WO2021123121A1 - Compositions à base de lipides comprenant des sels lipophiles et des modificateurs de ph acide - Google Patents

Compositions à base de lipides comprenant des sels lipophiles et des modificateurs de ph acide Download PDF

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Publication number
WO2021123121A1
WO2021123121A1 PCT/EP2020/086964 EP2020086964W WO2021123121A1 WO 2021123121 A1 WO2021123121 A1 WO 2021123121A1 EP 2020086964 W EP2020086964 W EP 2020086964W WO 2021123121 A1 WO2021123121 A1 WO 2021123121A1
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Prior art keywords
acid
acidic
modifier
composition
active ingredient
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PCT/EP2020/086964
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English (en)
Inventor
Hywel David Williams
Leigh FORD
Christopher John Hamilton Porter
Peter John Scammells
Yasemin SAHBAZ
Hassan Benameur
Annabel IGONIN
Anthony Lai
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Capsugel Belgium Nv
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Publication of WO2021123121A1 publication Critical patent/WO2021123121A1/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
    • A61K9/10—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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

Definitions

  • the present disclosure relates to lipid-based formulations, lipid formulations or compositions comprising lipophilic salts and acidic pH modifiers.
  • the acidic pH modifiers are able to yield stabilized lipid formulations and/or to increase the solubility of the lipophilic salts in the lipid formulations.
  • Lipid-based formulations are widely used in drug delivery.
  • the successful application of lipid formulations often relies on the drug meeting a target solubility in commonly used lipidic vehicles so that the clinical dose can be delivered in a single dosage unit.
  • lipophilic salts increase the possibility of delivering the clinical dose of a drug within a single dosage unit and ensure that more drugs can gain access to the benefits of the lipid formulations.
  • WO 2015013772 A1 discloses the utility of lipophilic salt forms in enhancing drug solubility in lipid formulations.
  • lipophilic salts are not physically stable following incorporation in lipid formulations or excipients. This instability is characterized by the formation of a solid-phase on prolonged storage or during incorporation of the salts.
  • the inventors have established that the solubility and/or stability of the lipophilic salt in lipid formulations containing lipophilic salts can be achieved by the addition of acidic pH modifiers.
  • lipid-based formulations, lipid formulations or compositions comprising, consisting essentially of or consisting of a basic active ingredient, a lipophilic counterion to the active ingredient, the lipophilic counterion being present in an amount of at least 90 mol% of the active ingredient so as to be capable of forming a lipophilic salt of the active ingredient, a lipid vehicle and an acidic pH modifier, said active ingredient, lipophilic counterion and acidic pH modifier being dissolved in the lipid vehicle, wherein the acidic pH modifier is present in a sufficient amount to improve the solubility and stability of the basic active ingredient in the lipid vehicle, and wherein the pK a of the acidic pH modifier is less than or equal to 11 and said acidic pH modifier is present in a concentration that is greater than 0.05 mol equivalents relative to the basic active ingredient.
  • the pK a of the acidic pH modifier is less than or equal to 1 and said acidic pH modifier is present in a concentration that is greater than 0.05 mol equivalents relative to the basic active ingredient. In certain embodiments, the pK a of the acidic pH modifier is greater than 1 and less than or equal to 4 and said acidic pH modifier is present in a concentration that is greater than 0.2 mol equivalents relative to the basic active ingredient.
  • the pK a of the acidic pH modifier is greater than 4 and less than or equal to 11 and said acidic pH modifier is present in a concentration that is greater than 0.5 mol equivalents relative to the basic active ingredient.
  • the acidic pH modifier may be an organic acid.
  • the acidic and organic pH modifier may be selected from the group consisting of docusic acid, lactic acid, acetic acid, mandelic acid, lauryl sulfonic acid, dichloroacetic acid, gentisic acid, citric acid, malic acid, adipic acid, benzoic acid, butyric acid, ascorbic acid, lauric acid, valeric acid, heptanoic acid, nonanoic acid, tridecanoic acid, methanesulfonic acid, ethanesulfonic acid, benzesulfonic acid, fumaric acid, galactaric acid, glucaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glycerophosphoric acid, glycolic acid, hippuric acid, lactobionic acid, maleic acid, palmitic acid, pyruvic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thioc
  • the acidic and organic pH modifier may be selected from the group consisting of lactic acid, docusic acid, lauryl sulfonic acid, methanesulfonic acid, acetic acid, formic acid, caprylic acid, hexanoic acid, oleic acid, benzoic acid, malic acid, gentisic acid, butyric acid, ethanesulfonic acid, mandelic acid, pamoic acid, napthalene-2-sulfonic acid, para-toluenesulfonic acid, lauric acid, heptafluorobutyric acid, dichloroacetic acid and capric acid.
  • the acidic and organic pH modifier may be selected from the group consisting of lactic acid, docusic acid, lauric acid, heptafluorobutyric acid, dichloroacetic acid and capric acid.
  • the acidic pH modifier may be an inorganic acid.
  • the acidic and inorganic pH modifier may be selected from the group consisting of hydrazoic acid, hydrofluoric acid, hypobromous acid, hypochlorous acid, hypophosphorous acid, nitrous acid, carbonic acid, phosphorous acid, selenous acid, sulfurous acid, tellurous acid, and phosphoric acid.
  • the acidic and inorganic pH modifier may be selected from the group consisting of phosphoric acid and phosphorous acid.
  • the composition may comprise the basic active ingredient present in the composition in an amount of at least 1.0 wt% (free base equivalent) of the total composition.
  • the lipid vehicle may comprise, consist essentially of or consist of a surfactant or a mixture of surfactants, optionally a cosurfactant or a mixture of cosurfactants, optionally an oil and/or optionally a cosolvent or a mixture of cosolvents.
  • the surfactant or surfactants may be polyoxyethylene sorbitan fatty acid esters, a mixture of (i) polyoxyethylene mono- and di-esters of C8-C22 fatty acids and (ii) glyceryl mono-, di-, and tri-esters of C8-C22 fatty acids, polyethoxylated castor oils and derivatives, polyoxyethylene fatty acid esters, Vitamin E TPGS or one or more derivatives thereof, polyoxyethylene- polyoxypropylene copolymers, or any combination thereof.
  • the surfactant is a polyoxyethylene sorbitan fatty acid ester.
  • the polyoxyethylene sorbitan fatty acid ester may be polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 85, or any combination thereof.
  • the surfactant is a mixture of (i) polyoxyethylene mono- and di-esters of C8-C22 fatty acids and (ii) glyceryl mono-, di-, and tri-esters of C8-C22 fatty acids selected from the group consisting of caprylocaproyl macrogol-8 glycerides, oleoyl macrogol-6 glycerides or linoleoyl macrogol- 6 glycerides, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides and macrogol stearate.
  • the surfactant is a polyethoxylated castor oil and/or a derivative thereof.
  • polyethoxylated castor oil is polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil or any combination thereof.
  • the surfactant is a polyoxyethylene fatty acid ester.
