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WO2010094792A1 - Ensemble de secours pour la production d'un médicament pour l'application nasale d'opioïdes en cas de dyspnée - Google Patents

Ensemble de secours pour la production d'un médicament pour l'application nasale d'opioïdes en cas de dyspnée Download PDF

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Publication number
WO2010094792A1
WO2010094792A1 PCT/EP2010/052189 EP2010052189W WO2010094792A1 WO 2010094792 A1 WO2010094792 A1 WO 2010094792A1 EP 2010052189 W EP2010052189 W EP 2010052189W WO 2010094792 A1 WO2010094792 A1 WO 2010094792A1
Authority
WO
WIPO (PCT)
Prior art keywords
emergency kit
container
drug
opioid
solution
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.)
Ceased
Application number
PCT/EP2010/052189
Other languages
German (de)
English (en)
Inventor
Thomas Sitte
Rainer Brosig
Axel Grimm
Joachim Kleinert
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.)
MARIEN-APOTHEKE FULDA oHG
Schmerz & Palliativ Zentrum Fulda
Original Assignee
MARIEN-APOTHEKE FULDA oHG
Schmerz & Palliativ Zentrum Fulda
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
Application filed by MARIEN-APOTHEKE FULDA oHG, Schmerz & Palliativ Zentrum Fulda filed Critical MARIEN-APOTHEKE FULDA oHG
Publication of WO2010094792A1 publication Critical patent/WO2010094792A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • the present invention relates to an emergency kit for the preparation of a drug formulation for nasal use of opioids, comprising at least a first container and a second container, wherein the first container contains a drug solution and the second container contains a first dilution solution. Furthermore, the present invention relates to the use of opioids for the production of an emergency kit according to the patent claims for use in respiratory distress.
  • Severe shortness of breath with suffocation anxiety is the most threatening symptom of dying patients. Shortness of breath is the most common cause of hospitalization in the end of life phase. In addition to cancer patients, others are also affected by this symptom; Patients with advanced coronary heart disease, COPD, renal insufficiency or neurodegenerative diseases.
  • Pulmonary causes include pneumonia, pleural effusion, secretions, tumors, pulmonary fibrosis and COPD.
  • Non-pulmonary causes include cachexia, heart failure, ascites, high respiratory rate and anxiety.
  • the respiratory center is sensitive to an increase in carbon dioxide partial pressure in the arterial blood. The body tries to reduce the carbon dioxide partial pressure by increasing the minute volume. Since this is exhausting, the feeling of air distress arises at normal oxygen saturation. Regardless of whether the air distress has a pulmonary or non-pulmonary cause, exertion and anxiety lead to high respiratory rates, which in turn leads to greater Totraumventilation leads at the same time increased oxygen consumption.
  • the therapy goal is to economise the work of breathing in order to reduce the air shortage.
  • the attending physician who is called to a patient with respiratory distress, is advised to calm the patient first.
  • symptom control e.g. Tranquillizers and retarded opioids are available. These are dosed as in the pain therapy. In an emergency, however, such drugs must act very quickly or directly lower the respiratory drive.
  • opioids have a bureaucratic obstacle to carrying many containers of nasal sprays of different dosages because the fate of anesthetics must be carefully documented. For example, the disposal of expired drugs with opioids as an active ingredient is extremely lavishly. The loss or theft of an opioid drug also leads to undesirable bureaucratic consequences.
  • an emergency kit for the preparation of a drug formulation for the nasal use of opioids comprising a first container and a second container, wherein the first container contains an active substance solution of an opioid and the second container contains a first dilution solution.
  • the emergency kit additionally comprises a third container, wherein the third container contains a second dilution solution.
  • the dilution solutions are preferably free of opioids.
  • the present invention is based on the finding that higher doses are required for successful use of opioids in the therapy of respiratory distress than has hitherto been mentioned in the literature. Further The inventors have recognized that opioids, if they are to be used successfully for the nasal therapy of respiratory distress, must be dosed individually.
  • the drug solution in the first container has an opioid concentration, which can be administered without further preparation to a patient who is already receiving high opioid doses for analgesia. If it is necessary to treat a patient receiving a lower opioid base therapy, dilute the drug solution in the first container with the dilution solution of the second container. The resulting solution has a lower concentration so that it is capable of adequately treating the patient. In the event that the patient to be treated receives a low base dosage of opioids, the drug solution in the first container is diluted with the dilution solution from the preferably present third container, etc.
  • the emergency kit comprises a total of three containers. It has been shown that adequate opioid doses can be administered nasally for most emergencies. Likewise, the emergency kit may also include other containers of dilution solution, such as a fourth container.
  • any opioid may be used as the active ingredient.
  • the skilled person can easily use the Fentanylcitratäquivalentes or morphine equivalent of the respective drugs determine what dosage he must use in the patient.
  • the dose to be administered per puff will be in the range of 0.025 mg to 2 mg fentanyl citrate equivalent dose. This means that a substance amount of opioid drug per stroke should be administered, which achieves such an effect equivalent to the effect that mediate 0.025 mg or 2 mg fentanyl citrate.
