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WO2016046847A1 - Polymère hydrophile à inclusions métalliques utilisable en vue de l'administration de médicaments - Google Patents

Polymère hydrophile à inclusions métalliques utilisable en vue de l'administration de médicaments Download PDF

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Publication number
WO2016046847A1
WO2016046847A1 PCT/IN2015/050118 IN2015050118W WO2016046847A1 WO 2016046847 A1 WO2016046847 A1 WO 2016046847A1 IN 2015050118 W IN2015050118 W IN 2015050118W WO 2016046847 A1 WO2016046847 A1 WO 2016046847A1
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polymer
drug
adsorption
poly
metal
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Nayaku Nivrati Chavan
Surendra PONRATHNAM
Sachin Tanaji MANE
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Council of Scientific and Industrial Research CSIR
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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles

Definitions

  • the present invention relates a porous polymer for the selective drug delivery using polymer supported gold (PSG). More particularly, the present invention relates to selectivity in adsorption-desorption profile of drugs using hydrophilic polymer supported most electronegative gold metal. Further, it relates to the selective metal efficiency in drug delivery and effect of controlled parameters such as pH, contact time, as well as drug desorption efficacy.
  • PSG polymer supported gold
  • Binding site of drugs may be covalent or coordinate depending on nature of drug that significantly affect in drug delivery. Drugs in the form of salt has higher adsorption rate and very poor desorption rate, on the contrary drugs containing more lone pairs have comparatively slow adsorption and fast desorption rate with polymer supported metal.
  • Nano- and micron-sized particles both have their own advantages and disadvantages.
  • Polymer microbeads are more useful than nps particularly in applications of drug delivery and catalytic activity. Owing to small size, nps may pass through filter during removal from reaction mixture which can be avoided using micron-sized polymer supported metal. PSG can be recovered, recycled, and reused which makes them industrially economical and environmentally benign.
  • PCT Publication No. WO/2006/082221 discloses a drug delivery materials made by sol/gel technology.
  • the polymer encapsulated active agents may be combined with a sol before subsequently being converted into a solid or semi-solid drug delivery material.
  • the polymers for encapsulating the active agents were used from trimethylolpropane-triacrylate or pentaerythritol-triacrylate and sol/gel forming components were used from gold, silver, and copper.
  • European Pat. No. 2325236 discloses metal containing dendritic polymers with enhanced amplification and interior functionality. Trimethylolpropane triacrylate was used as dendritic polymer and metal was selected from copper, silver, and gold.
  • U.S. Pat. Appl. No. 20110183140 discloses polymers and their use in coating metal nanorods (especially gold nanorods) and to the coated nanorods compositions. External cross-linked polymer coating was a polymer of an acrylate monomer. Nano rod comprised gold, nickel, palladium, platinum, copper, silver, zinc, or cadmium.
  • Chinese Pat. No. 101168597 discloses hollow polymer sub-micron sphere coated with gold case and preparation method. The material of the invention can combine a thermotherapy with the slow release of anti-tumor drug to be used for the cancer treatment.
  • the present invention disclosed a gold shell polymer coated submicron hollow ball, the ball submicron particle size distribution was narrow, the shell thickness and particle size control.
  • Polymer was a submicron spherical polystyrene microspheres, poly(methyl methacrylate) microspheres or polystyrene and poly (methyl methacrylate) composite ball.
  • Gold shell covering hollow polymer submicron spheres were in the particle size range between 50 - 1000 nm.
  • U.S. Pat. Appl. No. 20070190160 discloses polymeric nanoparticles useful for drug delivery with target molecules bonded to the surface of the particles and having sizes of up to 1000 nm. The gold-coated nanoparticles were observed by SEM.
  • European Pat. No. 2559429 discloses a method for effectively delivering an anticancer drug into cancer cells by binding the anticancer drug to pH-sensitive metal nanoparticles so as to be separated from cancer cells.
