WO2023287292A1 - Micelle-generating formulations for enhanced bioavailability - Google Patents

Micelle-generating formulations for enhanced bioavailability Download PDF

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Publication number
WO2023287292A1
WO2023287292A1 PCT/NL2022/050416 NL2022050416W WO2023287292A1 WO 2023287292 A1 WO2023287292 A1 WO 2023287292A1 NL 2022050416 W NL2022050416 W NL 2022050416W WO 2023287292 A1 WO2023287292 A1 WO 2023287292A1
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Prior art keywords
pharmaceutical composition
previous
api
composition according
hpmc
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PCT/NL2022/050416
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French (fr)
Inventor
Christian DEGELING
Michel VAN DE GRAAFF
Michiel VAN SPEYBROECK
Niall Hodgins
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Seranovo Holding B.V.
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Publication of WO2023287292A1 publication Critical patent/WO2023287292A1/en

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the invention is in the field of pharmaceutical compositions for enhanced bioavailabihty.
  • the invention is directed to a pharmaceutical composition comprising one or more non-ionic surfactants, an active pharmaceutical ingredient (API) and a hydroxypropyl methylcellulose acetate succinate (HPMC-AS).
  • API active pharmaceutical ingredient
  • HPMC-AS hydroxypropyl methylcellulose acetate succinate
  • BCS class II and IV are used for drugs that are considered to have low aqueous solubility.
  • GI gastrointestinal
  • API drug
  • active ingredient may be used interchangeably herein.
  • Bioavailabihty of the API relates i.a. to the solubility, membrane permeabihty and enzymatic degradation of the active ingredient in the patient.
  • Bioavailabihty may be measured as the area under a curve of the plasma concentration of a drug over a certain time period. The bioavailability may be denoted as a percentage and depends i.a. on the half- life of the drug.
  • processing these ingredients in dosage forms typically requires the use of less polar solvents such as dimethylsulfoxide, alcohols, acetone, ethyl acetate, chloroform and the like. These solvents present problems including toxicity and danger of explosion.
  • Solid dispersions are typically dispersions of a drug in an amorphous polymer matrix.
  • the matrix may further comprise i.a. a surfactant.
  • Solid dispersions can be manufactured through a variety of processes including melt extrusion, spray drying and co -precipitation.
  • Several reviews on solid dispersions are Huang and Dai (Acta Pharmaceutica Sinica B, 4, 2014, 18-25), Chivate et al. (Current Pharma Research, 2, 2012, 659-667) and Zhang et al. (Pharmaceutics, 3, 2018, 142).
  • disadvantages of solid dispersions include complex manufacturing, the physical instability of the product and a consequent decrease in dissolution rate over time.
  • SEDDS are typically isotropic mixtures of one or more hydrophilic solvents and co-solvents or surfactants that may form oil-in-water micro emulsions in aqueous media, as for instance detailed by Khedekar and Mittal (International Journal of Pharmaceutical Sciences and Research, 4(12), 2013, 4494-4507).
  • a particular type of SEDDS are super saturable SEDDS which comprise polymeric precipitation inhibitors to stabilize the drug in a supersaturated state.
  • a DES deep eutectic solvent
  • a DES is formed when one or more constituents are mixed together at a specific ratio resulting in the depression of the melting point of one or more of the constituents.
  • WO 2020/085904 discloses a DES platform for oral pharmaceutical formulations that also enhances the solubility and bioavailability of the API.
  • the present inventors have surprisingly found that a composition comprising one or more non-ionic surfactants as a major component and a hydroxypropyl methylcellulose acetate succinate (HPMC-AS) as a minor component allows for such a pharmaceutical composition.
  • HPMC-AS hydroxypropyl methylcellulose acetate succinate
  • a composition comprising the one or more non-ionic surfactants as a major component and the HPMC-AS as a minor component may create a micellar solution, with e.g. nano-sized micelles, within a short amount of time (e.g. minutes) of contact with an aqueous environment.
  • the present inventors beheve that release of high concentrations of API into an aqueous medium (e.g. arelease above its amorphous solubility) may lead to phase- separation of amorphous, API -rich droplets.
  • phase-separation of amorphous API is generally considered undesirable as it reduces the thermodynamic activity of the API in solution and thus reduces flux over the intestinal membrane.
  • formation of phase-separated amorphous API may be a predecessor of API crystalhzation, which lowers thermodynamic activity and flux over the intestinal membrane even further.
  • the present inventors believe that the micelles formed after hydration of the compositions of the current invention may act to prevent or reduce phase- separation of amorphous API droplets.
  • the present inventors have realized that the non-ionic surfactant may function to keep the API in a micelle and that only a small amount of HPMC-AS is required to stabilize these micelles.
  • Figure 1 illustrates a pharmacokinetic study completed in beagle dogs of a preferred composition according to the present invention compared to a micronized API pressed into a tablet.
  • Figure 2 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and for a composition without HPMC-AS.
  • Figure 3 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and the crystalline solubihty of the API in the medium.
  • Figure 4 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and the crystalline solubihty of the API in the medium.
  • Figure 5 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and the crystalline solubihty of a composition without HPMC-AS in the medium.
  • Figure 6 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and the crystalline solubihty of a composition without HPMC-AS in the medium.
  • Figure 7 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and for a composition without HPMC-AS.
  • Figure 8 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and for a composition without HPMC-AS.
  • Figure 9 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and three comparative compositions.
  • the present invention is directed to a pharmaceutical composition (herein also referred to as the composition) comprising 40-95 wt% of one or more non-ionic surfactants, 2-30 wt% of an API and 1-15 wt% of a hydroxypropyl methylcellulose acetate succinate (HPMC-AS), based on the total weight of the composition.
  • a pharmaceutical composition herein also referred to as the composition
  • HPMC-AS hydroxypropyl methylcellulose acetate succinate
  • the components of the composition are typically selected for being safe for oral administration, for example they may be on the generally recognized as safe (GRAS) list for oral administration.
  • GRAS safe list is established by the Food and Drug Administration (FDA) of the United States.
  • the composition may be produced by a method comprising forming a homogeneous solution comprising the relative amounts of the one or more non-ionic surfactants, API and HPMC-AS.
  • This method may entail mixing and hquifying all components to form the homogeneous solution, or if the non-ionic surfactant is liquid, the liquihcation may be omitted and the API and HPMC-AS can be directly added to the surfactant.
  • the order in which the components are added is typically not relevant, which may be advantageous for ease of production.
  • the homogenous solution is at an elevated temperature (i.e. above ambient temperature, approximately 20 °C), it may be let to cool down to ambient temperatures to obtain the composition.
  • the one or more non-ionic surfactants herein also referred to in
  • ‘non-ionic surfactant’, ‘non-ionic surfactants’, ‘surfactant’ and ‘surfactants’) preferably comprises one or more polyethylene glycol (PEG) mono- and/or diesters with fatty acids and further optionally one or more mono, di- and/or triglycerides.
  • Glycerides typically comprise a mono- di or tri-ester of glycerol (propane- 1, 2, 3-triol) with fatty acids.
  • the one or more mono, di- and/or triglycerides are typically present as a glyceride fraction and preferably non- covalently mixed, such as blended, with the PEG mono- and/or diesters with fatty acids.
  • the non-ionic surfactant may include one or more polyethoxylated sorbitan esters, such as commercially available Tween® 20, 60 or 80, polyethoxylated (hydrogenated) castor oil (e.g. Kolliphor® EL) and/or polyoxyethylated 12-hydroxystearic acid (e.g. Kolliphor® HS15).
  • the non ionic surfactants may alternatively or additionally include other polyethoxylated-based materials such as e.g. the commercially available Kolliphor® RH 40.
  • the composition is typically a single-phase composition.
  • a single physical phase instead of a multiphase system such as a emulsion, the stability of the composition is improved.
  • the non-ionic surfactant is a semi-solid, waxy material and may have an amphiphilic character.
  • the amphiphilic character can be expressed by a hydrophilic-lipophilic balance (HLB).
  • HLB hydrophilic-lipophilic balance
  • the HLB is typically determined by the balance of the size and strength of the hydrophilic and lipophihc moieties of a molecule.
  • the HLB is based on Griffin’s method that ranges from 0 (completely hydrophobic) to 20 (completely hydrophilic).
  • the HLB may accordingly be used to predict the surfactant properties of a molecule.
  • molecules with a HLB above 10 are considered water-soluble and below 10 are considered lipid-soluble.
  • Molecules with a HLB value from approximately 16 to 18 may be used as hydrotrope.
