WO2022029639A1 - Formulations pharmaceutiques améliorées comprenant des inhibiteurs de pi3k - Google Patents

Formulations pharmaceutiques améliorées comprenant des inhibiteurs de pi3k Download PDF

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Publication number
WO2022029639A1
WO2022029639A1 PCT/IB2021/057130 IB2021057130W WO2022029639A1 WO 2022029639 A1 WO2022029639 A1 WO 2022029639A1 IB 2021057130 W IB2021057130 W IB 2021057130W WO 2022029639 A1 WO2022029639 A1 WO 2022029639A1
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Prior art keywords
cyclodextrin
pharmaceutical composition
compound
composition according
cellulose
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PCT/IB2021/057130
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English (en)
Inventor
Leon ZARTNER
Stephanie BOSSELMANN
Veniamin Pevzner
Chrysantha FREITAS
Reinhard Schmitz
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Berlin-Chemie Ag
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Publication of WO2022029639A1 publication Critical patent/WO2022029639A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • A61K47/40—Cyclodextrins; 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to an oral pharmaceutical formulation endowed with pH independent improved solubility comprising as active ingredient a PI3K inhibitor, such as the pyrimidine derivative 5-(7-(methylsulfonyl)-2-morpholino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin- 2-amine.
  • a PI3K inhibitor such as the pyrimidine derivative 5-(7-(methylsulfonyl)-2-morpholino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin- 2-amine.
  • the European patent EP2050749 discloses a new class of potent inhibitors of the Phosphatidylinositol 3-kinase (PI3K) and their use as anticancer drugs. Some of the compounds of this class have low solubility at elevated pH such as 4.5 and 6.8. In particular, one of the most promising compounds of this class of inhibitors, the pyrimidine derivative 5-(7-(methylsulfonyl)-2- morpholino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-2-amine (hereinafter identified as “Compound A”), shows a solubility that is highly pH-dependent and increases at low pH.
  • Compound A the pyrimidine derivative 5-(7-(methylsulfonyl)-2- morpholino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-2-amine
  • compositions of the invention comprise a pyrimidine derivative PI3K inhibitor as active ingredient.
  • present invention provides a formulation that shows a fast, pH-independent dissolution profile.
  • the inventors surprisingly observed that, the promising results from the solubility trials could not be transferred to the dissolution trials.
  • it was the most effective combination in the dissolution trials despite the fact that a lower excipients/active ingredient(s) mixing ratio was used as compared to the solubility trials.
  • the pH-independent dissolution profile might result in a bioavailability less likely to be sensitive to co-medications or food effects influencing the pH in the gastrointestinal tract thus making the therapy with PI3K inhibitors potentially safer and more effective for the patients.
  • the inventors also demonstrated that an efficient dissolution could also be achieved by manufacturing the pharmaceutical compositions of the invention with standard pharmaceutical manufacturing techniques, for example but not limited to, granulation.
  • the improved oral formulation of the invention can be manufactured in a highly time- and cost-efficient manner also using simple standard techniques which are well suitable for industrial scale-up.
  • the invention provides a pharmaceutical composition in a solid oral dosage form, comprising: i) a PI3K inhibitor as active ingredient, in particular Compound A or a pharmaceutically acceptable salt thereof ii) a cyclodextrin; iii) a polysaccharide-based excipient.
  • the invention provides said pharmaceutical composition in a solid oral dosage form for use in the treatment of a proliferative disease, in particular in the treatment of a cancer.
  • the invention provides a method of manufacturing said pharmaceutical composition, wherein said method comprising a step of mixing the PI3K inhibitor, the cyclodextrin and the polysaccharide-based excipient, preferably without liquid or with water or methanol.
  • Figure 1 Dissolution profiles of the Reference Formulation recorded in 900 mL simulated gastric fluid without enzymes (pH 1.2), phosphate buffer pH 4.5 and phosphate buffer pH 6.8 employing the paddle apparatus at 75 rpm.
  • Figure 2 Dissolution profiles of Soluplus®/PVP VA64 formulations in 900 mL of phosphate buffer pH 6.8 employing the paddle apparatus at 75 rpm.
  • Figure 3 Dissolution profiles of HPMC/SDS formulations in 900 mL of phosphate buffer pH 6.8 employing the paddle apparatus at 75 rpm.
