WO2017037630A1 - Système d'administration par voie orale reposant sur un complexe polyélectrolyte - Google Patents

Système d'administration par voie orale reposant sur un complexe polyélectrolyte Download PDF

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Publication number
WO2017037630A1
WO2017037630A1 PCT/IB2016/055196 IB2016055196W WO2017037630A1 WO 2017037630 A1 WO2017037630 A1 WO 2017037630A1 IB 2016055196 W IB2016055196 W IB 2016055196W WO 2017037630 A1 WO2017037630 A1 WO 2017037630A1
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Prior art keywords
api
pec
drug
class
delivery system
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PCT/IB2016/055196
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English (en)
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Viness Pillay
Lisa Claire Du Toit
Yahya Essop Choonara
Margaret SIYAWAMWAYA
Pradeep Kumar
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University Of The Witwatersrand, Johannesburg
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Publication of WO2017037630A1 publication Critical patent/WO2017037630A1/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
    • A61K9/14—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
    • 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
    • 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
    • A61K9/148—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 compounds of unknown constitution, e.g. material from plants or animals
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • This invention relates to polyelectrolyte complexes (PECs) formulated to provide an oral drug delivery system.
  • PECs polyelectrolyte complexes
  • the invention relates to a humic acid (HA) and quaternized hydroxyethylcellulose ethoxylate (PQ-10) partial polyelectrolyte complex (HA-PQ-10-pPEC) and extends to a fully complexed humic acid quaternized hydroxyethylcellulose ethoxylate polyelectrolyte complex (fc-HA- PQ-10-PEC).
  • HA humic acid
  • PQ-10-pPEC quaternized hydroxyethylcellulose ethoxylate polyelectrolyte complex
  • Both HA-PQ-10-pPEC and the fc-HA-PQ-10-PEC may include dispersed therein an active pharmaceutical ingredient (API), preferably an API falling in the Biopharmaceutics Classification System (BCS) class II and/or IV.
  • API active pharmaceutical ingredient
  • BCS Biopharmaceutics Classification System
  • Both HA-PQ-10-pPEC and the fc-HA-PQ-10-PEC enhances solubility and the permeability of APIs.
  • API/drug active pharmaceutical ingredient
  • pharmaceutical delivery systems such as oral capsule and/or tablet formulations poses a barrier to effective treatment of medical conditions and/or diseases since the API/drug is prevented from being taken up in the bloodstream and/or is prevented from reaching its target site. This in turn results in low bioavailability of the drugs in vivo and consequentially, higher API/drug doses have to be administered in order to achieve optimal biological effects (Jones et al., 2013).
  • API/drug delivery systems often including a large amount of API/drug to ensure that at least a minor portion thereof reaches the target site and/or is absorbed into the bloodstream in order to provide for effective treatment and/or prevention of medical conditions and/or diseases in a human or animal body. Consequently, the cost to the patient is increased.
  • Dissolution of an API/drug loaded oral delivery system is achieved in two stages where, initially, a solid API/drug loaded delivery system interacts with a solvent (typically a fluid known to occur in the gastro-intestinal tract (GIT)). This is followed by a dissolution rate determining step where the solute particles are transported from a boundary layer into the bulk of the solution.
  • a solvent typically a fluid known to occur in the gastro-intestinal tract (GIT)
  • Reducing the drug particle size to nanoscale may alter physico-chemical properties, certain emulsions may result in unwanted side effects and the use of solid dispersions is known to result in the recrystallization of the API/drug negatively impacting on its bioavailability.
  • the permeability of drugs may be enhanced by utilizing polymeric delivery systems which increase the resident time of the drugs or by encapsulating the drugs in microspheres and nanoparticles which offer a high surface area to volume ratio.
  • this increased residence time may expose the AIP/drug to a harmful environment, for example, in the stomach where it will be exposed to pH conditions and enzymes that could readily compromise the structural integrity of the API/drug.
  • Permeability may also be increased by an addition of certain permeation enhancers which may act on specific cell types located at specific anatomical regions to allow for the API/drug to permeate through said cell type and eventually enter a target organ or bloodstream.
  • These permeation enhancers are extra chemical compounds included into the drug delivery system and may cause unwanted side effects and/or side reactions and/or add to the bulkiness of the delivery system negatively impacting on patient compliance.
  • Polymers are known to be used in the formulation of API/drug delivery systems for their ability to load a variety of active pharmaceutical ingredients (APIs/drugs) and the same applies for polyelectrolyte complexes (PECs) (Kim et al., 2014; Pandey et al., 2013). In has been reported that PECs lower or eliminate the number of excipients required to make a formulation thus leading to reduced production cost as well as less bulky formulations which encourage patients to adhere to treatment (Sinha et al., 2010). PECs form by electrostatic binding between a cation and an anion (Nath et al., 2015; Ankerfos et al., 2010).
  • an oral delivery system comprising a humic acid (HA) and quaternized hydroxyethylcellulose ethoxylate (PQ-10) partial polyelectrolyte complex (HA-PQ-10-pPEC).
  • the oral delivery system may further comprise an active pharmaceutical ingredient (API) dispersed within HA-PQ-10-pPEC.
  • API active pharmaceutical ingredient
  • the HA-PQ-10-pPEC may be fully complexed to form a fully complexed humic acid quaternized hydroxy ethylcellulose ethoxylate polyelectrolyte complex (fc-HA-PQ-10-PEC).
  • the fc-HA-PQ-10-PEC may be formed in situ when the HA-PQ-10-pPEC contacts an aqueous medium in the gastro-intestinal tract (GIT), the in situ formed fc-HA-PQ-10-PEC providing constant release of the API to a target site in the GIT of a human or animal body.
  • GIT gastro-intestinal tract
  • the active pharmaceutical ingredient may be a Biopharmaceutics Classification System (BCS) class II API (poorly soluble API) or a class IV API (poorly permeable API).
  • BCS Biopharmaceutics Classification System
  • class II API poorly soluble API
  • class IV API poorly permeable API
  • the Biopharmaceutics Classification System (BCS) class II or class IV active pharmaceutical ingredient (API) may be an anti-HIV API.
