WO2003004015A1 - Emulsions de type aqueux comprenant un medicament a base de benzodiazepine - Google Patents

Emulsions de type aqueux comprenant un medicament a base de benzodiazepine Download PDF

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Publication number
WO2003004015A1
WO2003004015A1 PCT/GB2002/003005 GB0203005W WO03004015A1 WO 2003004015 A1 WO2003004015 A1 WO 2003004015A1 GB 0203005 W GB0203005 W GB 0203005W WO 03004015 A1 WO03004015 A1 WO 03004015A1
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oil
composition
emulsion
phase
vitamin
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PCT/GB2002/003005
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English (en)
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Yu-Hui Cheng
Lisbeth Illum
John Bond
Peter Watts
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West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited
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Publication of WO2003004015A1 publication Critical patent/WO2003004015A1/fr

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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • This invention relates to new oil-in-water emulsion compositions.
  • Emulsion systems have long been used for pharmaceutical purposes. Such systems include oil-in-water emulsions, water-in-oil emulsions and more complex systems known as multiple emulsions.
  • Oil-in-water emulsions in which the continuous phase is aqueous and the dispersed phase is oily in nature, may be used for a variety of purposes and administered via a variety of routes, including injection as well as administration to the eye, nose, lung, gastrointestinal tract or vagina.
  • Benzodiazepine compounds which act on the central nervous system to cause sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia and to prevent convulsions, are widely used in medicine.
  • the benzodiazepine drug midazolam (8-chloro-6-(2-fluoro ⁇ henyl)-l-methyl- 4H-imidazo[l,5 ⁇ -][l,4]benzodiazepine) is used as a sedative, especially in a hospital setting and particularly as premedication prior to surgery.
  • aqueous solubility of midazolam is low, and to deliver a therapeutic dose to an adult by the intranasal route would require a prohibitively large dose volume.
  • WO 00/24373 describes oil-in-water emulsions of drugs that are poorly soluble in water, especially non-steroidal anti-inflammatory drugs and drugs for the treatment of pain, erectile dysf nction and Parkinson's disease.
  • Compositions comprising Vitamin E and benzodiazepines are neither disclosed nor suggested.
  • compositions comprising benzodiazepines are described in US 4,950,664.
  • vitamin E in such compositions is neither disclosed nor suggested.
  • preferred dosage forms are solutions, suspensions and gels.
  • WO 97/03651 describes emulsion compositions containing vitamin E as a solubilising agent.
  • Emulsion formulations of drug compounds are described in US 6,193,985.
  • the compositions comprise active agent dissolved in an oil phase comprising tocopherol (vitamin E), wherein the vitamin E comprises 20 to 95% w/w of the compositions.
  • the second phase of the emulsion comprises vitamin E TPGS as the emulsifying agent.
  • Vitamin E TPGS is a water soluble derivative of vitamin E and consists of tocopherol esterified with succinic acid, the other acidic group of the latter being esterified with polyethylene glycol 1000.
  • Compositions in which the oil phase comprises 1 to 35% (w/w) of vitamin E are neither disclosed nor suggested.
  • oil-in-water emulsion compositions for the delivery of a benzodiazepine drug to a patient comprising:
  • the emulsions according to the invention are adapted for intranasal administration.
  • vitamin E includes all tocol and tocotrienol derivatives that exhibit vitamin E activity. It is preferred that the vitamin E is water insoluble and/or non-water dispersible.
  • the nomenclature for vitamin E and related compounds is unclear in current practice and can vary when used by different compendia and organisations.
  • the United States Pharmacopoeia describes vitamin E as a form of ⁇ -tocopherol. This includes D- or D,L- ⁇ -tocopherol, D- or D,L- ⁇ -tocopherol acetate and D- or D,L- ⁇ -tocopherol succinate.
  • vitamin E should be used as a generic description for all tocol and tocotrienol derivatives that exhibit vitamin E activity.
  • tocopherols is synonymous with vitamin E but also for methyl tocols.
  • ⁇ -Tocopherol is a trivial name without defined stereochemistry.
  • the vitamin E is preferably in the form of the free alcohol, but suitable tocopherol derivatives include esters of tocopherol such as the linoleate, nicotinate, acetate or acid succinate ester.