  • the pH-sensitive gold nanoparticles were selective for cancer cells, thereby allowing a selective cancer therapy with minimal damage of an anticancer agent to normal cells.
  • U.S. Pat. No. 3854480 discloses drug-delivery system for releasing drug at a controlled rate for a prolonged period of time is formed from a solid inner matrix material having solid particles of drug dispersed therethrough.
  • Exemplary materials for fabricating the polymeric membrane included polymethylmethacrylate, polybutylmethacrylate.
  • Article titled "Preparation of porous polymer monoliths featuring enhanced surface coverage with gold nanoparticles" by Yongqin Lv et al. published in Journal of Chromatogr A, 2012, 1261, pp 121-128 reports preparation of porous polymer monoliths with enhanced coverage of pore surface with gold nanoparticles.
  • a generic poly(glycidyl methacrylate-co-ethylene dimethacrylate) monolith was reacted with cystamine followed by the cleavage of its disulfide bonds with tris(2-carboxylethyl)phosphine which liberated the desired thiol groups.
  • Dispersions of gold nanoparticles with sizes varying from 5 to 40 nm were then pumped through the functionalized monoliths.
  • porous adsorbents includes, silica (mesoporous), ethylene vinyl acetate (macroporous), polypropylene foam powder (microporous), titanium dioxide (nanoporous).
  • porous polymeric drug delivery system When porous polymeric drug delivery system is placed in contact with appropriate dissolution medium, release of drug to medium must be preceded by the drug dissolution in the water filled pores or from surface and by diffusion through the water filled channels.
  • the porous carriers are used to improve the oral bioavailability of poorly water soluble drugs, to increase the dissolution of relatively insoluble powders and conversion of crystalline state to amorphous state.
  • nps ranged between 10-1000 nm have the disadvantages of aggregation or agglomeration over micron sized particles during application time.
  • the main object of present invention is to provide metal embedded hydrophilic porous polymer for drug delivery.
  • Yet another object of the present invention is to provide selectivity in adsorption- desorption profile of drugs using hydrophilic polymer supported gold for in vitro adsorption- desorption drug delivery.
  • Yet another object of the present invention is to provide more reactive, higher surface area, and trimethylolpropane triacrylate (TMPTA) based hydrophilic polymer supported gold for drug profile.
  • TMPTA trimethylolpropane triacrylate
  • the present invention provides a metal embedded hydrophilic porous polymer for drug delivery comprising metal nanoparticles in the range of 3 to 10% and polymer in the range of 90 to 97% wherein metal nanoparticles is selected from group comprising of Au, Ag, or Cu and polymer is selected from poly(AA-co-TMPTA) or poly(MA-co-PETA) characterized in that the surface area of the polymer is > 70 m 2 /g with particle size in the range of 15-30 ⁇ .
  • the metal embedded hydrophilic porous polymer are useful in drug delivery wherein drug loading is in the range of 80-90%.
  • present invention provides a process for preparation of metal embedded hydrophilic porous polymer comprising the steps of:
  • step (b) heating the reactor to complete the polymerization work-up to obtain beaded polymer; c) modifying beaded polymer as obtained in step (b) with metal by aqueous reduction method to obtain Metal embedded hydrophilic porous polymer.
  • present invention provides a process wherein said monomer is selected from acryclic acid or methacrylic acid.
  • present invention provides a process wherein said porogen is selected from chlorobenzene or 1,2-dichlorobenezene.
  • present invention provides a process wherein said cross linker is selected from trimethylolpropane triacrylate or pentaerythritol triacrylate.
  • present invention provides the composition comprising a drug and the metal embedded hydrophilic porous polymer, wherein release of the drug is extended up to 30 h independent of the solubility, polarity, hydrophilicity or hydrophobicity of the drug.
  • present invention provides the composition, wherein said drug is selected from pantoprazole sodium, chloroquine, and salbutamol.
  • present invention provides the composition, wherein the adsorption and desorption of the drugs is in the range of 68 to 93% and 25 to 95% respectively.
