WO2022108572A1 - Formulations de systèmes d'administration de médicament auto-nanoémulsifiants chargés de bosentan monohydraté (snedds) préparés avec des mélanges de mono et diglycérides à longue chaîne - Google Patents

Formulations de systèmes d'administration de médicament auto-nanoémulsifiants chargés de bosentan monohydraté (snedds) préparés avec des mélanges de mono et diglycérides à longue chaîne Download PDF

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Publication number
WO2022108572A1
WO2022108572A1 PCT/TR2021/051258 TR2021051258W WO2022108572A1 WO 2022108572 A1 WO2022108572 A1 WO 2022108572A1 TR 2021051258 W TR2021051258 W TR 2021051258W WO 2022108572 A1 WO2022108572 A1 WO 2022108572A1
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Prior art keywords
snedds
liquid
polyoxyl
snedd
glyceryl
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English (en)
Inventor
Zeynep Safak TEKSIN
Duygu YILMAZ USTA
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Gazi Universitesi
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Gazi Universitesi
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Priority to EP21895278.6A priority Critical patent/EP4221689A4/fr
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Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

  • Different techniques are used (such as particle size reduction, nanonization, co-solvent use, surfactant use, functional polymer technology, controlled precipitation, inclusion complex, nanoparticle technology, nanocrystal technology, solid dispersion technique, inclusion complex, and selfemulsifying systems) to increase the solubility, dissolution rate, and thus bioavailability of waterinsoluble drugs.
  • Lipid-based formulations are considered a well-known strategy for increasing solubility and oral bioavailability, minimizing the in vivo variability of poorly soluble compounds.
  • Various dosage forms including solutions, emulsions and self-emulsifying/microemulsifying /nanoemulsifying drug delivery systems (SEDDS/SMEDDS/SNEDDS) can be developed to increase the solubility and bioavailability of BCS Class 2 and BCS Class 4 drugs using the lipids.
  • Self-nanoemulsifying drug delivery systems form a self-oil/water nanoemulsion smaller than 100 nm under gentle agitation with the aqueous phase in the gastrointestinal tract.
  • the systems contain natural or synthetic oils, solid or liquid surfactants, and co-surfactants, or isotropic mixtures of more hydrophilic solvents. These systems are used to improve the dissolution and absorption of BCS Class 2 drugs.
  • SNEDDSs not only show a remarkable increase in dissolution rate, solubility, and permeability, but also significantly reduce intra- and inter-individual variability, food effect, p-gp efflux, and the first pass through the liver depending on conditions in the gastrointestinal tract.
  • SNEDDS can provide increased physical and chemical stability, taste masking, and patient compliance when used in capsules as single dosage forms.
  • drugs developed in the form of self-emulsifying systems on the market which are Cyclosporine A (Sandimmune®/Neoral®), enzalutamide (Xtandi®), lubiprostone (Amitiza®), calcitriol (Rocaltrol®), fenofibrate (Lipofen®), ritonavir (Norvir®), and lopinavir-ritonavir (Kaletra®).
  • Bosentan monohydrate is an orally administered non-peptide endothelin receptor antagonist specifically for the treatment of pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • 62.5 and 125 mg film-coated tablet dosage forms on the pharmaceutical market for use in the treatment of PAH.
  • PAH pulmonary arterial hypertension
  • 62.5 mg twice a day for the first four weeks of treatment, and then at a dose of 125 mg twice a day.
  • This treatment requires lifelong drug use. This treatment is quite expensive. Therefore, the economic cost of this health expenditure is quite high for both the patient and the society.
  • EMA's report on Tracleer® 62.5 mg - 125 mg dosage forms states that the increase in liver aminotransferases (AST and ALT) in long-term BOS use is dose-dependent and that ALT-AST levels should be monitored against the risk of liver damage during the treatment. This increase is typically seen in the first 26 weeks of treatment, but can also be seen in the later stages of treatment. These increases may be due, in part, to competitive inhibition of bile salts elimination from hepatocytes, and although not conclusively identified, other mechanisms are thought to be associated with hepatic failure. It should be considered in the treatment that BOS will accumulate in hepatocytes and may cause possible serious liver damage or cytolysis up to an immunological mechanism.
  • bosentan which is a BCS Class 2 drug
  • appropriate formulation strategies to increase its bioavailability and treatment efficacy, and to reduce the dose amount/number of side effects.
  • SEDDS and SNEDDS formulation studies containing bosentan in the literature There are SEDDS and SNEDDS formulation studies containing bosentan in the literature.
  • the SEDDS formulation study was conducted by Gunnam et al. In this study, Gelucire 44/14 as oil, Cremophor EL as surfactant, and polyethylene glycol 400 (PEG 400) as co-surfactant were selected. The droplet size was 37.8 ⁇ 6.2 nm, and polydispersity index (PDI) was 0.279.
  • the stability study was also carried out for 15 days and 1 month.
  • the in vitro dissolution rate study was performed in 900 mL of distilled water, only a 1.8-fold increase in the cumulative amount of % dissolved drug was observed.
  • Another SNEDDS formulation study was conducted by Panigrahi et al.
  • Capmul MCM, Labrasol, and PEG 600 were selected as oil, surfactant, and cosurfactant, respectively.
  • the droplet size was 62.5 nm, the PDI was found to be 0.146.
  • the acceptable results were obtained for 6 months in the stability study.
  • the in vitro dissolution study was performed in 0.1 N HCI medium (pH 1.2) for SNEDDS. The 1.6-fold increase was observed in the % average amount of drug released compared to pure active substance alone.
  • the liquid SNEDDS formulations were prepared with long- chain mono and diglyceride mixtures.
  • Glyceryl monolinoleate (Maisine®) and glyceryl monooleate (Peceol®) as oil, which is long-chain mono and diglyceride mixtures, polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40) as surfactant, and caprylocaproyl polyoxyl-8 glycerides (Labrasol®) as co-surfactant were used in the preparation of SNEDDS.
  • the water titration method was chosen for the preparation of a liquid SNEDD system using long-chain mono and diglyceride mixtures.