  • a preferred non-ionic surfactant mixture has a HLB value between 12-18, preferably between 13-18.
  • the preferred non-ionic surfactant is accordingly hydrophilic and can be considered water-soluble.
  • the non-ionic surfactant comprises PEG32 mono- and/or diesters with Cs-Cis fatty acids, polyethoxylated sorbitan esters, polyethoxylated (hydrogenated) castor oil or polyoxyethylated 12- hydroxystearic acid.
  • Cs-Cis is used herein to indicate that the fatty acid comprises a carbon chain of 8 to 18 carbon atoms.
  • the number average molecular weight of PEG32 is typically around 1500 g/mol.
  • the non-ionic surfactant comprises one or more polyoxylglycerides.
  • Polyoxylglycerides are mixtures of monoesters, diesters, and triesters of glycerol, and monoesters and diesters of polyethylene glycols (PEG); see also Rowe et al., Handbook of Pharmaceutical Excipients, 6 th Edition, p. 557 et seq.
  • Certain polyoxylglycerides are known and commercially available as Gelucire®.
  • Certain Gelucire® mixtures such as Gelucire® 48/16 however lack the esters of glycerol that are usually present in polyoxylglycerides.
  • Polyoxylglycerides suitable for the present invention can be prepared by partial alcoholysis of glycerides with PEG. Accordingly, in a typical embodiment, the ester(s) of glycerol and the ester(s) of PEG in the non-ionic surfactant may be based on the same fatty acid(s), e.g. one or more of Cs-C is fatty acids.
  • a particularly preferred non -ionic surfactant for the present invention is commercially available as Gelucire®, such as Gelucire® 44/14, Gelucire® 48/16 and/or Gelucire® 50/13 (see also K.C. Panigrahi et al.
  • the first number following the name Gelucire® indicates the melting point in degrees centigrade while the second number (e.g. */ 13, */14, */16, */18, etc.) indicates the HLB value.
  • the second number indicates the HLB value.
  • Gelucire® comprises for instance PEG esters of fatty acids or a mixture of mono, di and or triglycerides with PEG esters of fatty acids.
  • the glyceride fraction compared to the PEG ester fraction may be small or large, dependent on the type of Gelucire®.
  • Gelucire® comprising only PEG esters are generally used for fast release formulations, while Gelucire® comprising PEG esters and glycerides are generally used for sustained release formulations.
  • the composition further comprises HPMC-AS, also known as hypromellose acetate succinate.
  • HPMC-AS is a generally known polymeric precipitation inhibitor that is used in various drug delivery systems (see also Rowe et al., Handbook of Pharmaceutical Excipients, 6 th Edition, p. 330- 332).
  • HPMC-AS comprises a cellulose backbone modified with methyl, acetate, hydroxypropyl and succinoyl groups. The ratio of these modifications typically determines the commercial grade of the HPMC-AS. These grades are commercially available as L, M, H and may each be available in different grain sizes such as fine or coarse. In particular the content of acetate and succinoyl groups influence the grade.
  • the content of succinoyl may further determine the pH at which the HPMC-AS solubilizes as the succinoyl groups may be deprotonated at higher pH and can accordingly ionize and solubilize the polymer in an aqueous environment.
  • a pH above 6.5 is typically preferred as this allows for most succinoyl groups to be deprotonated and accordingly appears to increase the stability of the composition.
  • a particularly preferred HPMC-AS has an acetyl content of 5-9 wt% (e.g. L-grade), 7-11 wt% (e.g. M-grade) or 10-14 wt% (e.g. H-grade), based on the total weight of the HPMC-AS.
  • the HPMC-AS has a succinoyl content of 14-18 wt% (e.g. L-grade), 10-14 wt% (e.g. M-grade) or 4-8 wt% (e.g. H-grade) based on the total weight of the HPMC-AS.
  • HPMC-AS constitutes a minor component of the composition.
  • the relatively small amount of HPMC-AS significantly improves the ability of the non-ionic surfactant to increase the concentration of poorly-soluble APIs in a dissolution medium.
  • the ratios of the non-ionic surfactant and the HPMC-AS in accordance with the present invention were found to lead to stable homogeneous composition. With stable herein is meant that that the homogeneous composition is transparent for at least 24 h at 20 °C.
  • the other ingredient of the composition is the API.
  • the API comprises a BCS class II API.
  • Class II API are considered to have low water solubility and administration to a patient can be a challenge.
  • the API may for example have an aqueous solubility of not more than 1 mg/mL at pH 6.8 when it is a weakly basic compound, of no more than 1 mg/mL at pH 1.2 when it is a weakly acidic compound. In the case of physiological pH of 1.0 to 8.0 for neutral or non-ionizable compounds the aqueous solubility may be no more than 1 mg/mL.
  • a drug is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1 to 7.5.
  • aqueous environment generally relates to gastrointestinal fluid at pH 5.0 to 8.0 or to the stomach at pH 1.0 to 2.0 in vivo or an aqueous test medium in vitro.
  • the composition comprises 40-95 wt%, preferably 50-90 wt%, more preferably 50-80 wt% of the non-ionic surfactant based on the total weight of the composition. Additionally or alternatively, it may be preferred that the composition comprises 2-30 wt%, preferably 2-20 wt% of the API and/or 1-10 wt%, preferably 1-8 wt% of the HPMC-AS, based on the total weight of the composition.
  • the composition is preferably free from any lipid. In particular, the composition is preferably free from any lipid that is used in conventional SEDDS.
  • the composition is free from lipids including fatty acids, mono-, di- or triglycerides, glycerophospholipids, sphingolipids, sterols, prenols, saccharolipids and/or polyketides.
  • the composition preferably consists essentially of the one or more non-ionic surfactants, the active pharmaceutical ingredient the HPMC-AS and the optional solubilizer as described herein.
  • the composition comprises more than 90 wt%, preferably more than 95 wt%, even more preferably more than 98 wt%, of the one or more non-ionic surfactants, the active pharmaceutical ingredient the HPMC-AS and the optional solubilizer as described herein, based on the total weight of the composition.
  • the composition of the invention may be solid, semi-sohd or liquid at ambient temperature and pressure.
  • the preferred non-ionic surfactant is typically sohd or semi-solid at ambient temperature and pressure.
  • a solid or semi-solid composition may further be particularly compatible for further processing.
  • the composition can accordingly be used in a medical treatment comprising enteral, preferably oral administration.
  • the composition can also be used in a medical treatment comprising injectable administration.
  • Oral administration is typically preferred due to the ease of administration resulting in an overall increased patient compliance.
  • the medical treatment comprises oral administration of capsules or tablets comprising the pharmaceutical composition.
  • the capsules may for instance release their contents ( i.a . the composition) at a pH above 5.
  • the injectable administration may comprise subcutaneous, intramuscular, and intravenous injections, as well as less common injections such as intraperitoneal, intraosseous, intracardiac, intraarticular, and intracavernous injections.
  • the present invention can particularly suitably be used for treatments comprising intravenous injections.
  • the composition can further comprise a solubilizer.
  • the solubilizer may be present in 1-50 wt%, preferably 1-25 wt%, based on the total weight of the composition.
  • the solubilizer may advantageously be added to increase the solubility of the API in the composition and accordingly increase the final drug loading in the composition.
  • the solubilizer may be added at any time, such as before, simultaneously, or after the other components to form the homogeneous composition.
  • the solubilizer comprises a co-solvent, a deep eutectic solvent (DES) and/or a pharmaceutically acceptable eutectic constituent that is capable of forming a eutectic mixture with the API.
  • DES deep eutectic solvent
  • the co-solvent can be any pharmaceutically acceptable conventional solvent and/or combination thereof.
  • suitable co solvents include one or more glycols, such as propylene glycol, dipropylene glycol, butylene glycol, glycerol, tetraglycol, 1,2-hexanediol, 1,2- butanediol, PEG, N-Methyl-2-pyrrolidone, dimethyl acetamide, ethyl lactate, propylene carbonate, diethyl malate, triethyl citrate, pyrrolidines and/or polyglycerol.
  • the co-solvent comprises PEG, such as PEG200, PEG400 and/or PEG600.
  • PEG is particularly preferred as the chemical structure is relatively similar to the preferred non-ionic surfactant.
  • the solubilizer may comprise a deep eutectic solvent (DES).
  • DESs are liquids with a melting point that is lower than the melting points of its constituents.
  • DESs can be used as solvents for API’s, as for example described in WO 2020/085904 (which is incorporated herein in its entirety) wherein a DES is described based on a combination of a glycol with a polymer solubilizer component.
