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WO2020150098A1 - Compositions pharmaceutiques et procédés pour des applications anesthésiologiques - Google Patents

Compositions pharmaceutiques et procédés pour des applications anesthésiologiques Download PDF

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Publication number
WO2020150098A1
WO2020150098A1 PCT/US2020/013116 US2020013116W WO2020150098A1 WO 2020150098 A1 WO2020150098 A1 WO 2020150098A1 US 2020013116 W US2020013116 W US 2020013116W WO 2020150098 A1 WO2020150098 A1 WO 2020150098A1
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Prior art keywords
pharmaceutical composition
pharmaceutically active
active compound
group
pharmaceutical formulation
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English (en)
Inventor
Dennis Elias Saadeh
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Melt Pharmaceuticals Inc
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Melt Pharmaceuticals Inc
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Priority claimed from US16/250,450 external-priority patent/US20190142841A1/en
Application filed by Melt Pharmaceuticals Inc filed Critical Melt Pharmaceuticals Inc
Publication of WO2020150098A1 publication Critical patent/WO2020150098A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates generally to the field of pharmacology and more specifically to compositions having anesthetic properties that are useful in various kinds of medical practice, such as surgery, and to methods of preparing and using such compositions.
  • the present disclosure relates to solid or liquid pharmaceutical formulations comprising combinations of active agents such as anesthetics, anti-emetics, blood pressure, anti-anxiety medications and/or analgesics, and methods for using the same for providing anesthesia by administering such compositions orally, including such administrations as sublingual or buccal.
  • the formulations may also include slow release reversal agents that would counteract the initial anesthesia effect.
  • compositions include a therapeutically effective quantity of at least one first pharmaceutically active compound comprising benzodiazepine moiety or
  • pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof a therapeutically effective quantity of at least one second pharmaceutically active compound that is an NMDA antagonist or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof, and at least one pharmaceutically acceptable excipient or carrier therefor.
  • compositions described above may further include a therapeutically effective quantity of at least one third pharmaceutically active compound that is a b-blocker, a nonsteroidal anti inflammatory drug (NS AID), or an anti emetic medicament, or a combination thereof, or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof.
  • a third pharmaceutically active compound that is a b-blocker, a nonsteroidal anti inflammatory drug (NS AID), or an anti emetic medicament, or a combination thereof, or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof.
  • the first pharmaceutically active compound may be any of midazolam, diazepam, lorazepam, flunitrazepam, alprazolam, chlordiazepoxide, clonazepam or clorazepate
  • the second pharmaceutically active compound may be any of ketamine, dextrorphan, etomidate, methadone, memantine, amantadine or dextromethorphan
  • the third pharmaceutically active compound may be (if a b-blocker) any of metoprolol, propranolol, acebutolol, nadolol, atenolol, betaxolol, esmolol, bisoprolol fumarate, carvedilol, nebivolol, penbutolol, timolol, or sotalol or (if an antiemetic
  • compositions such as any described above, wherein the compositions are formulated as a liquid or a solid item, e.g., a troche, a lozenge, a capsule, a pill, a cap and a bolus suitable for sublingual or oral administration.
  • a liquid or a solid item e.g., a troche, a lozenge, a capsule, a pill, a cap and a bolus suitable for sublingual or oral administration.
  • compositions described above for example, midazolam, ketamine and ondansetron, as well as methods for using above-mentioned composition(s) for the purposes of local anesthesia in various applications, such as ophthalmic surgery.
  • the above-mentioned methods of using the composition(s) include orally administering to a patient in need thereof (i.e., those patients who require conscious sedation or pre-sedation) a pharmaceutical composition described herein as the first step of a medical or surgical procedure, the procedure being an ophthalmic surgery (e.g., a cataract, glaucoma, comeal, eyelid surgery, or retinal surgery), a dental procedure (e.g., a tooth extraction, an oral surgery, or a root canal surgery), an outpatient medical procedure (e.g., medical imaging procedure, biopsy, bone marrow harvesting, colonoscopy, or endoscopy), a urological procedure, a laparoscopic procedure, obstetric and gynecological procedures, a gastrointestinal procedure, an otolaryngological procedure, a cosmetic surgery procedure, a dermatological procedure, a podiatric procedure, an orthopedic procedure, an emergency medical treatment, a psychi
  • ophthalmic surgery e.g.
