WO2022156836A1 - Préconcentré de microémulsion contenant de la cladribine, en particulier pour une administration orale et son procédé de préparation - Google Patents

Préconcentré de microémulsion contenant de la cladribine, en particulier pour une administration orale et son procédé de préparation Download PDF

Info

Publication number
WO2022156836A1
WO2022156836A1 PCT/CZ2022/050005 CZ2022050005W WO2022156836A1 WO 2022156836 A1 WO2022156836 A1 WO 2022156836A1 CZ 2022050005 W CZ2022050005 W CZ 2022050005W WO 2022156836 A1 WO2022156836 A1 WO 2022156836A1
Authority
WO
WIPO (PCT)
Prior art keywords
cladribine
microemulsion preconcentrate
hydrophilic
ionogenic
surfactant
Prior art date
Application number
PCT/CZ2022/050005
Other languages
English (en)
Inventor
Zdeňka ČÍŽKOVÁ
Michael Rost
Ivana KOLLÁROVÁ
Vladislav Čurn
Oleksandr Zabudkin
Vladimír MAŤHA
Original Assignee
Oncora S.R.O.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Oncora S.R.O. filed Critical Oncora S.R.O.
Priority to EP22708285.6A priority Critical patent/EP4281043A1/fr
Publication of WO2022156836A1 publication Critical patent/WO2022156836A1/fr

Links

Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • 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