  • Design Expert® Software Version 10 was used for the preparation of liquid SNEDDS containing optimum long-chain mono and diglyceride mixtures without active substance.
  • the droplet size and polydispersity index (PDI), evaluation of self-emulsification efficiency, % transmittance, the effect of pH and liquid volume on droplet size and PDI, turbidity, thermodynamic and long-term stability, morphological characterization studies have been carried out in optimum formulations without the active substance and after loading bosentan monohydrate.
  • bosentan monohydrate was successfully loaded into liquid SNEDDS prepared with long-chain mono and diglyceride mixtures and passed the all characterization studies successfully.
  • the prepared new system provided a much higher dissolution profile in fasted and fed states media that mimicked the gastrointestinal tract.
  • BOS-loaded glyceryl monooleate and glyceryl monolinoleate SNEDDS formulations released 95% and 96% of the active substance in their content, respectively.
  • the BOS-loaded glyceryl monooleate SNEDDS formulation released 85%, and the BOS-loaded glyceryl monolinoleate SNEDDS formulation 86% at the end of 90 minutes.
  • the ratio of components in liquid SNEDDS formulations prepared with long-chain mono and diglyceride mixtures is 0.9:7.2:0.8 by weight, as oiksurfactant: co-surfactant. Accordingly, the ratio of glyceryl monolinoleate, polyoxyl 40 hydrogenated castor oil, and caprylocaproyl polyoxyl-8 glycerides and the ratio of glyceryl monooleate, polyoxyl 40 hydrogenated castor oil, and caprylocaproyl polyoxyl-8 glycerides by weight are 0.9:7.2:0.8 (w/w/w).
  • the droplet size is below 50 nm, and the PDI is less than 0.2.
  • 1 gram of glyceryl monolinoleate SNEDDS formulation comprises 30 mg of bosentan monohydrate.
  • 1 gram of glyceryl monooleate SNEDDS formulation comprises 28 mg of bosentan monohydrate.
  • dispersibility studies 1 mL of each formulation was taken and added to 500 mL of distilled water at 37 ⁇ 0.5°C and mixed at 50 rpm, and the in vitro performance of the formulations was evaluated visually using the grading system.
  • To determine the self-emulsification time 1 mL of SNEDDS was evaluated visually to the appearance of the final emulsion at 37 ⁇ 0.5°C in 250 mL of water at the mixing time at 50 rpm.
  • the % transmittance of the system forming the formulations was measured at a wavelength of 638 nm in a UV spectrophotometer using distilled water as a blank.
  • Thermodynamic stability studies was included heating-cooling, centrifugation, freeze-thaw studies.
  • the droplet sizes of the formulations containing no active ingredient and loaded with BOS were also examined in terms of droplet size and PDI after dilution with 250 mL of water before and after the cycle.
  • glyceryl monolinoleate and glyceryl monooleate SNEDDS formulations which did not contain active substances and was loaded with BOS, was diluted 1 :250 with distilled water, mixed with a magnetic stirrer. The sample with 1% w/v phosphotungstic acid was dropped on the grid and kept at room temperature for 5 minutes examined with a transmission electron microscope (TEM).
  • TEM transmission electron microscope
  • Dissolution media 1 % SLS, FaSSIF, FeSSIF
  • the glyceryl monolinoleate SNEDD system containing 30 mg of BOS obtained comprised of 10.11 % glyceryl monolinoleate, 80.90% polyoxyl 40 hydrogenated castor oil, and 8.99% caprilocaproyl polyoxyl-8 glycerides.
  • the glyceryl monooleate SNEDD system containing 28 mg of BOS obtained comprised of 10.1 1 % glyceryl monolinoleate, 80.90% polyoxyl 40 hydrogenated castor oil, and 8.99% caprilocaproyl polyoxyl-8 glycerides.
  • Self-emulsification efficiency was evaluated by time to disperse and self-emulsify, and it was determined that both formulations spontaneously formed nanoemulsions when diluted with the gastrointestinal environment.
  • the formulations were self-emulsifying to form a transparent system in under a minute.
  • the droplet size is below 50 nm, and the PDI is less than 0.2 (Table 1 ) ( Figure 1 ).
  • GML Glyceryl monolinoleate
  • GMO Glyceryl monooleate
  • the developed formulations were found to be physically and chemically stable at 4°C, 25 ⁇ 2°C I 60 ⁇ 5% RH and 40 ⁇ 2°C I 75 ⁇ 5% RH for 6 months, and the results were shown.
  • no change in physical appearances such as turbidity or precipitation was observed in BOS-loaded glyceryl monolinoleate and glyceryl monooleate SNEDDS formulations.
  • droplet size and PDI it did not show any change and was stable for 6 months.
  • BOS-loaded glyceryl monooleate and glyceryl monolinoleate SNEDDS formulations were released approximately 69% and about 83% within 15 minutes, respectively.
  • BOS-loaded glyceryl monooleate and glyceryl monolinoleate SNEDDS formulations released 95% and 96% of the active substance in their content, respectively.
  • BOS-loaded glyceryl monolinoleate SNEDDS formulation increased the percentage of cumulative dissolved by 2.90-fold compared to the reference tablet in FaSSIF media.
  • BOS-loaded glyceryl monooleate SNEDDS formulation increased the percentage of cumulative dissolved by 2.88-fold compared to the reference tablet in FaSSIF media.
  • the commercial product released approximately 1 1 % of the active substance after 90 minutes, while the BOS-loaded glyceryl monooleate SNEDDS formulation released 85%, and the BOS-loaded glyceryl monolinoleate SNEDDS formulation 86%.
  • BOS-loaded glyceryl monolinoleate SNEDDS formulation increased the percentage of cumulative dissolved by 7.71 -fold compared to the reference tablet in FeSSIF media.
  • BOS-loaded glyceryl monooleate SNEDDS formulation increased the percentage of cumulative dissolved by 7.62-fold compared to the reference tablet in FaSSIF media.
  • the droplet size of glyceryl monolinoleate and glyceryl monooleate SNEDDS formulations that do not contain active ingredients should be less than 50 nm and PDI less than 0.2
  • - BOS-loaded glyceryl monolinoleate and glyceryl monooleate SNEDDS formulations are characterized by their droplet size below 50 nm and PDI less than 0.2.
  • BOS-loaded glyceryl monolinoleate and glyceryl monooleate SNEDDS formulations are used in the preparation of liquid drug forms by increasing the solubility and dissolution rate of bosentan, a BCS Class 2 drug with a solubility problem.
  • Figure 1 Image of particle size and distribution.
  • FIG. 1 TEM images. A- Glyceryl monolinoleate SNEDDS formulation without BOS, B- Glyceryl monooleate SNEDDS formulation without BOS, C- BOS-loaded glyceryl monolinoleate SNEDDS formulation, D- BOS-loaded glyceryl monooleate SNEDDS formulation