  • Standard techniques may be used for chemical syntheses, chemical analyses, formulating compositions and testing them.
  • the foregoing techniques and procedures can be generally performed according to conventional methods well known in the art.
  • “About” as used herein means that a number referred to as“about” comprises the recited number plus or minus 1-10% of that recited number. For example,“about” 100 degrees can mean 95-105 degrees or as few as 99-101 degrees depending on the context. Whenever it appears herein, a numerical range such as“1 to 20” refers to each integer in the given range; i.e., meaning only 1, only 2, only 3, etc., up to and including only 20.
  • composition is defined as a chemical or biological compound or substance, or a mixture or combination of two or more such compounds or substances, intended for use in the medical diagnosis, cure, treatment,
  • the terms“anesthetic,”“anesthesia,”“anesthesiology” and the like refer herein to substances, compounds, processes or procedures that induce insensitivity to pain such as a temporary loss of sensation.
  • the term“conscious sedation,” which for the purposes of this application, may be used interchangeably with terms“procedural sedation” and“analgesia” is used herein to refer to an induced state of sedation characterized by a minimally depressed consciousness such that the patient is able to continuously and independently maintain a patent airway, retain protective reflexes, and remain responsive to verbal cues and/or tactile or physical stimulation.
  • Conscious sedation is typically performed/induced to decrease the level of anxiety in a patient and to elicit an improved degree of cooperation from the patient prior to or during a procedure. Conscious sedation, therefore, refers to a condition that is medically different and distinct from deep sedation which is the next level of sedation defined as depression of consciousness when the patient’s ability to independently maintain ventilatory function may be impaired and he or she cannot be easily aroused; however, the patient will still purposefully respond to repeated or painful stimulation.
  • Conscious sedation is also clearly distinguishable for the purposes of the present application from the lower level of sedation (i.e., minimal sedation when the patient is able to maintain a normal response to verbal stimuli) as well as the highest level of sedation (i.e., general anesthesia when there is no response from the patient even with painful stimulus).
  • the lower level of sedation i.e., minimal sedation when the patient is able to maintain a normal response to verbal stimuli
  • the highest level of sedation i.e., general anesthesia when there is no response from the patient even with painful stimulus.
  • pre-sedation is defined for the purposes of this application as conscious sedation that is induced some time before a procedure, e.g., between about 5 minutes and about 1 hour prior.
  • solvate and“hydrate” are used herein to indicate that a compound or substance is physically or chemically associated with a solvent for“solvates” such as water (for“hydrates”).
  • NMDA antagonist is defined as a compound that inhibits
  • b-blocker refers to a compound of any kind that can prevent or reduce the stimulation of the adrenergic receptors responsible for increased cardiac action.
  • antiemetic is defined as a drug or medicament that treats, reduces, and/or prevents nausea and/or vomiting.
  • non-steroid anti-inflammatory drug or“NSAID” refers to a class of compounds that are free of any steroid moieties yet are capable of providing analgesic, antipyretic and/or anti-inflammatory effects.
  • antihistamine medicament refers to any compound that is capable of inhibiting or counteracting the physiological effects of histamine.
  • polyglycol is defined as a polymer or oligomer containing several ether- glycol linkages that yields one or more glycols when these linkages are cleaved, e.g., by hydrolysis.
  • carrier refers to a substance that serves as a vehicle for improving the efficiency of delivery and the effectiveness of a pharmaceutical composition.
  • excipient refers to a pharmacologically inactive substance that is formulated in combination with the pharmacologically active ingredient of pharmaceutical composition and is inclusive of bulking agents, fillers, diluents and products used for facilitating drug absorption or solubility or for other pharmacokinetic considerations.