  • Figure 1 depicts FT-IR spectrum of base (ATCB-10) and PSG (ATCBAU-10).
  • Figure 2 depicts FT-IR spectrum of base (MPDC-5) and PSG (MPDCCU-5 and MPDCSN-5).
  • Figure 3 depicts average particle size of base (MPDC) and PSG (MPDCCU and MPDCSN) at 5% crosslink density.
  • Figure 4 depicts SEM images of base (a) ATCB-10, (b) ATCB-25 and modified polymer, (c) ATCBAU-10, and (d) ATCBAU-25 for 10 and 25% CLD, respectively (250X magnification).
  • Figure 5 depicts SEM images of MPDC, MPDCCU, and MPDCSN at 5% (a, b, and c) and 25% (d, e and f) CLD at 500x magnification, respectively.
  • Figure 6 depicts effect of pH on adsorption of pantoprazole sodium and chloroquine.
  • Figure 7 depicts effect of pH on salbutamol adsorption.
  • Figure 8 depicts effect of contact time on adsorption of pantoprazole sodium and chloroquine.
  • Figure 9 depicts effect of contact time on salbutamol adsorption.
  • Figure 10 depicts effect of time on desorption selectivity on pantoprazole sodium and chloroquine.
  • Figure 11 depicts effect of time on salbutamol desorption.
  • Figure 12 depicts Langmuir adsorption isotherm plot of (a) pantoprazole sodium and (b) chloroquine.
  • Figure 13 depicts Langmuir adsorption isotherm of salbutamol with (a) MPDCCU and (b) MPDCSN at 5% crosslink density.
  • Scheme 1 depicts synthesis of gold embedded polymer .
  • Scheme 2 depicts plausible adsorption mechanism for gold embedded polymer.
  • Scheme 3 depicts synthesis of silver and copper embedded polymer .
  • Scheme 4 depicts plausible adsorption mechanism for silver and copper embedded polymer.
  • TMPTA Trimethylolpropane triacrylate
  • PETA Pentaerythritol triacrylate
  • Poly(MA-co-PETA) Poly(methacrylic acid-co-pentaerythritol triacrylate)
  • ATCB Acrylic acid-trimethylolpropane triacrylate -chlorobenzene
  • ATCBAU Acrylic acid-trimethylolpropane triacrylate-chlorobenzene-gold
  • MPDCSN Methyl methacrylate-pentaerythritol triacrylate- 1,2- dichlorobenzene: silver nitrate
  • nps nanoparticles
  • the present invention provides metal embedded hydrophilic porous polymer for drug delivery.
  • the present invention provides a porous polymer with surface area of the polymer > 70 m 2 /g, preferably in the range of 100-150 m 2 /g, and particle size in the range of 15-30 ⁇ , wherein the said polymer comprises an acid based monomer, preferably acryclic acid or methacrylic acid, a porogen, preferably chlorobenzene or 1,2 -dichlorobenzene and a crosslinker, preferably TMPTA or PETA.
  • an acid based monomer preferably acryclic acid or methacrylic acid
  • a porogen preferably chlorobenzene or 1,2 -dichlorobenzene
  • a crosslinker preferably TMPTA or PETA.
  • the present invention provides a porous polymer wherein the porous polymer is modified with a metal preferably Au, Ag, or Cu, but retaining the particle size of the porous polymer.
  • the present invention provides a porous polymer supported metal which is stable up to 200 °C.
  • the present invention provides a porous polymer supported metal which can be loaded drug up to 80-90%.
  • the present invention provides hydrophilic poly(methacrylic acid-co- pentaerythritol triacrylate) i.e. [poly(MA-co-PETA)] or hydrophilic poly(acrylic acid-co- trimethylolpropane triacrylate) i.e. poly(AA-co-TMPTA).
  • the present invention further provides synthesis of poly(AA-co-TMPTA) or poly(MA- co-PETA), its modification and applications thereof.