  • the amount of opioid to be administered is indicated by means of the fentanyl citrate equivalent, because this number makes the required dose of the respective opioid easier to detect than the morphine equivalent.
  • fentanyl is a very lipophilic drug that is almost quantitatively absorbed through the nasal mucosa.
  • the applied amount is proportional to the amount absorbed, the simple amount of ratio information can be used to calculate the required amount of drug.
  • Preferably used opioids are sufentanil, remifentanil, fentanyl, alfentanil, buprenorphine, hydromorphone and oxycodone. These active substances have such a strong potency that even low concentrations reach the effect equivalent to the fentanyl mentioned above.
  • the lower values of the indicated ranges correspond to 25 ⁇ g fentanyl citrate, the upper values correspond to 2 mg fentanyl citrate.
  • Fentanyl citrate is particularly preferred as a fentanyl salt, because it is easy to process and there is ample experience.
  • other fentanyl salts can also be used. It is always important to ensure that the stated equivalent amounts are met, so that the concentration used from 0.0009 mol / l to 0.076 mol / l fentanyl at a stroke volume of preferably 50 ul. This corresponds to an administered mass of 25 ⁇ g to 2 mg of fentanyl citrate and a mass of 15 ⁇ g to 1.3 mg of fentanyl base.
  • the undiluted drug solution in the first container has a fentanyl citrate equivalent concentration of preferably up to 2 mg / 50 ⁇ l. It has It has been shown that the active substance solution in the first container should preferably have a fentanyl citrate equivalent concentration of at least 250 ⁇ g per 50 ⁇ l so that useful active ingredient concentrations are available on site in conjunction with the diluting solution in the second container.
  • the drugs sufentanil, remifentanil, fentanyl, alfentanil and buprenorphine are particularly preferred as drugs in the emergency kit of the present invention. Even better, sufentanil, remifentanil and fentanyl are suitable for use in this emergency kit. Due to its solid data and extensive experience with this drug, fentanyl is the most suitable drug for the emergency kit.
  • Nasal fentanyl is excellent for controlling acute respiratory distress for a variety of reasons; On the one hand, this is the extremely rapid onset of nasal administration, which is comparable to intravenous administration; On the other hand, fentanyl has a very short duration of action and a high potency, so that even a spray can be sufficient to relieve the symptoms, while the effect of fentanyl after symptom control quickly dissipates.
  • the physician is allowed to replenish the drug solution of the first container with the dilution solution of another container during the emergency, so that the drug solution is diluted.
  • the dilution solutions in the second and each further container preferably differ only in terms of their volume, so that by mixing with the drug solution of the first container quickly the required concentration in the first container can be obtained.
  • the containers are marked differently colored. This allows the rapid identification of the containers and a safe preparation of a ready to use diluted drug solution without own error-prone computational work in the emergency situation.
  • the first container which contains the diluted or even undiluted solution, is then suitable for remaining in the patient.
  • the emergency set is preferably accompanied by a selection of suitable labels, of which the one corresponding to the concentration is attached to the first container in a self-adhesive manner. The product thus obtained can remain with the patient and allows him to independently treat further attacks of acute respiratory distress.
  • the present emergency kit has the advantage that the doctor or the palliative care team only has to carry one opioid medicine with them. This reduces the administrative burden since the fate of each narcotic must be meticulously documented.
  • the emergency kit the entire amount of opioid is always delivered to the patient so that there is no waste that would be expensive to dispose of.
  • the diluting solutions comprise saline, which more preferably has a tonicity in the range of from 127.5 mOsm to 574 mOsm.
  • saline which more preferably has a tonicity in the range of from 127.5 mOsm to 574 mOsm.
  • the dilution solutions are more likely to have tonicities in the range between 290 mOsm and 310 mOsm, because this makes application even less irritating possible.
  • the saline solutions are blood-isotonic because it makes the application virtually nontoxic.
  • surfactants are used for this purpose.
  • the surfactants are preferably selected from the group consisting of phospholipids, water-dispersible soybean lecithin, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, macrogol stearate, Poloxamer®, sodium lauryl sulfate and Pluronic® F68. These solubilizers are suitable for improving the solubility of the active ingredient used and also for reducing the adsorption of the active substance on the walls of the vessels.
  • the finished nasal spray includes resorption mediators selected from the group consisting of cyclodextrins and ⁇ -lecithin.
  • the patient may be administered a dose of opioid to treat respiratory distress, tailored to his condition, and in particular his premedication. It was found that the preferred dose, the one Patients who are already on opioid analgesics must be administered at least four times their equivalent hourly dose to elicit relief.
  • both the drug and diluent solutions comprise a preservative.
  • the preferred preservative is benzalkonium chloride.
  • the active ingredient and dilution solutions preferably comprise water as a solvent.
  • the tonicity is preferably adjusted by adding sodium chloride.
  • the first container is preferably a nasal spray bottle.
  • any nasal spray bottle can be used.
  • care must be taken to ensure that it is a nasal spray bottle that delivers a sufficiently reproducible solution volume per stroke.