  • Figure 4 Dissolution profiles of HPMC/ HPpCD formulations manufactured with varying amounts of HPMC via methanolic co-processing in 900 mL of phosphate buffer pH 6.8 employing the paddle apparatus at 75 rpm
  • Figure 5 Dissolution profiles of HPMC/ mannitol formulations manufactured with varying amounts of HPMC via methanolic co-processing in 900 mL of phosphate buffer pH 6.8 employing the paddle apparatus at 75 rpm.
  • Figure 6 Dissolution profiles of HPMC/ HPpCD formulations manufactured with varying processing liquids and as physical mixture recorded in 900 mL of phosphate buffer pH 6.8 employing the paddle apparatus at 75 rpm.
  • Figure 7 Dissolution profiles of HPMC/ HPpCD formulation and the “Reference Formulation” in 900 mL of phosphate buffer pH 6.8 employing the paddle apparatus at 75 rpm.
  • Figure 8 Dissolution profiles of HPMC/ HPpCD formulation and the “Reference Formulation” in 900 mL of phosphate buffer pH 4.5 employing the paddle apparatus at 75 rpm.
  • Figure 9 Dissolution profiles of HPMC/ HPpCD formulation and the “Reference Formulation” in 900 mL of simulated gastric fluid without enzymes pH 1.2 employing the paddle apparatus at 75 rpm. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention provides a pharmaceutical composition in a solid oral dosage form, comprising: i) a PI3K inhibitor; ii) a cyclodextrin; iii) a polysaccharide-based excipient.
  • the PI3K inhibitor is selected from one of the compounds listed in claim 15 of EP2050749 herein incorporated by reference in its entire content.
  • said PI3K inhibitor is the compound 5-(7-(methylsulfonyl)-2- morpholino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-2-amine (CAS number 1007207- 67-1 ; identified throughout the specification as Compound A).
  • Compound A can be present in the composition of the invention as a pharmaceutical acceptable salt such as, without being limited to, methansulfonate salt.
  • the pharmaceutical composition comprises said PI3K inhibitor, preferably in the following specific amounts of free base for each oral dosage unit: between 0.5 and 96 mg, preferably between 10 and 48 mg, more preferably between 16 and 32 mg.
  • the PI3K inhibitor can be present in the composition in an amount of about: 0.5, 1, 2, 3, 4, 5, 6, 7, 8 ,9 ,10, 11 , 12, 13, 14, 15, 16, 17,
  • the polysaccharide-based excipient in the pharmaceutical composition of the present invention may be cellulose or a cellulose derivative, such as for example micro-crystalline Cellulose, Carboxymethyl-cellulose, Celluloseacetate phthalate, Hydroxybutyl methylcellulose Hydroxyethyl cellulose, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose phthalate, Hydroxypropyl methyl-cellulose, Hydroxypropyl methyl-cellulose acetate succinate, Methyl-cellulose.
  • a cellulose derivative such as for example micro-crystalline Cellulose, Carboxymethyl-cellulose, Celluloseacetate phthalate, Hydroxybutyl methylcellulose Hydroxyethyl cellulose, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose phthalate, Hydroxypropyl methyl-cellulose, Hydroxypropyl methyl-cellulose acetate succinate, Methyl-cellulose.
  • the polysaccharide-based excipient is hydroxypropyl methylcellulose (also known as hypromellose).
  • Hydroxypropyl methylcellulose (HPMC) suitable for the pharmaceutical composition of the present invention is the commercially available hydroxypropyl methylcellulose E6.
  • the polysaccharide-based excipient and the PI3K inhibitor are in a ratio between 0.1 :1 and 1.6:1 , for example in a ratio of 0.2:1 or 0.4:1 or 0.8:1 (w/w) in each dosage unit form.
  • the ratio of the polysaccharide-based excipient and the PI3K inhibitor can be 0.1 :1, 0.2:1 , 0.3:1 , 0.4:1, 0.5:1, 0.6:1 , 0.7:1 , 0.8:1 , 0.9:1, 1.0:1, 1.1 :1 , 1.2:1 , 1.3:1, 1.4:1, 1.5:1 , 1.6:1 (w/w).
  • the composition may comprise in substitution of or in addition to such polysaccharide-based excipient one or more polymers.
  • polymers can be, for example, polyacrylates, polymethacrylates, polymethacrylamides, polyacrylamides, polyethylene glycols, polyethylene oxides, polyvinylacetate phthalates, polyvinylalcohols.