  • the emulsions according to the invention have an oil phase that comprises one or more pharmaceutically acceptable oils.
  • oils are preferably non-hydroxylated (i.e. they have a hydroxyl value of less than 20) and as such they include vegetable oils such as soybean oil, sesame oil, safflower oil, canola oil, corn oil, cottonseed oil and olive oil as well as marine oils such as cod liver oil and sardine oil.
  • Preferred oils are sesame oil, canola oil, corn oil, cottonseed oil, and, especially, soybean oil.
  • the emulsions according to the invention preferably have an oil phase that represents 12 to 50% (w/v) and more preferably 15 to 40% (w/v) of the total emulsion. Further, the emulsions according to the invention preferably have an oil phase that comprises 2.5 to 30% (w/w) (such as 5 to 25% (w/w)) vitamin E.
  • benzodiazepine drug will be understood by those skilled in the art to include all pharmacologically active compounds that possess the benzodiazepine (sub-)structure, and which may act on the central nervous system. See also the definition provided in Goodman & Gilman's "The Pharmacological Basis of Therapeutics", 9 th Edition (1996), McGraw-Hill at pages 363 and 364, the relevant disclosure in which document is hereby incorporated by reference.
  • benzodiazepine drugs include alprazolam, bentazepam, bromazepam, brotizolam, camazepam, chlordiazepoxide, cinolazepam, clobazam, clonazepam, clorazepic acid, clorazepate, clotiazepam, clozapine, delorazepam, diazepam, estazolam, ethyl loflazepate, etizolam, fludiazepam, flunitrazepam, flurazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, metaclazepam, mexazolam, midazolam, nimetazepam, nitrazepam, oxazepam, pinazepam, prazepam, quazepam, temazape
  • Preferred benzodiazepine drugs include alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, halazepam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazapem, triazolam and, especially, midazolam.
  • the benzodiazepine drug content of the emulsions according to the invention is dependent upon the solubility of the benzodiazepine drug in question and the dose that needs to be delivered to the patient.
  • the typical dose volume is in the range 0.1 to 0.4 mL although smaller or larger volumes may also be given.
  • the benzodiazepine drug may be incorporated into the emulsions according to the invention by being dissolved into the oil phase prior to emulsification.
  • the benzodiazepine drag content of the oil phase prior to preparation of the emulsions according to the invention is preferably in the range 1 to 1000 mg/mL, more preferably 2 to 800 mg/mL and most preferably 4 to 600 mg/mL.
  • the benzodiazepine drug content of the final oil-in-water emulsion is preferably in the range 0.1 to 300 mg mL, more preferably 0.5 to 250 mg/mL and most preferably 1 to 200 mg/mL.
  • emulsion stabiliser refers to agents that, when present in emulsions according to the invention, either prevent or retard phase separation (i.e. the formation of distinct oil and/or water layers) in the emulsions.
  • phase separation i.e. the formation of distinct oil and/or water layers
  • the term therefore includes agents that prevent phase separation in the emulsions according to the invention for one or more hours or, preferably, for one or more days (e.g. 3 or more days, such as one or more weeks, and, particularly, one or more months).
  • the emulsion stabiliser is preferably incorporated into the emulsions according to the invention via the aqueous phase.
  • Preferred emulsion stabilisers include one or more thickening and/or, particularly, emulsifying agents.
  • Suitable thickening agents include cellulose-based thickening agents such as methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
  • Suitable emulsifying agents include: (a) ionic surfactants (e.g. phospholipids such as lecithin); and (b) non-ionic surfactants (e.g. polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxyethylene castor oil derivatives and polyoxyethylene alkyl ethers).
  • lecithin Principle sources of lecithin are eggs and soybeans. Synonyms for lecithin include egg lecithin; mixed soybean phosphatides; ovolecithin; egg yolk phospholipids; soybean lecithin; soybean phospholipids; vegetable lecithin.
  • Preferred emulsions according to the invention include those that include an emulsion stabiliser that is an emulsifying agent (e.g. an ionic surfactant such as lecithin).
  • an emulsifying agent e.g. an ionic surfactant such as lecithin
  • preferred emulsions according to the invention also include those in which lecithin is employed as an emulsion stabiliser, and a non-ionic surfactant and/or a thickening agent, as hereinbefore defined, is/are optionally employed as (a) further emulsion stabiliser(s).
