nicht unerheblicher Anteil an Wasser eingeschlossen ist. Durch diesen Wassereinschluß besteht eine große Kontaminationsgefahr durch Bakterien, Pilze und Viren. Die Aufnahme über die Nasenschleimhaut ist zudem erschwert, da der Wirkstoff erst aus den Liposomenvesikeln freigesetzt werden muß, um durch die Schleimhaut zu gelangen. Aufgrund des natürlichen Clearance-Apparates der Nasenhaupthöhle wird ein auf die Nasenschleimhaut applizierter Wirkstoff innerhalb von 10 bis 20 Minuten rachenwärts transportiert, von wo aus dieser Wirkstoff dann entweder expektoriert oder geschluckt wird. Eine ausreichende Resorption ist also bei der Liposomenformulierung nicht immer gewährleistet.The pharmaceutical compositions hitherto used for the nasal application of active ingredients frequently require propellants in order to ensure appropriate application. Usual blowing agents are representatives of the fluorine-chlorine hydrocarbons, or fluorine hydrocarbons. The use of these blowing agents is to be avoided today for reasons of environmental protection, since they destroy the ozone layer. From an economic point of view, the use of blowing agents is an additional cost factor. The pump and valve sprays available on the market, which do not require any propellants for application, and nose drops contain active ingredients in aqueous solution. The problem with these aqueous solutions is that sterile manufacture is expensive and difficult. Contamination after opening can hardly be prevented without the addition of a preservative. Preservatives often have a high allergy potential, so allergy sufferers often cannot use these medicines. In addition, all common and approved preservatives are cytotoxic and impair the ciliary function and thus the clearance. The addition of preservatives also means that preservation stress tests must be carried out on the pharmaceutical composition in order to achieve a sufficient level To ensure conservation. These tests are lengthy, time-consuming and costly. Aqueous solutions are also relatively problematic in terms of their stability. The strong pH dependence of the nasal absorption of active substances from aqueous solutions represents a further problem. The optimal environment for the cilia of the nasal mucosa is between 7 and 9. However, the maximum absorption takes place at a pH value <6. A pH value of 4 leads to the destruction of the cilia. Many active substances also have an acid instability, so that at the pH value for optimal absorption a large part of the active substance is subject to a change in the chemical structure. This chemically modified active ingredient has no pharmacological activity, so that the bioavailability and the therapeutic activity are greatly reduced. A nasal application of acid-labile active ingredients has thus far hardly been possible. Another possibility for nasal application of active substances is to enclose the active substance in liposomes and to apply this liposome formulation into the nose by means of pump sprays and the like or with the aid of propellants. The preparation of these liposome formulations is complex. The stability is low since the enclosed active ingredient dissolves from these liposomes over time, so that the amount of active ingredient actually applied decreases. As with aqueous solutions, sterility can hardly be maintained over a longer period without the addition of preservatives, since a not inconsiderable proportion of water is included in the liposomes. This water inclusion poses a great risk of contamination by bacteria, fungi and viruses. Uptake through the nasal mucosa is also more difficult, since the active ingredient must first be released from the liposome vesicles in order to pass through the mucous membrane. Due to the natural clearance apparatus of the nasal cavity, an active substance applied to the nasal mucosa is transported to the throat within 10 to 20 minutes, from where this active substance is either expectorated or swallowed. Adequate absorption is therefore not always guaranteed with the liposome formulation.
Die Aufgabe der Erfindung ist es nun, eine pharmazeutische Zusammensetzung zur nasalen Anwendung von wasserunlöslichen oder in Wasser schlecht löslichen Wirkstoffen in Form einer Lösung bereitzustellen, wobei auf die Verwendung von Treibmitteln und Konservierungsmitteln verzichtet werden kann. Die Aufgabe wird erfindungsgemäß durch eine pharmazeutische Zusammensetzung gelöst, die mindestens einen wasserunlöslichen oder schwer löslichen Wirkstoff gelöst in einem Neutralöl enthält. Die Zusammensetzung ist im wesentlichen wasserfrei.The object of the invention is to provide a pharmaceutical composition for nasal use of water-insoluble or poorly water-soluble active ingredients in the form of a solution, the use of propellants and preservatives being unnecessary. The object is achieved according to the invention by a pharmaceutical composition which contains at least one water-insoluble or poorly soluble active ingredient dissolved in a neutral oil. The composition is essentially anhydrous.
Als im wesentlichen wasserfrei wird hier ein Wassergehalt in der Zusammensetzung verstanden, der durch Hydratwasser, Kristallwasser und/ oder Restfeuchtigkeit des Neutralöls, der Wirkstoffe und/ oder der Hilfsstoffe herrühren kann.Essentially water-free is understood here to mean a water content in the composition which can result from water of hydration, water of crystallization and / or residual moisture in the neutral oil, the active ingredients and / or the auxiliaries.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann ohne Zusatz von Treibmitteln mittels Vorrichtungen, die eine genau definierte Dosierung erzeugen können, auf die Nasenschleimhaut appliziert werden. Die bevorzugten Vorrichtungen umfassen gebräuchliche Pump- und Ventilsprays sowie Nasentropfen.The pharmaceutical composition according to the invention can be applied to the nasal mucosa without the addition of propellants by means of devices which can produce a precisely defined dosage. The preferred devices include common pump and valve sprays and nasal drops.
Die Zusammensetzung weist eine gute Resorption auf, da die Lösung gut auf der Nasenschleimhaut haftet, zudem durch das Neutralöl eine Zellspreizung erfolgt und der Wirkstoff somit sehr leicht aus der Lösung von der Nasenschleimhaut resorbiert wird.The composition has good absorption, since the solution adheres well to the nasal mucosa, the neutral oil also causes the cells to spread, and the active ingredient is thus very easily absorbed from the solution by the nasal mucosa.