  • binding refers to a substance or compound that promotes, provides or improves cohesion, i.e., a substance that causes the components of a mixture to cohere to form a solid item that possesses integrity.
  • troche refers to a small tablet or lozenge (i.e., a medicated candy intended to be dissolved in the mouth), typically in a form of a disk, a ball or rhombic in cross-section, comprising medication and processed into a paste and dried.
  • terapéuticaally effective amount is defined as the amount of a compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, medical doctor or other clinician.
  • pharmaceutically acceptable when used in the context of a carrier, diluent or excipient, refers to a substance that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions or“administering a composition” is defined to include an act of providing a compound of the invention or pharmaceutical composition to the subject in need of treatment.
  • oral administration and“orally administering” are broadly defined as a route of administration where a medication is taken through the mouth including“sublingual administration” and“buccal administration” where the medication is placed under the tongue or between the gums and the cheek, respectively, to be absorbed by the body, or to be administered sublingually or buccally as a liquid.
  • compositions for anesthetic purposes comprise, consist of or consist essentially of, a combination of therapeutically effective quantities of at least one first pharmaceutically active compound and at least one second pharmaceutically active compound.
  • compositions optionally comprise, in addition to the above-mentioned first and second pharmaceutically active compounds, at least one third pharmaceutically active compound.
  • the first pharmaceutically active compound that is used in such composition comprises a benzodiazepine moiety or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof.
  • benzodiazepine moiety is a structure where a benzene ring is condensed with diazepine ring, a seven-member heterocycle with two nitrogen atoms which for the purposes of this specification may be in any positions of the ring (e.g., 1,2-diazepine, 1,3-diazepine or 1,4-diazepine).
  • An example of a compound having benzodiazepine moiety with 1,4-diazepine structure is shown below:
  • first pharmaceutically active compound comprising a benzodiazepine moiety that can be used in pharmaceutical compositions described and claimed herein is midazolam.
  • first pharmaceutically active compounds comprising benzodiazepine moiety that can be used include diazepam, lorazepam, flunitrazepam, alprazolam, chlordiazepoxide, clonazepam, clobazam, bromazepam, prazepam, oxazepam and clorazepate.
  • Table 1 which also discloses chemical names of such compounds.
  • benzodiazepine-based compound for using in the compositions, if so desired.
  • the therapeutically effective quantity of the benzodiazepine-based compound(s) in the entire pharmaceutical composition can be between about 0.2 mass % and about 5.0 mass % of the composition. In some embodiments, the therapeutically effective amount of the benzodiazepine-based compound(s) can be between about 1.0 mass % and about 3.0 mass %, for example, about 2.5 mass % of the composition.
  • a patient may be extra sensitive to benzodiazepines (e.g., may become excessively drowsy).
  • benzodiazepine(s)-containing pharmaceutical compositions described above would additionally include a quantity of a receptor antagonist to benzodiazepines.
  • a receptor antagonist would begin counteracting the effect of benzodiazepine after the surgical procedure is complete, in essence providing a slow release feature.
  • flumazenil also known under trade names such as ANEXATE®, ROMAZICON® and others.
  • benzodiazepine-based compounds may be used in combination with non-benzodiazepine based sedatives such as
  • the second pharmaceutically active compound that is used in such compositions is an NMDA antagonist, as defined hereinabove, or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof.
  • One particular second pharmaceutically active compound that can be used in the pharmaceutical compositions described and claimed herein is ketamine.
  • Other specific, non-limiting examples of NMDA antagonists that can be used include dextrorphan, etomidate, methadone, memantine, amantadine and dextromethorphan. Each of these is also known under one or several trade names as shown in Table 2, which also discloses chemical names of such compounds. Those having ordinary skill in the art can select alternative suitable NMDA antagonists for using in the compositions, if so desired.