  • this reproducible volume is between 30 and 100 ⁇ l.
  • Such a volume is capable of being applied in a single puff without a significant amount immediately running down the nose or down the pharynx. Experiments have shown that a volume per stroke of 50 ul is best.
  • nasal spray bottles have a hose which absorbs a volume of the solution contained in the bottle on actuation of the triggering mechanism and atomizes with the aid of the spray attachment. It may happen that as soon as only small volumes of the solution are in the bottle, the amount of active ingredient administered per stroke becomes smaller. In particular, the patient gets the impression that he has not received the required amount of active ingredient. While this is not a problem in nasal sprays with only locally effective and less potent drugs, this can be highly potent Active ingredients such as the above-mentioned opioids quickly cause problems. It is therefore preferred in accordance with the invention to use nasal spray bottles which either have a bottle bottom sloping or rising off the center of the bottle bottom (FIG. 1 or FIG. 2). This ensures that the residual amount of active substance solution still remaining in the bottle after multiple use can be almost completely sprayed by actuation of the triggering mechanism. This has the additional advantage that no residual quantities remain, which would have to be disposed of consuming.
  • the ratio of the volumes of the drug solution to the first dilution solution is preferably in the range of 0.5 to 2, while the ratio of the volumes of the drug solution to the second dilution solution is in the range of 2 to 6.
  • the first container contains an opioid drug solution in a volume of between 1 and 10 ml and preferably between 1 and 3 ml.
  • the second container comprises dilution solution in a volume of preferably between 1 and 20 ml, more preferably between 1 and 5
  • a third container preferably comprises dilution solution in a volume of between 5 and 40 ml, more preferably between 6 and 12 ml.
  • the first container has a drug solution with an active ingredient concentration of between 501 and 2000 ⁇ g fentanyl citrate equivalent per 50 ⁇ l.
  • the emergency set comprises a first, a second and a third container, wherein the ratios of the volumes of active substance solution in the first container for dilution solution in the second or third container with 1 to 0.8 to 1, 2 to 3.5 to 4.5 can be described.
  • the resulting drug concentrations then behave as 1 to 0.45 to 0.56 at 0.18 to 0.22.
  • the active substance concentration in the active substance solution is preferably at least 250 ⁇ g fentanyl citrate equivalent per 50 ⁇ l, more preferably at least 501 ⁇ g fentanyl citrate equivalent per 50 ⁇ l, even more preferably 650 ⁇ g fentanyl citrate equivalent per 50 ⁇ l, further preferably at least 780 ⁇ g fentanyl citrate equivalent per 50 ⁇ l and also preferably at least 1000 ⁇ g fentanyl citrate equivalent per 50 ⁇ l.
  • the upper limit for the fentanyl citrate equivalent concentration is 2000 ⁇ g per 50 ⁇ l, preferably 2500 ⁇ g per 50 ⁇ l and more preferably 3000 ⁇ g per 50 ⁇ l.
  • the emergency set in a particularly preferred embodiment exactly three containers.
  • the present invention also encompasses the use of opioids for the preparation of an emergency kit for use in respiratory distress described above.
  • the emergency kit according to the invention is used in palliative patients with respiratory distress.
  • an emergency kit according to the invention is described below using the example of a kit with a first container comprising a drug solution and a second and a third container each comprising dilution solution.
  • a dilution solution is prepared.
  • 117 ml of 0.9% sodium chloride solution with 13 ml of benzalkonium chloride stock solution are added.
  • the solution thus obtained constitutes the dilution solution and is filled into ten prepared plastic containers (Redipac) in volumes of 2.05 ml each.
  • the containers thus obtained represent the second container according to the invention with the first dilution solution.
  • This emergency kit contains a nasal spray bottle containing drug solution, a first container of dilution solution and a third diluent solution container, and a yellow label as required by law for a fentanyl nasal spray containing 250 ⁇ g of active ingredient per stroke and a white label labeled 100 ⁇ g of active ingredient per hub. Thereafter, the emergency kit is securely closed and ready for use.
  • FIG. 1 shows a first container 1 with a bottle bottom 2 sloping conically away from the center of the bottom of the bottle in accordance with a preferred embodiment of the present invention.
  • the bottom of the bottle can also be designed such that it does not drop conically as in FIG. 1, but rather represents a section of a sphere.
  • FIG. 2 shows a first container 1 with a bottle bottom 3 that rises conically from the center of the bottle bottom according to a preferred embodiment of the present invention.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Otolaryngology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un ensemble de secours pour le traitement de patients palliatifs en cas de crises de dyspnée aiguë. L'ensemble de secours permet d'administrer rapidement et de manière sûre, un opioïde à la concentration requise. L'ensemble de secours comprend une solution de principe actif ayant une teneur en opioïde, qui est appropriée, seule ou mélangée avec une solution de dilution, pour préparer rapidement des pulvérisations nasales aux dosages fréquemment requis.
PCT/EP2010/052189 2009-02-20 2010-02-22 Ensemble de secours pour la production d'un médicament pour l'application nasale d'opioïdes en cas de dyspnée Ceased WO2010094792A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE200910001041 DE102009001041A1 (de) 2009-02-20 2009-02-20 Notfallset zur Herstellung eines Arzneimittels zur nasalen Anwendung von Opioiden bei Atemnot
DE102009001041.6 2009-02-20