Das Problem des pH- Wertes in wäßrigen Lösungen bezüglich der optimalen Resorption ergibt sich bei der erfindungsgemäßen Zusammensetzung nicht. Ohne die Zilien zu zerstören, ihre Funktion einzuschränken oder eine Veränderung der chemischen Struktur des Wirkstoffes zu verursachen kann eine maximale Resorption erreicht werden. Die Zusammensetzung ist gut filtrierbar, so daß durch eine Sterilfiltration (0,2 μm Porengröße) ohne großen Aufwand eine sterile Lösung hergestellt werden kann. Die Stabilität ist sehr hoch, da selbst bei einer späteren Kontamination eine Vermehrung und ein Überleben von humanpathogenen Mikroorganismen wie Bakterien, Pilze und Viren in dem Neutralöl nicht möglich ist. Aufgrund dieser Tatsache ist kein Zusatz eines Konservierungsmittels nötig. Die Schädigung der Nasenschleimhaut und eine Beeinträchtigung der Ziliarfunktion durch Konservierungsmittel kann somit vor allem bei einer Langzeitbehandlung verhindert und auf aufwendige, langwierige Konservierungsbelastungstests verzichtet werden. Zudem ist die Verträglichkeit der erfindungsgemäßen Öllösung auf der Nasenschleimhaut sehr gut, so daß Reizungen der Schleimhaut, hervorgerufen durch den Wirkstoff und/oder die Hilfsstoffe, minimiert und somit die Patientencompliance erhöht werden kann.The problem of the pH in aqueous solutions with regard to optimal absorption does not arise with the composition according to the invention. Maximum absorption can be achieved without destroying the cilia, restricting their function or causing a change in the chemical structure of the active ingredient. The composition is easy to filter, so that sterile filtration (0.2 μm pore size) can be used to produce a sterile solution without great effort. The stability is very high, since even in the event of subsequent contamination, it is not possible for human-pathogenic microorganisms such as bacteria, fungi and viruses to multiply and survive in the neutral oil. Due to this fact, no preservative has to be added. Damage to the nasal mucosa and impairment of the ciliary function by preservatives can thus be prevented, especially with long-term treatment, and complex, lengthy preservation stress tests can be dispensed with. In addition, the tolerance of the oil solution according to the invention on the nasal mucosa is very good, so that irritation of the mucous membrane caused by the active ingredient and / or the auxiliaries is minimized and patient compliance can thus be increased.
Die Herstellung ist einfach und kostengünstig, da keine weiteren Zusätze nötig sind und das Neutralöl als Träger billig ist. Unter dem Begriff Neutralöl werden mittelkettige Triglyceride verstanden. Diese können durch eine Veresterung von mittelkettige Fettsäuren wie z.B. Capron-, Caprin-, Capryl-, Laurin-, Myristin-, Linol- und Bernsteinsäure, insbesondere Caprin-, Capryl-, Linol- und Bernsteinsäure mit Glycerin und/ oder Propylenglykol erhalten werden (Miglyol 810, 812, 818, 840).The production is simple and inexpensive, since no further additives are necessary and the neutral oil as a carrier is cheap. The term neutral oil means medium-chain triglycerides. These can be obtained by esterification of medium-chain fatty acids such as capronic, capric, caprylic, lauric, myristic, linoleic and succinic acid, in particular capric, caprylic, linoleic and succinic acid with glycerol and / or propylene glycol ( Miglyol 810, 812, 818, 840).
Die Viskosität der verwendeten Neutralöle beträgt 1-40 mPa s, insbesondere 5-20 mPa s, bevorzugt wird eine Viskosität von 8-15 mPa s.The viscosity of the neutral oils used is 1-40 mPa s, in particular 5-20 mPa s, a viscosity of 8-15 mPa s is preferred.
Das bevorzugt verwendete erfindungsgemäße Neutralöl ist Miglyol 840.The preferred neutral oil according to the invention is Miglyol 840.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann wasserunlösliche oder schwer wasserlösliche Corticoide, Androgene, Östrogene, Gestagene, Protonenpumpenhemmer, 5-HT,-Antagonisten, Sympatholytika/ Sympathomimetika, Anticholinergika, Tranquillantio/Anxiolytika, Entwöhnungsmittel, Analgetika, Calcium- Antagonisten, Antiemetika, Hypophysen-/Hypothalamushormone; Antiparkinsonmittel, Antihistaminika, Angiotensin-II-Antagonisten, Lidocain und/oder Nitroglycerin als mögliche Wirkstoffkomponenten enthalten.The pharmaceutical composition according to the invention can be water-insoluble or sparingly water-soluble corticoids, androgens, estrogens, progestogens, proton pump inhibitors, 5-HT, antagonists, sympatholytics / sympathomimetics, anticholinergics, tranquillizers / anxiolytics, weaning agents, analgesics, calcium antagonists, hypersensitants, antiemetic agents ; Antiparkinson agents, antihistamines, angiotensin II antagonists, lidocaine and / or nitroglycerin as possible active ingredient components.