  • the therapeutically effective quantity of the NMDA antagonist(s) in the entire pharmaceutical composition can be between about 1.0 mass % and about 10.0 mass % of the composition. In some embodiments, the therapeutically effective amount of the NMDA antagonist(s) can be between about 4.0 mass % and about 6.0 mass %, for example, about 5.0 mass % of the composition. Accordingly, in various embodiments, the combined quantities of both the benzodiazepine-based compound(s) and the NMDA antagonist(s), taken together, in the entire pharmaceutical composition can be between about 1.2 mass % and about 15.0 mass % of the composition, such as between about 3.0 mass % and about 12.0 mass %, for example, about 10.0 mass % of the composition.
  • compositions may further optionally include at least one third pharmaceutically active compound.
  • the third pharmaceutically active compound is a b-blocker, as defined hereinabove, or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof, or alternatively, and a-2-adrenergic agonist or, as another alternative, a pain reliever.
  • the third pharmaceutically active compound may also include an antiemetic medicament, as defined hereinabove, or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof.
  • the third pharmaceutically active compound may include one or several non-steroid anti-inflammatory drug(s) (NSAIDs), as defined hereinabove.
  • NSAIDs non-steroid anti-inflammatory drug(s)
  • the third pharmaceutically active compound may also include an antihistamine medicament, as defined hereinabove.
  • antihistamine medicaments include, but are not limited to, any of hydroxyzine pamoate, hydroxyzine hydrochloride, diphenhydramine hydrochloride, meclizine, chlorpheniramine, clemastine, promethazine, or prochlorperazine, or any combination thereof.
  • antihistamine medicaments may be used in addition to, or instead of, any of the above- mentioned compounds that may be used as the third pharmaceutically active compound.
  • the therapeutically effective quantity of the third pharmaceutically active compound(s) in the entire pharmaceutical composition can be between about 0.1 mass % and about 5.0 mass % of the composition. In some embodiments, the therapeutic effective amount of the third pharmaceutically active compound(s) can be between about 1.0 mass % and about 4.0 mass %, for example, about 2.5 mass % of the composition.
  • One particular b-blocker that can be used as the third pharmaceutically active compound in pharmaceutical compositions described and claimed herein is metoprolol.
  • b-blockers or a-2-adrenergic agonists or pain relievers that can be used include, propranolol, acebutolol, nadolol, atenolol, betaxolol, esmolol, bisoprolol fumarate, carvedilol, nebivolol, penbutolol, timolol, sotalol,
  • dexmedetomidine hydrochloride and acetaminophen. Each of these is also known under one or several trade names as shown in Table 3, which also discloses chemical names of such compounds. Those having ordinary skill in the art can select alternative suitable b-blockers for using in the compositions, if so desired.
  • antiemetic that can be used as the third pharmaceutically active compound in pharmaceutical compositions described and claimed herein is ondansetron.
  • antiemetics include dolasetron, granisetron, palonosetron, promethazine, imenhydrinate, and meclizine. Each of these is also known under one or several trade names as shown in Table 4, which also discloses chemical names of such compounds. Those having ordinary skill in the art can select alternative suitable antiemetics for using in the compositions, if so desired.
  • pharmaceutically active compounds i.e., the benzodiazepine-based compound(s), the NMDA antagonist(s), the -blocker(s)), and/or the antiemetic(s) taken together, in the entire pharmaceutical composition can be between about 1.3 mass % and about 20.0 mass % of the composition, such as between about 3.0 mass % and about 12.0 mass %, for example, about 10.0 mass % of the composition.
  • benzodiazepine-based compound(s), the NMDA antagonist(s), the -blocker(s) and/or the antiemetic(s) taken together, in the entire pharmaceutical composition
  • the composition can be between about 1.3 mass % and about 20.0 mass % of the composition, such as between about 3.0 mass % and about 12.0 mass %, for example, about 10.0 mass % of the composition.