  • the anti-HIV API may be efavirenz (EFV) or ritonavir (RTV).
  • the delivery system may be encapsulated or coated by a protective layer allowing the delivery system to pass through the stomach of a gastro-intestinal tract without compromising the chemical structure of the API/drug.
  • a method of producing a humic acid (HA) and quaternized hydroxyethylcellulose ethoxylate (PQ-10) partial polyelectrolyte complex comprising the following steps: i. mixing humic acid (HA) and quaternized hydroxyethylcellulose ethoxylate (PQ-10) in a homogenizer to form a first mixture; ii. adding deionized water to the first mixture to form a second mixture; iii. pouring the second mixture into an extruder apparatus; iv. collecting extrudate from the extruder apparatus; and v.
  • HA- PQ-10-pPEC humic acid
  • PQ-10-pPEC quaternized hydroxyethylcellulose ethoxylate
  • Step (i) may further include adding an active pharmaceutical ingredient (API) to form the first mixture.
  • the API is a Biopharmaceutics Classification System (BCS) class II API (poorly soluble API) or a class IV API (poorly permeable API), preferably the class II API is efavirenz (EFV) and the class IV drug is ritonavir (RTV).
  • BCS Biopharmaceutics Classification System
  • EAV efavirenz
  • RTV ritonavir
  • Step (i) may further include adding an excipient.
  • the excipient may be at least one of ethyl cellulose (EC) and microcrystalline cellulose (MCC), preferably the excipient includes both EC and MCC.
  • the produced HA-PQ-10-pPEC may be produced as solid and spheronized particles which are formulated into an oral delivery system according to the first aspect of the invention.
  • the solid and spheronized HA-PQ-10-pPEC particles may be formulated as a tablet and/or capsule.
  • a method of producing a fully complexed humic acid quaternized hydroxyethylcellulose ethoxylate polyelectrolyte complex comprising the following steps: i. preparing a first aqueous solution of humic acid (HA); ii. preparing a second aqueous solution of quaternized hydroxyethylcellulose ethoxylate (PQ- 10); iii. adding the second aqueous solution to the first aqueous solution to form a fc-HA-PQ-10- PEC precipitate; iv.
  • Step (i) may further include adding an active pharmaceutical ingredient (API) to the first aqueous solution.
  • API active pharmaceutical ingredient
  • the API may be a Biopharmaceutics Classification System (BCS) class II API (poorly soluble API) or a class IV API (poorly permeable API), preferably the class II API is efavirenz (EFV) and the class IV drug is ritonavir (RTV).
  • BCS Biopharmaceutics Classification System
  • EAV efavirenz
  • RTV ritonavir
  • the produced fc-HA-PQ-10-PEC may be produced as solid powder particles which are formulated into an oral delivery system according to the first aspect of the invention.
  • the fc-HA-PQ-10-PEC particles may be formulated as a tablet and/or capsule.
  • FIGURE 1 shows a schematic diagram outlining the complexation precipitation method and extrusion spheronization method of producing the oral delivery systems according to the invention
  • FIGURE 2 shows SEM images of extruded pellet wherein (a) is PEC (E _ S) (b) is PE C -P ) (C) is
  • PEC ( E_s ) (powdered) and (d) is PEC (C P) (powdered) all at x 2000 magnification (abbreviations as per Table 1);
  • FIGURE 3 shows tapping mode amplitude AFM images of PEC (E _ S) (left) and PEC (C -P ) (right)
  • FIGURE 4 shows FTIR spectra for PEC-E (E S) , PEC-E (C -P ) , PEC-R (E S ) and PEC-R( C P ) and various other formulations as per Table 1 for comparison purposes;
  • FIGURE 5 shows FTIR spectra of PEC (E S) before and after soaking in SIF (abbreviations as per
  • FIGURE 6 shows DSC thermograms for PEC-E (E S) , PEC-E (C P) , PEC-R (E _ S) and PEC-R (C - P)
  • FIGURE 7 shows XRD spectra of (a) EFV and EFV formulations and (b) RTV and RTV formulations (abbreviations as per Table 1);
  • FIGURE 8 shows saturation solubilities of (a) EFV and EFV formulations and (b) RTV and RTV formulations (abbreviations as per Table 1);
  • FIGURE 9 shows API/drug release profiles for (a) EFV and (b) RTV loaded oral drug delivery systems according to the invention (abbreviations as per Table 1);
  • FIGURE 10 shows intestinal tissue permeation profiles for EFV and RTV loaded drug delivery systems according to the invention (abbreviations as per Table 1);
  • FIGURE 11 shows intestinal integrities of EFV and RTV loaded drug delivery systems according to the invention (TEER in Q.cm 2 10 4 ) (abbreviations as per Table 1);
  • FIGURE 12 shows API/drug release and intestinal tissue permeation profiles of optimized EFV
  • an oral delivery system comprising a humic acid (HA) and quaternized hydroxyethylcellulose ethoxylate (PQ-10) partial polyelectrolyte complex (HA-PQ-10-pPEC).
  • the oral delivery system further comprises an active pharmaceutical ingredient (API) dispersed within HA-PQ-10-pPEC.
  • API active pharmaceutical ingredient
  • the HA-PQ-10-pPEC may be fully complexed to form a fully complexed humic acid quaternized hydroxyethylcellulose ethoxylate polyelectrolyte complex (fc-HA-PQ-10-PEC). Again this fc-HA-PQ- 10-PEC may also include dispersed therein an API/drug and consequently may be formulated to provide a placebo or API/drug loaded embodiment.
  • the fc-HA-PQ-10-PEC is formed in situ when the HA-PQ-10-pPEC contacts an aqueous medium in the gastro-intestinal tract (GIT), the in situ formed fc-HA-PQ-10-PEC providing constant release of the API to a target site in the GIT of a human or animal body.
  • the HA-PQ-10-pPEC is manufactured by employing an extrusion-spheronization (E-S) technique which is described in more detail below.
  • E-S extrusion-spheronization
  • the fc-HA-PQ-10-PEC is formed in situ when the HA-PQ- 10-pPEC contacts an aqueous medium in the gastro-intestinal tract (GIT).