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dispersion Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne la préparation, l'optimisation et la caractérisation des formulations de systèmes d'administration de médicament auto-nanoémulsifiants liquides (SNEDDS) contenant du bosentan monohydraté (BOS) à l'aide de mélanges de mono et diglycérides à longue chaîne. Un SNEDDS liquide contenant du BOS, du monolinoléate de glycéryle (Maisine®) - huile de ricin hydrogénée polyoxyle 40 (Cremophor® RH 40) - caprilocaproyl polyoxyle-8 glycérides (Labrasol®) et du monooléate de glycéryle (Peceol®) - huile de ricin hydrogénée polyoxyle 40 (Cremophor® RH 40) - caprilocaproyl polyoxyle-8 glycérides (Labrasol®) dans certaines proportions sont formés, et les systèmes ont été déterminés par un procédé de titrage d'eau.
PCT/TR2021/051258 2020-11-23 2021-11-22 Formulations de systèmes d'administration de médicament auto-nanoémulsifiants chargés de bosentan monohydraté (snedds) préparés avec des mélanges de mono et diglycérides à longue chaîne Ceased WO2022108572A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP21895278.6A EP4221689A4 (fr) 2020-11-23 2021-11-22 Formulations de systèmes d'administration de médicament auto-nanoémulsifiants chargés de bosentan monohydraté (snedds) préparés avec des mélanges de mono et diglycérides à longue chaîne