  • Typical constituents of the DES for the present invention are selected from the group consisting of organic acids, phenolic compounds, terpenoids, fatty acids, organic bases, sugars or sweeteners, glycols, amino acids, quaternary ammonium compounds such as choline compounds, and derivatives of these classes.
  • the DES may comprise one or more esters and/or lactones of organic acids such as diethyl malate, triethyl citrate, ethyl lactate. These latter compounds can serve as a polymer solubilizing component in the DES.
  • Specific examples of such polymer solubilizing components include one or more dicarboxylic acids and/or esters of dicarboxylic acids such as mono-methyl adipate.
  • components that may accordingly be present in the DES include or more esters, ethers and carbonates of diols and/or triols, such as glycerol carbonate, propylene carbonate, ethylene carbonate, 1,2-butylene carbonate, glycerol formal, DL- 1,2 -isoprop ylideneglycerol, dipropylene glycol methyl ether acetate, propylene glycol methyl ether acetate, dipropylene glycol methyl ether, l-methoxy-2 -propanol, diethylene glycol monoethyl ether.
  • esters, ethers and carbonates of diols and/or triols such as glycerol carbonate, propylene carbonate, ethylene carbonate, 1,2-butylene carbonate, glycerol formal, DL- 1,2 -isoprop ylideneglycerol, dipropylene glycol methyl ether acetate, propylene glycol methyl
  • the solubihzer may comprise a pharmaceutically acceptable eutectic constituent that is capable of forming a eutectic mixture with the API.
  • a pharmaceutically acceptable eutectic constituent that is capable of forming a eutectic mixture with the API. Examples wherein an API and a pharmaceutically acceptable eutectic constituent form a eutectic mixture are described in the Dutch patent application NL2025092 and in WO202 1/034192, which are both incorporated herein in their entirety.
  • the pharmaceutically acceptable eutectic constituent typically has the ability to create hydrogen bonds with the API or other constituents in the formulation e.g. typically hydroxyl groups are present. These intermolecular forces can facilitate the increased solubility of the API in the formulation and thereby increase the physical stability of the formulation.
  • the pharmaceutically acceptable eutectic constituent preferably comprises one or more carboxylic acids, phenolic compounds, terpenoids, organic bases, sugars, sweeteners, glycols, amino acids, quaternary ammonium compounds, derivative of these classes and/or combinations thereof.
  • the pharmaceutically acceptable eutectic constituent comprises one or more organic acids that may include, but are not limited to, malic acid, citric acid, lactic acid, fumaric acid, tartaric acid, ascorbic acid, pimelic acid, gluconic acid, acetic acid and or derivatives thereof such as nicotinamide.
  • the pharmaceutically acceptable eutectic constituent may further or alternatively comprise one or more phenolic compounds that may include, but are not limited to, tyramine hydrochloride, tocopherol, butyl paraben and vanillin.
  • the pharmaceutically acceptable eutectic constituent may further comprise one or more terpenoids, which may be one of, but not limited to, terpineol, menthol and perillyl alcohol.
  • the pharmaceutically acceptable eutectic constituent may further or alternatively comprise one or more sugars or sweeteners, that may include, but are not limited to, sucrose, glucose, fructose, lactose, maltose, xylose, sucrose, inositol, xylitol, saccharin, sucralose, aspartame, acesulfame potassium and ribotol, as well as their phosphates.
  • sugars or sweeteners may include, but are not limited to, sucrose, glucose, fructose, lactose, maltose, xylose, sucrose, inositol, xylitol, saccharin, sucralose, aspartame, acesulfame potassium and ribotol, as well as their phosphates.
  • the pharmaceutically acceptable eutectic constituent may comprise one or more amino acids, these include, but are not limited to, cysteine, tyrosine, lysine, serine, glutamine, alanine and leucine.
  • the pharmaceutically acceptable eutectic constituent may further or alternatively comprise one or more quaternary ammonium compounds that include, but are not limited to, choline chloride, thiamine mononitrate and carnitine.
  • host-guest chemistry may be applicable, wherein the pharmaceutically acceptable eutectic constituent may be considered as host and the API as guest.
  • Host-guest chemistry is a term typically used for supramolecular complexes in which two or more molecules or ions are held together by forces other than fully covalent bonds. These non-covalent interactions may include ionic bonding, hydrogen bonds, Van der Waals forces or hydrophobic interactions.
  • the host usually comprises a void, core, cavity or a pocket, these terms are herein used interchangeably.
  • the core relates to a suitable shape for a second molecule to position into.
  • Molecules comprising such cores include, but are not limited to, cyclodextrins, cucurbiturils, calixarenes, catenanes, cryptands, crown ethers and pillararenes.
  • the exterior of the pharmaceutically acceptable eutectic constituent is hydrophilic and the core is hydrophobic.
  • the hydrophobic core is generally capable of forming hydrophobic interactions with the API.
  • non-ionic surfactant and/or HPMC-AS as well as the ratios thereof may depend on the particular API.
  • the most preferred materials and amounts are chosen dependent on i.a. the dissolution performance of the composition, the stability of the composition and the final drug loading.
  • the scope of the invention may include embodiments having combinations of all or some of the features described.
  • the invention may further be illustrated by the following non limiting examples.
  • API X is a weakly basic small molecule with a water solubility of less than 10 pg/mL.
  • the bar chart in Figure 1 shows a pharmacokinetic study completed in beagle dogs.
  • the bioavailability of the composition was compared to micronized API pressed into a tablet and significant bioavailability enhancement was observed.
  • a preferred example was formed comprising 5 wt% API Y as API, 80 wt% polysorbate 80 as non-ionic surfactant, 5 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade (i.e. HPMC-AS MF) and 10 wt% glycofurol as solubilizer.
  • the composition was formed by heating the mixture to 60 °C and gently stirring for 15 mins.
  • API Y is a weakly basic small molecule with a water solubility of less than 10 pg/mL.
  • the black line (entry 1 + Pol) with squares in Figure 2 shows the resulting formulation after in vitro dissolution.
  • the black line (entry 1) with circles in Figure 2 shows a similar composition but without the inclusion of HPMC-AS MF.
  • the in vitro dissolution occurred in a Biorelevant simulated intestinal medium with an pH of 6.5.
  • Figure 2 shows that higher concentrations of API can be maintained in the dissolution medium for longer periods of time with the compositions according to the present invention compared to other compositions.
  • API X is a weakly basic small molecule with a water solubility of less than 10 pg/mL.
  • the black line with squares in Figure 3 shows the resulting formulation after in vitro dissolution.
  • the dotted black hne shows the crystalline solubility of the API measured in Biorelevant simulated intestinal medium with an pH of 6.5.
  • Figure 3 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to crystalhne solubility.
  • a preferred example was formed comprising 5 wt% itraconazole as API, 84 wt% Kolliphor EL ® as non-ionic surfactant, 5 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade (i.e. HPMC-AS MF) and 6 wt% N-Methyl-2-Pyrrolidone.
  • the composition was formed by heating the mixture to 60 °C and gently stirring for 30 mins.
  • Itraconazole is a weakly basic small molecule with a water solubility of less than 1 pg/mL.
  • the gray line with circles in Figure 4 shows the resulting formulation after in vitro dissolution.
  • the dotted black hne shows the crystalline solubility of the API measured in Biorelevant simulated intestinal medium with an pH of 6.5 with the same amount of Kolhphor EL ® solubilized in the medium.
  • Figure 4 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to crystalhne API solubilized in simulated medium with the same amount of Kolhphor EL ® as in the formulation.
  • a preferred example was formed comprising 5 wt% glibenclamide as API, 90 wt% Tween 20 ® (i.e. polysorbate 20) as non-ionic surfactant, 5 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade (i.e. HPMC-AS MF).
  • the composition was formed by heating the mixture to 60 °C and gently stirring for 30 mins.
  • Glibenclamide is a weakly acidic small molecule with a water solubility of less than 50 pg/mL.
  • the black line with squares in Figure 5 shows the resulting formulation after in vitro dissolution.
  • the dotted black hne shows the crystalline solubility but without the inclusion of HPMC-AS MF.
  • the in vitro dissolution occurred in a Biorelevant simulated intestinal medium with an pH of 6.5.
  • Figure 5 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to crystalhne solubility.
  • Example 6 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to crystalhne solubility.
  • a preferred example was formed comprising 5 wt% fenofibrate as API, 90 wt% Kolliphor RH40 ® as non-ionic surfactant, 5 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade (i.e. HPMC-AS MF).
  • the composition was formed by heating the mixture to 60 °C and gently stirring for 30 mins.