  • the polyoxyethylene fatty acid esters is polyoxyl 40 stearate, polyoxyl 40 oleate, polyoxyl 8 stearate, polyoxyl 15 hydroxystearate or any combination thereof.
  • the surfactant is Vitamin E TPGS and/or a derivative thereof.
  • the surfactant is a polyoxyethylene-polyoxypropylene copolymer, such as poloxamer 124, poloxamer 188, poloxamer 407 or any combination thereof.
  • compositions or lipid-based formulations include a cosurfactant that comprises, consists essentially of or consists of propylene glycol mono- and di-esters of C8-C22 fatty acids, sorbitan fatty acid esters or a mixture thereof.
  • the cosurfactant is a propylene glycol mono- or di-ester of C8-C22 fatty acids comprising, consisting essentially thereof or consisting of propylene glycol monocaprylate, propylene glycol dicaprolate/dicaprate, propylene glycol monolaurate or any combination thereof.
  • the cosurfactant is a sorbitan fatty acid esters comprising sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate or any combination thereof.
  • the oil may comprise, consist essentially of or consist of a Cs-Cis fatty acid ester of glycerol.
  • the oil is a Cs to C18 triglyceride.
  • the oil is a mixture of Cs to Cie mono-, di- and/or triglycerides.
  • the oil is almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grape seed oil, mustard seed oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, soybean oil, sunflower oil, walnut oil, wheat germ oil, avocado oil, bran oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, caprylic/capric glycerides, fractionated triglycerides, glyceryl tricaprate, glyceryl tricaproate, glyceryl tricaprylate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate,
  • the oil may comprise, consist essentially of or consist of glyceryl laurate, glyceryl linoleate, glyceryl oleate, glyceryl stearate, glyceryl caprylate, glyceryl caprate or any mixture thereof.
  • the lipid vehicle may comprise, consist essentially of or consist of corn oil, medium-chain (Cs to C12) triglyceride, propylene glycol monocaprylate, glyceryl monolinoleate or monocaprylate and soybean oil.
  • the disclosed composition may include a cosolvent or a mixture of cosolvents.
  • the cosolvent is propylene carbonate, triacetin, glycerol, propylene glycol, polythethylene glycols such as PEG 400, glycofurol, ethanol, diethylene glycol monoethyl ether, oleic acid, N-methyl pyrrolidone, ethyl lactate, or triethyl citrate.
  • the lipophilic counterion comprises, consists essentially of or consists of carboxylic acids (R 1 C(0)0-), phosphates (R 1 0P(0)C> 2 - or (R 1 0)(R 2 0)P(0)0-), phosphonates (R 1 P(0)0 2 - or R 1 P(0)(0R 2 )0-), sulfonates (R 1 S(0) 2 0-), sulfates (R 1 0S(0) 2 0-), tetrazolyls (R 1 - tetrazolate), bis(sulfonyl)imides (R 1 S0 2 -N--SC> 2 R 2 ) or any combination thereof where R 1 and R 2 are independently the same or different and where R 1 and R 2 may be any suitable group, such as an optionally substituted hydrocarbon group containing between 1 and 40 carbon atoms, and where this hydrocarbon group is a saturated straight chained or branched hydrocarbon or a saturated cyclic hydrocarbon or an unsatur
  • the lipophilic counterion is an alkyl sulfate, a branched alkyl sulfate, a branched alkyl sulfonate or a fatty acid.
  • the lipophilic counterion is decylsulfate, lauryl sulfate, 7-ethyl-2-methyl-4- undecylsulfate, dioctylsulfosuccinate (docusate), any possible isomer of hexyldecyl sulfate, any possible isomer of butyloctyl sulfate, oleate, stearate, palmitate, laurate (dodecanoate), caprate (decanoate), caprylate (octanoate), or any combination thereof.
  • the lipophilic counterion is decylsulfate, lauryl sulfate, 7-ethyl-2-methyl-4- undecylsulfate, dioctylsulfosuccinate (docusate), 2-hexyl-1-decyl sulfate, oleate, stearate, palmitate, laurate (dodecanoate), caprate (decanoate), caprylate (octanoate), 3-butyl-1 -octyl sulfate or any combination thereof.
  • a fill formulation for a capsule comprising, consisting essentially of or consisting of the composition of the present invention.
  • oral dosage forms comprising the composition of the present invention
  • a capsule, sachet, syringe or dropper devise, ampoule, tube or bottle containing the composition of the present invention In a further aspect, there is provided a capsule, sachet, syringe or dropper devise, ampoule, tube or bottle containing the composition of the present invention.
  • compositions, lipid-based formulations or lipid formulations are used as synonyms.
  • An active ingredient is the ingredient in a pharmaceutical drug that is biologically active.
  • active ingredient includes any compound which when administered to a subject provides a beneficial effect to said subject, and includes, but is not limited to, disease and disorder preventative and ameliorating agents which interacts with the physiology or pharmacology of the subject, agents which interact with infective microorganisms (e.g. viruses and bacteria), and nutritional agents (e.g. vitamins, amino acids and peptides).
  • the active ingredient is a basic compound.
  • the basic active ingredient may be present in an amount of at least 1 .0 wt% of the composition, when expressed as free base equivalents. In certain embodiments the basic active ingredient may be present in an amount of at least 2.5 wt% of the composition, when expressed as free base equivalents.
  • basic active ingredients can be selected from the group consisting of analgesics, anti-inflammatory agents, anti-helminthics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-thrombogenic agents, anti- claudication agents, anti- atherosclerotic drugs, vascular agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents (e.g., anti-proliferative or chemotherapeutic agents), erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, b-blockers, cardiac inotropic agents, corticosteroids, diure
  • the basic active ingredients may have low molecular weight values of less than hundred molecular weight units or may have molecular weight values of several thousand molecular weight units (e.g. peptides).
  • examples of basic active ingredients include morphine, benzylmorphine, propoxyphene, methadone, pentazocine, sufenatanil, alfentanil, fentanyl, pethidine, butorphanol, buprenorphine, diamorphine, dihydrocodeine, dypyrone, oxycodone, dipipanone, alphaprodine, levorphanol, dextromoramide, hydromorphone, nalbuphine, oxymorphone, hydrocodone, nalorphine, naloxone, norfloxacin, ciprofloxacin, lomefloxacin, balofioxacin, ofloxacin, sparfloxacin, tosufloxacin, temafloxacin, clinafloxacin, perfloxacin, tosufloxacin, enoxacin, amifloxacin, fleroxacin,
  • procaine procaine, amethocaine, bupivacaine, butacaine, oxybuprocaine, mepivacaine, cocaine, prilocaine, amylocaine, chloroprocaine, cinchocaine, etidocaine, propoxycaine, tropacocaine, ropivacaine, cyclopentolate, methazolamide, dorzolamide, acetazolamide, oxytocin, vasopressin, naltrexone, varenicline, bacitracin, linezolid, daptomycin, granisetron, ondansetron, aripiprazole, risperidone, olanzapine, clozapine, thorazine, ipratropium, bethanecol, sildenafil, vardenafil, avanafil, udenafil, mirodenafil, lodenafil, abemaciclib, acalabru
  • Some exemplary but no limiting basic active ingredients examples contemplated by the disclosure are set out in the examples and include erlotinib, cinnarizine, itraconazole, cinnarizine, fexofenadine, sildenafil and posaconazole.