Definitions

  • cladribine is classified as a BCS (Biopharmaceutical Classification System) class 3 substance, i.e., a high solubility, low permeability substance (NDA 22561 Clinical Pharmacology Amendment Memo).
  • BCS Biopharmaceutical Classification System
  • drugs are considered highly soluble when the dose corresponding to the highest strength of the dosage form is soluble in ⁇ 250 ml of buffer in the pH range of 1.0 to 7.5.
  • microemulsions as potential therapeutic systems for oral administration is their specific structure, which allows the incorporation of hydrophilic, amphiphilic and lipophilic drugs to increase their solubility, speed and extent of absorption, to protect labile substances from the gastrointestinal environment, to reduce inter- and intra-individual variability of effect and to mask unpleasant odour and taste.
  • the object of the present invention is to provide a liquid formulation of a microemulsion preconcentrate containing cladribine, particularly for oral, administration providing higher stability of the active ingredient at acidic pH, and a method of preparing the same using a robust, cost-effective, safe and easily applied industrial production technology.
  • the applicant of the invention considers it crucial to develop a formulation that allows the cladribine molecule to be protected from degradation in the low pH of the stomach, while at the same time increasing solubility so that at any given time the excess of cladribine predominates over its degradative metabolite.
  • the optimal solution appears to be to use a liquid formulation with rapid solubility and the ability to protect the degradation of the active ingredient, or at least to allow faster absorption of cladribine from the immediately available higher concentration of the active ingredient.
  • the problem of solubilization of cladribine in LBDDS was solved by a suitable combination of an aprotic solvent with a hydrophilic auxiliary solvent and a mixture of non- ionogenic surfactants with HLB > 10 with a non-ionogenic water-insoluble surfactant with HLB ⁇ 10 and/or with lipophilic vehicles containing a high proportion of long-chain fatty acids, such as glycerol mono-oleate or glycerol mono-linoleate.
  • step (c) the combination of the components of step (a) and (b) of the said drug solution and the said surfactant system to form a microemulsion preconcentrate.
  • Cladribine was first dissolved in the minimum amount of aprotic solvent required and the resulting concentrated solution was diluted with organic solvent to the required viscosity. The resulting solution of cladribine was then mixed with the surfactant solution and possibly with lipophilic vehicles containing a high proportion of glycerol mono-oleate or glycerol monolinoleate or combinations thereof, resulting in optimization of the dispersion properties of the formulation. When the results were evaluated, it was surprisingly found that the resulting formulation significantly increased the resistance of cladribine to low pH while improving the solubility of the formulation.
  • microemulsion preconcentrate prepared in this way is that it spontaneously forms nanoparticles containing dissolved cladribine when diluted in an aqueous medium.
  • cladribine is dissolved in an aprotic polar solvent (e.g., DMSO, DMFA, DMA) or in organic auxiliary solvents having acceptable affinity for water (e.g., ethanol, Transcutol, glycols).
  • solvents examples include, but are not limited by enumeration, alcohols, glycols, glycerol, propylene glycol, and various polyethylene glycols.
  • Hydrophobic non-ionic surfactant is more soluble in oil than in water (with low HLB).
  • Transesterified ethoxylated vegetable oils are particularly suitable.
  • lipid excipients are a heterogeneous group of substances, all of which are called by the general name of lipids.
  • LCTs long-chain triglycerides
  • MCTs medium-chain triglycerides
  • propylene glycol esters propylene glycol esters, fatty acids, monoglycerides, di glycerides, and lipid mixtures (Cerpnjak et al. 2013, for review).
  • MCTs medium chain triglycerides
  • glycerides are fundamentally influenced by the type of glyceride used.
  • LBDDS type Illb microemulsion preconcentrate
  • the use of mixed mono-, di- and triglycerides has proven to be useful, which, due to their amphiphilic nature, exhibit better self-dispersibility and higher solubilization capacity for poorly water-soluble drugs.
  • the formulation according to the present invention is prepared once the mixture of non- ionogenic surfactants is thoroughly mixed with a solution of the active ingredient in an organic solvent/water miscible solvent.
  • the formulation according to the present invention when diluted with an aqueous medium or gastric fluids, forms a dispersion of non-ionogenic surfactant nanoparticles, preferably below 50 nm in size. This was measured using the Malvern ZS (Malvern Instruments Ltd, UK, Zetasizer Nano).
  • the formulation according to the present invention is primarily intended for oral administration of pharmaceuticals, e.g., as a solution, soft and hard gelatine capsule, but the invention could also be used for topically administered formulations, e.g., as a cream, paste, lotion, gel, etc.
  • Fig. 4 shows the comparative dissociation profile of the commercial formulation labelled Mavenclad, the preconcentrate containing Labrafil and the preconcentrate containing Maisine auxiliary as the hydrophobic component (Apparatus II, 37 °C, 50 rpm, 900 ml 0.1 M HC1, pH 1.0),
  • Fig. 6 shows Table 1 - Comparison of AUC and DE of a commercial formulation (Mavenclad) with a microemulsion preconcentrate according to the invention (Apparatus II, 37 °C, 50 rpm, 900 ml 0.1 M HC1, pH 1.0), and Table 2 - Comparison of dissociation profiles based on absolute values of drug released (mg) (Apparatus II, 37 °C, 50 rpm, 900 ml 0.1 M HC1, pH 1.0).
  • the microemulsion system was designed based on preliminary experiments with individual excipients and binary/ternary mixtures of excipients and APIs.
  • a ternary phase diagram of the hydrophilic phase (DMSO/Transcutol HP mixture), Cremophor RH40 and Labrafil Ml 944 (Maisine, Peceol, Capryol) was constructed using preconcentrates with different ratios of the individual components.
  • a target sub-region of the phase diagram ( Figure 1) was selected to meet the poly dispersity and particle size requirements of the microemulsion in aqueous media.
  • ANOVA, residue examination and prediction of external point values were performed to validate the model.
  • the final formulation was then selected within the above range of excipients so that higher proportions of organic solvents were present to ensure acceptable appearance and stability of the sample after dilution.
  • Microemulsion particles were evaluated by imaging and particle distribution measurements. Using transmission electron microscopy, the presence of round vesicles with a mean diameter of approximately 20 nm was demonstrated ( Figure 2). The vesicles were very sensitive to the electron beam and morphological changes occurred during focusing, which could account for the difference in size measured by LS and TEM.
  • Particle size measurements of diluted samples were performed by Photo-Correlation Spectroscopy (PCS) in a Malvern ZS particle size analyser at 20 °C, 150 s measurement time, in water or 0.1 M HC1. Solubilization was performed by gently mixing the pre concentrate in a flask. Z-averaged particle size and poly dispersity were reported as the average of three independent measurements.
  • the characteristic particle distribution of the preconcentrate prepared according to the subject patent is shown in Figure 3.
  • Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ⁇ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
  • Cladribine dissolves in a solution of DMSO and IPA when heated to T ⁇ 45-60 °C.
  • a second beaker dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize.
  • the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
  • Example 11 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
  • Cladribine dissolves in a solution of DMSO and MeOH when heated to T ⁇ 45-60 °C.
  • DMSO dimethyl methoxysulfoxide
  • Cremophor RH40 a compound that can be added to CLB solution and homogenize.
  • the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
  • Example 12 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
  • Cladribine dissolves in a solution of DMSO and EtOH when heated to T ⁇ 45-60 °C.
  • DMSO dimethyl sulfoxide
  • Cremophor RH40 a compound that can be used to dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize.
  • the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
  • Example 13 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
  • Cladribine dissolves in a solution of DMSO and PEG 400 when heated to T ⁇ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
  • Example 14 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
  • Cladribine dissolves in DMSO solution when heated to T ⁇ 45-60 °C.
  • Cremophor RH40 dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize.
  • the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
  • Example 16 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
  • Cladribine dissolves in a solution of DMSO and DMA when heated to T ⁇ 45-60 °C.
  • a second beaker dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize.
  • the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
  • Example 17 Comparative dissolution of a microemulsion preconcentrate prepared with a mixture of hydrophilic and hydrophobic non-ionogenic surfactants, a microemulsion preconcentrate prepared from a mixture of a hydrophilic non- ionogenic surfactant and glycerol mono-linoleate with a commercial formulation (Mavenlad).
  • the comparative dissolution was carried out under discriminative conditions (acidic pH) in a type II dissolution apparatus, in 900 ml of dissolution medium (0.1 M HC1 pH 1.0), at 50 rpm and 37 °C.
  • a 10 mg tablet of a commercially available preparation (Mavenclad, batch number 00015336) was used as a reference sample.
  • the tested microemulsion preconcentrate was filled into hard gelatine capsules just before use. The difference in the formulations used partially affected the profile of the dissociation curve but in no way affected the availability of cladribine from the formulations tested. For this reason, conversion to the absolute value of cladribine at each sampling interval was also used in the evaluation of the dissociation efficiency.
  • microemulsion preconcentrate containing cladribine especially for oral administration and a method of preparation according to the invention will find application in the field of treatment of haemato-oncological diseases, MS, autoimmune diseases and in medical and pharmaceutical research.