  • Those having ordinary skill in the art will determine the most appropriate quantities of each the pharmaceutically active compound that are within the above-mentioned ranges and that are most suitable for
  • the following mass ratios between the pharmaceutically active compounds may be used (Table 5) for compositions where the benzodiazepine-based compound is midazolam, the NMDA antagonist is ketamine hydrochloride and the b-blocker is propanolol hydrochloride: Table 5.
  • Table 5 Exemplary Mass Ratios between Midazolam, Ketamine Hydrochloride and Propanolol Hydrochloride in the Compositions
  • the mass mi dazolam: ketamine: odansetron ratio may be about 3:25:2.
  • the pharmaceutical compositions described herein may contain not only pharmaceutically active components but also, in some embodiments, may further include one or several inactive, neutral compounds which can be pharmaceutically acceptable excipient(s) or carrier(s), including, but not limited to, binder(s), antioxidant(s), adjuvant(s), synergist(s) and/or preservative(s).
  • the mass concentration of such inactive compounds can be between about 80 mass % and about 99 mass % of the entire pharmaceutical composition, such as between about 85 mass % and about 95 mass %, e.g., about 90 mass %.
  • Some embodiments of the invention are directed to pharmaceutical formulations that are formulated as solid articles suitable for sublingual or oral administration, such as troches, lozenges, capsules, pills, caps or boluses.
  • These solid compositions typically comprise binder(s) and/or excipient(s). They can be prepared by first mixing the
  • Typical binder(s) that can be used for fabricating solid articles mentioned above include, without limitation, polyglycols as defined above, such as, e.g., polyethylene glycols (PEGs), polyethylene oxides (POE), methoxypoly ethylene glycols, polypropylene glycols, polybutylene glycols or derivatives thereof having a molecular weight that is sufficient to provide the necessary hardness and time for dissolution of the troche; for example, the acceptable molecular weight can be within the range of between about 1,000 Daltons and about 8,000 Daltons.
  • PEG-1450 or PEG-400 can be used.
  • Non- limiting examples of some specific polyglycol derivatives that can be used are:
  • PEG-laureates and dilaureates e.g., PEG-10-, PEG-12-, PEG-20-, PEG-32- laurates, PEG-20- and PEG-32-dilaurates, PEG-20-glyceryl-, PEG-30-glyceryl- and PEG-40- glyceryl-laurates, PEG-80-sorbitan laurate);
  • PEG-oleates, dioleates and trioleates e.g., PEG-12-, PEG-15-, PEG-20-, PEG- 32, PEG-200- and PEG-400-oleates, PEG-20- and PEG-32- dioleates, PEG-20-trioleate, PEG-25- glyceryl trioleate, PEG-20-glyceryl- and PEG-30-glyceryl-oleates, PEG-40-sorbitan oleate
  • PEG-oleates, dioleates and trioleates e.g., PEG-12-, PEG-15-, PEG-20-, PEG- 32, PEG-200- and PEG-400-oleates, PEG-20- and PEG-32- dioleates, PEG-20-trioleate, PEG-25- glyceryl trioleate, PEG-20-glyceryl- and PEG-30-glyceryl-oleates, PEG-40-sorbitan o
  • PEG-stearates and distearates e.g., PEG- 15-, PEG-40-, PEG- 100-stearates, PEG-32-distearate and PEG-20-glyceryl stearate);
  • castor, palm kernel, com and soya oil derivatives of PEG e.g., PEG-35-, PEG-40- and PEG-60-castor oils, PEG-40-, PEG-50- and PEG-60-hydrogenated castor oils, PEG-40-palm kernel oil, PEG-60-com oil, PEG-30-soya sterol
  • PEG e.g., PEG-35-, PEG-40- and PEG-60-castor oils, PEG-40-, PEG-50- and PEG-60-hydrogenated castor oils, PEG-40-palm kernel oil, PEG-60-com oil, PEG-30-soya sterol
  • PEG derivatives e.g., PEG-24- and PEG-30-cholesterol, PEG-25- phytosterol, PEG-6- and PEG-8-caprate/caprylate glycerides, tocopheryl PEG-100 succinate, PEG- 15- 100 octylphenol products and PEG- 10- 100 nonylphenol products;
  • polyglyceryl-10-laurate POE-9- and POE-23-lauryl ethers, POE- 10- and POE-20-oleyl ethers, POE-20-stearyl ether, polysorbates-20 and 80, polyglyceryl-10-oleate, Tween 40, Tween 60, sucrose monostearate, monolaurate and monopalmitate and various products of Poloxamer series.