  • the amount of emulsion stabiliser (e.g. lecithin) used in the emulsion according to the invention is preferably in the range 0.01 to 15% (w/v), more preferably 0.05 to 10% (w/v) and most preferably 0.1 to 5% (w/v).
  • the non-ionic surfactant may have a concentration that is preferably in the range 0.01 to 25% (w/v), more preferably 0.05 to 20% (w/v) and most preferably 0.1 to
  • the thickening agent may have a concentration that is dependent upon its molecular weight. However, its concentration in an emulsion according to the invention is preferably in the range 0.01 to 20% (w/v), more preferably 0.05 to 15% (w/v) and most preferably 0.1 to 10% (w/v).
  • the pH of the emulsions according to the invention is an important determinant of how well they are tolerated when administered into the nasal cavity.
  • the emulsion may cause irritation and stinging if the pH is too high or low.
  • the emulsion according to the invention comprises midazolam, it is also preferable to avoid a low pH in order to minimise drug partitioning from the oil phase into the aqueous phase. High concentrations of midazolam in the aqueous phase may exacerbate irritation.
  • the pH of the aqueous phase of an emulsion according to the invention is preferably in the range pH 5.0 to 8.0, more preferably 5.25 to 7.8 and most preferably pH 5.5 to 7.6.
  • the pH of the aqueous phase of the emulsions according to the invention may be adjusted and controlled by means well known to those skilled in the art, such as buffer salts, acids and bases.
  • the aqueous phase may contain one or more of the following pH controlling agents: organic acids (e.g. citric acid and the like) or alkali metal (e.g. sodium) salts thereof, pharmaceutically acceptable salts (e.g. sodium, magnesium or calcium salts) of inorganic acids (such as carbonic acid or phosphoric acid), oxides of magnesium, as well as alkali, and alkaline earth, metal (e.g. sodium, calcium, potassium and the like) sulphates, metabisulphates, propionates and sorbates.
  • the aqueous phase may, in particular, comprise a buffered aqueous solution, such as phosphate-buffered saline, that has a pH within any of the above-mentioned ranges (e.g. pH 7.4).
  • the emulsions according to the invention may, if necessary, be adjusted to approximately the same osmotic pressure as that of the body fluids. This may be desirable where a composition is to be applied to delicate tissue membranes, such as those found in the nasal cavity. A composition that has been adjusted in this manner is said to be isotonic and will not tend to swell or contract the tissues with which it comes into contact and will result in minimal discomfort on application.
  • the formation of isotonic preparations may be achieved by adding an ionic compound, such as sodium chloride, or a non-ionic compound to the composition. Suitable non-ionic compounds include glycerol and mannitol.
  • the emulsions according to the invention may also contain other ingredients in the oil and/or aqueous phases such as antioxidants, chelating agents, preservatives or other agents generally used in pharmaceutical liquid or emulsion formulations. Such agents are well known to those skilled in the art.
  • Preferred emulsions according to the invention include those that are stable with respect to phase separation for one or more days (e.g. 3 or more days, such as one or more weeks, and, particularly, one or more months).
  • stable with respect to phase separation includes compositions that, on storage, either do not form a distinct oil layer or form a distinct layer of non-coalesced oil droplets that may be redispersed by gentle shaking (e.g. shaking by hand) alone. The latter process, by which a layer of stabilised oil droplets separates, is known as "creaming".
  • the emulsions according to the invention are prepared by dissolving or dispersing emulsion stabiliser in the aqueous phase.
  • the aqueous phase is then mixed with the oil phase (comprising vitamin E, oil and the benzodiazepine drug) to form a dispersion of oil droplets.
  • the size and size distribution of the oil droplets in the emulsions according to the invention will depend on the method of mixing.
  • the droplet size as measured by techniques such as light microscopy or laser diffraction, generally lies in the range 0.1 to 10 ⁇ m.
  • High shear mixing using equipment such as a homogeniser or a microfluidiser is the preferred method of preparing pharmaceutical emulsions.
  • an emulsion according to the invention for the manufacture of a medicament for the administration of a benzodiazepine drug (e.g. midazolam) to a patient in need of such administration.