  • a lipophilic salt is a salt formed from a lipophilic counterion and an active ingredient.
  • a lipophilic salt is a salt having increased solubility in lipidic vehicles relative to free base form of the basic active ingredient.
  • the lipophilic counterion is of anionic nature and is capable of forming a salt with the basic active ingredient.
  • “capable of forming a salt” means that the basic active ingredient and the anionic lipophilic counterion, under the proper conditions as known to those skilled in the art having the benefit of this disclosure, will react to form the corresponding salt form with the active ingredient either by (i) a direct acid-base reaction between the organic acid and the basic active ingredient or (ii) a metathesis reaction (i.e. , a counterion exchange reaction) between a salt form of the active ingredient (e.g., a hydrochloride salt) and a salt form of the lipophilic counterion (e.g., sodium salt).
  • a salt form of the active ingredient e.g., a hydrochloride salt
  • a salt form of the lipophilic counterion e.g., sodium salt
  • At least 80 mol% of the basic active ingredient has reacted with the anionic lipophilic counterion to form the corresponding salt form. In other embodiments, at least 90 mol% of the basic active ingredient has reacted with the anionic lipophilic counterion to form the corresponding salt form. In yet other embodiments, at least 95 mol% of the basic active ingredient has reacted with the anionic lipophilic counterion to form the corresponding salt form. In still other embodiments, essentially all of the basic active ingredient has reacted with the anionic lipophilic counterion to form the corresponding salt form.
  • the following properties can be used to identify preferred lipophilic counterions for basic active ingredients:
  • the counterion is an organic molecule containing carbon atoms.
  • the counterion has an acidic pK a value.
  • the counterion is lipophilic.
  • One measure of lipophilicity is the logP or clogP of the compound.
  • logP refers to the log of the partition coefficient of the active ingredient in octanol-water (and clogP refers to a calculated value of logP as is known in the art).
  • the logP value is greater than 0, and more preferably is greater than 2, and may be greater than 3.
  • the counterion has a molecular weight such that the counterion: active ingredient (free base) molar mass ratio in the salt is preferably less than 2.5, and more preferably the counterio active ingredient (free base) molar mass ratio in the salt is less than 1 .5.
  • the lipophilic counterion comprises, consists essentially of or consists of carboxylic acids (R 1 C(0)0-), phosphates (R 1 0P(0)C> 2 - or (R 1 0)(R 2 0)P(0)0-), phosphonates (R 1 P(0)0 2 - or R 1 P(0)(0R 2 )0-), sulfonates (R 1 S(0) 2 0-), sulfates (R 1 0S(0) 2 0-), tetrazolyls (R 1 - tetrazolate), bis(sulfonyl)imides (R 1 S0 2 -N--S0 2 R 2 ) or any combination thereof where R 1 and R 2 are independently the same or different and where R 1 and R 2 may be any suitable group, such as an optionally substituted hydrocarbon group containing between 1 and 40 carbon atoms, and where this hydrocarbon group is a saturated straight chained or branched hydrocarbon or a saturated cyclic hydrocarbon or an unsatur
  • the lipophilic counterion is an alkyl sulfate, a branched alkyl sulfate, a branched alkyl sulfonate or a fatty acid.
  • the lipophilic counterion is decylsulfate, lauryl sulfate, 7-ethyl-2-methyl-4- undecylsulfate, dioctylsulfosuccinate (docusate), any possible isomer of hexyldecyl sulfate, any possible isomer of butyloctyl sulfate, oleate, stearate, palmitate, laurate (dodecanoate), caprate (decanoate), caprylate (octanoate), or any combination thereof.
  • the lipophilic counterion is decylsulfate, lauryl sulfate, 7-ethyl-2-methyl-4- undecylsulfate, dioctylsulfosuccinate (docusate), 2-hexyl-1-decyl sulfate, oleate, stearate, palmitate, laurate (dodecanoate), caprate (decanoate), caprylate (octanoate), 3-butyl-1 -octyl sulfate or any combination thereof.
  • the composition may comprise at least 80% of the stoichiometric amount of the anionic lipophilic counterion necessary to form a salt form with the basic active ingredient or other embodiments at least 90% of the stoichiometric amount of the anionic lipophilic counterion necessary to form a salt form of the basic active ingredient, or other embodiments at least 100% of the stoichiometric amount of the anionic lipophilic counterion necessary to form a salt form of basic the active ingredient.
  • the lipid vehicle is designed to deliver the lipophilic salt of the active ingredient in the dissolved form.
  • the lipid vehicle may be liquid at 25°C, or may be liquid at 35°C, or may be liquid at 40°C, or may be liquid at 50°C.
  • the lipid vehicle may be semi-solid at 25°C, or may be semi-solid at 35°C, or may be semi-solid at 40°C, or may be semi-solid at 50°C.
  • semi-solid is meant that the amount of solids in the lipid vehicle (e.g., not including the basic active ingredient or lipophilic counterion or acidic pH modifier) is less than 100 wt% of the total weight of the lipid vehicle.
  • the amount of solids in the lipid vehicle may be less than 75 wt% of the total weight of the lipid vehicle, or may be less than 50 wt% of the total weight of the lipid vehicle.
  • an optimal formulation is one that does not show any phase-separation or precipitation of the active ingredient (i.e. , signs of physical instability) from the formulation over prolonged time-periods, for example, at 25°C over a minimum of 3 months.
  • the lipid vehicle comprises a surfactant, optionally a cosurfactant or a mixture of surfactants; and optionally an oil.
  • the lipid vehicle comprises optionally a cosolvent or a mixture of cosolvents.
  • Other properties of the lipid vehicle include the ability to rapidly disperse in aqueous fluids (e.g., gastric fluid) on rupture and release from a capsule. It is further preferable in certain embodiments that the lipid vehicle maintains the active ingredient in solution, particularly in the stomach and in the small intestine, for example, by formation of an emulsion, nanoemulsion or microemulsion. It is further advantageous in certain embodiments that the lipid vehicle does not negatively impact the physical properties of the capsule shell, namely its capacity to rapidly dissolve and rupture in the gastro-intestinal tract or its overall physical integrity.
  • the basic active ingredient, the lipophilic counterion and the acidic pH modifier are substantially completely or are completely dissolved in the lipid vehicle, meaning that the solids of these components are homogenously dispersed in the vehicle at the molecular level (no amorphous or crystalline particles of these components are present). Dissolution into the lipid vehicle may be evaluated by adding the basic active ingredient, the lipophilic counterion and the acidic pH modifier to the lipid vehicle at the applicable wt%, followed by mixing at 30°C (or another appropriate temperature) until the formulation appears as a clear, single phase system to the eye, and as confirmed by a lack of any undissolved particles in removed samples using polarized light microscopy or another suitable technique.
  • pH Modifier or another appropriate temperature
  • the pH modifier is an acid.
