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EP1189596A1 - Composition pharmaceutique pour administration nasale de principes actifs solubles dans l'eau - Google Patents

Composition pharmaceutique pour administration nasale de principes actifs solubles dans l'eau

Info

Publication number
EP1189596A1
EP1189596A1 EP00935121A EP00935121A EP1189596A1 EP 1189596 A1 EP1189596 A1 EP 1189596A1 EP 00935121 A EP00935121 A EP 00935121A EP 00935121 A EP00935121 A EP 00935121A EP 1189596 A1 EP1189596 A1 EP 1189596A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
macrogrog
use according
nasal use
acid
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Withdrawn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
EP00935121A
Other languages
German (de)
English (en)
Inventor
Norbert Dr.med. 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.)
Individual
Original Assignee
Individual
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 DE1999125289 external-priority patent/DE19925289A1/de
Priority claimed from DE1999136545 external-priority patent/DE19936545A1/de
Application filed by Individual filed Critical Individual
Publication of EP1189596A1 publication Critical patent/EP1189596A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0043Nose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14Esters 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-soluble active ingredient, neutral oil and optionally at least one solubilizer, it being possible to dispense with the addition of preservatives and propellants.
  • blowing agents are representatives from the group of the fluorochlorohydrocarbons, or fluorohydrocarbons.
  • 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 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.
  • maximum absorption takes place at a pH ⁇ 6.
  • a pH 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 been difficult.
  • a liposome formulation is an oil / water or water / oil emulsion.
  • the preparation of these liposome formulations is complex. The stability is very 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.
  • the object of the invention is to provide a pharmaceutical composition for the nasal application of water-soluble active ingredients in the form of a dispersion or solution, it being possible to dispense with the use of propellants and preservatives and the composition being essentially water-free.
  • the object is achieved according to the invention by a pharmaceutical composition which contains at least one water-soluble active ingredient, neutral oil and, if appropriate, a solubilizer.
  • 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 it adheres well to the nasal mucosa, and due to the neutral oil there is a cell spread and the active ingredient is thus very easily absorbed from the composition by the nasal mucosa.
  • the problem of 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 can be easily filtered, so that a sterile solution (OJ ⁇ m pore size) can be prepared without great effort using a sterile filtration. If a dispersion is present, sterility can be achieved without any problems by first filtering the neutral oil in a sterile manner and then preparing the dispersion in a closed circuit.
  • 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 composition 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 auxiliary substances is minimized and patient compliance can thus be increased.
  • the production is simple and inexpensive, since no further additives are necessary and the neutral oil as a carrier is cheap.
  • 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.
  • neutral oil means medium-chain triglycerides. These can be achieved by esterifying medium-chain fatty acids such as Capronic, capric, caprylic, lauric, myristic, linoleic and succinic acid, in particular capric, caprylic, linoleic and
  • Succinic acid can be obtained with glycerol and / or propylene glycol (Miglyol 810, 812,
  • 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 contain water-soluble corticoids, 5-HT, antagonists, sympatholytics / sympathomimetics, anticholinergics,
  • Weaning agents, analgesics, calcium antagonists, antiemetics, pituitary / hypothalamic hormones, opiate antagonists, anticoagulants, antiparkinson agents, ACE inhibitors, insulin, polihexanide, allicin, sildenafil citrate, lidocaine HCl, oxytocin and / or possible co-enzyme components contain Q.