  • the fc-HA-PQ-10-PEC is manufactured using a complexation- precipitation (C-P) technique which is described in more detail below.
  • C-P complexation- precipitation
  • Both E-S and C-P techniques may include the introduction of an API/drug to produce a drug loaded delivery system.
  • the Applicant surprisingly found that the API/drug loaded in situ formed fc-HA-PQ-10-PEC provided a longer sustained and constant API/drug release when compared to the fc-HA-PQ-10-PEC formed by the C-P technique.
  • the active pharmaceutical ingredient (API)/drug may be a Biopharmaceutics Classification System (BCS) class II API (poorly soluble API) or a class IV API (poorly permeable API).
  • the Biopharmaceutics Classification System (BCS) class II or class IV active pharmaceutical ingredient (API) may be an anti-HIV API.
  • model drugs are utilized and such model drugs are not intended to limit the scope of this invention.
  • the model drugs utilized herein below include the anti-HIV APIs efavirenz (EFV) and/or ritonavir (RTV).
  • the delivery system may be encapsulated or coated by a protective layer allowing the delivery system to pass through the stomach of a gastro-intestinal tract without compromising the chemical structure or the API/drug.
  • a method of producing a humic acid (HA) and quaternized hydroxyethylcellulose ethoxylate (PQ-10) partial polyelectrolyte complex comprising the following steps: i. mixing humic acid (HA) and quaternized hydroxyethylcellulose ethoxylate (PQ-10) in a homogenizer to form a first mixture; ii. adding deionized water to the first mixture to form a second mixture; iii. pouring the second mixture into an extruder apparatus; iv. collecting extrudate from the extruder apparatus; and v.
  • HA-PQ-10-pPEC humic acid
  • PQ-10-pPEC quaternized hydroxyethylcellulose ethoxylate
  • This method is termed the extrusion-spheronization (E-S) technique.
  • E-S technique produces a HA-PQ-10-pPEC which is utilized to produce the in situ formed fc-HA-PQ-10-PEC.
  • Step (i) may further include adding an active pharmaceutical ingredient (API) to form the first mixture.
  • API active pharmaceutical ingredient
  • the API is a Biopharmaceutics Classification System (BCS) class II API (poorly soluble API) or a class IV API (poorly permeable API), preferably the class II API is efavirenz (EFV) and the class IV drug is ritonavir (RTV).
  • BCS Biopharmaceutics Classification System
  • EAV efavirenz
  • RV ritonavir
  • Step (i) may further include adding an excipient.
  • the excipient may be at least one of ethyl cellulose (EC) and microcrystalline cellulose (MCC), preferably the excipient includes both EC and MCC.
  • the produced HA-PQ-10-pPEC is typically produced as solid and spheronized particles which are formulated into an oral delivery system according to the first aspect of the invention.
  • the solid and spheronized HA-PQ-10-pPEC particles may be formulated as a tablet and/or capsule.
  • the solid and spheronized HA-PQ-10-pPEC particles are encapsulated in an empty gelatin capsule to provide a capsulated embodiment of the oral delivery system according to the invention described herein.
  • a method of producing a fully complexed humic acid quaternized hydroxyethylcellulose ethoxylate polyelectrolyte complex comprising the following steps:
  • HA humic acid
  • C-P complexation-precipitation
  • Step (i) may further include adding an active pharmaceutical ingredient (API) to the first aqueous solution.
  • API active pharmaceutical ingredient
  • the API may be a Biopharmaceutics Classification System (BCS) class II API (poorly soluble API) or a class IV API (poorly permeable API), preferably the class II API is efavirenz (EFV) and the class IV drug is ritonavir (RTV).
  • BCS Biopharmaceutics Classification System
  • EAV efavirenz
  • RV ritonavir
  • the invention provides for an oral delivery system comprising HA-PQ-10-pPEC, which HA-PQ-10- pPEC may produce an in situ formed fc-HA-PQ-10-PEC.
  • the invention also provides for an oral delivery system comprising fc-HA-PQ-10-PEC which is produced without first forming an intermediary HA-PQ-10-pPEC.
  • the produced fc-HA-PQ-10-PEC is typically produced as solid, milled powder particles which are formulated into an oral delivery system according to the first aspect of the invention.
  • the fc-HA-PQ- 10-PEC particles may be formulated as a tablet and/or capsule.
  • fc-HA-PQ-10-PEC particles are encapsulated in an empty gelatin capsule to provide a capsulated embodiment of the oral delivery system according to the invention described herein.
  • All the oral delivery systems according to the various embodiments of this invention may be API/drug loaded and provide for improved solubility of the API/drug in use, and provide for improved permeability of the API/drug when in use.
  • Humic acid belongs to a family of humic substances which are weakly acidic and heterogeneous compounds.
  • humic acids comprise a mixture of weak aliphatic (carbon chains) and aromatic (carbon rings) organic acids.
  • Humic acids (HAs) are termed polydisperse because of their variable chemical features. From a three dimensional aspect these complex carbon containing compounds are considered to be flexible linear polymers that exist as random coils with cross linked bonds. On average 35% of the humic acid (HA) molecules are aromatic (carbon rings), while the remaining components are in the form of aliphatic (carbon chains) molecules.
  • the molecular weight of humic acids (HAs) ranges from approximately 10,000 to 100,000 g/mol.
  • the HA purchased from Sigma Aldrich and utilized in the example embodiments below had an average molecular weight is 32000 g/mol with a carbon content of approximately 39% (average humic acid content of 66%).
  • the acidic behaviour of HA is exhibited by the ionization of carboxylic and phenolic groups and it has been shown to exhibit good complexing properties with cations.
  • HA contains both a supramolecular and macromolecular structure with a significant aromatic character and the more aromatic a humic substance is, the more carboxylic acid groups are present in the structure (Baigorri et al., 2009).
  • HA is partially soluble in water and the solubility increases with increase in pH.
  • the alkaline medium will cause deprotonization of some HA molecules and therefore peptization occurs as the molecules repel each other (Klucakova and Pekar, 2005; Wandruszka 2000).
  • commercial brown HA was used.