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Corticoide z. B. Beclomethasondipropionat, Budesonidbase, Dexamethason, Hydrocortison, Flunisolid, Prednison, Triamcinolonacetonid, Methylprednisolon, Fluticason, Betamethason, Deflazacort, Cortison, Cortisonacetat, Prednilyden, Cloprednol, Fluocortolon-21-hexanoat und/ oder deren Derivate, insbesondere Beclomethasondipropionat und/ oder Budesonidbase als Wirkstoffkomponente enthalten.The pharmaceutical composition according to the invention can be selected from the group of corticoids e.g. B. beclomethasone dipropionate, budesonide base, dexamethasone, hydrocortisone, flunisolide, prednisone, triamcinolone acetonide, methylprednisolone, fluticasone, betamethasone, deflazacort, cortisone, cortisone acetate, prednilyden, cloprednol or undodomolecidanoid or /, Active ingredient component included.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Androgene z.B. Testosteron, Testosteronundecanoat, Androsteron und/ oder deren Derivate als Wirkstoffkomponente enthalten.The pharmaceutical composition according to the invention can be selected from the group of androgens e.g. Contain testosterone, testosterone undecanoate, androsterone and / or their derivatives as active ingredient.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Östrogene z.B. Estradiol, Estradiolbenzoat, Estradiolvalerat, Estradioldipropionat, Estron, Estriol, Diethylstilbestrol, Diethylstilbestroldimethylether, Diethylstilbestroldiphosphat, Diethylstilbestroldipropionat und/ oder deren Derivate als Wirkstoffkomponente enthalten. Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Gestagene z.B. Progesteron und/ oder dessen Derivate als Wirkstoffkomponente enthalten.The pharmaceutical composition according to the invention can from the group of estrogens, for example, estradiol, estradiol benzoate, estradiol valerate, estradiol dipropionate, estrone, estriol, diethylstilbestrol, diethylstilbestrol dimethyl ether, diethylstilbestrol diphosphate, diethylstilbestrol dipropionate and / or their derivatives contain active ingredients and / or their derivatives. The pharmaceutical composition according to the invention can contain progesterone and / or its derivatives from the group of progestogens as active ingredient.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Protonenpumpenhemmer z.B. Omeprazol, Esomeprazol, Lansoprazol, Leminoprazol, Pantoprazol, Rabeprazol, Polaprezinc und/ oder deren Derivate, insbesondere Omeprazol als Wirkstoffkomponente enthalten.The pharmaceutical composition according to the invention can be selected from the group of proton pump inhibitors e.g. Omeprazole, esomeprazole, lansoprazole, leminoprazole, pantoprazole, rabeprazole, polaprezinc and / or their derivatives, in particular omeprazole as an active ingredient component.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der 5-HTr Antagonisten z.B. Sumatriptan, Rizatriptan, Almotriptan, Avitriptan, Eletriptan, Frovatriptan, Naratriptan, Zolmitriptan und/ oder deren Derivate als Wirkstoffkomponente enthalten.The pharmaceutical composition according to the invention can contain from the group of 5-HT r antagonists, for example sumatriptan, rizatriptan, almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, zolmitriptan and / or their derivatives as active ingredient components.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Sympatholytika/ Sympathomimetika z.B. Acebutolol, Adimolol, Adrenalin, Albuterol, Alpenolol, Amosulalol, Arotinolol, Atenolol, Bambuterol, Betaxolol, Bevantolol, Bisoprolol, Bitolterol, Bopindolol, Broxaterol, Bucindolol, Bucumolol, Bufuralol, Bunitrolol, Bupranolol, Butofilolol, Carazolol, Carbuterol, Carteolol, Carvedilol, Celiprolol, Cetamolol, Cicloprolol, Clenbuterol, Cloranolol, Crateolol, Celiprolol, Dihydroergotamin, Dihydroergotamintartrat, Dihydroergotaminmesylat, Dilevalol, Dopamin, Dobutamin, Etilefrin, Epanolol, Esatenolol, Esmolol, Fenetyllin, Fenoterol, Formoterol, Ibuterol, Isoprenalin, Labetalol, Landiolol, Levobetaxolol, Levobunolol, Levosalbutamol, Mabuterol, Mepindolol, Metipranolol, Metoprolol, Morazon, Nadolol, Nebivolol, Nipradilol, Norfenefrin, Noradrenalin, Oxprenolol, Penbutolol, Picumeterol, Pimolol, Pindolol, Pirbuterol, Phenmetrazin Phenylephedrin, Phentolamin, Phenoxybenzamin, Prazosin, Procaterol, Propanolol, Rimiterol, Reproterol, Salbutamol, Salmeterol, Sotalol, Sulfonterol, Terbutalin, Tertatolol, Tienoxolol, Tilisolol, Timolol, Toliprolol, Tolubuterol, und/ oder deren Derivate als Wirkstoffkomponente enthalten.The pharmaceutical composition according to the invention can be selected from the group of sympatholytics / sympathomimetics e.g. Acebutolol, Adimolol, Adrenalin, Albuterol, Alpenolol, Amosulalol, Arotinolol, Atenolol, Bambuterol, Betaxolol, Bevantolol, Bisoprolol, Bitolterol, Bopindolol, Broxaterol, Bucindolol, Bucumolol, Bufuralol, Buprololololol, Buprololololol, Bofilrololololol, Buprololololol, Bofilrolololol Celiprolol, Cetamolol, Cicloprolol, Clenbuterol, Cloranolol, Crateolol, Celiprolol, Dihydroergotamine, Dihydroergotamine Tartrate, Dihydroergotamine Mesylate, Dilevalol, Dopamine, Dobutamine, Etilefrin, Epanolol, Esatenolol, Fenololol, Esolololol, Esmolololrenololol, Esololololrenolololololololol, Esmolololrenolol, Esolololrenolol, Esolololol, Esolololol, Esmolololrenolololololololololololololololol levobunolol, levosalbutamol, mabuterol, mepindolol, metipranolol, metoprolol, morazone, nadolol, nebivolol, nipradilol, norfenefrine, norepinephrine, oxprenolol, penbutolol, picumeterol, Pimolol, pindolol, pirbuterol, phenmetrazine phenylephrine, phentolamine, phenoxybenzamine, prazosin, procaterol, propanolol, rimiterol , Reproterol, salbutamol, salmeterol, sotalol, sulfonterol, terbutaline, ter tatolol, tienoxolol, tilisolol, timolol, toliprolol, tolubuterol, and / or their derivatives as active ingredient components.