Publications (1)

Publication Number Publication Date
WO2010094792A1 true WO2010094792A1 (fr) 2010-08-26

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Application Number Title Priority Date Filing Date
PCT/EP2010/052189 Ceased WO2010094792A1 (fr) 2009-02-20 2010-02-22 Ensemble de secours pour la production d'un médicament pour l'application nasale d'opioïdes en cas de dyspnée

Country Status (2)

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DE (1) DE102009001041A1 (fr)
WO (1) WO2010094792A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050004155A1 (en) * 2003-04-08 2005-01-06 Boyd Thomas A. Use of methylnaltrexone to treat irritable bowel syndrome
US20070209660A1 (en) * 2000-05-10 2007-09-13 Wermeling Daniel P Intranasal Opioid Compositions, Delivery Devices and Methods of Using Same
WO2009040595A1 (fr) * 2007-09-28 2009-04-02 Wockhardt Research Centre Composition pharmaceutique à multiples doses d'un analgésique pour administration nasale

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040115133A1 (en) * 2000-05-10 2004-06-17 Wermeling Daniel P. Intranasal opioid compositions
AU2001281746C1 (en) * 2000-07-31 2010-09-09 ISTITUTO GENTILI S.r.l. Fentanyl composition for nasal administration
DE10064219B9 (de) * 2000-12-22 2009-02-12 Nasalis Pain Relief International Gmbh Neue Fentanyl und/oder dessen Derivate enthaltende pharmazeutische Zusammensetzung zur nasalen Anwendung
FR2818963B1 (fr) * 2001-01-04 2003-04-11 Valois Sa Dispositif de distribution de produit fluide du type combidose
US7666876B2 (en) * 2002-03-19 2010-02-23 Vernalis (R&D) Limited Buprenorphine formulations for intranasal delivery

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070209660A1 (en) * 2000-05-10 2007-09-13 Wermeling Daniel P Intranasal Opioid Compositions, Delivery Devices and Methods of Using Same
US20050004155A1 (en) * 2003-04-08 2005-01-06 Boyd Thomas A. Use of methylnaltrexone to treat irritable bowel syndrome
WO2009040595A1 (fr) * 2007-09-28 2009-04-02 Wockhardt Research Centre Composition pharmaceutique à multiples doses d'un analgésique pour administration nasale

Non-Patent Citations (2)

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Title
BOOTH S ET AL.: "The etiology and management of intractable breathlessness in patients with advanced cancer: a systemic review of pharmacological therapy", NATURE CLINICAL PRACTICE ONCOLOGY, vol. 5, no. 2, February 2008 (2008-02-01), pages 90 - 100
CLEMENS-K-E. KLASCHIK-E.: "Morphine in the management of dyspnoea in ALS. A pilot study", EUROPEAN JOURNAL OF NEUROLOGY, vol. 15, 1 May 2008 (2008-05-01), pages 445 - 450, XP002580239 *

Also Published As

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