  • the pharmaceutical composition according to the invention can be selected from the group of corticoids e.g. B. beclomethasone, budesonide propionate, flunisolide acetate, triamcinolone, fluticasone, betamethasone 17-valerate, glycic acid, fluocortolone and / or their derivatives as an active ingredient component.
  • corticoids e.g. B. beclomethasone, budesonide propionate, flunisolide acetate, triamcinolone, fluticasone, betamethasone 17-valerate, glycic acid, fluocortolone and / or their derivatives as an active ingredient component.
  • the pharmaceutical composition according to the invention can contain, for example, sumatriptan hydrogen succinate, rizatriptan benzoate and / or their derivatives from the group of 5-HT, antagonists as active ingredient.
  • the pharmaceutical composition according to the invention can be selected from the group of the sympatholytic / sympathomimetic, for example acebutolol hydrochloride, adimolol hydrochloride, adrenaline hydrogen tartrate, amosulalol hydrochloride, arotinolol monohydrochloride, betaxolol hydrochloride, bevantolol hydrochloride, bisoprolololololate, baterolololololate, baterolololololate, baterolololololate, baterolololololate, baterolololololate, baterolololololate, baterolololol
  • the pharmaceutical composition according to the invention can from the group of anticholinergics, for example ipratropium bromide, oxitropium bromide, atropine methyl bromide, atropine methyl nitrate, atropine sulfate, atropine valerianate, scopolamine hydrobromide, scopolamine hydrochloride, scopolamine hydroiodide and / or contain derivatives thereof as active ingredient.
  • the pharmaceutical composition according to the invention can contain, for example, nicotine, disulfiram and / or their derivatives, in particular nicotine, as an active ingredient component from the group of weaning agents.
  • the pharmaceutical composition according to the invention can be selected from the group of analgesics e.g. Codeine, Codein Hydrochloride, Codeine Phosphate, Tilidine, Tilidine Mesylate, Tilidine Hydrochloride, Metamizole Sodium, Dextropropoxyphenhydrochloride, Diclofenac Sodium, Aceclofenac Sodium, Amfenac Sodium, Bromfenac Sodium, Clidanac Sodium, Etodolac Sodium, Felbinac Sodium, F Lonazolac sodium, mofezolac sodium, oxindanac sodium, tifurac sodium, indomethacin sodium, acemetacin sodium, piroxicam, ampiroxicam, meloxicam cyclodextrin, isoxicam, lornoxicam, tenoxicam, bupreno hydrochloride, morphine acetate, morphine acetate, morphine acetate
  • the pharmaceutical composition according to the invention can be selected from the group of calcium antagonists e.g. Contain diltiazem hydrochloride, clentiazem hydrochloride and / or their derivatives as active ingredient.
  • calcium antagonists e.g. Contain diltiazem hydrochloride, clentiazem hydrochloride and / or their derivatives as active ingredient.
  • the pharmaceutical composition according to the invention can be selected from the group of antiemetics e.g. Alizaprid hydrochloride, batanopride hydrochloride, cleboprid hydrochloride, dazoprid hydrochloride, metoclopramide hydrochloride, pancoprid hydrochloride and / or their derivatives as an active ingredient component.
  • antiemetics e.g. Alizaprid hydrochloride, batanopride hydrochloride, cleboprid hydrochloride, dazoprid hydrochloride, metoclopramide hydrochloride, pancoprid hydrochloride and / or their derivatives as an active ingredient component.
  • the pharmaceutical composition according to the invention can be selected from the group of the pituitary / hypothalamic hormones e.g. Contain tetracosactide acetate, choringonadotrophin, follitropin, menotropin, somatropin, desmopressin acetate, nafarelin acetate, leuprorelin acetate, buserelin acetate, deslorelin acetate, goserelin acetate, triptorelin acetate and / or their derivatives as an active ingredient.
  • the pituitary / hypothalamic hormones e.g. Contain tetracosactide acetate, choringonadotrophin, follitropin, menotropin, somatropin, desmopressin acetate, nafarelin acetate, leuprorelin acetate, buserelin acetate, deslorelin acetate, goserelin
  • the pharmaceutical composition according to the invention can from the group of opiate antagonists z. B. naloxone, naltrexone and / or their derivatives, especially naloxone as an active ingredient component.