  • Fenofibrate is a non-ionisable small molecule with a water solubility of less than 50 pg/mL.
  • the black line with squares in Figure 6 shows the resulting formulation after in vitro dissolution.
  • the dotted black line shows the crystalline solubility but without the inclusion of
  • HPMC-AS MF The in vitro dissolution occurred in a Biorelevant simulated intestinal medium with an pH of 6.5.
  • Figure 6 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to crystalline solubility.
  • a preferred example was formed comprising 6,7 wt% Griseofulvin as API, 57 wt% Gelucire ® 48/14 as non-ionic surfactant, 3,3 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade (i.e. HPMC-AS MF) and 33,3 wt% PEG 200.
  • the composition was formed by heating the mixture to 60 °C and gently stirring for 30 mins.
  • Griseofulvin is a non-ionisable small molecule with a water solubility of less than 50 pg/mL.
  • the gray line (Composition A) with circles in Figure 7 shows the resulting formulation after in vitro dissolution.
  • the black line (Composition B) with squares in Figure 7 shows a similar composition but without the inclusion of HPMCAS-MF.
  • the in vitro dissolution occurred in a Biorelevant simulated intestinal medium with an pH of 6.5.
  • Figure 7 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to similar compositions.
  • a preferred example was formed comprising 10 wt% mefenamic acid as API, 50 wt% Tween 80 ® as non-ionic surfactant, 3,3 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade (i.e. HPMCAC-MF) and 16,7 wt% PEG 200.
  • the composition was formed by heating the mixture to 60 °C and gently stirring for 30 mins.
  • Mefenamic acid is a weakly acidic small molecule with a water solubility of less than 50 pg/mL.
  • composition A with circles in Figure 8 shows the resulting formulation after in vitro dissolution.
  • the in vitro dissolution occurred in a Biorelevant simulated intestinal medium with an pH of 6.5.
  • Figure 8 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to similar compositions.
  • a preferred example (F2) was formed comprising 5 wt% API X as API, 90 wt% Gelucire ® 48/16 (PEG-32 (MW 1500) esters of palmitic ( ⁇ ib) and stearic (Cis) acids and 5 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade (i.e. HPMC-AS MF).
  • the composition was formed by heating the mixture to 60 °C and gently stirring for 15 mins.
  • API X is a weakly basic small molecule with a water solubihty of less than 10 pg/mL.
  • a comparative example (FI) was formed comprising 95 wt% Gelucire® 48/16 and 5 wt% API X. The composition was formed by heating the mixture to 60 °C and gently stirring for 15 mins.
  • Another comparative example (F3) was formed comprising 15 wt% Gelucire® 48/16, 80 wt% HPMC-AS MF, 5 wt% API X as API without a non ionic surfactant. Due to the high viscosity and low solubihty of HPMC-AS, the composition was made by a solvent evaporation method. The constituents were dissolved in (methylene chloride/methanol) followed by evaporation of the solvent to obtain a sohd.
  • a further comparative example (F4) was formed comprising 95 wt% HPMC-AS and 5 wt% API X. Due to the high viscosity, the composition was made by a solvent evaporation method. The constituents were dissolved in (methylene chloride/methanol) followed by evaporation of the solvent to obtain a sohd.
  • Figure 9 the shows the resulting formulations after in vitro dissolution.
  • the in vitro dissolution occurred in a Biorelevant simulated intestinal medium with a pH of 6.5.
  • Figure 9 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to comparative compositions.

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Abstract

The invention is in the field of pharmaceutical compositions for enhanced bioavailability. In particular the invention is directed to a pharmaceutical composition comprising one or more non-ionic surfactants, an active pharmaceutical ingredient (API) and a hydroxypropyl methylcellulose acetate succinate (HPMC-AS). The invention further relates to a method to prepare such a pharmaceutical composition.

Description

Title: Micelle-generating formulations for enhanced bioavailability
The invention is in the field of pharmaceutical compositions for enhanced bioavailabihty. In particular the invention is directed to a pharmaceutical composition comprising one or more non-ionic surfactants, an active pharmaceutical ingredient (API) and a hydroxypropyl methylcellulose acetate succinate (HPMC-AS). The invention further relates to a method to prepare such a pharmaceutical composition.
The number of drugs that are classified as Biopharmaceutics Classification System (BCS) class II and IV compounds has increased over the past years. BCS class II and IV are used for drugs that are considered to have low aqueous solubility. In the pharmaceutical industry, it remains challenging to solubilize these poorly water-soluble APIs and to improve their bioavailability. Complex formulations are therefore often required to effectively absorb the API in e.g. the gastrointestinal (GI) tract. The terms “API”, “drug”, “active ingredient” may be used interchangeably herein.
Bioavailabihty of the API relates i.a. to the solubility, membrane permeabihty and enzymatic degradation of the active ingredient in the patient. Bioavailabihty may be measured as the area under a curve of the plasma concentration of a drug over a certain time period. The bioavailability may be denoted as a percentage and depends i.a. on the half- life of the drug. As most of the APIs are poorly soluble in water, processing these ingredients in dosage forms typically requires the use of less polar solvents such as dimethylsulfoxide, alcohols, acetone, ethyl acetate, chloroform and the like. These solvents present problems including toxicity and danger of explosion.
Several alternative methods have been proposed to enhance the solubility of APIs and their bioavailabihty. For instance, physical modifications such as solid dispersions and self-emulsifying drug delivery systems (SEDDS) or chemical modifications such as salt formation have been proposed. Salt formation is a tool to obtain solid-state forms as the ionic interactions in a crystal lattice may be beneficial to crystal lattice stabilization. The ion-ion interactions, moreover, typically contribute strongly to the lattice enthalpy. However, disadvantageously, salts tend to form hydrates as the ions within the salt interact strongly with water and the stability may accordingly be easily compromised. In addition, not all APIs can be formulated into salts.
Solid dispersions are typically dispersions of a drug in an amorphous polymer matrix. The matrix may further comprise i.a. a surfactant. Solid dispersions can be manufactured through a variety of processes including melt extrusion, spray drying and co -precipitation. Several reviews on solid dispersions are Huang and Dai (Acta Pharmaceutica Sinica B, 4, 2014, 18-25), Chivate et al. (Current Pharma Research, 2, 2012, 659-667) and Zhang et al. (Pharmaceutics, 3, 2018, 142). However, disadvantages of solid dispersions include complex manufacturing, the physical instability of the product and a consequent decrease in dissolution rate over time.
Another alternative are SEDDS. SEDDS are typically isotropic mixtures of one or more hydrophilic solvents and co-solvents or surfactants that may form oil-in-water micro emulsions in aqueous media, as for instance detailed by Khedekar and Mittal (International Journal of Pharmaceutical Sciences and Research, 4(12), 2013, 4494-4507). A particular type of SEDDS are super saturable SEDDS which comprise polymeric precipitation inhibitors to stabilize the drug in a supersaturated state.
Another proposed method to enhance the solubility and bioavailability of poorly-soluble APIs is by using a deep eutectic solvent (DES). A DES is formed when one or more constituents are mixed together at a specific ratio resulting in the depression of the melting point of one or more of the constituents. For instance, a study of several DES formulations and APIs is presented in Aroso et al. (European Journal of Pharmaceutics and Biopharmaceutics, 98, 2016, 57-66). The study illustrates a higher dissolution rate for the API in a DES than the API alone.
WO 2020/085904 discloses a DES platform for oral pharmaceutical formulations that also enhances the solubility and bioavailability of the API.
It is an object of the present inventors to provide a pharmaceutical composition that at least in part overcomes the above- mentioned drawbacks. In particular, it is an object of the present inventors to provide a pharmaceutical composition with high bioavailabihty and wherein an API can be present in a concentration above its crystal solubility. The present inventors have surprisingly found that a composition comprising one or more non-ionic surfactants as a major component and a hydroxypropyl methylcellulose acetate succinate (HPMC-AS) as a minor component allows for such a pharmaceutical composition. The present inventors realized that a composition comprising the one or more non-ionic surfactants as a major component and the HPMC-AS as a minor component may create a micellar solution, with e.g. nano-sized micelles, within a short amount of time (e.g. minutes) of contact with an aqueous environment. Without wishing to be bound by theory, the present inventors beheve that release of high concentrations of API into an aqueous medium (e.g. arelease above its amorphous solubility) may lead to phase- separation of amorphous, API -rich droplets. Extensive phase-separation of amorphous API is generally considered undesirable as it reduces the thermodynamic activity of the API in solution and thus reduces flux over the intestinal membrane. In addition, formation of phase-separated amorphous API may be a predecessor of API crystalhzation, which lowers thermodynamic activity and flux over the intestinal membrane even further. The present inventors believe that the micelles formed after hydration of the compositions of the current invention may act to prevent or reduce phase- separation of amorphous API droplets. The present inventors have realized that the non-ionic surfactant may function to keep the API in a micelle and that only a small amount of HPMC-AS is required to stabilize these micelles.