  • the brown colour emanates from the conjugated double bond systems which are randomly distributed in the structure.
  • Brown HA is known to dissolve in alkaline solution and dissolution is independent of ionic strength unlike grey HA whose solubility depends on low ionic strength.
  • the condensed aromatic structures and oxygen containing groups are responsible for the molecular aggregates formed in solution by the brown HA (Baigorri et al., 2009).
  • HA also exhibits amphiphilic properties (Bahvalov et al., 2010).
  • the negative charges take part in complex formation with cationic groups and the hydrophobic site becomes exposed thus forming a water insoluble complex (Stepanov, 2008; Yeh et al, 2006).
  • Polyquaternium-10 is a cationic cellulose derivative which is also known as quaternized hydroxyethylcellulose ethoxylate. It is extensively incorporated into skincare and/or haircare cosmetic preparations largely because of its bioadhesive properties which enable it to bind to the anionic and hydrophobic surface of the skin and/or hair, thus prolonging duration of action of the cosmetic preparation.
  • the ammonium group in PQ-10 is situated at the end of the poly (ethylene glycol) chains therefore enabling it to possess a very high affinity for negatively charged groups (Daly et al., 1998; Rodriguez et al., 2003). During the aggregation process, as the PEC forms, these hydroxyethyl substituents may be included in the complex and therefore they also contribute to the precipitation process.
  • PQ-10 is known to be non-toxic, mucoadhesive, biocompatible, stable against gastrointestinal enzymes and is known to have an ability to attain a high viscosity upon swelling (Mazoniene et al., 2011).
  • the HA-PQ-10-pPEC, in situ formed fc-HA-PQ-10-PEC and fc-HA-PQ-10-PEC according to the invention were all prepared for the purposes of API/drug-loading to investigate API/drug solubility, API/drug permeability and API/drug release.
  • the HA-PQ-10-pPEC, in situ formed fc-HA-PQ-10-PEC, and fc-HA-PQ-10-PEC, all according to the invention are types of solid dispersions.
  • Example or model drugs were used to show that the HA-PQ-10-PEC provided for improved solubility and permeation of Biopharmaceutics Classification System (BCS) Class II/IV APIs/drugs.
  • Efavirenz (EFV) BCS class II
  • RTV ritonavir
  • the use of solid dispersions facilitates the molecular dispersion of the drug within a carrier-type matrix and this prevents agglomeration of the API/drug while encouraging its solubility.
  • the main drawback on their use is the tendency of the drug to recrystallize due to the metastable nature of the amorphous formulation (Six et al., 2004).
  • HAART Highly active antiretroviral therapy
  • NRTI nucleoside reverse transcriptase inhibitor
  • NRTI non-nucleoside reverse transcriptase inhibitor
  • PI protease inhibitor
  • INSTI integrase strand transfer inhibitor
  • NNRTIs bind to the reverse transcriptase in a non-competitive manner.
  • RTV is classified as a PI which inhibits the formation of mature infectious virions. It possesses a bioavailability of 5% and an aqueous solubility of 1.26 ⁇ g/mL (Dengale et al., 2015). Consequently, in HIV treatment there is a need to improve both the solubility and permeability of HIV related APIs/drugs.
  • Brown humic acid (HA) and polyquaternium-10 (PQ-10) also termed quaternized hydroxyethylcellulose ethoxylate
  • HA Brown humic acid
  • PQ-10 polyquaternium-10
  • Efavirenz Efavirenz
  • RTV ritonavir
  • Synthesis of an API/drug loaded fc-HA-PQ-10-PEC according to the invention involved dissolving a known amount of API/drug in methanol (20 mL) prior to titrating one polymer solution into the other.
  • the API/drug solution was added to the HA solution in water and left to stir for 5 minutes.
  • an aqueous solution of PQ-10 was slowly added to that of HA-API/drug solution to facilitate the self-assembly of a drug-loaded fc-HA-PQ-10-PEC which occurred within seconds of adding the second polymer.
  • the precipitate was filtered as soon as it separated from the supernatant.
  • the fc-HA-PQ-10-PEC was dried in an oven at 40°C for at least 12 hours after which it was milled and filled into hard gelatin capsule shells.
  • E-S technique formation of humic acid (HA) and quaternized hydroxyethylcellulose ethoxylate (PQ-10) partial polyelectrolyte complex (HA-PQ-10-pPEC)]
  • a mixture of polymers (HA and PQ-10) (>4 g) and excipients were mixed in a homogenizer for 5 minutes.
  • Deionized water was added to form wet granules of the powder mass.
  • Equal amounts of ethyl cellulose (EC) and microcrystalline cellulose (MCC) were added to facilitate the E-S process.
  • EC and EC absorb the granulating fluid (water) so that it behaves as a plasticizer. This water is pushed onto the outer surface of the extrudates thus further lubricating the surface so that the extrusion process occurs.
  • the homogenous wet granules were poured into the barrel of the mini screw extruder (Caleva Ltd.
  • % API/drug loading was ascertained by adding finely ground HA-PQ-10-pPEC powders (100 mg) to simulated intestinal fluid (SIF) (40 mL) at pH 6.8 containing SLS (1%) (according to USP monograph).
  • SIF simulated intestinal fluid
  • the SIF containing SLS (1%) was utilized for all studies requiring the use of SIF.
  • the powders were incubated in an orbital shaker bath to allow for complete API/drug release. After 24 hours, the samples were filtered with 0.22 ⁇ filters and API/drug concentrations were determined spectrophotometrically (LAMBDA 25 UV Vis spectrophotometer, PerkinElmer, MA, USA) at 247 nm for EFV and 241 nm for RTV.
  • Topographic imaging was conducted utilizing AFM (Veeco Dimension 3100 Atomic Force Microscope, Veeco, Santa Barbara, CA, USA) in order to ascertain the shape of the oral delivery systems according to the invention (i.e. HA-PQ-10-pPEC, in situ formed fc-HA-PQ-10-PEC and fc- HA-PQ-10-PEC) particles as well as the homogeneity of the surface.