  • Typical excipient(s) that can be used for fabricating solid articles mentioned above include, without limitation, gelatin, sodium saccharin, stevioside, peppermint oil, or any natural or artificial fruit, vegetable, flower, beverage or candy flavor.
  • compositions may optionally further include one or several antioxidant(s).
  • antioxidant(s) include a-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxy toluene, cysteine, cysteine hydrochloride, tocopherol natural, tocopherol synthetic, dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thiourea and tocopherols.
  • compositions may optionally further include one or several adjuvant(s) or synergists(s).
  • adjuvant(s) or synergists(s) include citric acid, EDTA (ethylenediaminetetraacetate) and salts, hydroxy quinoline sulfate, phosphoric acid and tartaric acid.
  • compositions may optionally further include one or several preservative(s).
  • preservative(s) include benzalkonium chloride, benzethonium chloride, benzoic acid and salts, benzyl alcohol, boric acid and salts, cetylpyridinium chloride, cetyltrimethyl ammonium bromide, chlorobutanol, chlorocresol, chorhexidine gluconate or chlorhexidine acetate, cresol, ethanol, imidazolidinyl urea, metacresol, methylparaben, nitromersol, o-phenyl phenol, parabens, phenol, phenylmercuric acetate/nitrate, propylparaben, sodium benzoate, sorbic acids and salts, b-phenylethyl alcohol and thimerosal.
  • the pharmaceutical formulation can be administered to a subject in need of conscious sedation, procedural sedation, analgesia and/or pre-sedation, and in general for any kind of non-general anesthesia, by various local administrations.
  • the pharmaceutical formulations described herein may be prescribed by ordinarily skilled medical practitioners such as physicians, as the means of conscious sedation or pre-sedation. This is intended to be used for certain patients who experience or expect to experience high anxiety, bouts of panic attacks, disquietude, apprehension, angst or similar feelings of psychological discomfort or distress prior to, or during, medical or surgical procedures as described in more detail below.
  • the patients may be of any age, i.e., including children, adolescents and adults.
  • the formulation can be used prior to various outpatient surgeries and medical procedures, both invasive and non-invasive, such as an ophthalmic surgery, outpatient medical or surgical procedures, dental procedures, urological procedures, obstetric and gynecological procedures, gastrointestinal procedures, otolaryngological procedures, cosmetic surgery procedures, dermatological procedures, podiatric procedures, orthopedic procedures, emergency medical treatments, psychiatric treatments, and veterinarian procedures.
  • invasive and non-invasive such as an ophthalmic surgery, outpatient medical or surgical procedures, dental procedures, urological procedures, obstetric and gynecological procedures, gastrointestinal procedures, otolaryngological procedures, cosmetic surgery procedures, dermatological procedures, podiatric procedures, orthopedic procedures, emergency medical treatments, psychiatric treatments, and veterinarian procedures.
  • Specific representative examples of the procedures that are amenable to use of the formulation include, without limitation, cataract surgery, glaucoma surgery, comeal surgery, eyelid surgery, retinal surgery, tooth extraction, oral surgery, root canal surgery, medical imaging procedures (e.g., MRI or CAT scanning, especially for patients suffering from claustrophobia), biopsy, bone marrow harvesting, colonoscopy, endoscopy and laparoscopy.
  • medical imaging procedures e.g., MRI or CAT scanning, especially for patients suffering from claustrophobia
  • biopsy e.g., MRI or CAT scanning, especially for patients suffering from claustrophobia
  • bone marrow harvesting e.g., colonoscopy, endoscopy and laparoscopy.