  • the acid may be any organic acidic compound or an inorganic acidic compound.
  • the pH modifier is capable of increasing the stability and/or solubility of the lipophilic salt form of the active ingredient.
  • the addition of a pH modifier can (i) increase the shelf-life, (ii) reduce the risk of physical instability on product storage and (iii) allow the use of a higher concentration of active ingredient without compromising physical stability.
  • R may be any
  • R is alkyl.
  • alkyl may be a saturated straight chained or branched hydrocarbon.
  • alkyl refers to a hydrocarbon group having from 4-40 carbon atoms, including ranges of from 8-12, 13-16, 17-20, 20-24 and 25-40 carbon atoms.
  • alkyl refers to C1 C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39 or C40 straight or branched hydrocarbons.
  • R has at least 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23 or 24 carbon atoms.
  • R is a saturated cyclic hydrocarbon (cycloalkyl).
  • the cycloalkyl group may be monocyclic, or polycyclic, including bicyclic or tricyclic fused or bridged ring systems (e.g. norpinane, norbornane and adamantane).
  • R is a C3, C4, C5, C6, C7, C8, C9 or C10 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R is alkenyl or alkynyl wherein R is a straight chained or branched hydrocarbon group having at least one (for example 1 , 2, 3, 4, 5, 6 or more) double or triple bonds respectively, or a combination of both.
  • alkenyl or alkynyl refers to an unsaturated hydrocarbon group having from 4-40 carbon atoms, such as from 4-24 carbon atoms, including ranges of from 8-12, 13-16, 17-20, 20-24 and 25-40 carbon atoms.
  • alkenyl or alkynyl refers to C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23 C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39 or C40 hydrocarbons.
  • R is an unsaturated cyclic hydrocarbon group having at least one (for example, 1 , 2, 3, 4. 5, 6 or more) double (cycloalkenyl) or triple bonds (cycloalkynyl) or a combination of both as permitted by steric constraints.
  • the cycloalkyl group may be monocyclic, or polycyclic, including bicyclic or tricyclic fused or bridged ring systems.
  • R is a C3, C4, C5, C6, C7, C8, C9, C10 cycloalkyl group.
  • the unsaturated cyclic hydrocarbon group may be aromatic or heteroaromatic.
  • R may include monocyclic or polycyclic aromatic or heteroaromatic groups such as phenyl, naphthyl, pyridyl or pyrimidyl.
  • R group as described herein may be unsubstituted or may be substituted by 1 , 2, 3, 4, 5. or 6 or more same or different optional substituents.
  • optional substituents may be selected from C1-6alkyl, C3-6cycloalkyl, phenyl, C1-6alkylphenyl, halo (chloro, fluoro, bromo, iodo), hydroxyl, carboxyl, S(0) 2 0H, C(0)alkyl, C(0)N-- and C(0)H.
  • R may be substituted by 1 , 2, 3, 4, or more fluoro substituents.
  • R may be substituted by 1 , 2, 3, 4, or more hydroxyl substituents.
  • R may be substituted by 1 , 2, 3, 4, or more additional carboxyl groups.
  • R is or contains an amide, a keto or an aldehyde group.
  • Examples thereof include maleate and fumarate.
  • the organic acid may derive from the oxidative ring cleavage of a carbohydrate.
  • R is attached to the acidic functional group by one or two positions, such as saccharin.
  • the organic acid is selected from the group consisting of docusic acid, lactic acid, acetic acid, mandelic acid, lauryl sulfonic acid, dichloroacetic acid, gentisic acid, citric acid, malic acid, adipic acid, benzoic acid, butyric acid, ascorbic acid, lauric acid, valeric acid, heptanoic acid, nonanoic acid, tridecanoic acid, methanesulfonic acid, ethanesulfonic acid, benzesulfonic acid, fumaric acid, galactaric acid, glucaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glycerophosphoric acid, glycolic acid, hippuric acid, lactobionic acid, maleic acid, palmitic acid, pyruvic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocynaic acid, alg
  • the organic acid is selected from the group consisting of lactic acid, docusic acid, lauryl sulfonic acid, methanesulfonic acid, acetic acid, formic acid, caprylic acid, hexanoic acid, oleic acid, benzoic acid, malic acid, gentisic acid, butyric acid, ethanesulfonic acid, mandelic acid, pamoic acid, napthalene-2-sulfonic acid, para-toluenesulfonic acid, lauric acid, heptafluorobutyric acid, dichloroacetic acid and capric acid.
  • the organic acid is selected from the group consisting of lactic acid, docusic acid, lauric acid, heptafluorobutyric acid, dichloroacetic acid and capric acid.
  • the acid is inorganic.
  • the inorganic acid is selected from the group consisting of hydrazoic acid, hydrofluoric acid, hypobromous acid, hypochlorous acid, hypophosphorous acid, nitrous acid, carbonic acid, phosphorous acid, selenous acid, sulfurous acid, tellurous acid, and phosphoric acid.
  • the inorganic acid is selected from the group consisting of phosphorous acic and phosphoric acid.
  • the acidic pH modifier and the counterion in the lipophilic salt form of the basic active ingredient are the same molecule and in some embodiments, the acidic pH modifier and the counterion in the lipophilic salt form of the basic active ingredient are not the same molecule.
  • the pKa of the acidic pH modifier may be less than the pKa of the lipophilic counterion.
  • the pKa of the acidic pH modifier may be equal to the pKa of the lipophilic counterion.
  • the pKa of the acidic pH modifier may be greater than the pKa of the lipophilic counterion.
  • the pK a is the negative base-10 logarithm of the acid dissociation constant (K a ).
  • the concentration and nature of the pH modifier is chosen so as to achieve a good solubility and/or stability of the active ingredient and the lipophilic counterion in the lipid vehicle.
  • the amount of acidic pH modifier necessary to improve the solubility and/or stability of the active ingredient in the lipid vehicle depends on the strength of the pH modifier.
  • the lower the pK a of the pH modifier the lower the amount of pH modifier needed to improve the stability and/or of the active ingredient in the lipid vehicle.
  • the pK a of the acidic pH modifier is less than or equal to 11 and the concentration of acidic pH modifier is greater than 0.05 mol equivalents relative to the basic active ingredient.
  • the pKa of the acidic pH modifier is less than or equal to 11 and the concentration of acidic pH modifier is greater than 0.1 mol equivalents relative to the basic active ingredient.
  • the pKa of the acidic pH modifier is less than or equal to 7 and the concentration of acidic pH modifier is greater than 0.05 mol equivalents relative to the basic active ingredient.
  • the pKa of the acidic pH modifier is less than or equal to 7 and the concentration of acidic pH modifier is greater than 0.1 mol equivalents relative to the basic active ingredient.
  • the pK a of the acidic pH modifier is less than or equal to 1 and the concentration of acidic pH modifier is greater than 0.05 mol equivalents relative to the basic active ingredient.
  • the pK a of the acidic pH modifier is less than or equal to 1 and the concentration of acidic pH modifier is greater than 0.1 mol equivalents relative to the basic active ingredient.