Figure 1 illustrates a pharmacokinetic study completed in beagle dogs of a preferred composition according to the present invention compared to a micronized API pressed into a tablet.
Figure 2 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and for a composition without HPMC-AS.
Figure 3 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and the crystalline solubihty of the API in the medium.
Figure 4 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and the crystalline solubihty of the API in the medium.
Figure 5 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and the crystalline solubihty of a composition without HPMC-AS in the medium.
Figure 6 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and the crystalline solubihty of a composition without HPMC-AS in the medium.
Figure 7 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and for a composition without HPMC-AS.
Figure 8 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and for a composition without HPMC-AS.
Figure 9 illustrates the API concentration in a dissolution medium over time for a preferred composition according to the present invention and three comparative compositions.
Thus, in a first aspect, the present invention is directed to a pharmaceutical composition (herein also referred to as the composition) comprising 40-95 wt% of one or more non-ionic surfactants, 2-30 wt% of an API and 1-15 wt% of a hydroxypropyl methylcellulose acetate succinate (HPMC-AS), based on the total weight of the composition.
It may be appreciated that the components of the composition are typically selected for being safe for oral administration, for example they may be on the generally recognized as safe (GRAS) list for oral administration. The GRAS list is established by the Food and Drug Administration (FDA) of the United States.
The composition may be produced by a method comprising forming a homogeneous solution comprising the relative amounts of the one or more non-ionic surfactants, API and HPMC-AS. This method may entail mixing and hquifying all components to form the homogeneous solution, or if the non-ionic surfactant is liquid, the liquihcation may be omitted and the API and HPMC-AS can be directly added to the surfactant. The order in which the components are added is typically not relevant, which may be advantageous for ease of production. If the homogenous solution is at an elevated temperature (i.e. above ambient temperature, approximately 20 °C), it may be let to cool down to ambient temperatures to obtain the composition. The one or more non-ionic surfactants (herein also referred to in
‘non-ionic surfactant’, ‘non-ionic surfactants’, ‘surfactant’ and ‘surfactants’) preferably comprises one or more polyethylene glycol (PEG) mono- and/or diesters with fatty acids and further optionally one or more mono, di- and/or triglycerides. Glycerides typically comprise a mono- di or tri-ester of glycerol (propane- 1, 2, 3-triol) with fatty acids. The one or more mono, di- and/or triglycerides are typically present as a glyceride fraction and preferably non- covalently mixed, such as blended, with the PEG mono- and/or diesters with fatty acids. Longer PEG chains may be used to increase the melting point, while shorter PEG chains are typically employed to lower the melting point. Further, the non-ionic surfactant may include one or more polyethoxylated sorbitan esters, such as commercially available Tween® 20, 60 or 80, polyethoxylated (hydrogenated) castor oil (e.g. Kolliphor® EL) and/or polyoxyethylated 12-hydroxystearic acid (e.g. Kolliphor® HS15). The non ionic surfactants may alternatively or additionally include other polyethoxylated-based materials such as e.g. the commercially available Kolliphor® RH 40.
The composition is typically a single-phase composition. By providing a single physical phase instead of a multiphase system such as a emulsion, the stability of the composition is improved.
Generally, the non-ionic surfactant is a semi-solid, waxy material and may have an amphiphilic character. The amphiphilic character can be expressed by a hydrophilic-lipophilic balance (HLB). The HLB is typically determined by the balance of the size and strength of the hydrophilic and lipophihc moieties of a molecule. Herein the HLB is based on Griffin’s method that ranges from 0 (completely hydrophobic) to 20 (completely hydrophilic). The HLB may accordingly be used to predict the surfactant properties of a molecule. Typically, molecules with a HLB above 10 are considered water-soluble and below 10 are considered lipid-soluble. Molecules with a HLB value from approximately 16 to 18 may be used as hydrotrope. A preferred non-ionic surfactant mixture has a HLB value between 12-18, preferably between 13-18. The preferred non-ionic surfactant is accordingly hydrophilic and can be considered water-soluble.
Preferably, the non-ionic surfactant comprises PEG32 mono- and/or diesters with Cs-Cis fatty acids, polyethoxylated sorbitan esters, polyethoxylated (hydrogenated) castor oil or polyoxyethylated 12- hydroxystearic acid. Cs-Cis is used herein to indicate that the fatty acid comprises a carbon chain of 8 to 18 carbon atoms. The number average molecular weight of PEG32 is typically around 1500 g/mol.
In a particular embodiment of the present invention, the non-ionic surfactant comprises one or more polyoxylglycerides. Polyoxylglycerides are mixtures of monoesters, diesters, and triesters of glycerol, and monoesters and diesters of polyethylene glycols (PEG); see also Rowe et al., Handbook of Pharmaceutical Excipients, 6th Edition, p. 557 et seq. Certain polyoxylglycerides are known and commercially available as Gelucire®. Certain Gelucire® mixtures such as Gelucire® 48/16 however lack the esters of glycerol that are usually present in polyoxylglycerides. Polyoxylglycerides suitable for the present invention can be prepared by partial alcoholysis of glycerides with PEG. Accordingly, in a typical embodiment, the ester(s) of glycerol and the ester(s) of PEG in the non-ionic surfactant may be based on the same fatty acid(s), e.g. one or more of Cs-C is fatty acids. A particularly preferred non -ionic surfactant for the present invention is commercially available as Gelucire®, such as Gelucire® 44/14, Gelucire® 48/16 and/or Gelucire® 50/13 (see also K.C. Panigrahi et al.
Future Journal of Pharmaceutical Sciences 4 (2018) 102-108, which is incorporated herein in its entirety). The first number following the name Gelucire® (e.g. 50/*, 44/*, 48/*, 55/*, etc.) indicates the melting point in degrees centigrade while the second number (e.g. */ 13, */14, */16, */18, etc.) indicates the HLB value. Dependent on the particular type of Gelucire®, it comprises for instance PEG esters of fatty acids or a mixture of mono, di and or triglycerides with PEG esters of fatty acids. The glyceride fraction compared to the PEG ester fraction may be small or large, dependent on the type of Gelucire®. Gelucire® comprising only PEG esters are generally used for fast release formulations, while Gelucire® comprising PEG esters and glycerides are generally used for sustained release formulations.
The composition further comprises HPMC-AS, also known as hypromellose acetate succinate. HPMC-AS is a generally known polymeric precipitation inhibitor that is used in various drug delivery systems (see also Rowe et al., Handbook of Pharmaceutical Excipients, 6th Edition, p. 330- 332). HPMC-AS comprises a cellulose backbone modified with methyl, acetate, hydroxypropyl and succinoyl groups. The ratio of these modifications typically determines the commercial grade of the HPMC-AS. These grades are commercially available as L, M, H and may each be available in different grain sizes such as fine or coarse. In particular the content of acetate and succinoyl groups influence the grade. The content of succinoyl may further determine the pH at which the HPMC-AS solubilizes as the succinoyl groups may be deprotonated at higher pH and can accordingly ionize and solubilize the polymer in an aqueous environment. A pH above 6.5 is typically preferred as this allows for most succinoyl groups to be deprotonated and accordingly appears to increase the stability of the composition. A particularly preferred HPMC-AS has an acetyl content of 5-9 wt% (e.g. L-grade), 7-11 wt% (e.g. M-grade) or 10-14 wt% (e.g. H-grade), based on the total weight of the HPMC-AS. Additionally, or alternatively it may be preferred that the HPMC-AS has a succinoyl content of 14-18 wt% (e.g. L-grade), 10-14 wt% (e.g. M-grade) or 4-8 wt% (e.g. H-grade) based on the total weight of the HPMC-AS.
In the present invention, HPMC-AS constitutes a minor component of the composition. Surprisingly, the relatively small amount of HPMC-AS significantly improves the ability of the non-ionic surfactant to increase the concentration of poorly-soluble APIs in a dissolution medium. Thereby advantageously cutting back on research and development, as well as on production costs. Additionally, the ratios of the non-ionic surfactant and the HPMC-AS in accordance with the present invention were found to lead to stable homogeneous composition. With stable herein is meant that that the homogeneous composition is transparent for at least 24 h at 20 °C.