  • the present invention provides a process for the synthesis of porous polymer comprising the steps of:
  • the hydrophilic acrylic acid based copolymer is synthesized using trimethylolpropane triacrylate as a crosslinker and chlorobenzene as a porogen at different CLD.
  • the present invention provides polymers with high metal loading and sufficient surface area selected from MPDCSN or MPDCCU at 5% CLD for drug delivery.
  • the present invention provides polymers comprising metals that display excellent drug adsorption and slow salbutamol drug release.
  • the present invention provides the study of the effect of Cu, Ag stabilized polymer for in vitro drug adsorption-desorption profile.
  • the present invention provides a composition comprising a drug and the metal modified porous polymer such that the release of the drug is extended up to 30 h.
  • compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent, or excipient, and may be formulated into preparations in solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, injections, gels, and microspheres.
  • the present invention relates to administering an effective amount of the composition of invention to a subject suffering from disease.
  • pharmaceutical compositions containing drug may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for treating the disease.
  • Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
  • compositions of the present invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Compositions that will be administered to a subject or patient may take the form of one or more dosage units.
  • the dosage forms can also be prepared as sustained, controlled, modified, and immediate dosage forms.
  • Poly(AA-co-TMPTA) and poly(MA-co-PETA) was synthesized by suspension polymerization using chlorobenzene and 1 ,2-dichlorobenzene as a porogen, respectively varying 5 to 25% CLD to obtain copolymer beads.
  • the aqueous phase was prepared by dissolving the protective colloid (PVP, 1 wt%) in deionised water.
  • the organic phase was prepared by mixing monomer, crosslinker, initiator (2,2'-azobisisobutyronitrile), and pore generating solvent in nitrogen atmosphere at room temperature.
  • Suspension polymerization was carried out in a double walled cylindrical glass reactor equipped with a condenser, thermostat, nitrogen inlet, and overhead stirrer.
  • the oil phase comprising 7.1710 g (0.0995 mol) of acrylic acid, 3.3676 g (0.0099 mol) of trimethylolpropane triacrylate (TMPTA), 2.5 mol% of 2,2'-azobisisobutyronitrile, and 48 mL of chlorobenzene (porogen) were added to the suspension reactor containing 1 wt% of poly(vinylpyrrolidone) as a protective colloid dissolved in 200 mL of distilled water with constant stirring speed of 500 rotations per min.
  • the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerisation.
  • the product obtained in the form of beads was cooled, filtered, and washed several times with water, methanol, and dried in oven at 60 °C under reduced pressure for 8 h.
  • Monomer-crosslinker feed composition of copolymer synthesized by suspension polymerization at different CLD is reported in Table 1.
  • Table 1 Feed composition of poly(AA-co-TMPTA) and poly(MA-co-PETA)
  • FT-IR Fourier transform infrared spectroscopy
  • FT-IR spectrum of gold embedded polymer was also recorded after reduction of chloroauric acid. The spectrum indicates that acid peak shifted towards 1737 with vanishing broad peak at 3400-3500.
  • FT-IR spectra of poly(AA-co-TMPTA) and poly(AA-co-TMPTA)/Au is shown in Fig. 1.
  • polymer supported copper revealed a peak at 1738 for -COO- indicated shifting of carboxylic acid peak due to metal modification.
  • polymer supported silver shift the acid peak towards 1730.
  • broad absorbance peak at 3400-3500 is due to -C-OH which was significantly diminished in polymer embedded metal.
  • peak in the range of 3400-3500 illustrated the embedded acid functionality in polymer matrix. Obviously, most of the acid functionality buried into the polymer matrix which are not available for modification and detected in FT-IR (KBr pellet) spectroscopy.
  • FT-IR spectra of base and polymer modified Cu/Ag is shown in Fig. 2.
  • Porogen is a crucial parameter which intensively affects to the surface area.
  • 1 ,2-dichlorobenzene was used as a solvating (SOL) porogen to obtain higher surface area even for lower CLD.