  • the pharmaceutical composition according to the invention can contain, for example, heparin sodium, certoparin, dalteparin, danaparoid, enoxaparin, nadroparin, reviparin, tinzaparin, heparinoids and / or their derivatives as active ingredient components from the group of anticoagulants.
  • the pharmaceutical composition according to the invention can be selected from the group of antiparkinsonian agents, the water-soluble salts of e.g. Aptiganel, Budipin, Cabergolin, Droxidopa, Etacapon, Idazoxan, Lazabemid, Milacemid, Mofegilin, Pergolid (Pergolidmesylat, Pergolidhydrochlorid), Pramipexol, Quineloran, Rasagelin, Remacemid, Ropinorol, Seleginhydonol or their component ( contain.
  • the water-soluble salts e.g. Aptiganel, Budipin, Cabergolin, Droxidopa, Etacapon, Idazoxan, Lazabemid, Milacemid, Mofegilin, Pergolid (Pergolidmesylat, Pergolidhydrochlorid), Pramipexol, Quineloran, Rasagelin, Remacemid, Ropinorol, Seleginhydonol or their
  • the pharmaceutical composition according to the invention can be selected from the group of ACE inhibitors e.g. Alacepril, benazepril, captopril, ceronapril, cilazapril, denapril, enalapril, enalapril maleate, fosinopril, imidapril, lisinopril, moexipril, moveltipril, perindopril, derinaprilap, riliprilap, biliprilap included as active ingredient.
  • ACE inhibitors e.g. Alacepril, benazepril, captopril, ceronapril, cilazapril, denapril, enalapril, enalapril maleate, fosinopril, imidapril, lisinopril, moexipril, moveltipril, perindopril, derinaprilap, riliprilap, bil
  • 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 0J, 0J, 0.5 and 1% by weight.
  • the percentages relate to the total amount of the pharmaceutical composition.
  • the pharmaceutical composition according to the invention may optionally also contain antioxidants such as, for example, ⁇ -tocopherol, ⁇ -tocopherol esters, ascorbic acid, ascorbic acid esters (myristate, palmitate and stearate), ⁇ -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, glutathione, glutathione esters, ⁇ -lipoic acid, ubiquinone, nordihydroguaiaretic acid (NDGA), gallic acid esters (Ethyl, propyl, octyl, dodecyl gallate), phosphoric acid derivatives (monophosphates, polyphosphates), butylated hydroxyto
  • 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. Lysophosphatidylcholine, lysophosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol (ol) e, spingophospholipids, sodium dodecyl sulfate, sodium cetylstearyl sulfate, sodium dioctyl sulfosuccinate,
  • solubilizers such as e.g. Lysophosphatidylcholine, lysophosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol (ol) e, spingophospholipids, sodium dodecyl sulfate, sodium cetylstearyl sulfate, sodium dioctyl sulfosucc
  • Glycerol monooleate macrogol stearate, polyoxyl 40 stearate, polyoxyl 50 stearate,
  • solubilizers can support or enable a solution of the water-soluble active ingredient in the neutral oil and, among other things, Prevent any adsorption compound of the active ingredient from occurring with the wall of the container (deposit).
  • the pharmaceutical composition according to the invention can optionally also be absorption enhancers such as e.g. Dimethyl-ß-cyclodextrin, permethyl-ß-cyclodextrin, hydroxypropyl-ß-cyclodextrin, randomized methylated ß-cyclodextrin, carboxymethyl-ß-cyclodextrin, maltosyl-ß-cycodextrin, ⁇ -cyclodextrin, sodium taurofusidate,
  • absorption enhancers such as e.g. Dimethyl-ß-cyclodextrin, permethyl-ß-cyclodextrin, hydroxypropyl-ß-cyclodextrin, randomized methylated ß-cyclodextrin, carboxymethyl-ß-cyclodextrin, maltosyl-ß-cycodextrin, ⁇ -cyclodextrin, sodium taurofusidate,
  • Example 1 The invention is illustrated in more detail by the following examples, but without restricting the scope of the invention.
  • Example 1 The invention is illustrated in more detail by the following examples, but without restricting the scope of the invention.
  • 1 g (-) - nicotine is introduced into 100 ml Miglyol 840. This composition is sterilized and filled into a pump spray with a dose volume of 50 ⁇ l.
  • the active substance concentration for a 50 ⁇ l spray is 500 ⁇ g (-) - nicotine.
  • Concentrate of polyhexanide 20 g of polyhexanide are introduced into 100 ml of Miglyol 840 (20% formulation).