The other ingredient of the composition is the API. It is preferred that the API comprises a BCS class II API. Class II API’s are considered to have low water solubility and administration to a patient can be a challenge. The API may for example have an aqueous solubility of not more than 1 mg/mL at pH 6.8 when it is a weakly basic compound, of no more than 1 mg/mL at pH 1.2 when it is a weakly acidic compound. In the case of physiological pH of 1.0 to 8.0 for neutral or non-ionizable compounds the aqueous solubility may be no more than 1 mg/mL. A drug is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1 to 7.5. If it does not dissolve in 250 ml at each of the aforementioned conditions, it is generally considered poorly water-soluble. An extensive hst of possible APIs is mentioned in Pharmacopeia. The dosage for therapeutically effective amounts for a given API is typically known to a person skilled in the art. The term “aqueous environment” used herein generally relates to gastrointestinal fluid at pH 5.0 to 8.0 or to the stomach at pH 1.0 to 2.0 in vivo or an aqueous test medium in vitro.
It is preferred that the composition comprises 40-95 wt%, preferably 50-90 wt%, more preferably 50-80 wt% of the non-ionic surfactant based on the total weight of the composition. Additionally or alternatively, it may be preferred that the composition comprises 2-30 wt%, preferably 2-20 wt% of the API and/or 1-10 wt%, preferably 1-8 wt% of the HPMC-AS, based on the total weight of the composition. The composition is preferably free from any lipid. In particular, the composition is preferably free from any lipid that is used in conventional SEDDS. Accordingly, in preferred embodiments, the composition is free from lipids including fatty acids, mono-, di- or triglycerides, glycerophospholipids, sphingolipids, sterols, prenols, saccharolipids and/or polyketides. Concomitantly, the composition preferably consists essentially of the one or more non-ionic surfactants, the active pharmaceutical ingredient the HPMC-AS and the optional solubilizer as described herein. This means that preferably the composition comprises more than 90 wt%, preferably more than 95 wt%, even more preferably more than 98 wt%, of the one or more non-ionic surfactants, the active pharmaceutical ingredient the HPMC-AS and the optional solubilizer as described herein, based on the total weight of the composition.
The composition of the invention may be solid, semi-sohd or liquid at ambient temperature and pressure. The preferred non-ionic surfactant is typically sohd or semi-solid at ambient temperature and pressure. A solid or semi-solid composition may further be particularly compatible for further processing. The composition can accordingly be used in a medical treatment comprising enteral, preferably oral administration. The composition can also be used in a medical treatment comprising injectable administration. Oral administration is typically preferred due to the ease of administration resulting in an overall increased patient compliance. More preferably the medical treatment comprises oral administration of capsules or tablets comprising the pharmaceutical composition. The capsules may for instance release their contents ( i.a . the composition) at a pH above 5.
The injectable administration may comprise subcutaneous, intramuscular, and intravenous injections, as well as less common injections such as intraperitoneal, intraosseous, intracardiac, intraarticular, and intracavernous injections. The present invention can particularly suitably be used for treatments comprising intravenous injections.
The composition can further comprise a solubilizer. Typically, the solubilizer may be present in 1-50 wt%, preferably 1-25 wt%, based on the total weight of the composition. The solubilizer may advantageously be added to increase the solubility of the API in the composition and accordingly increase the final drug loading in the composition. When preparing the composition, the solubilizer may be added at any time, such as before, simultaneously, or after the other components to form the homogeneous composition.
In particular embodiments, the solubilizer comprises a co-solvent, a deep eutectic solvent (DES) and/or a pharmaceutically acceptable eutectic constituent that is capable of forming a eutectic mixture with the API.
The co-solvent can be any pharmaceutically acceptable conventional solvent and/or combination thereof. Examples of suitable co solvents include one or more glycols, such as propylene glycol, dipropylene glycol, butylene glycol, glycerol, tetraglycol, 1,2-hexanediol, 1,2- butanediol, PEG, N-Methyl-2-pyrrolidone, dimethyl acetamide, ethyl lactate, propylene carbonate, diethyl malate, triethyl citrate, pyrrolidines and/or polyglycerol. Preferably the co-solvent comprises PEG, such as PEG200, PEG400 and/or PEG600. PEG is particularly preferred as the chemical structure is relatively similar to the preferred non-ionic surfactant.
In cases where the drug loading enhancement from incorporation of the co-solvent is not sufficiently high the solubilizer may comprise a deep eutectic solvent (DES). DESs are liquids with a melting point that is lower than the melting points of its constituents. DESs can be used as solvents for API’s, as for example described in WO 2020/085904 (which is incorporated herein in its entirety) wherein a DES is described based on a combination of a glycol with a polymer solubilizer component.
Typical constituents of the DES for the present invention are selected from the group consisting of organic acids, phenolic compounds, terpenoids, fatty acids, organic bases, sugars or sweeteners, glycols, amino acids, quaternary ammonium compounds such as choline compounds, and derivatives of these classes. In addition, the DES may comprise one or more esters and/or lactones of organic acids such as diethyl malate, triethyl citrate, ethyl lactate. These latter compounds can serve as a polymer solubilizing component in the DES. Specific examples of such polymer solubilizing components include one or more dicarboxylic acids and/or esters of dicarboxylic acids such as mono-methyl adipate. Further examples of components that may accordingly be present in the DES include or more esters, ethers and carbonates of diols and/or triols, such as glycerol carbonate, propylene carbonate, ethylene carbonate, 1,2-butylene carbonate, glycerol formal, DL- 1,2 -isoprop ylideneglycerol, dipropylene glycol methyl ether acetate, propylene glycol methyl ether acetate, dipropylene glycol methyl ether, l-methoxy-2 -propanol, diethylene glycol monoethyl ether.
Alternatively or additionally, the solubihzer may comprise a pharmaceutically acceptable eutectic constituent that is capable of forming a eutectic mixture with the API. Examples wherein an API and a pharmaceutically acceptable eutectic constituent form a eutectic mixture are described in the Dutch patent application NL2025092 and in WO202 1/034192, which are both incorporated herein in their entirety.
The pharmaceutically acceptable eutectic constituent typically has the ability to create hydrogen bonds with the API or other constituents in the formulation e.g. typically hydroxyl groups are present. These intermolecular forces can facilitate the increased solubility of the API in the formulation and thereby increase the physical stability of the formulation.
The pharmaceutically acceptable eutectic constituent preferably comprises one or more carboxylic acids, phenolic compounds, terpenoids, organic bases, sugars, sweeteners, glycols, amino acids, quaternary ammonium compounds, derivative of these classes and/or combinations thereof.
Preferably, the pharmaceutically acceptable eutectic constituent comprises one or more organic acids that may include, but are not limited to, malic acid, citric acid, lactic acid, fumaric acid, tartaric acid, ascorbic acid, pimelic acid, gluconic acid, acetic acid and or derivatives thereof such as nicotinamide.
The pharmaceutically acceptable eutectic constituent may further or alternatively comprise one or more phenolic compounds that may include, but are not limited to, tyramine hydrochloride, tocopherol, butyl paraben and vanillin.
Additionally or alternatively, the pharmaceutically acceptable eutectic constituent may further comprise one or more terpenoids, which may be one of, but not limited to, terpineol, menthol and perillyl alcohol.
The organic bases that the pharmaceutically acceptable eutectic constituent may additionally or alternatively comprise may include, but are not limited to, urea and guanine.
In another embodiment the pharmaceutically acceptable eutectic constituent may further or alternatively comprise one or more sugars or sweeteners, that may include, but are not limited to, sucrose, glucose, fructose, lactose, maltose, xylose, sucrose, inositol, xylitol, saccharin, sucralose, aspartame, acesulfame potassium and ribotol, as well as their phosphates.
Additionally or alternatively, the pharmaceutically acceptable eutectic constituent may comprise one or more amino acids, these include, but are not limited to, cysteine, tyrosine, lysine, serine, glutamine, alanine and leucine.
The pharmaceutically acceptable eutectic constituent may further or alternatively comprise one or more quaternary ammonium compounds that include, but are not limited to, choline chloride, thiamine mononitrate and carnitine.
More generally, host-guest chemistry may be applicable, wherein the pharmaceutically acceptable eutectic constituent may be considered as host and the API as guest. Host-guest chemistry is a term typically used for supramolecular complexes in which two or more molecules or ions are held together by forces other than fully covalent bonds. These non-covalent interactions may include ionic bonding, hydrogen bonds, Van der Waals forces or hydrophobic interactions. The host usually comprises a void, core, cavity or a pocket, these terms are herein used interchangeably. The core relates to a suitable shape for a second molecule to position into. Molecules comprising such cores include, but are not limited to, cyclodextrins, cucurbiturils, calixarenes, catenanes, cryptands, crown ethers and pillararenes. Preferably, the exterior of the pharmaceutically acceptable eutectic constituent is hydrophilic and the core is hydrophobic. The hydrophobic core is generally capable of forming hydrophobic interactions with the API.