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Anticholinergika z.B. Ipratropium, Oxitropium, Atropin, Scopolaminbase und/ oder deren Derivate, insbesondere Scopolaminbase als Wirkstoffkomponente enthalten. Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe derThe pharmaceutical composition according to the invention can contain from the group of anticholinergics, for example ipratropium, oxitropium, atropine, scopolamine base and / or their derivatives, in particular scopolamine base, as the active ingredient. The pharmaceutical composition according to the invention can be selected from the group of
Tranquillantio/Anxiolytika z.B. Alprazolam, Bentazepam, Bromazepam, Camazepam,Tranquillizers / anxiolytics e.g. Alprazolam, bentazepam, bromazepam, camazepam,
Clorazepat, Clonazepam, Clotiazepam, Diazepam, Etiracetam, Etiolam, Fludiazepam,Clorazepate, clonazepam, clotiazepam, diazepam, etiracetam, etiolam, fludiazepam,
Flunitrazepam, Flurazepam, Flutazolam, Flutoprazepam, Halazepam, Ketazolam, Loprazolam, Lorazepam, Lormetazepam, Medazepam, Metaclazapam, Mexazolam,Flunitrazepam, flurazepam, flutazolam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, metaclazapam, mexazolam,
Midazolam, Nitrazepam, Norazepam, Oxazepam, Oxazolam, Prazepam, Temazepam, Triazolam und/ oder deren Derivate als Wirkstoffkomponente enthalten.Contain midazolam, nitrazepam, norazepam, oxazepam, oxazolam, prazepam, temazepam, triazolam and / or their derivatives as active ingredient.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Entwöhnungsmittel z.B. Lobelin und oder dessen Derivate als Wirkstoffkomponente enthalten.The pharmaceutical composition according to the invention can be selected from the group of weaning agents e.g. Lobelin and or its derivatives contain as active ingredient.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Analgetika z.B. Acetylsalicylsäure, Ibuprofen, Ketoprofen, Alminoprofen, Bermoprofen, Carprofen, Dexibuprofen, Dexketoprofen, Fenoprofen, Flobufen, Flunoxaprofen, Flurbiprofen, Loxoprofen, Pelobiprofen, Pranoprofen, Pentazocin, Tilnoprofen, Ximoprofen, Zaltroprofen, Dextropropoxyphen, Phenylbutazon, Mofebutazon, Diclofenac, Aceclofenac, Amfenac, Bromfenac, Clidanac, Etodolac, Felbinac, Fentiazac, Lonazolac, Mofezolac, Oxindanac, Tifurac, Indomethacin, Acemetacin, Piroxicam, Ampiroxicam, Meloxicam, Isoxicam, Lornoxicam, Tenoxicam, Butorphanol Buprenorphin, Morphin, Hydromorphon, Dihydrocodein, Oxycodon, Piritramid, Pethidin, Pentazocin, Levomethadon, Tramadol, Fentanyl und/ oder dessen Derivate als Wirkstoffkomponente enthalten.The pharmaceutical composition according to the invention can be selected from the group of analgesics e.g. Acetylsalicylic acid, ibuprofen, ketoprofen, alminoprofen, Bermoprofen, carprofen, dexibuprofen, dexketoprofen, fenoprofen, flobufen, flunoxaprofen, flurbiprofen, loxoprofen, Pelobiprofen, pranoprofen, pentazocine, Tilnoprofen, Ximoprofen, Zaltroprofen, dextropropoxyphene, phenylbutazone, mofebutazone, diclofenac, Aceclofenac, amfenac, Bromfenac, Clidanac, Etodolac, Felbinac, Fentiazac, Lonazolac, Mofezolac, Oxindanac, Tifurac, Indomethacin, Acemetacin, Piroxicam, Ampiroxicam, Meloxicam, Isoxicam, Lornoxidamine, Morphine, Morphine, Morphine, Morphine , Levomethadon, Tramadol, Fentanyl and / or its derivatives contain as active ingredient.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Calcium- Antagonisten z.B. Amlodipin, Arandipin, Azelmidipin, Bamidipin, Benidipin, , Cilnidipin, Efonidipin, Felodipin, Flordipin, Iganidipin, Isradipin, Lacidipin, Lercanidipin, Manidipin, Nicardipin, Nifedipin, Nilvadipin, Nisoldipin, Nitrendipin, Palonidipin, Pranidipin, Ticlopidin, Vatanidipin, Diltiazem, Clentiazem und/ oder deren Derivate als Wirkstoffkomponente enthalten.The pharmaceutical composition according to the invention can be selected from the group of calcium antagonists e.g. Amlodipine, Arandipine, Azelmidipine, Bamidipine, Benidipine,, Cilnidipine, Efonidipine, Felodipine, Flordipine, Iganidipine, Isradipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilvadipinidine, Nidvadipinidine, Nidvadipinidine, and / or contain their derivatives as active ingredient.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Antiemetika z.B. Alizaprid, Azasetron, Batanoprid, Cleboprid, Dazoprid, Dolasetron, Domperidon, Granisetron, Itasetron, Levosulpirid, Metoclopramid, Nabilon, Ondansetron, Pancoprid, Ramosetron, Tropisetron, Zatosetron und/ oder deren Derivate als Wirkstoffkomponente enthalten.The pharmaceutical composition according to the invention can be selected from the group of antiemetics, for example alizapride, azasetron, batanopride, clebopride, dazopride, dolasetron, domperidone, granisetron, itasetron, levosulpiride, metoclopramide, nabilone, ondansetron, Contain pancoprid, ramosetron, tropisetron, zatosetron and / or their derivatives as active ingredient.