  • the tapping mode was utilized and different areas of the samples scanned with the aid of a silicon tip. Samples were mounted onto glass slides by adsorbing them onto carbon double sided-tape. Surfaces were better observed at 10 x 10 ⁇ 2.
  • Table 1 Table 1 below. The abbreviations used throughout this description and the figures are listed in Table 1 below. Table 1 List of abbreviations for the formulations
  • Attenuated total reflectance-Fourier transform infrared, ATR-FTIR, (PerkinElmer® Spectrum 100 Series FT-IR Spectrometer PerkinElmerLtd., Beaconsfield, UK) was employed to assess the interactions between the API/drug and native polymers (HA and PQ-10). This was conducted over a wavenumber of 6000 cm 1 and 450 cm 1 . Thermal analysis of oral delivery systems and the physical polymer/drug mixture
  • the saturation solubilities of EFV and RTV were determined by adding formulations containing 2.5 mg/mL in SIF. This was incubated in an orbital shaker bath for 36 hours and drug concentrations were determined using the UV (Viral et ah, 2010). Sampling was conducted every 12 hours and the highest amount of API/drug concentration determined was considered the supersaturation amount.
  • API/Drug release rate from the capsules containing EFV (200 mg) and RTV (100 mg) was conducted using the paddle stirrer at 50 rpm (USP 24) (Erweka DT 700, Erweka GmbH, Heusenstamm, Germany). The temperature was maintained at 37°C and sample aliquots (5 mL) were collected at predetermined times for 12 hours. Sink conditions in the dissolution fluid (900 mL) were maintained by replacing the samples withdrawn immediately with fresh media. Simulated intestinal fluid (SIF) at pH 6.8 was utilized. It was necessary to perform the studies under physiologically relevant conditions since the solubility of poorly aqueous soluble drugs is affected by the presence of surfactants.
  • SIF Simulated intestinal fluid
  • Blank FeSSIF was prepared by dissolving sodium hydroxide (NaOH) (20.2 g), glacial acetic acid (43.25 g) and sodium chloride (NaCl) (59.37 g) in deionized water (5L) and pH was adjusted to 5.0. 500 mL of the blank FeSSIF was used to dissolve sodium taurocholate (59.08 g) and 59.08 mL of lecithin dissolved in methylene chloride (lOOmg/mL) was added to the solution. The methylene chloride was eliminated from the emulsion by evaporation and volume of the media was adjusted to 2L (Sinha et al., 2010). Ex vivo intestinal tissue permeation studies
  • the Franz diffusion apparatus (PermeGear Inc. Bethlehem, PA, USA) was utilized to measure the permeation behaviour of the API/drug from the delivery systems in comparison to the commercial brands of capsules (Sonke Efavirenz® 200 mg capsules and Norvir® 100 mg).
  • Phosphate buffered saline (PBS) (12 mL) at pH 7.4 was added to the acceptor compartment, which contains a magnetic stirrer bar.
  • An emulsion of capsule contents (4 mg/mL) in SIF and FeSSIF for the optimized formulations was added to the donor compartment.
  • the two compartments were separated by a piece of porcine small intestinal tissue (ileum). The intestinal tissue was freshly obtained from the white large pig and then frozen in normal saline.
  • M is the mass of the API/drug present in the acceptor compartment at time, t and A the area available for permeation (Tang et al., 2005).
  • Permeability can be defined as the rate of API/drug permeation per unit concentration (Dezani et al., 2013) and the permeability coefficient was calculated according to Fick' s first law according to the following equation:
  • P (cm.h _1 ) is the permeability coefficient
  • V (ml) is the volume of the acceptor compartment (12mL)
  • a (cm 2 ) is the effective permeation area (1.767cm 2 )
  • t (h) is the time interval
  • Q (mg.mL ! ) is the concentration in donor compartment
  • C 2 (mg.mL _1 ) is the concentration in the acceptor compartment (Lavon et al., 2005).
  • the transepithelial electrical resistance (TEER) of the porcine tissue was measured using the SevenMultiTM dual meter pH/conductivity (Mettler Toledo, Zurich, Switzerland) at 25°C. Permeability enhancement was determined as follows: Permeability coefficient of formulation
  • Table 2 Depicts the formulation utilized for the HA-PQ-10-pPEC.
  • Characterization included showing the differences between the two oral delivery systems without the APIs/drugs loaded in them (PEC (C -p) and PEC (E S) ) as well as ascertaining the differences between the drug-loaded delivery systems and the physical polymer/drug mixtures.
  • Figure 1 shows how the delivery systems were synthesized utilizing the C-P and E-S techniques. Physical differences between PEC( E _s) and PEC (C p)
  • Stoichiometric PECs are insoluble in any known solvent (Shovsky et al., 2009).
  • the delivery systems according to the invention were insoluble in all the representation solvents; ethyl acetate (electron donor), DMSO (electron acceptor), formic acid (proton donor), ethanol (proton donor), acetone (proton acceptor), DCM (dipole-dipole interaction) and hot water (neutral).
  • the slight solubility of PEC ( E S) in hot water was attributed to the partial complexation which left polymers which were readily soluble in the hot water.
  • Table 3 below highlights the results from the solvent test.
  • Formic acid was included to validate the typical behaviour of cellulosic PECs which are soluble in formic acid.
  • the FTIR spectra show that there was an interaction between the APIs/drugs and the polymers (HA and PQ-10) in both the solution and extruded samples.
  • the unprocessed EFV exhibited absorption bands similar to those reported by da Costa and co-workers (da Costa et al., 2012). Shifts in wave numbers were negligible for all spectra and this might be due to the nature of the polymers and excipients used herein.
  • the C-0 stretching vibrations (1700 cm 1 ) which are present in both APIs/drugs are also found in all the complexes although at lower intensities than in the pure drugs.
  • the juxtaposed DSC thermograms in Figure 6 reveal the differences in thermal properties of the oral delivery systems, pure APIs/drugs and the physical mixtures.
  • the peak melting point for PEC-E C p) lies at 90°C which is higher than that of PEC (C p) and lower than the melting point of the drug.
  • the physical mixture shows various melting points some of which correspond to the melting points of PEC (E S ) or PEC (C - P) and of the drug.
