WO2000074651A1 - Composition pharmaceutique pour administration par voie nasale de substances actives insolubles et/ou difficilement solubles dans l'eau - Google Patents

Composition pharmaceutique pour administration par voie nasale de substances actives insolubles et/ou difficilement solubles dans l'eau Download PDF

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Publication number
WO2000074651A1
WO2000074651A1 PCT/EP2000/004799 EP0004799W WO0074651A1 WO 2000074651 A1 WO2000074651 A1 WO 2000074651A1 EP 0004799 W EP0004799 W EP 0004799W WO 0074651 A1 WO0074651 A1 WO 0074651A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
agents
use according
acid
nasal use
Prior art date
Application number
PCT/EP2000/004799
Other languages
German (de)
English (en)
Inventor
Norbert KLÖCKER
Original Assignee
Hexal Ag
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/de
Priority claimed from DE1999136543 external-priority patent/DE19936543A1/de
Application filed by Hexal Ag filed Critical Hexal Ag
Priority to EP00938686A priority Critical patent/EP1185246A1/fr
Priority to JP2001501188A priority patent/JP2004525854A/ja
Priority to AU53973/00A priority patent/AU5397300A/en
Publication of WO2000074651A1 publication Critical patent/WO2000074651A1/fr

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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

La présente invention concerne une composition pharmaceutique pour administration par voie nasale, comprenant au moins une substance active insoluble ou difficilement soluble dans l'eau, présente à l'état soluble dans l'huile neutre. L'administration de la composition pharmaceutique de l'invention sur la muqueuse nasale peut se faire sans avoir recours à des agents propulseurs et des agents de conservation, au moyen de dispositifs qui délivrent des dosages bien définis.
PCT/EP2000/004799 1999-06-02 2000-05-26 Composition pharmaceutique pour administration par voie nasale de substances actives insolubles et/ou difficilement solubles dans l'eau WO2000074651A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP00938686A EP1185246A1 (fr) 1999-06-02 2000-05-26 Composition pharmaceutique pour administration par voie nasale de substances actives insolubles et/ou difficilement solubles dans l'eau
JP2001501188A JP2004525854A (ja) 1999-06-02 2000-05-26 水中に不溶性及び／又は難溶性である活性物質の鼻腔内投与用薬剤組成物
AU53973/00A AU5397300A (en) 1999-06-02 2000-05-26 Pharmaceutical composition for intranasal use of active substances that are insoluble and/or hardly soluble in water

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19925290.4 1999-06-02
DE1999125290 DE19925290A1 (de) 1999-06-02 1999-06-02 Neue pharmazeutische Zusammensetzung zur nasalen Anwendung von wasserunlöslichen und/oder schwer wasserlöslichen Wirkstoffen
DE1999136543 DE19936543A1 (de) 1999-08-03 1999-08-03 Neue pharmazeutische Zusammensetzung zur nasalen Anwendung von wasserunlöslichen und/oder schwer wasserlöslichen Wirkstoffen
DE19936543.1 1999-08-03

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EP1250925A2 (fr) * 2001-04-20 2002-10-23 AHN-Gook Pharma Co., Ltd. Pulvérisateur nasale contenant du chlorhydrate d'ondansétron
WO2003015782A2 (fr) * 2001-07-25 2003-02-27 Kox Wolfgang J Sevrage a la nicotine adapte aux recepteurs par blocage anticholinergique et antinoradrenergique
JP2006523620A (ja) * 2003-02-19 2006-10-19 バイオヴェイル ラボラトリーズ インコーポレイテッド 急速吸収選択的５−ｈｔ作用剤製剤
WO2007125318A1 (fr) * 2006-04-25 2007-11-08 Optinose As Formulation liquide non aqueuse pour administration nasale ou buccale
US7700588B2 (en) 2004-01-14 2010-04-20 Merkus Franciscus Wilhelmus He Pharmaceutical compositions comprising midazolam in a high concentration
EP2425842A1 (fr) * 2010-09-02 2012-03-07 Lorentz, Eckart Composition pour la thérapie locale symptomatique de la muqueuse nasale et gouttes pour le nez contenant cette composition
US9155700B2 (en) 2003-10-22 2015-10-13 Chiesi Farmaceutici S.P.A. Process for the preparation of pharmaceutical suspensions for inhalation

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JP2009526064A (ja) * 2006-02-09 2009-07-16 シェーリング コーポレイション 薬学的調合物
CN109758435A (zh) * 2017-11-09 2019-05-17 郑州泰丰制药有限公司 奥美拉唑气雾剂及其制备方法
WO2024026463A1 (fr) * 2022-07-28 2024-02-01 Happy Healing Inc. Composition pour l'administration nasale d'un composé actif

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1250925A2 (fr) * 2001-04-20 2002-10-23 AHN-Gook Pharma Co., Ltd. Pulvérisateur nasale contenant du chlorhydrate d'ondansétron
EP1250925A3 (fr) * 2001-04-20 2003-11-26 AHN-Gook Pharma Co., Ltd. Pulvérisateur nasale contenant du chlorhydrate d'ondansétron
WO2003015782A2 (fr) * 2001-07-25 2003-02-27 Kox Wolfgang J Sevrage a la nicotine adapte aux recepteurs par blocage anticholinergique et antinoradrenergique
WO2003015782A3 (fr) * 2001-07-25 2003-08-07 Wolfgang J Kox Sevrage a la nicotine adapte aux recepteurs par blocage anticholinergique et antinoradrenergique
JP2006523620A (ja) * 2003-02-19 2006-10-19 バイオヴェイル ラボラトリーズ インコーポレイテッド 急速吸収選択的５−ｈｔ作用剤製剤
US9155700B2 (en) 2003-10-22 2015-10-13 Chiesi Farmaceutici S.P.A. Process for the preparation of pharmaceutical suspensions for inhalation
US7700588B2 (en) 2004-01-14 2010-04-20 Merkus Franciscus Wilhelmus He Pharmaceutical compositions comprising midazolam in a high concentration
WO2007125318A1 (fr) * 2006-04-25 2007-11-08 Optinose As Formulation liquide non aqueuse pour administration nasale ou buccale
EP2425842A1 (fr) * 2010-09-02 2012-03-07 Lorentz, Eckart Composition pour la thérapie locale symptomatique de la muqueuse nasale et gouttes pour le nez contenant cette composition

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EP1185246A1 (fr) 2002-03-13
JP2004525854A (ja) 2004-08-26

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