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Hypophysen-/Hypothalamushormone z.B. Tetracosactid, Desmopressin, Nafarelin, Leuprorelin, Buserelin, Deslorelin, Goserelin, Triptorelin und/ oder deren Derivate als Wirkstoffkomponente enthalten.The pharmaceutical composition according to the invention can be selected from the group of the pituitary / hypothalamic hormones e.g. Contain tetracosactide, desmopressin, nafarelin, leuprorelin, buserelin, deslorelin, goserelin, triptorelin and / or their derivatives as active ingredient.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Antiparkinsonmittel z.B. Aptiganel, Budipin, Cabergolin, Droxidopa, Etacapon, Idazoxan, Lazabemid, Milacemid, Mofegilin, Pergolid, Pramipexol, Quineloran, Rasagelin, Remacemid, Ropinorol, Selegilin, Talipexol, Tolcapon und/ oder deren Derivate als Wirkstoffkomponente enthalten.The pharmaceutical composition according to the invention can be selected from the group of anti-Parkinson agents e.g. Aptiganel, Budipin, Cabergolin, Droxidopa, Etacapon, Idazoxan, Lazabemid, Milacemid, Mofegilin, Pergolid, Pramipexol, Quineloran, Rasagelin, Remacemid, Ropinorol, Selegilin, Talipexol, Tolcapon and / or contain derivatives as active ingredient.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Antihistaminika z.B. Acrivastin, Asremizol, Desloratadin, Ebestin, Emedastin, Epinastin, Fexofenadin, Levocabastin, Loratadin, Mequitazin, Misoprostol, Mizolastin, Nafamostat, Norastemizol, Olopatidin, Oxatomid, Rupatadin, Tazifyllin, Temelastin, Terfenadin, Traxanox, Cimetidin, Famotidin, Nicatidin, Ranitidin, Roxatidin und/ oder deren Derivate als Wirkstoffkomponente enthalten.The pharmaceutical composition according to the invention can be selected from the group of antihistamines e.g. Acrivastine, asremizole, desloratadine, ebestin, emedastine, epinastine, fexofenadine, levocabastine, loratadine, mequitazine, misoprostol, mizolastine, nafamostat, norastemizole, olopatidine, oxatomide, rupatadine, tazifylxidine, faminastinidine, teminate Contain roxatidine and / or their derivatives as active ingredient.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Angiotensin-II- Antagonisten z.B. Candesartan, Candesartan-Cilexetil, Eprosartan, Irbesartan, Losartan, Tasosartan, Telmisartan, Valsartan und/ oder deren Derivate als Wirkstoffkomponente enthalten.The pharmaceutical composition according to the invention can be selected from the group of angiotensin II antagonists e.g. Contain candesartan, candesartan-cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, valsartan and / or their derivatives as active ingredient.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann einen Wirkstoffgehalt von 0.01-15 Gew.%, insbesondere 0.08-5 Gew.%, bevorzugt 0.1, 0.2, 0.5 und 1 Gew.% aufweisen. Die Prozentangaben beziehen sich auf die Gesamtmenge der pharmazeutischen Zusammensetzung.The pharmaceutical composition according to the invention can have an active substance content of 0.01-15% by weight, in particular 0.08-5% by weight, preferably 0.1, 0.2, 0.5 and 1% by weight. The percentages relate to the total amount of the pharmaceutical composition.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann gegebenenfalls noch Antioxidantien wie z.B. α-Tocopherol, α-Tocopherolester, Ascorbinsäure, Ascorbinsäureester (-myristat, -palmitat und -stearat), ß-Carotin, Cystein, Acetylcystein, Folsäure (Vitamin-B2- Gruppe), Phytinsäure, eis- und/ oder trans-Urocansäure, Karnosin (N-ß-Alanin-L-Histidin), Histidin, Flavone, Flavonoide, Lycopin, Tyrosin, Gluthation, Gluthationester, -Liponsäure, Ubichinon, Nordihydroguaiaretsäure (NDGA), Gallussäureester (Ethyl-, Propyl-, Octyl-, Dodecylgallat), Phosphorsäurederivate (Monophosphate, Polyphosphate), Butylhydroxytoluol (BHT), Butylhydroxyanisol (BHA), Tetraoxydimethylbiphenyl (TDBP), Polyalkohole, Citronensäure, Weinsäure, Edetinsäure (EDTA als Di-Na- oder Di-Na-Ca-Salz), Coniferylbenzoat und/ oder deren Derivate enthalten, die die Aufnahme durch die Nasenschleimhaut fordern und/ oder das Neutralöl zusätzlich stabilisieren.The pharmaceutical composition according to the invention can optionally also contain antioxidants such as, for example, α-tocopherol, α-tocopherol esters, ascorbic acid, ascorbic acid esters (myristate, palmitate and stearate), ß-carotene, cysteine, acetylcysteine, folic acid (vitamin B 2 group), phytic acid, ice and / or trans-urocanoic acid, carnosine (N-ß-alanine-L- Histidine), histidine, flavones, flavonoids, lycopene, tyrosine, glutation, glutation ester, -liponic acid, ubiquinone, nordihydroguaiaretic acid (NDGA), gallic acid ester (ethyl, propyl, octyl, dodecyl gallate), phosphoric acid derivatives (monophate phosphate), polyphosphol BHT), butylated hydroxyanisole (BHA), tetraoxydimethylbiphenyl (TDBP), polyalcohols, citric acid, tartaric acid, edetic acid (EDTA as di-Na or di-Na-Ca salt), coniferyl benzoate and / or their derivatives, which contain the uptake by Demand nasal mucosa and / or additionally stabilize the neutral oil.