  • the base polymer has surface area of 69 and 122 m 2 /g for 5 and 25% CLD, respectively.
  • PSM copper revealed the surface area of 57 m 2 /g whereas PSM silver has the surface area of 65 m 2 /g for 5% CLD. Observation demonstrated that, surface area increases as concentration of crosslinker increases. In another, surface area was attenuated slightly after modification. Thus, PSM with higher surface area and more reactivity was screened for drug adsorption-desorption profile.
  • Average particle size of base polymer [poly(AA-co-TMPTA)] was determined from CLD 10 to 25% and PSG for 10% CLD. Copolymer, ATCB showed 20.74, 20.23, 18.84, and 17.90 ⁇ particle size for 10, 15, 20, and 25% CLD, respectively. Results showed that, particle size was attenuated with increase in CLD. On the other hand, PSG showed slightly increase in particle size (21.81 ⁇ ) due to covalent modification with gold. Effect of micron-sized PSM on drug adsorption-desorption profile was invented using poly (MA-co -PET A) obtained by suspension polymerization and modified it with Cu and Ag individually. Interestingly, PSM Cu/Ag displayed the slightly increase in average particle size than the base polymer. Overall, the average particle size of synthesized polymer was in the range of 15-25 urn. Average particle size of base and PSM Cu/Ag is represented in Fig. 3. f) Acid content determination
  • Acid content determination is an important to understand the concentration of acid functionality on the external as well as internal surface. Polymer dried at 80 °C under reduced pressure was used to determine the acid content of polymer matrix. Acid content was determined by well-known KOH method, titrimetrically.
  • Theoretical acid content of poly(AA-co-TMPTA) was 9.44, 8.144, 7.15, and 6.38 mmol/g whereas observed acid content demonstrated 2.64, 2.20, 1.79, and 1.47 mmol/g for 10, 15, 20, and 25% CLD, respectively. Notably, observed acid content was much lower than theoretical. In addition, higher CLD lowers the observed acid content. However, acid content was increased with decrease in CLD and it is directly related to the reactivity of polymer.
  • Theoretical and observed acid contents of poly(MA-co-PETA) were also reported.
  • Theoretical acid content was 9.90, 8.86, 7.64, 6.86, and 6.22 mmol/g whereas observed acid content was 2.67, 2.21, 1.83, 1.51, and 1.25 mmol/g for 5, 10, 15, 20, and 25% CLD, respectively.
  • present invention synthesizes the base polymer of methacrylic acid with pentaerythritol triacrylate using 1 ,2-dichlorobenzene as a porogen.
  • DTG of base polymer MPDC - 5 and 25% CLD
  • DTG of PSM Cu and Ag for 5 and 25% CLD were also studied.
  • DTG curve From differential thermogravimetric analysis (DTG curve), it was revealed that base polymer (MPDC) showed the Tmax of 450 and 449 °C for 5 and 25% CLD, respectively, whereas PSM Cu displayed 357 and 332 °C for 5 and 25% CLD, respectively.
  • PSM Ag displayed Tmax of 371 and 351 °C for 5 and 25% CLD, respectively.
  • the base polymer revealed the glass transition temp (Tg) of 228 and 223 °C for 10 and 25% CLD, respectively.
  • PSG ATCBAU
  • Tg glass transition temp
  • the base polymer demonstrated the Tg of 290 and 286 °C for 5 and 25% CLD, respectively.
  • PSM Cu displayed the Tg at 215 and 206 °C whereas PSM Ag displayed 216 and 208 °C for 5 and 25% CLD, respectively.
  • the reason of difference in Tg of base polymer and PSM Cu/Ag as well as CLD is same as aforementioned in DTG. Safe temperature of PSM Cu/Ag was at or below 200 °C.
  • SEM images displayed the external as well as internal morphology of polymer beads.