  • a benzodiazepine drug e.g. midazolam
  • another aspect of the invention provides a method of administering a benzodiazepine drug (e.g. midazolam) to a patient, which method comprises administering to the patient an emulsion according to the invention.
  • an emulsion according to the invention in the manufacture of a medicament for the treatment of a condition in which benzodiazepine drug treatment is indicated.
  • benzodiazepine drug treatment may be indicated.
  • anxiety disorders e.g. febrile convulsions and convulsions from status epilepticus
  • disturbed behaviour e.g. parasomnias (e.g. insomnia, restless leg syndrome, sleepwalking or night terrors)
  • dyspnoea e.g. muscle spasm (e.g. from spasticity, dystonias, stiff-man syndrome, cerebral palsy, poisoning or tetanus)
  • emesis e.g. nausea and vomiting associated with, for example, cancer chemotherapy
  • Benzodiazepine drugs may also be given for premedication (e.g. before general anaesthesia or to provide sedative cover for minor surgical or investigative procedures) and/or to induce sedation, hypnosis and/or anterograde amnesia.
  • Preferred indications include the provision of sedative cover for minor surgical or investigative procedures.
  • the emulsions according to the invention may be administered orally or parenterally.
  • parenterally includes administration to the muscles, subcutaneous tissue, peritoneal cavity, venous system, arterial system, lymphatic system, spinal fluid (intrathecal, epidural) and joint cavities.
  • Parenteral formulations will be sterile and usually pyrogen-free.
  • the emulsions according to the invention may also be administered to the gastrointestinal tract or other mucosal surfaces, such as the eye, nose, vagina or rectal cavity.
  • the emulsions according to the invention are administered intranasally.
  • the emulsions according to the invention may be administered to the nasal cavity in forms including drops or sprays.
  • Spray devices can be single ("unit") dose or multiple dose systems and are available from various commercial sources, including Pfeiffer, Valois, Bespak and Becton-Dickinson.
  • Emulsions according to the invention have the advantage that they may be more stable than (particularly with respect to phase separation), be better tolerated than, be less toxic than, have fewer side effects than, have better pharmacokinetic properties than, be more easily prepared than, or have any other useful properties over, compositions known in the prior art.
  • emulsions according to the invention also have the advantage that they may be prepared using established pharmaceutical processing methods and employ materials that are approved for use in food or pharmaceuticals or are of like regulatory status.
  • Placebo emulsion comprising 25% w/v oil phase in which oil phase comprises 40% w/w vitamin E
  • the oil phase was prepared by mixing 10 g of vitamin E (Sigma, Poole, UK) with 15 g of soybean oil (Oleificio SABO, Manno, Switzerland). Into 50 mL of phosphate buffered saline solution (PBS; Sigma) was dispersed 1.2 g of egg yolk phospholipid (lecithin; Kabi Pharmacia, Sweden), followed by the addition of 2.2 g of glycerol (Sigma). A coarse emulsion was prepared by mixing the oil and aqueous phases using a Silverson L4R homogeniser. The coarse emulsion was adjusted to a 100 mL volume with PBS and further emulsified by passing through a Rannie Mini-Lab high pressure valve homogeniser set at 1000 bar pressure.
  • PBS phosphate buffered saline solution
  • a coarse emulsion was prepared by mixing the oil and aqueous phases using a Silverson L4R homogeniser. The coarse emulsion was adjusted to a 100 mL volume
  • Placebo emulsion comprising 25 % w/v oil phase in which oil phase comprises 20% w/w vitamin E
  • the oil phase was prepared by mixing 5 g of vitamin E with 20 g of soybean oil.
  • the emulsion was then prepared in an identical manner to Example 1.
  • Placebo emulsion comprising 33.3% w/v oil phase in which oil phase comprises 20% w/w vitamin E
  • the oil phase was prepared by mixing 6.66 g of vitamin E with 26.64 g of soybean oil.
  • the emulsion was then prepared in an identical manner to Example 1.
  • Example 4 Placebo emulsion comprising 40% w/v oil phase in which oil phase comprises 20% w/w vitamin E
  • the oil phase was prepared by mixing 8 g of vitamin E with 32 g of soybean oil.
  • the emulsion was then prepared in an identical manner to Example 1.
  • Example 1 with an oil phase comprising 40% w/w vitamin E, had poor stability and the oil phase readily separated. It was not possible to restore the emulsion to its original uniform state by means of shaking.