Der Gehalt der gegebenenfalls zugefügten Antioxidantien kann 0,001-1 Gew.%, bezogen auf die Gesamtmenge der pharmazeutischen Zusammensetzung, betragen.The content of the optionally added antioxidants can be 0.001-1% by weight, based on the total amount of the pharmaceutical composition.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann gegebenenfalls noch Lösungsvermittler wie z.B. Lysophosphatidylcholin, Lysophosphatidylglycerol, Phosphatidylethanolamin, Phosphatidylserin, Phosphatidylinosit(ol)e und/ oder Spingophospholipide enthalten.The pharmaceutical composition according to the invention can optionally also provide solubilizers such as e.g. Contain lysophosphatidylcholine, lysophosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol (ol) e and / or spingophospholipids.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann gegebenenfalls noch Detergenzien (Tenside) wie z.B. Genapol®, Natriumdodecylsulfat, ,The pharmaceutical composition according to the invention may optionally also contain detergents (surfactants) such as e.g. Genapol®, sodium dodecyl sulfate,,
Natriumcetylstearylsulfat, Natriumdioctylsulfosuccinat, Cetylstearylalkohol, Cetylalkohol,Sodium cetyl stearyl sulfate, sodium dioctyl sulfosuccinate, cetyl stearyl alcohol, cetyl alcohol,
Stearylalkohol, Cholesterol, Sorbitanmonooleat, Sorbitanmonopalmitat, Sorbitanmonostearat,Stearyl alcohol, cholesterol, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate,
Sorbitantrioleat, Sorbitantristearat, Sorbitanmonolaurat, Polysorbat 20, Polysorbat 60,Sorbitan trioleate, sorbitan tristearate, sorbitan monolaurate, polysorbate 20, polysorbate 60,
Polysorbat 80, Polysorbat 40, Macrogol-1500-glyceroltriricinnoleat, Macrogol- Glycerolhydroxystearat, Macrogol-1000-Glycerolmonolaurat, Macrogol-Polysorbate 80, polysorbate 40, macrogol 1500 glycerol triricinnoleate, macrogol glycerol hydroxystearate, macrogol 1000 glycerol monolaurate, macrogol
1 OOO.Glycerolmonolaurat, Macrogol- 1000-Glycerolmonooleat, Macrogolstearat,1 OOO glycerol monolaurate, macrogol 1000 glycerol monooleate, macrogol stearate,
Polyoxyl40stearat, Polyoxyl50stearat, Polyoxyl231aurylether, Polyoxyl20cetostearylether,Polyoxyl 40 stearate, polyoxyl 50 stearate, polyoxyl 231 auryl ether, polyoxyl 20 cetostearyl ether,
PolyoxyllOolylether, Glycerolmonostearat und/ oder Poloxamer enthalten. Die Detergenzien können u.a. eine evtl. auftretende Adsorptionsverbindung des Wirkstoffes mit der Wandung des Behälters (Ablagerung) verhindern. Die verabreichte Wirkstoffkonzentration kann somit konstant gehalten und ein problemloser Transport garantiert werden. Die erfindungsgemäße pharmazeutische Zusammensetzung kann gegebenenfalls noch Resorptionsverstärker wie z.B. Dimethyl-ß-Cyclodextrin, Permethyl-ß-Cyclodextrin, Hydroxypropyl-ß-Cyclodextrin, randomisiertes methyliertes ß-Cyclodextrin, Carboxymethyl- ß-Cyclodextrin, Maltosyl-ß-Cycodextrin, γ-Cyclodextrin, Natriumtaurofusidat, Natriumglykocholat, Laureth-9 und/ oder α-Lecithin enthalten.Contain PolyoxyllOolylether, Glycerolmonostearat and / or Poloxamer. The detergents can prevent, among other things, any adsorption compound of the active ingredient from occurring with the wall of the container (deposit). The administered drug concentration can thus be kept constant and easy transport can be guaranteed. The pharmaceutical composition according to the invention may optionally also contain absorption enhancers such as, for example, dimethyl-β-cyclodextrin, permethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, randomized methylated β-cyclodextrin, carboxymethyl-β-cyclodextrin, maltosyl-β-cycodextrin, γ-cyclodextrin, Contain sodium taurofusidate, sodium glycocholate, Laureth-9 and / or α-lecithin.
Die Erfindung wird durch nachstehende Beispiele näher erläutert, ohne aber den Erfindungsumfang damit einzuschränken.The invention is illustrated in more detail by the following examples, but without restricting the scope of the invention.
Beispiel 1:Example 1:
69,2 mg Scopolamin werden in 100 ml Miglyol 840 gelöst. Diese Ollösung wird über einen 0,2 μm Pall Fluorodyne II Grad DFL Pharmaqualität Filter steril filtriert und in ein Pumpspray (S4-Pumpe) mit einem Dosisvolumen von 100 oder 50 μl abgefüllt. Die Wirkstoffkonzentration beträgt bei einem 50 μl Sprühstoß 36,4 μg Scopolamin (0,00692 %ig) und bei einem 100 μl Sprühstoß 69,2 μg Scopolamin. Diese Dosierung ist besonders für die pädiatrische Anwendung geeignet.69.2 mg of scopolamine are dissolved in 100 ml of Miglyol 840. This oil solution is sterile filtered through a 0.2 μm Pall Fluorodyne II grade DFL pharmaceutical grade filter and filled into a pump spray (S4 pump) with a dose volume of 100 or 50 μl. The active substance concentration is 36.4 μg scopolamine (0.00692%) with a 50 μl spray and 69.2 μg scopolamine with a 100 μl spray. This dosage is particularly suitable for pediatric use.
Beispiel 2:Example 2:
138,4 mg Scopolamin werden in 100 ml Miglyol 840 gelöst. Diese Ollösung wird über einen 0,2 μm Pall Fluorodyne II Grad DFL Pharmaqualität Filter steril filtriert und in ein Pumpspray (S4-Pumpe) mit einem Dosisvolumen von 100 oder 50 μl abgefüllt. Die Wirkstoffkonzentration beträgt bei einem 50 μl Sprühstoß 72,8 μg Scopolamin und bei einem 100 μl Sprühstoß 138,4 μg Scopolamin. Diese Dosierung ist für die Anwendung bei Erwachsenen geeignet.138.4 mg scopolamine are dissolved in 100 ml Miglyol 840. This oil solution is sterile filtered through a 0.2 μm Pall Fluorodyne II grade DFL pharmaceutical grade filter and filled into a pump spray (S4 pump) with a dose volume of 100 or 50 μl. The active substance concentration is 72.8 μg scopolamine with a 50 μl spray and 138.4 μg scopolamine with a 100 μl spray. This dosage is suitable for use in adults.