  • the pK a of the acidic pH modifier is greater than 1 and less than or equal to 4 and the concentration of the acidic pH modifier is at least 0.2 mol equivalents relative to the basic active ingredient.
  • the pK a of the acidic pH modifier is greater than 1 and less than or equal to 4 and the concentration of the acidic pH modifier is at least 0.4 mol equivalents relative to the basic active ingredient.
  • the pK a of the acidic pH modifier is greater than 4 and less than or equal to 11 and the concentration of the pH modifier is at least 0.5 mol equivalents relative to the basic active ingredient.
  • the pK a of the acidic pH modifier is greater than 4 and less than or equal to 11 and the concentration of the acidic pH modifier is at least 1 mol equivalents relative to the basic active ingredient.
  • the surfactant (or surfactant mixture) is chosen to dissolve the lipophilic salt of the active and to solubilize the lipophilic salt of the active on dispersion in aqueous fluids.
  • the surfactant is included to also function as an emulsifier, and to function synergistically with the oil in dissolving the lipophilic salt of the active when undiluted and in the gastro-intestinal fluids.
  • the surfactant and cosurfactant also work synergistically in dissolving the lipophilic salt of the active when undiluted and in the gastrointestinal fluids, and in emulsifying the oil component of the vehicle if present.
  • the surfactant has the following properties: non-ionic; a hydrophilic-lipophilic balance greater than 8.
  • the surfactant may be polyethoxylated castor oil and/or derivatives thereof, polyoxyethylene sorbitan fatty acid esters, a mixture of (i) polyoxyethylene mono- and di-esters of Cs- C22 fatty acids and (ii) glyceryl mono-, di-, and tri-esters of C8-C22 fatty acids, polyoxyethylene fatty acid esters, Vitamin E TPGS and/or derivatives thereof polyoxyethylene-polyoxypropylene copolymers or any combination thereof.
  • Polyethoxylated castor oil and derivatives may be polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, or polyoxyl 60 hydrogenated castor oil, and are sold under tradenames such as Kolliphor®, EtocasTM and CroduretTM.
  • Polyoxyethylene sorbitan fatty acid esters may be polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or polysorbate 85, and are sold under tradenames such as Tween® and Montanox®.
  • Polyoxyethylene mono- and di-esters of C8-C22 fatty acids and glycerol mono-, di-, and tri esters of Cs- C22 fatty acids include caprylocaproyl macrogol-8 glycerides (also called PEG-8 caprylic/capric glycerides), oleoyl macrogol-6 glycerides, linoleoyl macrogol-6 glycerides, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides and macrogol stearate, and are sold under tradenames such as Labrasol®, Labrafil®, Acconon® and Gelucire®.
  • Polyoxyethylene fatty acid esters include but are not limited to polyoxyl 15 hydroxystearate, polyoxyl 8 stearate, polyoxyl 40 stearate and polyoxyl 40 oleate, sold under tradenames such as MyrjTM and Kolliphor® HS-15.
  • Polyoxyethylene-polyoxypropylene copolymers include, but are not limited to poloxamer 124, poloxamer 188, poloxamer 407 sold under tradenames such as Pluronic® or Lutrol® or SynperonicTM.
  • the amount of surfactant present in the composition may be from 10 to 96 wt%, may be from 15 to 75 wt%, and may be from 25 to 65 wt% (where the amount of the composition includes the mass of the active ingredient, lipophilic counterion, the lipid vehicle, the pH modifier and any other optional excipients).
  • the optional cosurfactant (or cosurfactant mixture) is chosen to work synergistically with the surfactant in dissolving the lipophilic salt of the active and to solubilize the lipophilic salt of the active on dispersion in aqueous fluids.
  • the cosurfactants are non-ionic and have a hydrophilic-lipophilic balance between 1 and 8.
  • Exemplary cosurfactants include: propylene glycol mono- and di-esters of C8-C22 fatty acids, such as, but not limited to, propylene glycol monocaprylate, propylene glycol dicaprolate/dicaprate, propylene glycol monolaurate, sold under tradenames such as CapryolTM 90, LauroglycolTM 90, Labrafac® PG, Capmul®; and sorbitan fatty acid esters such as, but not limited to, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate, sold under tradenames such as Span® and Montane®.
  • propylene glycol mono- and di-esters of C8-C22 fatty acids such as, but not limited to, propylene glycol monocaprylate, propylene glycol dicaprolate/dicaprate, propylene glycol monolaurate, sold under tradenames such as CapryolTM 90,
  • the amount of cosurfactant (or cosurfactant mixture) present in the composition may be from 0 to 60 wt%, or from 0.5 to 60 wt%, or may be from 5 to 50 wt%, or may be from 10 to 40 wt% of the composition (where the amount of the composition includes the mass of the active ingredient, lipophilic counterion, the lipid vehicle, the pH modifier and any other optional excipients).
  • the optional oil also commonly called “lipid” is chosen to work synergistically with the surfactant and cosurfactant (if present) to dissolve the lipophilic salt of the active and to solubilize the lipophilic salt of the active on dispersion in aqueous fluids.
  • the oil has the following properties: largely immiscible with water, contains digestible ester functional groups.
  • oils which may be used in the present invention include Cs-Cis triglycerides including but not limited to almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grape seed oil, mustard seed oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, soybean oil, sunflower oil, walnut oil, wheat germ oil, avocado oil, bran oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, caprylic/capric glycerides, fractionated triglycerides, glyceryl tricaprate, glyceryl tricaproate, glyceryl tricaprylate, glyceryl tricaprylate/caprate, glyceryl tricaprylate,
  • oils may be sold under various tradenames such as PeceolTM, MaisineTM, Geleol®, Capmul®, Miglyol®, Suppocire®, Gelucire®, Witepsol®, Captex®, Labrafac® and Imwitor®.
  • the amount of oil present in the composition may be from 0 to 60 wt%, may be from 0.5 to 60 wt%, may be from 5 to 50 wt%, or may be from 5 to 30 wt% of the composition (where the amount of the composition includes the mass of the active ingredient, lipophilic counterion, the lipid vehicle, the pH modifier and any other optional excipients).
  • the lipid vehicle comprises a cosolvent (or cosolvent mixture).
  • a cosolvent is a water-soluble organic solvent. Because cosolvents are often miscible with surfactants, cosurfactants and surfactant/oil or cosurfactant/oil blends, they can be used to increase drug solubility in lipid-based vehicles or to facilitate the dispersion of the lipid vehicle on contact with aqueous fluids in the Gl tract. A cosolvent can also be used as the lipid-vehicle itself in the absence of surfactants, cosurfactants or oils.
  • cosolvents include propylene carbonate, triacetin, glycerol, propylene glycol, polythethylene glycols such as PEG 400, glycofurol, ethanol, diethylene glycol monoethyl ether, oleic acid, N-methyl pyrrolidone, ethyl lactate, and triethyl citrate.
  • composition contains less than or equal to 10 wt % cosolvent, such as less than or equal to 7 or 5 or 2 or 1 wt% cosolvent.
  • lipid composition or the lipid vehicle contains no cosolvent.