Landscapes

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

Abstract

L'invention concerne un préconcentré de microémulsion anhydre contenant de la cladribine et comprenant : de la cladribine dissoute dans au moins un solvant polaire aprotique et dans au moins un solvant organique auxiliaire ayant une affinité acceptable pour l'eau, un mélange d'un tensioactif non ionogène ayant un équilibre hydrophile-lipophile > 10 avec un tensioactif non ionogène insoluble dans l'eau ayant un équilibre hydrophile-lipophile < 10 et/ou avec des véhicules lipophiles contenant une proportion élevée d'acides gras à longue chaîne, tels que, par exemple, le mono-oléate de glycérol ou le monolinoléate de glycérol. Les composants hydrophiles et hydrophobes sont mélangés pour former un mélange homogène. Ce mélange homogène est ensuite mélangé avec une solution de cladribine pour obtenir une formulation qui, lorsqu'elle est introduite dans le tractus gastro-intestinal, forme spontanément une dispersion de nanoparticules tensioactives non ionogènes contenant des molécules de cladribine dissoutes.
PCT/CZ2022/050005 2021-01-22 2022-01-21 Préconcentré de microémulsion contenant de la cladribine, en particulier pour une administration orale et son procédé de préparation WO2022156836A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP22708285.6A EP4281043A1 (fr) 2021-01-22 2022-01-21 Préconcentré de microémulsion contenant de la cladribine, en particulier pour une administration orale et son procédé de préparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2021-25A CZ309587B6 (cs) 2021-01-22 2021-01-22 Mikroemulzní prekoncentrát s obsahem kladribinu a způsob jeho přípravy
CZPV2021-25 2021-01-22

Publications (1)

Publication Number Publication Date
WO2022156836A1 true WO2022156836A1 (fr) 2022-07-28

Family

ID=80682214

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2022/050005 WO2022156836A1 (fr) 2021-01-22 2022-01-21 Préconcentré de microémulsion contenant de la cladribine, en particulier pour une administration orale et son procédé de préparation

Country Status (3)

Country Link
EP (1) EP4281043A1 (fr)
CZ (1) CZ309587B6 (fr)
WO (1) WO2022156836A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999056727A2 (fr) * 1998-05-07 1999-11-11 Elan Corporation, Plc Systemes d'apport de medicament de preconcentre de microemulsion et d'emulsion depourvues de solvant/cosolvant
WO2008089272A1 (fr) * 2007-01-16 2008-07-24 Bipar Sciences, Inc. Préparations pour le traitement du cancer
WO2016071515A1 (fr) * 2014-11-07 2016-05-12 Sigmoid Pharma Limited Compositions comprenant de la cyclosporine