Beispiel 3:Example 3:
71,42 mg Budenosid werden in 100 ml Miglyol 840 gelöst. Diese Ollösung wird über einen 0,2 μm Pall Fluorodyne II Grad DFL Pharmaqualität Filter steril filtriert und in ein Pumpspray (3K-Pumpe; Füllvolumen: 14 ml) mit einem Dosisvolumen von 140 μl abgefüllt. Die Wirkstoffkonzentration beträgt bei einem 140 μl Sprühstoß 100 μg Budenosid. Beispiel 4:71.42 mg budenoside are dissolved in 100 ml Miglyol 840. This oil solution is sterile filtered through a 0.2 μm Pall Fluorodyne II grade DFL pharmaceutical grade filter and filled into a pump spray (3K pump; filling volume: 14 ml) with a dose volume of 140 μl. The active substance concentration is 100 μg budenoside with a 140 μl spray. Example 4:
71,42 mg Beclomethason Dipropionat werden in 100 ml Miglyol 840 gelöst. Diese Ollösung wird über einen 0,2 μm Pall Fluorodyne II Grad DFL Pharmaqualität Filter steril filtriert und in ein Pumpspray (3K-Pumpe; Füllvolumen: 14 ml) mit einem Dosisvolumen von 140 μl abgefüllt. Die Wirkstoffkonzentration beträgt bei einem 140 μl Sprühstoß 100 μg Beclomethason Dipropionat. 71.42 mg of beclomethasone dipropionate are dissolved in 100 ml of Miglyol 840. This oil solution is sterile filtered through a 0.2 μm Pall Fluorodyne II grade DFL pharmaceutical grade filter and filled into a pump spray (3K pump; filling volume: 14 ml) with a dose volume of 140 μl. The active ingredient concentration for a 140 μl spray is 100 μg beclomethasone dipropionate.

Claims

Patentansprücheclaims
1. Pharmazeutische Zusammensetzung zur nasalen Anwendung, gekennzeichnet durch mindestens einen wasserunlöslichen oder schwer wasserlöslichen Wirkstoff gelöst in Neutralöl.1. Pharmaceutical composition for nasal use, characterized by at least one water-insoluble or poorly water-soluble active ingredient dissolved in neutral oil.
2. Pharmazeutische Zusammensetzung zur nasalen Anwendung nach Anspruch 1, gekennzeichnet durch mittelkettige Triglyceride als Neutralöl.2. Pharmaceutical composition for nasal use according to claim 1, characterized by medium-chain triglycerides as neutral oil.
3. Pharmazeutische Zusammensetzung zur nasalen Anwendung nach Anspruch 2, gekennzeichnet durch Ester, gebildet durch Veresterung von Capron-, Caprin-, Capryl-, Laurin-, Myristin-, Linol- und/ oder Bernsteinsäure mit Glycerin oder Propylenglykol, als mittelkettigen Triglyceride 4. Pharmazeutische Zusammensetzung zur nasalen Anwendung nach Anspruch 2 oder 3, gekennzeichnet durch Ester, gebildet durch Veresterung von Caprin-, Capryl-, Linol- und/ oder Bernsteinsäure mit Glycerin oder Propylenglykol, als mittelkettige Triglyceride.3. Pharmaceutical composition for nasal use according to claim 2, characterized by esters, formed by esterification of capronic, capric, caprylic, lauric, myristic, linoleic and / or succinic acid with glycerol or propylene glycol, as medium-chain triglycerides 4. Pharmaceutical composition for nasal use according to claim 2 or 3, characterized by esters, formed by esterification of capric, caprylic, linoleic and / or succinic acid with glycerol or propylene glycol, as medium-chain triglycerides.
5. Pharmazeutische Zusammensetzung zur nasalen Anwendung nach einem der vorangegangenen Ansprüche, gekennzeichnet durch eine Viskosität des Neutralöls von l- 40 mPa s.5. Pharmaceutical composition for nasal use according to one of the preceding claims, characterized by a viscosity of the neutral oil of 1-40 mPa s.
6. Pharmazeutische Zusammensetzung zur nasalen Anwendung nach Anspruch 5, gekennzeichnet durch eine Viskosität des Neutralöls von 5- 20 mPa s.6. Pharmaceutical composition for nasal use according to claim 5, characterized by a viscosity of the neutral oil of 5- 20 mPa s.
7. Pharmazeutische Zusammensetzung zur nasalen Anwendung nach Anspruch 5 oder 6, gekennzeichnet durch eine Viskosität des Neutralöls von 8- 15 mPa s. 8. Pharmazeutische Zusammensetzung zur nasalen Anwendung nach Anspruch 1, gekennzeichnet durch mindestens einen Wirkstoff aus der Gruppe der Corticoide, Androgene, Östrogene, Gestagene, Protonenpumpenhemmer, 5 -HTj -Antagonisten, Sympatholytika/ Sympathomimetika, Anticholinergika, Tranquillantio/Anxiolytika, Entwöhnungsmittel, Analgetika, Calcium-Antagonisten, Antiemetika, Hypophysen- /Hypothalamushormone, Antiparkinsonmitttel, Antihistaminika, Angiotensin-II- Antagoniosten, Lidocain und/oder Nitroglycerin.7. Pharmaceutical composition for nasal use according to claim 5 or 6, characterized by a viscosity of the neutral oil of 8-15 mPa s. 8. Pharmaceutical composition for nasal use according to claim 1, characterized by at least one active ingredient from the group of corticoids, Androgens, estrogens, progestogens, proton pump inhibitors, 5 -HT j antagonists, sympatholytics / sympathomimetics, anticholinergics, tranquillizers / anxiolytics, weaning agents, analgesics, calcium antagonists, antiemetics, hypophysis / hypothalamic hormones, antiparkinsonian hormones, antiparonicinostatic agents, antiparonicinostatic agents, antiparonicinostatic agents, antiparkinsonian hormones, antiparisoning agents, antiparisoning agents, antiparisoning agents, antiparisoning agents, antiparisoning agents, antiparisoning agents, antiparisoning agents, antiparisoning agents, antiparisoning agents, antiparisoning agents Lidocaine and / or nitroglycerin.