  • the cyclodextrin (CDx) in the pharmaceutical composition of the present invention may be for example Alpha- Cyclodextrin, Beta-Cyclodextrin, Hydroxy-propyl-beta-cyclodextrin, Gamma-Cyclodextrin, Dimethyl-Alpha-Cyclodextrin, Trimethyl-Alpha-Cyclodextrin, Hydroxypropyl-Alpha-Cyclodextrin, Carboxymethyl-Beta-Cyclodextrin, Dimethyl-Beta-Cyclodextrin, T rimethyl-Beta-Cyclodextrin, Hydroxyethyl-Beta-Cyclodextrin, Sulfobutylether-Beta-Cyclodextrin, Randomly-methylated-Beta- Cyclodextrin, Dimethyl-Gamma-Cyclodextrin, Trimethyl-Gamma-Cyclodext
  • the CDx is hydoxypropyl p-cyclodextrin, more preferably hydoxypropyl p-cyclodextrin with high molar substitution namely with a (hydroxypropyl) molar substitution range from about 0.80 to about 0.99.
  • the cyclodextrin and the PI3K inhibitor are in a ratio between 6:1 and 23:1, for example in a ratio of 8:1 or 10:1 or 12:1(w/w) in each dosage unit form.
  • the ratio of the cyclodextrin and the PI3K inhibitor can be 6:1 , 7:1 , 8:1, 9:1 , 10:1 , 11:1, 12:1 , 13:1, 14:1, 15:1 , 16:1, 17:1, 18:1 , 19:1 , 20:1 , 21 :1, 22:1 , 23:1 (w/w).
  • the pharmaceutical composition may further comprise one or more of the following excipients:
  • the pharmaceutical composition of the present invention may be in any solid form suitable for oral administration, such as for example but not limited to, capsules, tablets, lozenges, granules.
  • compositions of the invention can be in form of capsules that comprise Compound A, hydoxypropyl p-cyclodextrin and hydroxypropyl methylcellulose.
  • Compound A, hydoxypropyl [3-cyclodextrin and hydroxypropyl methylcellulose are present at a ratio of 1 : 10: 0.4 or 1 :12:0.8 (w/w) for each dose unit form.
  • compositions of the invention are for use in the treatment of a proliferative disease, preferably cancer.
  • said compositions are for use in an anticancer treatment of colon cancer, prostate cancer, breast cancer, ovarian cancer, lung cancer.
  • a further object of the present invention is a method of manufacturing the pharmaceutical composition according to any one of embodiments herein disclosed, wherein said method comprising a step of mixing, preferably using no liquid or using water or methanol as a solvent, the ingredients of the pharmaceutical composition of the invention.
  • the method can also comprise a drying step that, optionally, can be followed by a step in which the dried mixture is filled into capsules.
  • the concentration of Compound A is decreased by factor 97 and factor 29 for the active substance and Reference Formulation, respectively, when the pH value is increased from 1.2 to 6.8. Consequently, sink conditions - defined as the volume of dissolution medium at least greater than three times the volume that is required to form a saturated solution of the drug substance - were achieved only in simulated gastric fluid (without enzymes) for both, Compound A active substance and the Reference Formulation.
  • sink conditions are given when the concentration of Compound A free base is not less than 53.3 pg/mL.
  • solubility trials were performed in phosphate buffered medium of pH 6.8 reflecting the most challenging conditions in terms of the solubility of Compound A. Solubility trials were also performed with the aim at identifying excipients capable of increasing Compound A free base concentration to > 53.3 pg/mL in order to enable sink conditions.
  • Excipients were selected from the class of polymers (e.g. HPMC), carrier molecules (e.g. cyclodextrins), surfactants (e.g. SDS and Soluplus) and pH modifiers (e g. citric acid).
  • class of polymers e.g. HPMC
  • carrier molecules e.g. cyclodextrins
  • surfactants e.g. SDS and Soluplus
  • pH modifiers e g. citric acid
  • Solubility of Compound A in combination with various polymers such as albumin as well as various grades of hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), polyethyleneimine and polyvinylpyrrolidone were tested at pH 6.8. As shown in Table 4, of all tested polymers, only HPMC and MC achieved at least 10-fold increase of solubility of Compound A compared to that of the solubility of the active substance alone (Table 2 above).
  • Table 4 Results from the solubility trials performed on Compound A, active substance, and polymers.