  • Emulsion containing 10 mg/mL midazolam and 25% w/v oil phase Vitamin E (5 g) and 20 g of soybean oil were weighed into a 50 mL beaker.
  • Midazolam (1 g; R. W. Unwin, Welwyn, UK) was added to the vitamin E/soybean oil and the mixture was warmed and stirred at 30-40°C until the drug had dissolved.
  • Egg yolk phospholipid 1.2 g; lecithin
  • Glycerol (2.2 g) was added to the lecithin dispersion.
  • the oil phase was added to the aqueous phase and the two were mixed together by homogenisation for 1 minute at 7000-8000 rpm using a Silverson L4R mixer.
  • the coarse emulsion thus formed was made up to a volume of 100 mL and then passed three times through a Rannie Mini-Lab homogeniser at a pressure of 1000 bar.
  • the final product was a milky white to off-white emulsion.
  • Emulsion containing 10 mg/mL midazolam and 33% w/v oil phase Vitamin E (6.66 g) and 26.64 g of soybean oil were weighed into a 50 mL beaker.
  • Midazolam (1 g) was added to the vitamin E/soybean oil and the mixture was warmed and stirred at 30-40°C until the drug had dissolved.
  • the emulsion was then prepared according to Example 6.
  • Vitamin E (5 g) and 20 g of soybean oil are weighed into a 50 mL beaker.
  • Midazolam (1 g) is added to the vitamin E/soybean oil and the mixture is warmed and stirred at 30-40°C until the drug has dissolved.
  • Egg yolk phospholipid (1.2 g; lecithin) and 0.5 g of polyoxyethylene 20 sorbitan monooleate (Sigma) is weighed into a 250 mL beaker and dispersed into 50 mL of pH 7.4 phosphate buffered saline solution at 30-40.C.
  • Glycerol (2.2 g) is added to this aqueous phase.
  • the oil phase is added to the aqueous phase and the two are mixed together by homogenisation for 1 minute at 7000-8000 rpm using a Silverson L4R mixer.
  • the coarse emulsion thus formed is made up to a volume of 100 mL and then passed three times through a Rannie Mini-Lab homogeniser at a pressure of 1000 bar.
  • the final product will be a milky white to off-white emulsion.
  • Example 9 Emulsion containing 10 mg/mL midazolam with methylcellulose as thickening agent
  • Vitamin E (6.66 g) and 26.64 g of soybean oil are weighed into a 50 mL beaker.
  • Midazolam (1 g) is added to the vitamin E/soybean oil and the mixture is warmed and stirred at 30-40°C until the drug has dissolved.
  • Egg yolk phospholipid (1.2 g; lecithin) and 0.5 g of methylcellulose (Methocel® A15LV; Colorcon, Orpington, UK) are weighed into a 250 mL beaker and dispersed into 50 mL of pH 7.4 phosphate buffered saline solution at 30-40°C.
  • Glycerol (2.2 g) is added to the lecithin dispersion.
  • the oil phase is added to the aqueous phase and the two are mixed together by homogenisation for 1 minute at 7000-8000 rpm using a Silverson L4R mixer.
  • the coarse emulsion thus formed is made up to a volume of 100 mL and then passed three times through a Rannie Mini-Lab homogeniser at a pressure of 1000 bar.
  • the final product will be a milky white to off-white emulsion.
  • Emulsion containing 10 mg/mL midazolam with polyoxyl 40 stearate as additional emulsifier and hydroxypropyl methylcellulose as thickening agent Vitamin E (6.66 g) and 26.64 g of soybean oil are weighed into a 50 mL beaker.
  • Midazolam (1 g) is added to the vitamin E/soybean oil and the mixture is warmed and stirred at 30-40°C until the drug has dissolved.
  • Egg yolk phospholipid (1.2 g; lecithin), 0.5 g of polyoxyl 40 stearate (polyoxyethylene (40) stearate; Sigma) and 0.5 g of hydroxypropyl methylcellulose (Methocel® K4M; Colorcon) are weighed into a 250 mL beaker and dispersed into 50 mL of pH 7.4 phosphate buffered saline solution at 30-40°C.
  • Glycerol (2.2 g) is added to the lecithin dispersion.