  • the cosolvent is present in an amount of at least 10 wt%, may be present in an amount of 50 wt%, and may be present in an amount of 96 wt% (where the wt% refers to the percentage weight fraction of the total formulation).
  • the composition consists essentially of the active ingredient, the lipophilic counterion, the pH modifier and the cosolvent (or cosolvent mixture).
  • the lipid vehicle contains one or more oils or lipids, without additional surfactants, co-surfactants, or cosolvents, that is to say consists essentially of one or more oils or lipids.
  • the lipid vehicle contains one or more oils or lipids together with one or more surfactants, optionally together with one or more cosolvents.
  • the lipid vehicle contains one or more oils or lipids together with one or more water-soluble surfactants, optionally together with one or more cosolvents.
  • the lipid vehicle contains a mixture of oil/lipid, surfactant and cosolvent. In some embodiments, the lipid vehicle is consists essentially of one or more surfactants/cosurfactants, and/or solvents/cosolvents.
  • lipid vehicle examples include anti-oxidants to minimize chemical degradation of the active and/or lipid vehicle.
  • Example antioxidants include but are not limited to vitamin E, tocopheryl polyethylene glycol succinate (TPGS), rosemary extract, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), or any combination thereof.
  • the amount of antioxidant in the lipid vehicle may be from 0 to 5 wt% or from 0.1 to 2.5 wt% (where the wt% refers to the percentage weight fraction of the total formulation).
  • excipients such as thickeners or dyes may be present in relatively minor amounts so long as such excipients do not adversely affect the solubility of the active ingredient in the lipid vehicle.
  • excipients make up less than 5 wt% of the lipid vehicle, and may be present in an amount of less than 2 wt% of the lipid vehicle (where the wt% refers to the percentage weight fraction of the total formulation).
  • compositions may be presented in any form suitable for oral administration to a subject.
  • composition, lipid-based formulation or lipid formulation of the present disclosure can be a fill formulation for a capsule.
  • the lipid formulation or composition of the present disclosure is presented in a hard or soft capsule shell.
  • the capsule contains the fill formulation.
  • Soft shell capsules or sealable hard shell capsules may be particularly useful for the lipid-based compositions described herein.
  • the capsule shell may be made from any suitable material known therefor. Suitable materials for the capsule shell include gelatin, polysaccharides, modified starches, or synthetic polymers.
  • Non-limiting examples thereof include generally known agents, for example: cellulose based polymers such as methyl cellulose, ethyl cellulose, methylhydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and the like, polysaccharides such as pullulan, carrageenan, gellan, alginates, and the like; or gelatin; synthetic polymers such as polyvinyl alcohol, polyvinylacetal diethylamino acetate, aminoalkylmethacrylate copolymer E (Eudragit-E -Rohm Pharma Co.
  • cellulose based polymers such as methyl cellulose, ethyl cellulose, methylhydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate
  • (meth)acrylate based polymers such as ethyl acrylate-methyl methacrylate copolymer suspensions (Eudragit NE (commercial name), Rohm Pharma Co. Ltd.), and the like; acrylate based polymers such as methacrylate copolymer L (Eudragit L - Rohm Pharma Co. Ltd.), methacrylate copolymer LD (Eudragit L-30D55 - Rohm Pharma Co. Ltd.), and the like; as well as any combination thereof.
  • (meth)acrylate based polymers such as ethyl acrylate-methyl methacrylate copolymer suspensions (Eudragit NE (commercial name), Rohm Pharma Co. Ltd.), and the like
  • acrylate based polymers such as methacrylate copolymer L (Eudragit L - Rohm Pharma Co. Ltd.), methacrylate copolymer LD (Eudragit L-30D55 - Rohm Pharma Co. Ltd.), and the like;
  • the lipid formulation may be presented in container such as a sachet, ampoule, syringe or dropper device or tube or bottle, (for example, a tube or bottle which can be squeezed to deliver its contents), optionally as a fixed dosage, the contents of which may be taken directly or mixed or dispersed into food or liquid.
  • the lipid formulation may adsorbed onto a suitable solid carrier, such as lactose or silica, which may be filled into a capsule shell or taken directly or mixed in with, or sprinkled onto food or liquid as above.
  • a physically unstable formulation refers to the presence of solid particles in the sample that appear over time, confirmed by polarized light microscopy.
  • the solid particles consist of the active ingredient.
  • Physical instability of the active ingredient is important to avoid in lipid-based formulations as it can negatively affect the ability of the active ingredient to be absorbed in the gastrointestinal tract, in turn potentially compromising the therapeutic effectiveness of the active ingredient.
  • a well-known example of this is ritonavir physical instability in softgel capsules containing a lipid-based formulation (see Bauer et al. Pharmaceutical Research, Vol. 18, No. 6, 2001 , pp 859 - 866).
  • a formulation may become physically unstable immediately during incorporation of the active ingredient or lipophilic salt form of the active ingredient.
  • a formulation may become unstable on prolonged storage, for example, after 1 week, or after 2 weeks, or after 1 month, or after 3 months or after more than 3 months.
  • the stability of a formulation containing fully incorporated active ingredient is routinely assessed over prolonged time periods to provide assurances that the formulation will exhibit a suitable shelf-life. It is common in the industry to therefore perform stability tests under accelerated conditions including 25°C and 60% relative humidity (RH) or 30°C and 65% RH or 40°C and 75% RH.
  • a physically stable formulation refers to the absence of solid particles (of the active ingredient) in the sample, confirmed by polarized light microscopy.
  • the sample is placed between a microscope slide and a glass coverslip.
  • the sample is then viewed under a microscope equipped with a polarizer in the light path before the sample and one after the sample (also called the analyzer).
  • polarizers When these polarizers are oriented at right angles to each other, they block directly transmitted light and only allow light oscillating in one orientation to pass.
  • polarized light interacts with a “birefringent” material, the velocity of the polarized light changes as does the color of the light.
  • Crystalline materials such as active ingredients are often birefringent meaning that polarized light microscopy is a common technique used to detect for suspended active particles in lipid-based formulations (Pharmaceutical Microscopy, Robert Allen Carlton, 2011 , Springer-Verlag New York).
  • a physical stability advantage in this application of combining pH modifiers in lipophilic salt containing lipid-based formulations was considered where physical stability significantly improved at room temperature or under controlled conditions in comparison to formulations where there was no pH modifier. In some cases, this meant physically stable formulations fora minimum of 1 month, or 3 months or 6 months.
  • a lipophilic salt form of an active ingredient exhibits physical instability during the incorporation step (meaning that the lipophilic salt form of the active ingredient does not fully dissolve in the formulation)
  • Solubility tests involve the addition of excess amount of lipophilic salt of the active ingredient to a fixed volume of formulation, followed by agitation and incubation under controlled conditions for several days. At specific time points, the formulations are centrifuged at high-speed and sample aliquots removed from the particle-free supernatant.
  • solubility of the active ingredient in removed samples is measured by HPLC and a saturated solubility value is defined as when the measured concentration of active ingredient across consecutive time points varies by less than 5%.