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2020/18841A TR202018841A2 (tr) 2020-11-23 2020-11-23 Uzun zi̇nci̇rli̇ mono ve di̇gli̇seri̇t karişimlari i̇le hazirlanan bosentan monohi̇drat yüklü kendi̇li̇ği̇nden nanoemülsi̇fi̇ye i̇laç taşiyici si̇stemleri̇n (snedds) formülasyonu
TR2020/18841 2020-11-23

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009095933A2 (fr) * 2008-01-10 2009-08-06 Msn Laboratories Limited Procédé perfectionné et nouveau pour la préparation de bosentan
KR101058860B1 (ko) * 2008-10-20 2011-08-23 조선대학교산학협력단 수소화 코코-글리세라이드를 이용한 난용성 약물의 자가유화형 나노에멀젼 조성물
WO2012139736A1 (fr) * 2011-04-11 2012-10-18 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Composition pharmaceutique comprenant du bosentan

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR201915787A2 (tr) * 2019-10-14 2021-04-21 Yilmaz Usta Duygu Bosentan monohi̇drat yüklenmi̇ş sivi kendi̇li̇ği̇nden nanoemülsi̇fi̇ye i̇laç taşiyici si̇stem ve tablet formülasyonu

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009095933A2 (fr) * 2008-01-10 2009-08-06 Msn Laboratories Limited Procédé perfectionné et nouveau pour la préparation de bosentan
KR101058860B1 (ko) * 2008-10-20 2011-08-23 조선대학교산학협력단 수소화 코코-글리세라이드를 이용한 난용성 약물의 자가유화형 나노에멀젼 조성물
WO2012139736A1 (fr) * 2011-04-11 2012-10-18 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Composition pharmaceutique comprenant du bosentan

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4221689A4 *

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EP4221689A4 (fr) 2024-11-13
EP4221689A1 (fr) 2023-08-09
TR202018841A2 (tr) 2021-01-21

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