  • the oil phase is added to the aqueous phase and the two are mixed together by homogenisation for 1 minute at 7000-8000 rpm using a Silverson L4R mixer.
  • the coarse emulsion thus formed is made up to a volume of 100 mL and then passed three times through a Rannie Mini-Lab homogeniser at a pressure of 1000 bar.
  • the final product will be a milky white to off-white emulsion.
  • the sheep is an excellent animal model for nasal pharmacokinetic studies with a large nasal cavity and the ability to receive human-sized doses of drags and formulations. If an irritant drag or formulation is administered intranasally to the sheep, it may cause the animal to sneeze and snort and the extent of sneezing and snorting may be related to the irritancy of the formulation.
  • a group of five sheep were each administered with a midazolam emulsion formulation of identical composition to Example 7 as part of a pharmacokinetic study. Each animal, weighing approximately 55 kg, was administered intranasally with the emulsion at a dose volume of 0.02 mL/kg divided equally between both nostrils i.e.

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  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des compositions d'émulsions de type aqueux comprenant un médicament à base de benzodiazépine, tel que le midazolam, dissous dans une phase huileuse comprenant de 1 à 35 % en poids de vitamine E.
PCT/GB2002/003005 2001-06-30 2002-07-01 Emulsions de type aqueux comprenant un medicament a base de benzodiazepine WO2003004015A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0116107.4 2001-06-30
GBGB0116107.4A GB0116107D0 (en) 2001-06-30 2001-06-30 Pharmaceutical composition

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WO2003004015A1 true WO2003004015A1 (fr) 2003-01-16

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7700588B2 (en) 2004-01-14 2010-04-20 Merkus Franciscus Wilhelmus He Pharmaceutical compositions comprising midazolam in a high concentration
GB2481407A (en) * 2010-06-22 2011-12-28 Special Products Ltd A rapid onset liquid midazolam composition for buccal administration
CN102579533A (zh) * 2012-04-01 2012-07-18 王国恩 一种治疗亚健康的药物制剂
EP2720699A2 (fr) * 2011-06-14 2014-04-23 Hale Biopharma Ventures, Llc Administration de benzodiazépine
US20150359738A1 (en) * 2014-06-16 2015-12-17 Loewi LLC Methods of Anesthetizing Nerve Tissue in the Trigeminal Nerve Pathway and Medical Uses Thereof
EP2958593A4 (fr) * 2013-02-22 2016-08-03 Eastgate Pharmaceuticals Inc Composition pharmaceutique pour l'administration transmuqueuse de benzodiazépines
CN105919956A (zh) * 2016-06-14 2016-09-07 安徽省逸欣铭医药科技有限公司 依替唑仑的稳定片剂及制备方法
WO2017056075A1 (fr) 2015-10-01 2017-04-06 Solutex Na, Lcc Procédé pour la préparation et la stabilisation d'émulsions à base d'oméga 3 par l'intermédiaire de réseaux cristallins isométriques de dérivés de cellulose
US10736842B2 (en) 2014-06-25 2020-08-11 Synergia Bio Sciences Private Limited Pharmaceutical oil-in-water nano-emulsion
US11241414B2 (en) 2008-03-28 2022-02-08 Neurelis, Inc. Administration of benzodiazepine compositions
US11400048B2 (en) 2014-06-25 2022-08-02 Synergia Bio Sciences Private Limited Pharmaceutical oil-in-water nano-emulsion

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EP0163924A1 (fr) * 1984-05-02 1985-12-11 Roshdy Dr. Ismail Médicament vitaminique pour le traitement et pour la protection des muqueuses ainsi qu'application de la vitamine E pour la fabrication du médicament
EP0391369A2 (fr) * 1989-04-05 1990-10-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Emulsions pour médicaments
WO1997003651A1 (fr) * 1995-07-20 1997-02-06 Danbiosyst Uk Limited Composition a vehicule lipidique pour l'administration de medicaments contenant de la vitamine e