  • HPMC was tested in combination with other excipients (for example, pH modifier such as citric acid and HCI; surfactants such as Solupus and SDS; cyclodextrins)
  • pH modifier such as citric acid and HCI
  • surfactants such as Solupus and SDS
  • cyclodextrins for example, pH modifier such as citric acid and HCI
  • surfactants such as Solupus and SDS
  • cyclodextrins for example, pH modifier such as citric acid and HCI; surfactants such as Solupus and SDS; cyclodextrins
  • Compound A was dispersed in an HPMC gel containing pH modifiers citric acid or hydrochloric acid. No beneficial effect of the pH modifiers could be identified as the measured Compound A free base concentration after 2 hours was comparable to that of Compound A dispersed in an HPMC gel without the addition of any pH modifier (see Table 6).
  • HPMC E15 and SDS or Soluplus® was the combination of HPMC and SDS in form of a pre-dissolved solution at concentrations of 1 mg/mL and 25 mg/mL for HMPC and SDS, respectively, corresponding to an API:HPMC:SDS ratio of 1 :1.5:37.5 resulted in a Compound A free base concentration (44.4 pg/mL) close to the limit defined for sink conditions (53.3 pg/mL).
  • Table 7 A summary of the results can be found in Table 7.
  • HPMC E6 was chosen as it is already used in the Reference Formulation.
  • Table 8 Results from the solubility trials performed on Compound A active substance and combinations of HPMC E6 and cyclodextrins
  • Soluplus® Solubility trials with Soluplus® in combination with other excipients Soluplus® was tested in combination with other excipients (for example, pH modifier such as citric acid, surfactants such as SDS; polymer such as PVP VA64).
  • pH modifier such as citric acid, surfactants such as SDS; polymer such as PVP VA64.
  • Table 9 Results from the solubility trials performed on Soluplus® in combination with other excipients and Compound A
  • Compound A was dispersed in a Soluplus® gel containing also citric acid.
  • the measured Compound A free base concentration after 2 hours was comparable to the one determined for Compound A dispersed in a Soluplus® gel without citric acid (see Tables 5 and 9).
  • Soluplus® was dissolved in an aqueous 5 % citric acid solution, a synergistic effect was observed with a Compound A free base concentration of 386 pg/mL.
  • Dissolution profiles were in all cases recorded at pH 6.8 as this is considered the most challenging condition in terms of Compound A solubility. Optionally, dissolution profiles were also recorded at pH 4.5 and pH 1.2.
  • Batch A and batch B yielded dissolution profiles with 14 % and 47 % Compound A free base in solution at pH 6.8 after 60 min, respectively (see Figure 2), demonstrating that an increase in the amount of these excipients results in an increase in the concentration of Compound A in solution. Nevertheless, a further increase in the amount of these excipients was not feasible due to the limited filling volume of the utilised size 0 capsule.
  • Soluplus®/PVP VA64 formulation as a decrease in the percentage of Compound A in solution from 47 % to 32 % after 60 min was observed than compared to the physical mixture.
  • Formulations comprising HPMC and SDS
  • Dissolution testing of batch D resulted in only 8 % and 13 % Compound A free base in solution after 20 min and 60 min of dissolution testing at pH 6.8, respectively.
  • the amount of SDS was further increased and the mixture was co-processed with methanol (batch E) an improved dissolution profile with 49 % and 54 % Compound A free base in solution after 20 min and 60 min of dissolution testing at pH 6.8, respectively, was obtained.
  • the corresponding dissolution profiles are depicted in Figure 3.
  • HPMC and HPpCD that had an intermediate performance in the solubility trials were further investigated within the formulation trials.
  • Table 14 Composition of batches L, M and N When the pH of the dissolution medium was reduced to pH 4.5, the dissolution of the modified formulation prepared by co-processing with water was further improved compared to pH 6.8 with 86% and 91% of Compound A free base in solution after 20 min and 60 min, respectively. The results obtained at pH 6.8 and pH 4.5 were also confirmed with another batch of the same composition and manufacturing procedure (batch O).
  • Table 15 Composition of batches L and O and Reference Formulation Additionally, batch O was tested at pH 1.2 where a rapid dissolution with 98 % Compound A free base in solution after 20 minutes was obtained ( Figure 9).
  • the dissolution performance of the confirmation batch O was comparable to the previous batch L and showed a low susceptibility to the pH of the dissolution medium with 86 % Compound A free base in solution after 60 minutes at pH 6.8 for both batches ( Figure 7) and 91 % and 86 % Compound A free base in solution after 60 minutes at pH 4.5 for batch L and O, respectively (see
  • Compound A active substance from manufacturer SAFC Inc. was used within the described feasibility study.