  • the local administration is by oral route, such as sublingually or buccally, typically being delivered to the patient via a solid delivery vehicle such as a troche, a lozenge, a capsule, a pill, a cap, and a bolus, as mentioned above.
  • the pharmaceutical composition may be formulated as a liquid item adapted for sublingual or buccal administration (in which case it will include all the pharmaceutically active compounds described above, but no pharmaceutically suitable binder); such liquid formulations may be delivered by any method to be selected by one having ordinary skill in the art of delivery of medications, e.g., via a syringe or a pipette.
  • Such local administration may be used instead or intravenous administration or to complement the latter, as appropriate.
  • the pharmaceutical compositions of the present invention may be incorporated into vehicles allowing extended release of the compositions over a period of time.
  • the compositions may be combined with polymers forming such vehicles.
  • the product will be extended release capsules ensconcing or enveloping the pharmaceutical formulation, or alternatively, a matrix polymer structure holding the pharmaceutical formulation that is embedded into the matrix.
  • the vehicle carrying the pharmaceutical formulation may be configured to allow the gradual release of the pharmaceutical formulation over not less than about 12 hours, such as between about 12 hours and about 20 hours, for example, about 16 hours.
  • the rate of release may be uniform throughout the entire period of release; alternatively, those having ordinary skill in the art may formulate the release vehicle in such a way as to allow different rates of release at different times, for example, faster release at the beginning of the process of release and slower at later stages, or vice versa, or in any other way that may be necessary.
  • the vehicle may be manufactured from any pharmaceutically acceptable polymer that is capable of releasing at least 95 mass % of the pharmaceutical formulation that the vehicle incorporates within the above-mentioned time periods, i.e., within not less than 12 hours, or 12-20 hours.
  • the vehicle may be formulated to ensure the release of at least 97 mass % of the pharmaceutical formulation, for example, at least 99.5 mass %.
  • poly(lactic-co-gly colic acid) PLGA
  • polylactic acid polyglycolide
  • dextrin poly(ethylene glycol)
  • polyacetals poly(N-(2- hydroxypropyl)methacrylamide)
  • polycaprolactone poly-3-hydroxybutyrate.
  • One particular type of product that can be used in fabricating the vehicle carrying the pharmaceutical formulation may be water-soluble methylcellulose and hydroxypropyl methylcellulose polymers, such as METHOCEL® family of products, for example, a hydroxypropyl methylcellulose product METHOCEL®E4M, 20% METHOCEL®K4M, or 10% METHOCEL®K100 or, alternatively and particularly useful for hot melt extrusion, another hydroxypropyl methylcellulose product AFFINISOL TM HPMC (all mentioned hydroxypropyl methylcellulose polymers are available from Dow Chemical Co., Midland, Mich.).
  • METHOCEL® family of products for example, a hydroxypropyl methylcellulose product METHOCEL®E4M, 20% METHOCEL®K4M, or 10% METHOCEL®K100 or, alternatively and particularly useful for hot melt extrusion, another hydroxypropyl methylcellulose product AFFINISOL TM HPMC (all mentioned hydroxypropyl methylcellulose polymers are available from Dow Chemical Co
  • compositions of the present invention are useful for treating all the medical, surgical and other procedures mentioned above, those having ordinary skill in the art may find these systems particularly suitable and advantageous in the treatments of depression (including major depression or treatment-resistant depression), PTSD, alcohol or substance
  • a one-batch formulation method may be used, where the components of the pharmaceutical formulation can be combined in single container; the components may be added to the container simultaneously or consecutively.
  • a two- or multiple-batch method(s) may be used if desired, where each component of the pharmaceutical formulation can be combined in separate container followed by combining the contents of each container.
  • pre-measured quantities of each ingredient in the form of dry powder can be mixed to form a dry blend followed by mixing it with a pre-molten troche base.
  • the composition can then be molded to form a troche.
  • kits are provided.