WO2000024373A1 (fr) * 1998-10-24 2000-05-04 West Pharmaceutical Services Drug Delivery & Clinical Research Centre, Ltd. Emulsion huile dans eau comprenant une huile hydroxylee
US6193985B1 (en) * 1994-05-16 2001-02-27 A/S Dumex (Dumex Ltd) Tocopherol compositions for delivery of biologically active agents

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0163924A1 (fr) * 1984-05-02 1985-12-11 Roshdy Dr. Ismail Médicament vitaminique pour le traitement et pour la protection des muqueuses ainsi qu'application de la vitamine E pour la fabrication du médicament
EP0391369A2 (fr) * 1989-04-05 1990-10-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Emulsions pour médicaments
US6193985B1 (en) * 1994-05-16 2001-02-27 A/S Dumex (Dumex Ltd) Tocopherol compositions for delivery of biologically active agents
WO1997003651A1 (fr) * 1995-07-20 1997-02-06 Danbiosyst Uk Limited Composition a vehicule lipidique pour l'administration de medicaments contenant de la vitamine e
WO2000024373A1 (fr) * 1998-10-24 2000-05-04 West Pharmaceutical Services Drug Delivery & Clinical Research Centre, Ltd. Emulsion huile dans eau comprenant une huile hydroxylee

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7700588B2 (en) 2004-01-14 2010-04-20 Merkus Franciscus Wilhelmus He Pharmaceutical compositions comprising midazolam in a high concentration
US11241414B2 (en) 2008-03-28 2022-02-08 Neurelis, Inc. Administration of benzodiazepine compositions
US11793786B2 (en) 2008-03-28 2023-10-24 Neurelis, Inc. Administration of benzodiazepine compositions
US9763876B2 (en) 2008-03-28 2017-09-19 Hale Biopharma Ventures, Llc Administration of benzodiazepine compositions
US8455478B2 (en) 2010-06-22 2013-06-04 Special Products, Ltd. Rapid onset liquid midazolam composition for buccal administration
GB2481407B (en) * 2010-06-22 2012-05-23 Special Products Ltd A rapid onset liquid midazolam composition for buccal administration
JP2012006925A (ja) * 2010-06-22 2012-01-12 Special Products Ltd 医薬組成物
AU2011268706B2 (en) * 2010-06-22 2014-11-27 Veriton Pharma Limited Pharmaceutical composition comprising midazolam
WO2011161439A1 (fr) * 2010-06-22 2011-12-29 Special Products Limited Composition pharmaceutique comprenant du midazolam
GB2481407A (en) * 2010-06-22 2011-12-28 Special Products Ltd A rapid onset liquid midazolam composition for buccal administration
EP2720699A2 (fr) * 2011-06-14 2014-04-23 Hale Biopharma Ventures, Llc Administration de benzodiazépine
EP2720699A4 (fr) * 2011-06-14 2015-04-29 Hale Biopharma Ventures Llc Administration de benzodiazépine
EP3415139A1 (fr) * 2011-06-14 2018-12-19 Hale Biopharma Ventures, Llc Administration de benzodiazépine
CN102579533A (zh) * 2012-04-01 2012-07-18 王国恩 一种治疗亚健康的药物制剂
EP2958593A4 (fr) * 2013-02-22 2016-08-03 Eastgate Pharmaceuticals Inc Composition pharmaceutique pour l'administration transmuqueuse de benzodiazépines
US20150359738A1 (en) * 2014-06-16 2015-12-17 Loewi LLC Methods of Anesthetizing Nerve Tissue in the Trigeminal Nerve Pathway and Medical Uses Thereof
US10736842B2 (en) 2014-06-25 2020-08-11 Synergia Bio Sciences Private Limited Pharmaceutical oil-in-water nano-emulsion
US11400048B2 (en) 2014-06-25 2022-08-02 Synergia Bio Sciences Private Limited Pharmaceutical oil-in-water nano-emulsion
WO2017056075A1 (fr) 2015-10-01 2017-04-06 Solutex Na, Lcc Procédé pour la préparation et la stabilisation d'émulsions à base d'oméga 3 par l'intermédiaire de réseaux cristallins isométriques de dérivés de cellulose
US10856564B2 (en) 2015-10-01 2020-12-08 Solutex Na, Lcc Process for the preparation and stabilization of emulsions with Omega-3 by means of isometric crystalline networks of cellulose derivatives
CN105919956A (zh) * 2016-06-14 2016-09-07 安徽省逸欣铭医药科技有限公司 依替唑仑的稳定片剂及制备方法

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