  • SEM images of base and modified polymer was scanned at 500X magnifications. SEM showed that, base polymer was non-conglomerated whereas PSG is slightly conglomerated, spherical with rigid morphology even after modification.
  • SEM images of copolymers before and after modification indicated in Fig. 4.
  • SEM images of base polymer and PSM Cu/Ag were scanned with magnification of 500X for 5 and 25% CLD.
  • SEM images provides external morphology of base polymer as well as PSM Cu/Ag.
  • SEM demonstrated the rigid morphology with spherical shape.
  • Scanning electron microscopy images of MPDC, MPDCCU, and MPDCSN for 5 and 25% CLD at 500X magnification is depicted in Fig. 5.
  • base polymer contains carbon and oxygen only.
  • PSG contains 9.17 and 4.56 wt% of gold for 10 and 25% CLD along with carbon and oxygen.
  • EDX analysis revealed the higher loading of gold with lower crosslinked polymer (5%) than higher crosslinked polymer (25%) due to the presence of much higher reactive sites at lower CLD compared to higher CLD.
  • base polymer contains only carbon and oxygen.
  • PSM copper revealed the presence of carbon, oxygen along with copper (5.36, 4.12 wt%) for 5 and 25% CLD, respectively.
  • PSM silver revealed the presence of carbon, oxygen along with silver (6.02, 3.05 wt%) for 5 and 25% CLD, respectively.
  • greater polymer modification with metal was obtained for lower CLD (5%) compared to higher CLD (25%) polymer.
  • the elemental composition of base and modified polymer is reported in Table 3.
  • Buffer solution of different pH (3, 4, 5, and 6) was prepared using acetic acid (0.1 M) and sodium acetate (0.1 M).
  • acetic acid 0.1 M
  • sodium acetate 0.1 M
  • the results of pH effect on drug adsorption are depicted in Fig. 6.
  • Drug adsorption was carried out in 30 mL of glass vial for pH 3, 4, 5, and 6.
  • a 20 mg of PSM Cu/Ag was added to separate glass vials containing 20 mL (25 ppm) of drug solution prepared in different pH buffer. Vials were placed under shaking at room temperature. Sample was removed after 20 h to analyze the UV absorbance. It was observed that, adsorption increases in more acidic pH. It was revealed that, adsorption of salbutamol was 74 and 76% with respect to PSM Cu (MPDCCU) and PSM Ag (MPDCSN), respectively at pH 3.
  • Contact time is the second crucial parameter after pH that affects adsorption of drug.
  • Drug adsorption was carried out in 30 mL of glass vials wherein 20 mg of PSG was added to glass vial containing 20 mL (25 ppm) of drug solution at room temperature. Vials were placed under shaking and sample was removed after certain interval of time to analyze UV absorbance. It was observed that, adsorption of both drugs were increased with contact time. Nevertheless, adsorption rate was exponential for pantoprazole sodium whereas rate was gradually increased for chloroquine. The reason is same as aforementioned in pH effect. Pantoprazole sodium adsorbed 72% and chloroquine of 26% in initial 2 h. Moreover, pantoprazole sodium adsorption was 91% whereas chloroquine adsorption was 62% in 30 h. Initial 2 h are the exponential adsorption period of pantoprazole sodium whereas exponential adsorption begins after 12 h for chloroquine. Contact time effect on drug adsorption is illustrated in Fig. 8.
  • Equilibrium adsorption was carried out at room temperature using 20 mg of PSM Cu/Ag and 20 mL (50 ppm) of drug solution in pH 3 buffer. Procedure and conditions are similar as aforementioned in pH effect. Drug sample was removed at 30 h and pH 3. Equilibrium adsorption was 14.07 mg/g and 12.89 mg/g drug for MPDCCU and MPDCSN at 5% crosslink density, respectively.