  • the kit includes a sealed container approved for the storage of solid pharmaceutical compositions, the container containing one of the above-described pharmaceutical compositions an instruction for the use of the composition and the information about the composition are to be affixed to the container or otherwise enclosed with it.
  • a pharmaceutical composition may be prepared as described below.
  • the following products can be used in the amounts and concentrations specified:
  • troche base comprising polyglycol 1450, polyglycol 400, gelatin, sodium saccharin and steviaside.
  • the troche base can be melted at low heat while being stirred; when completely molten, the heat can be turned off with continued stirring. All the dry ingredients, pre weighed can be added into the molten base followed by adding the flavoring and mixing all components together.
  • a half-moon shaped troche mold can be lightly sprayed with PAM® (or a suitable oil/releasing agent) to cover the entire surface of the mold and the mixture prepared as explained above can then be poured into the mold and allowed to cool and harden at room temperature.
  • a heat gun can then be used to smooth out the surface followed by another round of cooling at room temperature followed by removing the so prepared troche from the mold, placing it into a prescription vial and labeling the vial. The troche is now ready to be administered.
  • An extended release pharmaceutical composition may be prepared as described below.
  • the following products can be used in the amounts and concentrations specified:
  • Midazolam and ketamine hydrochloride may be triturated to a fine powdery constituency using standard mortar and pestle. Using the principles of geometric dilution, the rest of ingredients (i.e., the two Methocell® powders and the microcrystalline cellulose powder) may be then mixed in with trituration in the mortar. The use of a V-blender and a powder food coloring may be employed to verify that the mixture is homogenous followed by sieving through an 80 mesh sieve to ensure the evenness or the particle sizes which can then be encapsulated in the clear gelatin capsules (size 0).
  • a portion of an ingredient of a large quantity (L) is to be mixed into an ingredient of a smaller quantity (S) in small portions.
  • S ingredient of a smaller quantity
  • a portion of L is to be mixed with a portion of S, the two portions having the same volume as a portion of S thus obtaining a mixture Ml.
  • another portion of L is to be mixed with a portion of Ml, the two portions having the same volume. This process is to be continued until the entire quantity of L is used up.

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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)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques et des procédés pour induire une sédation consciente à l'aide de telles compositions, les compositions comprenant un composé à base de benzodiazépine, un antagoniste de NMDA, et éventuellement un bêta-bloquant, un antiémétique, un AINS et/ou un médicament antihistaminique. Les compositions peuvent être incorporées dans des véhicules pour une libération prolongée. L'invention concerne également des procédés de fabrication des compositions et d'utilisation ce celles-ci pour des applications anesthésiologiques.
PCT/US2020/013116 2019-01-17 2020-01-10 Compositions pharmaceutiques et procédés pour des applications anesthésiologiques Ceased WO2020150098A1 (fr)

Applications Claiming Priority (2)

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US16/250,450 US20190142841A1 (en) 2015-06-19 2019-01-17 Pharmaceutical compositions and methods for anesthesiological applications
US16/250,450 2019-01-17

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2746295C1 (ru) * 2020-09-09 2021-04-12 Петр Александрович Попов Способ обезболивания и седации в стоматологии

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090306051A1 (en) * 2004-02-13 2009-12-10 Meyerson Laurence R Methods and compositions for the treatment of epilepsy, seizure disorders, and other CNS disorders
US10166240B2 (en) * 2015-06-19 2019-01-01 Imprimis Pharmaceuticals, Inc. Pharmaceutical compositions and methods for anesthesiological applications

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090306051A1 (en) * 2004-02-13 2009-12-10 Meyerson Laurence R Methods and compositions for the treatment of epilepsy, seizure disorders, and other CNS disorders
US10166240B2 (en) * 2015-06-19 2019-01-01 Imprimis Pharmaceuticals, Inc. Pharmaceutical compositions and methods for anesthesiological applications

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2746295C1 (ru) * 2020-09-09 2021-04-12 Петр Александрович Попов Способ обезболивания и седации в стоматологии

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