It may be appreciated that the most preferred non-ionic surfactant and/or HPMC-AS as well as the ratios thereof may depend on the particular API. In principle, the most preferred materials and amounts are chosen dependent on i.a. the dissolution performance of the composition, the stability of the composition and the final drug loading. For the purpose of clarity and a concise description features are described herein as part of the same or separate embodiments, however, it will be appreciated that the scope of the invention may include embodiments having combinations of all or some of the features described. The invention may further be illustrated by the following non limiting examples.
Example 1
A preferred example was formed comprising 5 wt% API X as API, 80 wt% Gelucire® 48/16 (PEG-32 (MW 1500) esters of palmitic (ϋib) and stearic (Cis) acids) as non-ionic surfactant, 5 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade and 10 wt% PEG 400 solubilizer. The composition was formed by heating the mixture to 60 °C and gently stirring for 15 mins. API X is a weakly basic small molecule with a water solubility of less than 10 pg/mL.
The bar chart in Figure 1 shows a pharmacokinetic study completed in beagle dogs. The bioavailability of the composition was compared to micronized API pressed into a tablet and significant bioavailability enhancement was observed.
Example 2
A preferred example was formed comprising 5 wt% API Y as API, 80 wt% polysorbate 80 as non-ionic surfactant, 5 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade (i.e. HPMC-AS MF) and 10 wt% glycofurol as solubilizer. The composition was formed by heating the mixture to 60 °C and gently stirring for 15 mins. API Y is a weakly basic small molecule with a water solubility of less than 10 pg/mL.
The black line (entry 1 + Pol) with squares in Figure 2 shows the resulting formulation after in vitro dissolution. The black line (entry 1) with circles in Figure 2 shows a similar composition but without the inclusion of HPMC-AS MF. The in vitro dissolution occurred in a Biorelevant simulated intestinal medium with an pH of 6.5.
Figure 2 shows that higher concentrations of API can be maintained in the dissolution medium for longer periods of time with the compositions according to the present invention compared to other compositions.
Example 3
A preferred example was formed comprising 7.5 wt% API X as API, 68 wt% Gelucire® 48/16 (PEG-32 (MW 1500) esters of palmitic (ϋib) and stearic (Cis) acids) as non-ionic surfactant, 5 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade, 12,5 wt% PEG 200 solubilizer and 6 wt% acesulfame potassium eutectic solvent constituent. The composition was formed by heating the mixture to 60 °C and gently stirring for 15 mins. API X is a weakly basic small molecule with a water solubility of less than 10 pg/mL.
The black line with squares in Figure 3 shows the resulting formulation after in vitro dissolution. The dotted black hne (at the bottom of the graph) shows the crystalline solubility of the API measured in Biorelevant simulated intestinal medium with an pH of 6.5.
Figure 3 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to crystalhne solubility.
Example 4
A preferred example was formed comprising 5 wt% itraconazole as API, 84 wt% Kolliphor EL® as non-ionic surfactant, 5 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade (i.e. HPMC-AS MF) and 6 wt% N-Methyl-2-Pyrrolidone. The composition was formed by heating the mixture to 60 °C and gently stirring for 30 mins. Itraconazole is a weakly basic small molecule with a water solubility of less than 1 pg/mL.
The gray line with circles in Figure 4 shows the resulting formulation after in vitro dissolution. The dotted black hne (at the bottom of the graph) shows the crystalline solubility of the API measured in Biorelevant simulated intestinal medium with an pH of 6.5 with the same amount of Kolhphor EL® solubilized in the medium.
Figure 4 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to crystalhne API solubilized in simulated medium with the same amount of Kolhphor EL® as in the formulation.
Example 5
A preferred example was formed comprising 5 wt% glibenclamide as API, 90 wt% Tween 20® (i.e. polysorbate 20) as non-ionic surfactant, 5 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade (i.e. HPMC-AS MF). The composition was formed by heating the mixture to 60 °C and gently stirring for 30 mins. Glibenclamide is a weakly acidic small molecule with a water solubility of less than 50 pg/mL.
The black line with squares in Figure 5 shows the resulting formulation after in vitro dissolution. The dotted black hne (at the bottom of the graph) shows the crystalline solubility but without the inclusion of HPMC-AS MF. The in vitro dissolution occurred in a Biorelevant simulated intestinal medium with an pH of 6.5.
Figure 5 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to crystalhne solubility. Example 6
A preferred example was formed comprising 5 wt% fenofibrate as API, 90 wt% Kolliphor RH40® as non-ionic surfactant, 5 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade (i.e. HPMC-AS MF). The composition was formed by heating the mixture to 60 °C and gently stirring for 30 mins. Fenofibrate is a non-ionisable small molecule with a water solubility of less than 50 pg/mL.
The black line with squares in Figure 6 shows the resulting formulation after in vitro dissolution. The dotted black line (at the bottom of the graph) shows the crystalline solubility but without the inclusion of
HPMC-AS MF. The in vitro dissolution occurred in a Biorelevant simulated intestinal medium with an pH of 6.5.
Figure 6 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to crystalline solubility.
Example 7
A preferred example was formed comprising 6,7 wt% Griseofulvin as API, 57 wt% Gelucire® 48/14 as non-ionic surfactant, 3,3 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade (i.e. HPMC-AS MF) and 33,3 wt% PEG 200. The composition was formed by heating the mixture to 60 °C and gently stirring for 30 mins. Griseofulvin is a non-ionisable small molecule with a water solubility of less than 50 pg/mL.
The gray line (Composition A) with circles in Figure 7 shows the resulting formulation after in vitro dissolution. The black line (Composition B) with squares in Figure 7 shows a similar composition but without the inclusion of HPMCAS-MF. The in vitro dissolution occurred in a Biorelevant simulated intestinal medium with an pH of 6.5.
Figure 7 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to similar compositions.
Example 8
A preferred example was formed comprising 10 wt% mefenamic acid as API, 50 wt% Tween 80® as non-ionic surfactant, 3,3 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade (i.e. HPMCAC-MF) and 16,7 wt% PEG 200. The composition was formed by heating the mixture to 60 °C and gently stirring for 30 mins. Mefenamic acid is a weakly acidic small molecule with a water solubility of less than 50 pg/mL.
The gray line (Composition A) with circles in Figure 8 shows the resulting formulation after in vitro dissolution. The black line (Composition B) with squares in Figure 8 shows a similar composition but without the inclusion of HPMCAS-MF. The in vitro dissolution occurred in a Biorelevant simulated intestinal medium with an pH of 6.5. Figure 8 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to similar compositions.
Example 9
A preferred example (F2) was formed comprising 5 wt% API X as API, 90 wt% Gelucire® 48/16 (PEG-32 (MW 1500) esters of palmitic (ϋib) and stearic (Cis) acids and 5 wt% hydroxypropyl methylcellulose acetate succinate medium fine grade (i.e. HPMC-AS MF). The composition was formed by heating the mixture to 60 °C and gently stirring for 15 mins. API X is a weakly basic small molecule with a water solubihty of less than 10 pg/mL.
A comparative example (FI) was formed comprising 95 wt% Gelucire® 48/16 and 5 wt% API X. The composition was formed by heating the mixture to 60 °C and gently stirring for 15 mins.
Another comparative example (F3) was formed comprising 15 wt% Gelucire® 48/16, 80 wt% HPMC-AS MF, 5 wt% API X as API without a non ionic surfactant. Due to the high viscosity and low solubihty of HPMC-AS, the composition was made by a solvent evaporation method. The constituents were dissolved in (methylene chloride/methanol) followed by evaporation of the solvent to obtain a sohd.
A further comparative example (F4) was formed comprising 95 wt% HPMC-AS and 5 wt% API X. Due to the high viscosity, the composition was made by a solvent evaporation method. The constituents were dissolved in (methylene chloride/methanol) followed by evaporation of the solvent to obtain a sohd.
Figure 9 the shows the resulting formulations after in vitro dissolution. The in vitro dissolution occurred in a Biorelevant simulated intestinal medium with a pH of 6.5. Figure 9 shows that higher concentrations of API can be maintained in dissolution medium for longer period of time with the compositions according to the present invention compared to comparative compositions.