  • Drug desorption was carried out using drug adsorbed polymer. Drug adsorbed at pH 3 in 30 h with PSM gold (20 mg) was placed in 30 mL glass vial containing 1 M NaOH in deionized water (20 mL). Drug sample was removed after certain interval of time to analyze the absorbance. Interestingly, pantoprazole sodium desorbed much less compared to chloroquine. Presumably, covalently bonded pantoprazole sodium was difficult to desorb whereas coordinately bonded chloroquine desorbed immediately. Effect of time on desorption rate of drug is reported in Fig. 10.
  • Desorption rate of salbutamol was also studied with respect to MPDCCU-5 and MPDCSN- 5 for certain interval of time.
  • a 20 mg of PSM (copper or silver) used for drug adsorption at 30 h and pH 3 was taken in glass vial containing 20 mL 1 M NaOH in deionized water. This mixture was placed at room temperature under shaking. Drug sample was removed after certain interval of time to confirm quantitative drug desorption. It was observed that, desorption rate was exponential initially whereas gradually increased after 2 h. Maximum desorption obtained was 94 and 77% for PSM Cu and Ag, respectively in 30 h.
  • MPDCSN-5 displayed high desorption rate compared to MPDCCU-5. Time effect on desorption of salbutamol is depicted in Fig. 11. o) Adsorption isotherm
  • Langmuir adsorption isotherm was carried out for pantoprazole sodium and chloroquine to investigate the adsorption capacity of PSM gold at pH 3 and room temperature.
  • the adsorption profile was well-fitted by least square method to linearly transformed Langmuir adsorption isotherm.
  • the results obtained by adsorption profile conducted at room temperature were fitted with Langmuir linear adsorption isotherm.
  • the Langmuir adsorption isotherm was plotted as CJq e versus Ce is depicted in Fig. 12.
  • the plot of pantoprazole sodium and chloroquine are in good agreement with parameter studied. Results confirm that adsorption of pantoprazole sodium and chloroquine was monolayer.
  • the suspension polymerization was carried out in a double walled cylindrical glass reactor equipped with a condenser, thermostat, nitrogen inlet and overhead stirrer.
  • the oil phase comprising 6.1881 g (0.0859 mol) of acrylic acid, 4.3589 g (0.0129 mol) of trimethylolpropane triacrylate (TMPTA), 2.5 mol% of 2,2'-azobisisobutyronitrile, and 48 mL of chlorobenzene (porogen) were added to the suspension reactor containing 1 wt% of poly(vinylpyrrolidone) as a protective colloid dissolved in 200 mL of distilled water with constant stirring speed of 500 rotations per min.
  • the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerisation.
  • the product obtained in the form of beads was cooled, filtered, and washed several times with water, methanol, and dried in oven at 60 °C under reduced pressure for 8 h.
  • the suspension polymerization was carried out in a double walled cylindrical glass reactor equipped with a condenser, thermostat, nitrogen inlet and overhead stirrer.
  • the oil phase comprising 5.4421 g (0.0755 mol) of acrylic acid, 5.1113 g (0.0151 mol) of trimethylolpropane triacrylate (TMPTA), 2.5 mol% of 2,2'-azobisisobutyronitrile, and 48 mL of chlorobenzene (porogen) were added to the suspension reactor containing 1 wt % of poly(vinylpyrrolidone) as a protective colloid dissolved in 200 mL of distilled water with constant stirring speed of 500 rotations per min.
  • the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerisation.
  • the product obtained in the form of beads was cooled, filtered, and washed several times with water, methanol, and dried in oven at 60 °C under reduced pressure for 8 h.
  • the suspension polymerization was carried out in a double walled cylindrical glass reactor equipped with a condenser, thermostat, nitrogen inlet and overhead stirrer.
  • the oil phase comprising 4.8566 g (0.0674 mol) of acrylic acid, 5.7018 g (0.0168 mol) of trimethylolpropane triacrylate (TMPTA), 2.5 mol% of 2,2'-azobisisobutyronitrile, and 48 mL of chlorobenzene (porogen) were added to the suspension reactor containing 1 wt% of poly(vinylpyrrolidone) as a protective colloid dissolved in 200 mL of distilled water with constant stirring speed of 500 rotations per min.