  • the melting point of PEC-E E _ S) falls at 150°C and this coincides with that of PEC (E S) -
  • the thermal behaviour of PEC-R (E _ S) closely resembles that of the PEC (E _ S) .
  • PEC-E/R shows lower melting points while PEC-E/R (E S) presents with higher melting points to those of the pure drugs.
  • the melting points of the PECs are altered by the addition of the API/drug.
  • the PEC-E/R (C p) show a diminished crystallinity property compared to the pure drugs and this is characteristic of solid dispersions. This is further corroborated by the XRD results which show a decrease in crystallinity in the solid dispersions. Importantly, altough diminshed crystallinity was observed, no recystallization of the API/drug was observed.
  • PEC( E S ) is expected to be more stable than PEC (C p) since it exhibits the onset of the crystalline state at higher temperatures.
  • the stability is attributed to the solid dispersion of the drug within PEC and good drug-polymer interaction.
  • the drug/polymer interactions are vital in order to prevent clumping of the drug which ultimately leads to recrystallization of the drug from the polymer matrix.
  • EFV had better drug-polymer miscibility compared to RTV which exhibited multiple endothermic events. Ion-dipole interactions and intermolecular hydrogen bonding between EFV, HA and PQ-10 may be responsible for this good compatibility (Tiwari et al., 2009).
  • Drug release for cE was incomplete ( ⁇ 50%) with the possibility of some of the API/drug precipitating into the dissolution medium since the release pattern shows a gradual decrease in drug concentration with time.
  • cR exhibited total drug release within 2 hours and the results do not show any possibility of drug precipitation to have occurred. All the API/drug loaded oral delivery systems according to the invention had more controlled release of the API/drug in contrast to the comparator products and are therefore capable of targeted drug release over time.
  • the amount of drug released by PEC-E E _ S) and PEC-E C p) was remarkably elevated than that released by cE.
  • pE and pR also showed a controlled release pattern due to in situ complexation.
  • the controlled release pattern is advantageous in providing a constant release over a period of time. Their drug release was poor ( ⁇ 40%) and this corroborates the need for using a PEC instead of the physical mixtures for drug delivery.
  • the rate of API/drug dissolution was influenced by the amphiphilic nature of HA.
  • the polymer was responsible for lowering the solid/liquid interfacial tension and therefore increased the wetting properties of the API/drug which was trapped in the hydrophobic core of the polymer. This prevented the agglomeration of the API/drug particles.
  • PQ-10 being hydrophilic, attracted more water into the system. Loading the drug into the polymeric PECs was beneficial in delaying the occurrence of any precipitation which is common in supersaturated solutions.
  • Transmembrane permeation profiles of the oral delivery systems were superior to those of the comparator products as illustrated in Figure 10.
  • the constant API/drug permeation from the PECs revealed that there was no saturation in the intestinal membrane.
  • the permeability coefficient (Table 4), which is higher in PEC-E E S) and PEC-E C _ P) was elevated by the presence of larger amounts of free drug due to supersaturation.
  • solid dispersions in the form of oral delivery systems according to the invention i.e. HA-PQ- 10-pPEC, in situ formed fc-HA-PQ-10-PEC and fc-HA-PQ-10-PEC
  • HA-PQ- 10-pPEC in situ formed fc-HA-PQ-10-PEC and fc-HA-PQ-10-PEC
  • fc-HA-PQ-10-PEC solid dispersions in the form of oral delivery systems according to the invention
  • the extruded formulation was chosen for optimization based on the solubility enhancement and stability of the system.
  • One of the industrially favourable attributes of the E-S technique is that it can be achieved without the addition of a large amount of water or any solvents.
  • Synthesis of the PECs described herein occurs by self-assembly and therefore is economically viable.
  • the use of the oral delivery systems according to the invention will slowly deliver adequate therapeutic amounts of the drug over time. This ensures a steady release of the active pharmaceutical ingredient (API) thus reducing the frequency of API/drug administration in patients.
  • the specific physico-chemical properties of the oral delivery systems increased the solubility and permeability of the active pharmaceutical ingredient incorporated therein.
  • the drug loaded PECs were found to provide a mucoadhesive amorphous drug delivery system.
  • the component polymers (HA and PQ-10) are affordable and ubiquitous in nature.
  • Betageri GV Makarla KR. Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques. Int J Pharm. 1995; 126: 155-60. da Costa MA, Seiceira RC, Rodrigues CR, Hoffmeister CRD, Cabral LM, Rocha HVA. Efavirenz Dissolution Enhancement I: Co-Micronization. Pharmaceutics. 2012; 5:1-22. Daly WH, Guerrini MM, Culberson D, Macossay J. Preparation and Potential for Application of Cationic Polysaccharides in Cosmetic Formulations. Springer US; 1998 p. 493-512.
  • Stepanov AA Separation and characterization of amphiphilic humic acid fractions. Mosc Univ Soil Sci Bull. 2008; 63: 125-9.

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Abstract

L'invention concerne un complexe polyélectrolyte partiel (HA-PQ-10-pPEC) d'éthoxylate d'hydroxyéthylcellulose quaternisée (PQ -10) et d'acide humique (HA) et concerne aussi un complexe polyélectrolyte d'éthoxylate d'hydroxyéthylcellulose d'acide humique totalement complexé (fc-HA-PQ-10-PEC) En outre, l'invention concerne également un procédé de fabrication d'HA-PQ-10-pPEC par extrusion-sphéronisation, et une procédé de fabrication de fc-HA-PQ-10-PEC par complexation-précipitation.