  • solubility tests were performed at 37°C over a minimum of 14 days. Centrifugation was performed at 37°C at 14 000 g.
  • a physical stability advantage in this application of combining pH modifiers in lipophilic salt containing lipid-based formulations was considered where the solubility of the lipophilic salt form of the active ingredient in the formulation increased by more than 10%, or more than 20%, or more than 50% or more than 100% relative to the control (the solubility value of the lipophilic salt form of the active ingredient in the absence of pH modifier).
  • the pK a values reported in the examples and tables are taken from the literature. They have not been calculated. The calculated values may slightly differ from the bibliographic data as there are different methods to calculate pK a and often the bibliographic value is given for a simple aqueous system and in the compositions of the present disclosure the water content is low.
  • Erlotinib docusate, itraconazole docusate, sildenafyl lauryl sulfate, fexofenadine lauryl sulfate, fexofenadine 2-hexyl-1-decyl sulfate, fexofenadine decylsulfate and posaconazole docusate were prepared according to the method 2 described on page 24 of WO 2015013772 A1 .
  • Cinnarizine decanoate and sildenafil laurate were prepared according to the method 3 described on pages 24 and 25 of WO 2015013772 A1 .
  • Examples 1-6 Lipid formulations containing erlotinib docusate and acidic pH modifiers
  • Placebo (drug-free) lipid formulations were initially prepared followed by the addition of the acidic pH modifier.
  • Oils long-chain triglyceride (corn oil), medium-chain triglyceride (Miglyol® 812) and/or glyceryl monolinoleate (MaisineTM 35-1);
  • Cosurfactants propylene glycol monocaprylate (CapryolTM 90)
  • Surfactants polyoxyl 35 castor oil (Kolliphor® EL)
  • Formulations were vortex-mixed for complete incorporation of the acid into the formulation.
  • the lipophilic salt erlotinib docusate was then added into the formulation at a 31 .1 wt% salt loading. This equated to 15wt% erlotinib free base, which was notably higher than the solubility of erlotinib free base in the same formulations (no greater than 5wt%).
  • the lipophilic salt was incorporated into the lipid formulation by brief (no more than 90 minutes) ultrasonication at 30-40°C to yield an isotropic solution. In each formulation, the final composition was 31 .1 wt% lipophilic salt, 68.9wt% lipid formulation and 2% wt acid.
  • Control formulations 1-3 i.e., no acid
  • 31.1 wt% lipophilic salt were prepared in a similar manner. For details see Table 1 . Samples were stored at room temperature.
  • Example 7 Lipid formulations containing itraconazole docusate and an acidic pH modifier
  • Placebo lipid formulation consisting of 30 wt% soybean oil and 30 wt% glyceryl monolinoleate (MaisineTM 35-1) (as oils/cosurfactant), 30 wt% polyoxyl 35 castor oil (Kolliphor® EL) (as the surfactant) and 10wt% ethanol (as the cosolvent) was first prepared followed by the addition of free docusic acid. This formulation was vortex-mixed for complete incorporation of the acid in the formulation.
  • the lipophilic salt itraconazole docusate was added to the formulation at 20.0 wt% salt loading.
  • This loading equates to a 12.5wt% itraconazole free base, and notably, significantly higher than the solubility of itraconazole free base in the same formulation (no greater than 1 wt%).
  • the lipophilic salt was incorporated at 37°C with periodic mixing to yield an isotropic solution.
  • the control formulation 4 containing no acid was prepared in a similar manner. Samples were stored at room temperature.
  • Example 8 Lipid formulations containing sildenafil lauryl sulfate and acidic pH modifier
  • Placebo lipid formulation consisting of propylene glycol monocaprylate (CapryolTM 90) (acting as an oil/cosurfactant) and PEG-8 caprylic/capric glycerides (Labrasol®) and poloxyl 35 castor oil (Kolliphor® EL) (as surfactants) was first prepared followed by the addition of lactic acid. Formulations were vortex- mixed for complete incorporation of the acid into the formulation. The lipophilic salt sildenafil lauryl sulfate was then added to the formulation at a 20.0 wt% salt loading. This loading equates to 12.8wt% sildenafil free base, and notably, significantly higher than the solubility of sildenafil free base in the same formulation (no greaterthan 1-2 wt%).
  • CapryolTM 90 propylene glycol monocaprylate
  • Labrasol® PEG-8 caprylic/capric glycerides
  • Kolliphor® EL poloxyl 35 cast
  • the lipophilic salt was incorporated by brief (no more than 90 min) ultrasonication at 30-40°C to yield an isotropic solution.
  • the control formulation 5 containing no acid was prepared in a similar manner. Samples were stored at room temperature with ongoing stability analysis at 25°C/60% RH.
  • Example 9 Lipid formulations containing sildenafil laurate and acidic pH modifiers
  • Placebo lipid formulation consisting of 20 wt% propylene glycol monocaprylate (CapryolTM 90) (as the oil/cosurfactant), 40wt% PEG-8 caprylic/capric glycerides (Labrasol®) (as a surfactant) and 40 wt% polyoxyl 35 castor oil (Kolliphor® EL) (as an additional surfactant) was first prepared followed by the addition of lauric acid. This formulation was vortex-mixed for complete incorporation of the acid in the formulation.
  • CapryolTM 90 propylene glycol monocaprylate
  • Labrasol® as a surfactant
  • Kolliphor® EL polyoxyl 35 castor oil
  • the lipophilic salt sildenafil laurate was added to the formulation at a target loading of 3.5 wt%. These loadings equates to 2.5 wt% sildenafil free base, and notably, significantly higher than the solubility of the free base forms of these API in the same formulation (no greaterthan 1 wt%).
  • the lipophilic salt was incorporated at 30-40 °C with periodic mixing to yield an isotropic solution.
  • the control formulation 6 containing no acid was prepared in a similar manner.
  • Table 4 Example 9 / Control 6, Data and Results
  • Example 10 Lipid formulations containing posaconazole docusate and acidic pH modifier
  • Placebo lipid formulation consisting of 20 wt% glyceryl monocaprylate (Imwitor® 308) (as the oil), 40 wt% propylene glycol monocaprylate (CapryolTM 90) (as the cosurfactant) and 40 wt% poloxyl 35 castor oil (Kolliphor® EL) (as the surfactant) was first prepared followed by the addition of 5 wt% lactic acid. This formulation was then vortex-mixed for complete incorporation of the acid into the formulation. The lipophilic salt posaconazole docusate was then added to the formulation at 8.0 wt% salt loading. This loading equates to 5.0 wt% posaconazole free base, and notably, significantly higher than the solubility of posaconazole free base in the same formulation (no greater than 0.5 wt%).
  • the lipophilic salt was incorporated by brief (no more than 90 min) ultrasonication at 30-40°C to yield an isotropic solution.
  • the control formulation 7 containing no acid was prepared in a similar manner. Samples were stored at 25°C/60% RH with ongoing stability analysis.