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2873585B1 (fr) * 2004-07-27 2006-11-17 Aventis Pharma Sa Nouvelles formulations galeniques de principes actifs
CN101675918A (zh) * 2008-09-18 2010-03-24 上海药明康德新药开发有限公司 一种自乳化微乳组合物及其制备方法和用途
WO2013105101A1 (fr) * 2012-01-13 2013-07-18 Department Of Biotechnology Nanoparticules lipidiques solides encapsulant un médicament hydrophile/amphiphile et leur procédé de préparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999056727A2 (fr) * 1998-05-07 1999-11-11 Elan Corporation, Plc Systemes d'apport de medicament de preconcentre de microemulsion et d'emulsion depourvues de solvant/cosolvant
WO2008089272A1 (fr) * 2007-01-16 2008-07-24 Bipar Sciences, Inc. Préparations pour le traitement du cancer
WO2016071515A1 (fr) * 2014-11-07 2016-05-12 Sigmoid Pharma Limited Compositions comprenant de la cyclosporine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GURSOY R N ET AL: "Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs", BIOMEDICINE & PHARMACOTHERAPY, ELSEVIER, FR, vol. 58, no. 3, 1 April 2004 (2004-04-01), pages 173 - 182, XP002500493, ISSN: 0753-3322, DOI: 10.1016/J.BIOPHA.2004.02.001 *

Also Published As

Publication number Publication date
CZ202125A3 (cs) 2022-08-03
EP4281043A1 (fr) 2023-11-29
CZ309587B6 (cs) 2023-05-03

Similar Documents

Publication Publication Date Title
Panigrahi et al. Gelucire: A versatile polymer for modified release drug delivery system
Kaur et al. Developments of Polysorbate (Tween) based microemulsions: Preclinical drug delivery, toxicity and antimicrobial applications
Itoh et al. Improvement of physicochemical properties of N-4472 part I formulation design by using self-microemulsifying system
Sriamornsak et al. A new self-emulsifying formulation of mefenamic acid with enhanced drug dissolution
Hong et al. A new self-emulsifying formulation of itraconazole with improved dissolution and oral absorption
Shafiq et al. Design and development of oral oil in water ramipril nanoemulsion formulation: in vitro and in vivo assessment
Dong et al. Development of new lipid-based paclitaxel nanoparticles using sequential simplex optimization
US20140056974A1 (en) Spontaneously Dispersible N-Benzoyl Staurosporine Compositions
JP2002509877A (ja) 抗癌組成物
Goyal et al. Self microemulsifying drug delivery system: A method for enhancement of bioavailability
Arida et al. Improving the high variable bioavailability of griseofulvin by SEDDS
Pattewar et al. Self microemulsifying drug delivery system: A lipid based drug delivery system
US9278065B2 (en) Delivery systems for solubilising water-insoluble pharmaceutical active ingredients
KR20160101167A (ko) 라세카도트릴 조성물
KR20150023876A (ko) 라세카도트릴 지질 조성물
JP2005513096A (ja) シクロスポリン、親水性界面活性剤及び親油性界面活性剤を含んで成る医薬組成物
Hussain et al. In vitro–in vivo–in silico simulation studies of anti-tubercular drugs doped with a self nanoemulsifying drug delivery system
Duc Hanh et al. Development of phyllanthin-loaded self-microemulsifying drug delivery system for oral bioavailability enhancement
Madan et al. Formulation and development of self-microemulsifying drug delivery system of pioglitazone
WO2005014048A1 (fr) Preparations a emulsification spontanee et a micro-emulsification spontanee pour l&#39;administration orale de taxoides
Anand et al. Self-micro emulsifying drug delivery system
WO2022156836A1 (fr) Préconcentré de microémulsion contenant de la cladribine, en particulier pour une administration orale et son procédé de préparation
EP1715848B1 (fr) Formulations sous forme de micro-emulsion renfermant certains antagonistes de la substance p
Singh et al. Enhanced oral bioavailability of (+)-catechin by a self double-emulsifying drug delivery system (SDEDDS): a new platform for oral delivery of biopharmaceutics classification system class III drugs
Qader et al. Novel oral solid self-nanoemulsifying drug delivery system (S-SNEDDS) of rosuvastatin calcium: Formulation, characterization, bioavailability and pharmacokinetic study

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22708285

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2022708285

Country of ref document: EP

Effective date: 20230822