  • the excipient in question was pre-dissolved in the respective medium for the solubility trial in order to avoid lumping. Subsequently 100 mg Compound A were added to 150 mL of the pre-dissolved excipient solution.
  • Compound A and the respective excipient(s) were mixed in a porcelain dish with a spatula under the addition of either methanol or water until a paste-like consistency was obtained. Subsequently samples were dried at room temperature in the case of methanol and at elevated temperatures (40°C to 60°C) in a drying oven in the case of water. If required, the co-processed mixture was grinded after drying and before addition of the 150 mL of medium.
  • Aqueous gels were prepared in phosphate buffer pH 6.8 at an excipient concentration of 20 % (w/w) (HPMC or Soluplus®) and Compound A active substance was dispersed within the gel.
  • HPMC HPMC
  • the excipient was added to the buffer medium at > 90°C with subsequent cooling of the dispersion upon which the gel is formed.
  • the excipient was added to the buffer medium at room temperature upon which a gel was formed.
  • a pH modifier e.g. citric acid
  • Compound A dispersed in the gel before the addition of Compound A.
  • Compound A dispersed within 750 mg of the respective gel by mixing with a spatula for 30 min. Afterwards 150 mL of the respective medium was added to the gel.
  • Solubility Trials were performed at room temperature under continuous stirring with a magnetic stirrer. After 2 hours and optionally after 4 hours samples were withdrawn and passed through a suitable membrane filter. Two test solutions were prepared and Compound A free base concentrations were determined by HPLC according to Ph. Eur. 2.2.29, USP ⁇ 621>. As result of the solubility trials the mean value of the Compound A free base concentration in both test solutions was reported.
  • the dissolution method performed in the dissolution media (listed in Table A) is based on the dissolution method of the Reference Formulation performed in QC medium.
  • the content of Compound A free base during dissolution testing was determined with an HPLC method according to Ph. Eur. 2.2.29, USP ⁇ 621>.
  • the HPLC method was based on the HPLC method for dissolution testing of the Reference Formulation.

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Abstract

L'invention concerne une formulation pharmaceutique orale dotée d'une solubilité améliorée indépendante du pH comprenant comme principe actif un inhibiteur de PI3K, tel que le dérivé de pyrimidine 5-(7-(méthylsulfonyl)-2-morpholino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-2-amine.
PCT/IB2021/057130 2020-08-07 2021-08-04 Formulations pharmaceutiques améliorées comprenant des inhibiteurs de pi3k WO2022029639A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2050749A1 (fr) 2006-08-08 2009-04-22 Chugai Seiyaku Kabushiki Kaisha Derive de pyrimidine comme inhibiteur de la pi3k et son utilisation
WO2013147649A2 (fr) * 2012-03-29 2013-10-03 ХОЛИН, Максим Николаевич Inhibiteurs de la voie de signalisation pi3k/akt/ikk/nf-kb, leurs sels pharmaceutiquement acceptables et compositions les comprenant pour la prévention et le traitement de maladies virales

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2050749A1 (fr) 2006-08-08 2009-04-22 Chugai Seiyaku Kabushiki Kaisha Derive de pyrimidine comme inhibiteur de la pi3k et son utilisation
WO2013147649A2 (fr) * 2012-03-29 2013-10-03 ХОЛИН, Максим Николаевич Inhibiteurs de la voie de signalisation pi3k/akt/ikk/nf-kb, leurs sels pharmaceutiquement acceptables et compositions les comprenant pour la prévention et le traitement de maladies virales

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BREWSTER ET AL: "Cyclodextrins as pharmaceutical solubilizers", ADVANCED DRUG DELIVERY REVIEWS, ELSEVIER, AMSTERDAM , NL, vol. 59, no. 7, 24 August 2007 (2007-08-24), pages 645 - 666, XP022211985, ISSN: 0169-409X, DOI: 10.1016/J.ADDR.2007.05.012 *
DOMAGOJ ET AL.: "Impact of Acid-Reducing Agents on Gastrointestinal Physiology and Design of Biorelevant Dissolution Tests to Reflect These Changes", J. PHARM. SCI.,, vol. 108, no. 11, November 2019 (2019-11-01), pages 3461 - 3477

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