9. Pharmazeutische Zusammensetzung zur nasalen Anwendung nach Anspruch 8, gekennzeichnet durch Beclomethasondipropionat, Scopolaminbase, Budesonidbase, Diazepam und/ oder Omeprazol als Wirkstoff. lO.Pharmazeutische Zusammensetzung zur nasalen Anwendung nach einem der vorangegangenen Ansprüche, gekennzeichnet durch einen Wirkstoffgehalt von 0,01- 159. Pharmaceutical composition for nasal use according to claim 8, characterized by beclomethasone dipropionate, scopolamine base, budesonide base, diazepam and / or omeprazole as active ingredient. 10. Pharmaceutical composition for nasal use according to one of the preceding claims, characterized by an active ingredient content of 0.01-15
Gew.%, jeweils bezogen auf das Gesamtgewicht der pharmazeutischen Zusammensetzung. 11.Pharmazeutische Zusammensetzung zur nasalen Anwendung nach Anspruch 10, gekennzeichnet durch einen Wirkstoffgehalt von 0,08- 5 Gew.%, jeweils bezogen auf das Gesamtgewicht der pharmazeutischen Zusammensetzung. 12. Pharmazeutische Zusammensetzung zur nasalen Anwendung nach Anspruch 10 oder 11, gekennzeichnet durch einen Wirkstoffgehalt von 0.1, 0.2, 0.5 oder 1 Gew.%, jeweils bezogen auf das Gesamtgewicht der pharmazeutischen Zusammensetzung. 13. Pharmazeutische Zusammensetzung zur nasalen Anwendung nach einem der vorangegangenen Ansprüche, gekennzeichnet durch mindestens ein Antioxidationsmittel. H.Pharmazeutische Zusammensetzung zur nasalen Anwendung nach Anspruch 13, gekennzeichnet durch α-Tocopherol, α-Tocopherolester, Ascorbinsäure, Ascorbinsäureester, ß-Carotin, Cystein, Acetylcystein, Folsäure, Phytinsäure, eis- und/ oder trans-Urocansäure, Karnosin, Histidin, Flavone, Flavonoide, Lycopin, Tyrosin, Gluthation, Gluthationester, α-Liponsäure, Ubichinon, Nordihydroguaiaretsäure, Gallussäureester, Phosphorsäurederivate, Butylhydroxytoluol, Butylhydroxyanisol,% By weight, in each case based on the total weight of the pharmaceutical composition. 11.Pharmaceutical composition for nasal use according to claim 10, characterized by an active ingredient content of 0.08-5% by weight, in each case based on the total weight of the pharmaceutical composition. 12. Pharmaceutical composition for nasal use according to claim 10 or 11, characterized by an active substance content of 0.1, 0.2, 0.5 or 1% by weight, in each case based on the total weight of the pharmaceutical composition. 13. Pharmaceutical composition for nasal use according to one of the preceding claims, characterized by at least one antioxidant. H. Pharmaceutical composition for nasal use according to claim 13, characterized by α-tocopherol, α-tocopherol ester, ascorbic acid, ascorbic acid ester, β-carotene, cysteine, acetylcysteine, folic acid, phytic acid, ice and / or trans-urocanoic acid, carnosine, histidine, Flavones, flavonoids, lycopene, tyrosine, glutation, glutation esters, α-lipoic acid, ubiquinone, nordihydroguaiaretic acid, gallic acid esters, phosphoric acid derivatives, butylated hydroxytoluene, butylated hydroxyanisole,
Tetraoxydimethylbiphenyl, Polyalkohole, Citronensäure, Weinsäure, Edetinsäure (EDTA als Di-Na- oder Di-Na-Ca-Salz), Coniferylbenzoat und/ oder deren Derivate alsTetraoxydimethylbiphenyl, polyalcohols, citric acid, tartaric acid, edetic acid (EDTA as di-Na or di-Na-Ca salt), coniferyl benzoate and / or their derivatives as
Antioxidationsmittel .Antioxidant.
15. Pharmazeutische Zusammensetzung zur nasalen Anwendung nach einem der vorangegangenen Ansprüche, gekennzeichnet durch mindestens einen Lösungsvermittler,15. Pharmaceutical composition for nasal use according to one of the preceding claims, characterized by at least one solubilizer,
Resorptionsverstärker und/ oder ein Detergenz. Absorption enhancer and / or a detergent.
EP00938686A 1999-06-02 2000-05-26 Pharmaceutical composition for intranasal use of active substances that are insoluble and/or hardly soluble in water Withdrawn EP1185246A1 (en)

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DE19925290 1999-06-02
DE1999125290 DE19925290A1 (en) 1999-06-02 1999-06-02 Stable, well-tolerated composition for intranasal administration of water-insoluble drugs e.g. scopolamine, comprising solution of drug in neutral oil, especially triglyceride
DE1999136543 DE19936543A1 (en) 1999-08-03 1999-08-03 Composition for intranasal administration of water-insoluble drugs, e.g. scopolamine, budesonide or diazepam, comprising a solution of the water-insoluble or sparingly water-soluble drug in a neutral oil e.g. a triglyceride
DE19936543 1999-08-03
PCT/EP2000/004799 WO2000074651A1 (en) 1999-06-02 2000-05-26 Pharmaceutical composition for intranasal use of active substances that are insoluble and/or hardly soluble in water

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