  • Examples 11-13 Lipid formulations containing cinnarizine decanoate and acidic pH modifiers
  • Placebo formulation consisting of 30% wt. medium-chain triglycerides (Captex® 355), 30% wt. glyceryl monocaprylate (Capmul® MCM), 30% wt. polyoxyl 35 castor oil (Kolliphor® EL) and 10% wt. ethanol was first prepared followed by the addition of acid (heptafluorobutyric acid, dichloroacetic acid or capric acid) to achieve the target mol equivalence (see table). This formulation then vortex-mixed for complete incorporation of the acid into the formulation. The lipophilic salt cinnarizine decanoate (also known as cinnarizine caprate) was then added to the formulation at a target concentration of 22% wt.
  • acid heptafluorobutyric acid, dichloroacetic acid or capric acid
  • the formulation was vortex-mixed and stored at 37°C over several days with regular mixing to resuspend the undissolved lipophilic salt.
  • concentration of dissolved cinnarizine in the lipid formulation i.e. , the solubility of cinnarizine decanoate in the formulation
  • the formulation was centrifuged (14000 c g, 37 °C, 10 min) and the cinnarizine concentration in the supernatant measured by HPLC. Values were determined in triplicate. The results below confirm that the target solubility of 15% wt. cinnarizine free base could only be achieved using the lipophilic salt of the active plus a pH modifier.
  • control formulation 8 containing no acid was prepared in a similar manner.
  • Table 6 Examples 11-13 / Control 8, Data and Results
  • Example 14 Additional Lipid formulations containing erlotinib docusate with an acidic pH modifier
  • Placebo lipid formulation consisting of 50 wt% PEG-8 caprylic/capric glycerides (Labrasol®) (as the oil) 40 wt% propylene glycol monolaurate (LauroglycolTM 90) (as the co surfactant), 10 wt% sorbitan monolaurate (Span® 20) (as the surfactant) was first prepared, in the stabilization experiment this was followed by the addition of 5 wt% phosphorous acid. The lipophilic salt erlotinib docusate was added at 32.0 wt% (15 wt% erlotinib free base). Incorporation was performed at 60°C with constant magnetic stirring (500 rpm) on a hot plate for 45-60 minutes followed by monitoring at room temperature.
  • control formulation 9 containing no acid was prepared in a similar manner.
  • Placebo lipid formulation consisting of 50 wt% PEG-8 caprylic/capric acid glycerides (Labrasol®) (as the oil) 40 wt% propylene glycol monolaurate (LauroglycolTM 90) (as the co surfactant), 10 wt% sorbitan monolaurate (Span® 20) (as the surfactant) was first prepared, in the stabilization experiment this was followed by the addition of 5 wt% or 8 wt% phosphorous acid. The lipophilic salt fexofenadine lauryl sulfate was added at 35.0 wt% (23 wt% fexofenadine free base). Incorporation was performed at 60°C with constant magnetic stirring (500 rpm) on a hot plate for 45-60 minutes followed by monitoring at room temperature.
  • control formulation 10 containing no acid was prepared in a similar manner.
  • Examples 17 and 18 Lipid formulations containing fexofenadine 2-hexyl-1-decyl sulfate with acidic pH modifiers
  • Placebo lipid formulation consisting of 50 wt% PEG-8 caprylic/capric glycerides (Labrasol®) (as the oil) 40 wt% propylene glycol monolaurate (LauroglycolTM 90) (as the co surfactant), 10 wt% sorbitan monolaurate (Span® 20) (as the surfactant) was first prepared, in the stabilization experiment this was followed by the addition of 5.5 wt% phosphorous acid. The lipophilic salt fexofenadine 2-hexyl-1-decyl sulfate was added at 37.0 wt% (23 wt% fexofenadine free base). Incorporation was performed at 60°C with constant magnetic stirring (500 rpm) on a hot plate for 45-60 minutes followed by monitoring at room temperature.
  • Example 18 Phosphoric acid
  • Placebo lipid formulation consisting of 50 wt% PEG-8 caprylic/capric glycerides (Labrasol®) (as the oil) 40 wt% propylene glycol monolaurate (LauroglycolTM 90) (as the co surfactant), 10 wt% sorbitan monolaurate (Span® 20) (as the surfactant) was first prepared.
  • the lipophilic salt fexofenadine 2-hexyl- 1-decyl sulfate was added at 37.0 wt% (23 wt% fexofenadine free base) in the stabilization experiment this was followed by the addition of 5.0 wt% phosphoric acid. Incorporation was performed at 60°C with constant magnetic stirring (500 rpm) on a hot plate for 45-60 minutes followed by monitoring at room temperature.
  • control formulation 11 containing no acid was prepared in a similar manner.
  • Example 19 Lipid formulations containing fexofenadine decyl sulfate with an acidic pH modifier
  • Placebo lipid formulation consisting of 50 wt% PEG-8 caprylic/capric glycerides (Labrasol®) (as the oil) 40 wt% propylene glycol monolaurate (LauroglycolTM 90) (as the co surfactant), 10 wt% sorbitan monolaurate (Span® 20) (as the surfactant) was first prepared, in the stabilization experiment this was followed by the addition of 5.0 wt% phosphorous acid. The lipophilic salt fexofenadine 1 -decyl sulfate was added at 33.0 wt% (23 wt% fexofenadine free base). Incorporation was performed at 60°C with constant magnetic stirring (500 rpm) on a hot plate for 45-60 minutes followed by monitoring at room temperature.

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Abstract

La présente invention concerne des formulations à base de lipides, des formulations lipidiques ou des compositions comprenant des sels lipophiles et des modificateurs de pH acide. Les modificateurs de pH acide peuvent produire des formulations de lipides stabilisées et/ou augmenter la solubilité des sels lipophiles dans les formulations de lipides.
PCT/EP2020/086964 2019-12-18 2020-12-18 Compositions à base de lipides comprenant des sels lipophiles et des modificateurs de ph acide WO2021123121A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015013772A1 (fr) 2013-08-01 2015-02-05 Monash University Compositions et procédés de préparation de sels ioniques à bas point de fusion de médicaments faiblement hydrosolubles
WO2019081451A1 (fr) * 2017-10-26 2019-05-02 Mw Encap Limited Formulations remplies liquides d'inhibiteurs de pde5

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015013772A1 (fr) 2013-08-01 2015-02-05 Monash University Compositions et procédés de préparation de sels ioniques à bas point de fusion de médicaments faiblement hydrosolubles
WO2019081451A1 (fr) * 2017-10-26 2019-05-02 Mw Encap Limited Formulations remplies liquides d'inhibiteurs de pde5

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BAUER ET AL., PHARMACEUTICAL RESEARCH, vol. 18, no. 6, 2001, pages 859 - 866
STOIMENOVSKI J. ET AL.: "Crystalline vs. Ionic Liquid Salt Forms of Active Pharmaceutical Ingredients: A Position Paper", PHARMACEUTICAL RESEARCH, KLUWER ACADEMIC PUBLISHERS-PLENUM PUBLISHERS, NL, vol. 27, no. 4, 9 February 2010 (2010-02-09), pages 521 - 526, XP019793921, ISSN: 1573-904X, DOI: 10.1007/S11095-009-0030-0 *

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