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Otolaryngology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une composition pharmaceutique pour administration nasale, qui comprend au moins un principe actif soluble dans l'eau, de l'huile neutre et éventuellement au moins un agent de solubilisation. Cette composition permet de ne plus avoir recours à l'adjonction d'agents de conservation et d'agents propulseurs. Cette composition est sensiblement exempte d'eau.
EP00935121A 1999-06-02 2000-05-26 Composition pharmaceutique pour administration nasale de principes actifs solubles dans l'eau Withdrawn EP1189596A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE19925289 1999-06-02
DE1999125289 DE19925289A1 (de) 1999-06-02 1999-06-02 Neue pharmazeutische Zusammensetzung zur nasalen Anwendung von wasserlöslichen Wirkstoffen
DE19936545 1999-08-03
DE1999136545 DE19936545A1 (de) 1999-08-03 1999-08-03 Neue pharmazeutische Zusammensetzung zur nasalen Anwendung von wasserlöslichen Wirkstoffen
PCT/EP2000/004800 WO2000074652A1 (fr) 1999-06-02 2000-05-26 Composition pharmaceutique pour administration nasale de principes actifs solubles dans l'eau

Publications (1)

Publication Number Publication Date
EP1189596A1 true EP1189596A1 (fr) 2002-03-27

Family

ID=26053615

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00935121A Withdrawn EP1189596A1 (fr) 1999-06-02 2000-05-26 Composition pharmaceutique pour administration nasale de principes actifs solubles dans l'eau

Country Status (4)

Country Link
EP (1) EP1189596A1 (fr)
JP (1) JP2005505491A (fr)
AU (1) AU5072000A (fr)
WO (1) WO2000074652A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040191207A1 (en) * 2003-03-31 2004-09-30 Lipari John M. Alpha-hydroxy acid ester drug delivery compositions and methods of use
FR2856302B1 (fr) * 2003-06-20 2005-12-02 Anben Pharma Composition pharmaceutique utilisee en tant qu'agent anti-infectueux des voies respiratoires superieures
GB2437488A (en) * 2006-04-25 2007-10-31 Optinose As Pharmaceutical oily formulation for nasal or buccal administration
US9192570B2 (en) 2013-12-20 2015-11-24 AntiOP, Inc. Intranasal naloxone compositions and methods of making and using same
RU2020112530A (ru) 2014-03-14 2021-07-21 ОПИАНТ ФАРМАСЮТИКАЛС, Инк. Назальные готовые лекарственные формы и способы их применения
US9480644B2 (en) 2014-03-14 2016-11-01 Opiant Pharmaceuticals, Inc. Nasal drug products and methods of their use
US10085937B2 (en) 2014-03-14 2018-10-02 Adapt Pharma Limited Nasal drug products and methods of their use
US9561177B2 (en) 2014-03-14 2017-02-07 Adapt Pharma Limited Nasal drug products and methods of their use

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1222395B (it) * 1987-07-30 1990-09-05 Pierrel Spa Composizione farmaceutica per somministrazione intranasale comprendente l'ormone ghrh,un agonista colinergico e/o un sale biliare
EP0532546B1 (fr) * 1990-05-10 1998-03-18 Bechgaard International Research And Development A/S PREPARATION PHARMACEUTIQUE CONTENANT DES n-GLYCOFUROLS ET DES n-ETHYLENE GLYCOLS
CA2050425A1 (fr) * 1990-09-03 1992-03-04 Yoshiaki Uda Composition pharmaceutique et son utilisation avec du mucus
US5955098A (en) * 1996-04-12 1999-09-21 Flemington Pharmaceutical Corp. Buccal non polar spray or capsule

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0074652A1 *

Also Published As

Publication number Publication date
WO2000074652A1 (fr) 2000-12-14
JP2005505491A (ja) 2005-02-24
AU5072000A (en) 2000-12-28

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