PCT/IB2016/055196 2015-09-04 2016-08-31 Système d'administration par voie orale reposant sur un complexe polyélectrolyte WO2017037630A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2172193A1 (fr) * 2008-10-02 2010-04-07 Capsulution Nanoscience AG Compositions de nanoparticules améliorées de composés faiblement solubles
US20130315991A1 (en) * 2011-11-14 2013-11-28 Aqua+Tech Specialties Sa Gastro-retentive drug delivery system for controlled drug release in the stomach and into the upper intestines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2172193A1 (fr) * 2008-10-02 2010-04-07 Capsulution Nanoscience AG Compositions de nanoparticules améliorées de composés faiblement solubles
US20130315991A1 (en) * 2011-11-14 2013-11-28 Aqua+Tech Specialties Sa Gastro-retentive drug delivery system for controlled drug release in the stomach and into the upper intestines

Non-Patent Citations (43)

* Cited by examiner, † Cited by third party
Title
BAHVALOV AV; ROZANOVA MS; TROFIMOV SY.: "The elemental composition and amphiphilic properties of humic acids in southern taiga soils", MOSC UNIV SOIL SCI BULL., vol. 65, 2010, pages 168 - 71
BAIGORRI R; FUENTES M; GONZALEZ-GAITANO G; GARCFA-MINA JM; ALMENDROS G; GONZALEZ-VILA FJ.: "Complementary multianalytical approach to study the distinctive structural features of the main humic fractions in solution: gray humic acid, brown humic acid, and fulvic acid.", J AGRIC FOOD CHEM., vol. 57, 2009, pages 3266 - 72
BALL P, NATURE, vol. 381, 1996, pages 648
BETAGERI GV; MAKARLA KR.: "Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques", INT J PHANN., vol. 126, 1995, pages 155 - 60, XP055005315, DOI: doi:10.1016/0378-5173(95)04114-1
DA COSTA MA; SEICEIRA RC; RODRIGUES CR; HOFFMEISTER CRD; CABRAL LM; ROCHA HVA.: "Efavirenz Dissolution Enhancement I: Co-Micronization", PHARMACEUTICS, vol. 5, 2012, pages 1 - 22
DALY WH; GUERRINI MM; CULBERSON D; MACOSSAY J.: "Preparation and Potential for Application of Cationic Polysaccharides in Cosmetic Formulations", 1998, SPRINGER, pages: 493 - 512
DENGALE SJ; HUSSEN SS; KRISHNA BSM; MUSMADE PB; GAUTHAM SHENOY G; BHAT K., EUR J PHARM BIOPHARM., vol. 89, 2015, pages 329 - 38
DEZANI, AB; PEREIRA TM; CAFFARO AM; REIS JM; SERRA CH; DOS REIS SERRA CH., J PHARMACOL TOXICOL METHODS, vol. 67, 2013, pages 194 - 202
DINUNZIO JC; MILLER DA; YANG W; MCGINITY JW; WILLIAMS III RO.: "Amoiphous compositions using concentration enhancing polymers for improved bioavailability of itraconazole", MOL PHARM., vol. 5, 2008, pages 968 - 80, XP008178189, DOI: doi:10.1021/mp800042d
GAO Y; HONG Y; XIAN J; LIN X; SHEN L; ZHANG X; FENG Y.: "A protocol for the classification of wet mass in extrusion-spheronization", EUR J PHARM BIOPHARM., vol. 85, 2013, pages 996 - 1005, XP028790979, DOI: doi:10.1016/j.ejpb.2013.03.016
HUISINGA LR; EDWARDS C; LOCHHEAD RY.: "Investigation of the structure of poly electrolyte-based complex coacervates and the effects of electrolyte order of addition", POLYM PREPR., vol. 46, 2005, pages 515
ITO, H.; MIYAMOTO, T.; INAGAKI, H; NOISHIKI, Y.; IWATA, H.; MATSUDA, J APPL POLYM SCI., vol. 32, 1986, pages 3413 - 21
JONES E; OJEWOLE E; PILLAY V; KUMAR P; RAMBHAROSE S; GOVENDER T.: "Monolayered multipolymeric buccal films with drug and polymers of opposing solubilities for ARV therapy: Physico-mechanical evaluation and molecular mechanics modelling", INT J PHARM., vol. 455, 2013, pages 197 - 212, XP028699744, DOI: doi:10.1016/j.ijpharm.2013.07.037
JOSHI HN; TEJWANI RW; DAVIDOVICH M; SAHASRABUDHE VP; JEMAL M; BATHALA MS ET AL.: "Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture", INT J PHARM., vol. 269, 2004, pages 251 - 8, XP002570376, DOI: doi:10.1016/J.IJPHARM.2003.09.002
KABANOV VA; ZEZIN AB.: "A new class of complex water-soluble polyelectrolytes", MAKROMOL CHEM., vol. 6, 1984, pages 259 - 76
KIM JH; RAMASAMY T; TRAN TH; CHOI JY; CHO HJ; YONG CS; KIM JO.: "Polyelectrolyte complex micelles by self-assembly of polypeptide-based triblock copolymer for doxorubicin delivery", ASIAN J PHARM SCI., vol. 9, 2014, pages 191 - 8
KIM JY; ZAOUTIS T; CHU J; ZHAO H; RUTSTEIN R.: "Effects of highly active antiretroviral therapy (HAART) on cholesterol in HIV-1 infected children: a retrospective cohort study", PHARMACOEPIDEMIOL DRUG SCIF., vol. 18, 2009, pages 589 - 94
KLUCAKOVA M; PEKAR M.: "Solubility and dissociation of lignitic humic acids in water suspension", COLLOIDS SURF PHYSICOCHEM ENG ASP., vol. 252, 2005, pages 157 - 63, XP025315738, DOI: doi:10.1016/j.colsurfa.2004.10.019
LAVON I; GROSSMAN N; KOST J.: "The nature of ultrasound-SLS synergism during enhanced transdermal transport", J CONTROLLED RELEASE, vol. 107, 2005, pages 484 - 94, XP005095083, DOI: doi:10.1016/j.jconrel.2005.06.011
LIN WC; YU DG; YANG, MC.: "Blood compatibility of thermoplastic polyurethane membrane immobilized with water-soluble chitosan/dextran sulfate", COLLOIDS AND SURFACES B: BIOINTERFACES, vol. 44, 2005, pages 82 - 92, XP025316046, DOI: doi:10.1016/j.colsurfb.2005.05.015