Claims

Claims
1. A pharmaceutical composition comprising 40-95 wt% of one or more non -ionic surfactants, 2-30 wt% of an active pharmaceutical ingredient (API) and 1-15 wt% of a hydroxypropyl methylcellulose acetate succinate (HPMC-AS), based on the total weight of the composition.
2. Pharmaceutical composition according to the previous claim, comprising 50-90 wt%, preferably 50-80 wt% of the one or more non-ionic surfactants based on the total weight of the composition.
3. Pharmaceutical composition according to any of the previous claims, comprising 2-20 wt% of the API and/or 1-10 wt%, preferably 1-8 wt% of the HPMC-AS, based on the total weight of the composition.
4. Pharmaceutical composition according to any of the previous claims, further comprising 1-50 wt% of a solubilizer, preferably 1-25 wt%, based on the total weight of the composition.
5. Pharmaceutical composition according to the previous claim, wherein the solubilizer comprises a co-solvent, a deep eutectic solvent (DES) and/or a pharmaceutically acceptable eutectic constituent that is capable of forming a eutectic mixture with the API.
6. Pharmaceutical composition according the previous claim, wherein the co-solvent comprises a pharmaceutically acceptable co-solvent, preferably a pharmaceutically acceptable co-solvent selected from the group consisting of: PEG, propylene glycol, dipropylene glycol, butylene glycol, glycerol, tetraglycol, 1,2-hexanediol, 1,2-butanediol, N-methyl-2-pyrrolidone, dimethyl acetamide, ethyl lactate, propylene carbonate, diethyl malate, triethyl citrate pyrrolidines, polyglycerol and/or a combination thereof, and/or wherein the pharmaceutically acceptable eutectic constituent comprises one or more carboxylic acids, phenolic compounds, terpenoids, organic bases, sugars, sweeteners, glycols, amino acids, quaternary ammonium compounds, derivative of these classes and/or combinations thereof.
7. Pharmaceutical composition according to any of the previous claims, wherein the one or more non-ionic surfactants comprises PEG mono- and/or diesters with Cs-Cis fatty acids, polyethoxylated sorbitan esters, polyethoxylated (hydrogenated) castor oil and polyoxyethylated 12- hydroxystearic acid or combinations thereof.
8. Pharmaceutical composition according to any of the previous claims, wherein the one or more non-ionic surfactants comprise one or more polyethylene glycol (PEG) mono- and/or diesters with fatty acids with further optionally one or more mono, di- and/or triglycerides.
9. Pharmaceutical composition according to the previous claim, wherein the one or more non-ionic surfactants comprise one or more mono, di- and/or triglycerides, that are present as a glyceride fraction and that are non-covalently mixed with the PEG mono- and/or diesters with fatty acids.
10. Pharmaceutical composition according to any of the previous claims, wherein the one or more non-ionic surfactants have a hydrophilic - lipophihc balance (HLB) value between 12-18, preferably between 13-18, based on Griffin’s method.
11. Pharmaceutical composition according to any of the previous claims, wherein the HPMC-AS has an acetyl content of 5-9 wt%, 7-11 wt% or 10-14 wt% and/or wherein the HPMC-AS has a succinoyl content of 14-18 wt%, 10-14 wt% or 4-8 wt% based on the total weight of the HPMC-AS.
12. Pharmaceutical composition according to any of the previous claims, wherein the composition is a single-phase composition.
13. Pharmaceutical composition according to any of the previous claims, wherein the composition is absent of any lipids, including comprising fatty acids, mono-, di- or triglycerides, glycerophospholipids, sphingolipids, sterols, prenols, saccharolipids and/or polyketides.
14. Pharmaceutical composition according to any of the previous claims for use in a medical treatment comprising enteral administration or injectable administration, preferably oral administration, more preferably comprising oral administration of capsules or tablets comprising the pharmaceutical composition.
15. Method for producing a pharmaceutical composition according to any of the previous claims comprising forming a homogeneous solution comprising 40-95 wt% of one or more non-ionic surfactants, 2-30 wt% of an active pharmaceutical ingredient (API) and 2-15 wt% of a hydroxypropyl methylcellulose acetate succinate (HPMC-AS), based on the total weight of the solution.
16. Method according to the previous claim, wherein the one or more surfactants comprise polyethoxylated sorbitan esters, polyethoxylated (hydrogenated) castor oil, polyoxy ethylated 12 -hydroxy stearic acid and/or one or more polyethylene glycol (PEG) mono- and or diesters with fatty acids with further optionally one or more mono, di- and/or triglycerides.
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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2579855A2 (en) * 2010-06-09 2013-04-17 Abbott Laboratories Solid dispersions containing kinase inhibitors
WO2013101550A1 (en) * 2011-12-29 2013-07-04 Abbvie Inc. Solid compositions comprising an hcv inhibitor
WO2014081581A2 (en) * 2012-11-08 2014-05-30 Isp Investments Inc. Highly loaded amorphous efavirenz composition and process for preparing the same
WO2015103230A1 (en) * 2013-12-31 2015-07-09 Ascendia Pharmaceuticals, Llc Pharmaceutical compositions for poorly water-soluble compounds
WO2016033611A1 (en) * 2014-08-29 2016-03-03 Lipocine Inc. (17-β)-3-OXOANDROST-4-EN-17-YL UNDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE
WO2017196712A1 (en) * 2016-05-09 2017-11-16 Dispersol Technologies, Llc Improved drug formulations
WO2020085904A2 (en) 2018-10-24 2020-04-30 SeraNovo B.V. Deep eutectic solvent platform for oral pharmaceutical formulations
WO2021005101A1 (en) * 2019-07-09 2021-01-14 Idorsia Pharmaceuticals Ltd Pharmaceutical composition comprising a tetrahydropyrazolopyrimidinone compound
WO2021007172A1 (en) * 2019-07-08 2021-01-14 Belite Bio, Llc Formulations of rbp4 inhibitors and methods of use
WO2021034192A1 (en) 2019-08-19 2021-02-25 Seranovo Holding B.V. Pharmaceutical eutectic salt formulation
NL2025092B1 (en) 2020-03-10 2021-10-19 Seranovo Holding B V Solid deep eutectic solvent formulation platform

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2579855A2 (en) * 2010-06-09 2013-04-17 Abbott Laboratories Solid dispersions containing kinase inhibitors
WO2013101550A1 (en) * 2011-12-29 2013-07-04 Abbvie Inc. Solid compositions comprising an hcv inhibitor
WO2014081581A2 (en) * 2012-11-08 2014-05-30 Isp Investments Inc. Highly loaded amorphous efavirenz composition and process for preparing the same
WO2015103230A1 (en) * 2013-12-31 2015-07-09 Ascendia Pharmaceuticals, Llc Pharmaceutical compositions for poorly water-soluble compounds
WO2016033611A1 (en) * 2014-08-29 2016-03-03 Lipocine Inc. (17-β)-3-OXOANDROST-4-EN-17-YL UNDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE
WO2017196712A1 (en) * 2016-05-09 2017-11-16 Dispersol Technologies, Llc Improved drug formulations
WO2020085904A2 (en) 2018-10-24 2020-04-30 SeraNovo B.V. Deep eutectic solvent platform for oral pharmaceutical formulations
WO2021007172A1 (en) * 2019-07-08 2021-01-14 Belite Bio, Llc Formulations of rbp4 inhibitors and methods of use
WO2021005101A1 (en) * 2019-07-09 2021-01-14 Idorsia Pharmaceuticals Ltd Pharmaceutical composition comprising a tetrahydropyrazolopyrimidinone compound
WO2021034192A1 (en) 2019-08-19 2021-02-25 Seranovo Holding B.V. Pharmaceutical eutectic salt formulation
NL2025092B1 (en) 2020-03-10 2021-10-19 Seranovo Holding B V Solid deep eutectic solvent formulation platform

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
AROSO ET AL., EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 98, 2016, pages 57 - 66
CHIVATE ET AL., CURRENT PHARMA RESEARCH, vol. 2, 2012, pages 659 - 667
HUANGDAI, ACTA PHARMACEUTICA SINICA B, vol. 4, 2014, pages 18 - 25
K.C. PANIGRAHI ET AL., FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 4, 2018, pages 102 - 108
KHEDEKARMITTAL, INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES AND RESEARCH, vol. 4, no. 12, 2013, pages 4494 - 4507
ROWE ET AL.: "Handbook of Pharmaceutical Excipients", pages: 330 - 332
ZHANG ET AL., PHARMACEUTICS, vol. 3, 2018, pages 142

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