MADDOX J, NATURE, 1988, pages 335
MAZONIENE E; JOCEVICIUTE S; KAZLAUSKE J; NIEMEYER B; LIESIENE J.: "Interaction of cellulose-based cationic polyelectrolytes with mucin", COLLOIDS SURF B BIOINTERFACES, vol. 83, 2011, pages 160 - 4, XP027562748
MICHIE H; PODCZECK F; NEWTON JM.: "The influence of plate design on the properties of pellets produced by extrusion and spheronization", INT J PHARM., vol. 434, 2012, pages 175 - 82, XP028428041, DOI: doi:10.1016/j.ijpharm.2012.05.050
MOHD. AAMIR MIRZA ET AL: "Role of humic acid on oral drug delivery of an antiepileptic drug", DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, vol. 37, no. 3, 1 March 2011 (2011-03-01), pages 310 - 319, XP055099876, ISSN: 0363-9045, DOI: 10.3109/03639045.2010.512011 *
NATH SD; ABUEVA C; KIM B; LEE BT.: "Chitosan-hyaluronic acid polyelectrolyte complex scaffold crosslinked with genipin for immobilization and controlled release of BMP-2", CARBOHYDR POLYM., vol. 115, 2015, pages 160 - 9, XP029019620, DOI: doi:10.1016/j.carbpol.2014.08.077
NIELSEN LH; GORDON S; HOLM R; SELEN A; RADES T; MULLERTZ A.: "Preparation of an amorphous sodium furosemide salt improves solubility and dissolution rate and leads to a faster T max after oral dosing to rats", EUR J PHARM BIOPHARM., vol. 85, 2013, pages 942 - 51
PANDEY S; MISHRA A; RAVAL P; PATEL H; GUPTA A; SHAH D.: "Chitosan-pectin polyelectrolyte complex as a carrier for colon targeted drug delivery", J YOUNG PHARM., vol. 5, 2013, pages 160 - 6
PRASAD D; CHAUHAN H; ATEF E.: "Amorphous stabilization and dissolution enhancement of amorphous ternary solid dispersions: combination of polymers showing drug-polymer interaction for synergistic effects", J PHARM SCI., vol. 103, 2014, pages 3511 - 23
RODRIGUEZ R; ALVAREZ-LORENZO C; CONCHEIRO A.: "Cationic cellulose hydrogels: kinetics of the crosslinking process and characterization as pH-/ion-sensitive drug delivery systems", J CONTROLLED RELEASE, vol. 86, 2003, pages 253 - 65, XP004401120, DOI: doi:10.1016/S0168-3659(02)00410-8
RODRIGUEZ R; ALVAREZ-LORENZO C; CONCHEIRO A.: "Influence of cationic cellulose structure on its interactions with sodium dodecylsulfate: implications on the properties of the aqueous dispersions and hydrogels", EUR J PHARM BIOPHARM., vol. 56, 2003, pages 133 - 42, XP004434929, DOI: doi:10.1016/S0939-6411(03)00034-1
SHOVSKY A; VARGA I; MAKUSKA R; CLAESSON PM.: "Formation and stability of water-soluble, molecular poly electrolyte complexes: effects of charge density, mixing ratio, and poly electrolyte concentration", LANGMUIR, vol. 25, 2009, pages 6113 - 21
SIMSEK-EGE FA; BOND GM; STRINGER J.: "Polyelectrolyte complex formation between alginate and chitosan as a function of pH", J APPL POLYM SCI., vol. 88, 2003, pages 346 - 51
SINHA S; ALI M; BABOOTA S; AHUJA A; KUMAR A; ALI J.: "Solid dispersion as an approach for bioavailability enhancement of poorly water-soluble drug ritonavir", AAPS PHARMSCITECH., vol. 11, 2010, pages 518 - 27, XP055272117, DOI: doi:10.1208/s12249-010-9404-1
SIX K; VERRECK G; PEETERS J; BREWSTER M; MOOTER GV DEN.: "Increased physical stability and improved dissolution properties of itraconazole, a class II drug, by solid dispersions that combine fast-and slow-dissolving polymers", J PHARM SCI., vol. 93, 2004, pages 124 - 31, XP001185341, DOI: doi:10.1002/jps.10522
SOSNIK A; CHIAPPETTA DA; CARCABOSO AM.: "Drug delivery systems in HIV pharmacotherapy: what has been done and the challenges standing ahead", J CONTROLLED RELEASE., vol. 138, 2009, pages 2 - 15, XP026319252, DOI: doi:10.1016/j.jconrel.2009.05.007
SRUTI J; NIRANJAN PATRA C; SWAIN S; PANIGRAHI KC; PATRO AP; BEG S; RAO MEB., ACTA PHARM SIN B., vol. 3, 2013, pages 113 - 22
STEPANOV AA.: "Separation and characterization of amphiphilic humic acid fractions", MOSC UNIV SOIL SCI BULL., vol. 63, 2008, pages 125 - 9
TANG M; DETTMAR P; BATCHELOR H., INT J PHARM., vol. 292, 2005, pages 169 - 77
TAPIA C; ESCOBAR Z; COSTA E; SAPAG-HAGAR J; VALENZUELA F; BASUALTO C; YAZDANI-PEDRAM M.: "Comparative studies on polyelectrolyte complexes and mixtures of chitosan-alginate and chitosan-carrageenan as prolonged diltiazem clorhydrate release systems", EUR J PHARM BIOPHCIRM., vol. 57, 2004, pages 65 - 75, XP004518752, DOI: doi:10.1016/S0939-6411(03)00153-X
TIWARI R; TIWARI G; SRIVASTAVA B; RAI AK.: "Solid dispersions: an overview to modify bioavailability of poorly water soluble drugs", INT J PHARMTECH RES., vol. 1, 2009, pages 1338 - 49, XP009137553
USACH I; MELIS V; PERIS J-E.: "Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability", J INT AIDS SOC., vol. 16, 2013
VIRAL S; DHIREN P; MANE S; UMESH U.: "Solubility and Dissolution Rate Enhancement of Licofelone by Using Modified Guar Gum", INT J PHARMTECH RES., vol. 2, 2010, pages 1847 - 54
WANDRUSZKA R: "Humic acids: Their detergent qualities and potential uses in pollution remediation", GEOCHEM TRANS., vol. 1, 2000, pages 10, XP021013380

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