  • the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerisation.
  • the product obtained in the form of beads was cooled, filtered, and washed several times with water, methanol, and dried in oven at 60 °C under reduced pressure for 8 h.
  • the suspension polymerization was carried out in a double walled cylindrical glass reactor equipped with a condenser, thermostat, nitrogen inlet and overhead stirrer.
  • the oil phase comprising 14.1134 g (0.1639 mol) of methacrylic acid, 2.4451 g (0.0082 mol) of pentaerythritol triacrylate, 2.5 mol% of 2,2'-azobisisobutyronitrile, and 48 mL of 1,2- dichlorobenzene (porogen) were added to the suspension reactor containing 1 wt% of poly(vinylpyrrolidone) as a protective colloid dissolved in 200 mL of distilled water with constant stirring speed of 500 rotations per min.
  • the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerization.
  • the product obtained in the form of beads was cooled, filtered, and washed several times with water, methanol, and dried in oven at 60 °C under reduced pressure for 8 h.
  • the suspension polymerization was carried out in a double walled cylindrical glass reactor equipped with a condenser, thermostat, nitrogen inlet and overhead stirrer.
  • the oil phase comprising 12.04792 g (0.1450 mol) of methacrylic acid, 4.3240 g (0.0145 mol) of pentaerythritol triacrylate, 2.5 mol% of 2,2'-azobisisobutyronitrile, and 48 mL of 1,2- dichlorobenzene (porogen) were added to the suspension reactor containing 1 wt% of poly(vinylpyrrolidone) as a protective colloid dissolved in 200 mL of distilled water with constant stirring speed of 500 rotations per min.
  • the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerization.
  • the product obtained in the form of beads was cooled, filtered, and washed several times with water, methanol, and dried in oven at 60 °C under reduced pressure for 8 h.
  • the suspension polymerization was carried out in a double walled cylindrical glass reactor equipped with a condenser, thermostat, nitrogen inlet and overhead stirrer.
  • the oil phase comprising 11.1842 g (0.1299 mol) of methacrylic acid, 5.8129 g (0.0195 mol) of pentaerythritol triacrylate, 2.5 mol% of 2,2'-azobisisobutyronitrile, and 48 mL of 1,2- dichlorobenzene (porogen) were added to the suspension reactor containing 1 wt% of poly(vinylpyrrolidone) as a protective colloid dissolved in 200 mL of distilled water with constant stirring speed of 500 rotations per min.
  • the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerization.
  • the product obtained in the form of beads was cooled, filtered, and washed several times with water, methanol, and dried in oven at 60 °C under reduced pressure for 8 h.
  • the suspension polymerization was carried out in a double walled cylindrical glass reactor equipped with a condenser, thermostat, nitrogen inlet and overhead stirrer.
  • the oil phase comprising 10.133 g (0.118 mol) of methacrylic acid, 7.022 g (0.024 mol) of pentaerythritol triacrylate, 2.5 mol% of 2,2'-azobisisobutyronitrile, and 48 mL of 1,2- dichlorobenzene (porogen) were added to the suspension reactor containing 1 wt% of poly(vinylpyrrolidone) as a protective colloid dissolved in 200 mL of distilled water with constant stirring speed of 500 rotations per min.
  • the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerization.
  • the product obtained in the form of beads was cooled, filtered, and washed several times with water, methanol, and dried in oven at 60 °C under reduced pressure for 8 h.
  • the suspension polymerization was carried out in a double walled cylindrical glass reactor equipped with a condenser, thermostat, nitrogen inlet and overhead stirrer.
  • the oil phase comprising 9.2619 g (0.1076 mol) of methacrylic acid, 8.0231 g (0.02690 mol) of pentaerythritol triacrylate, 2.5 mol% of 2,2'-azobisisobutyronitrile, and 48 mL of 1,2- dichlorobenzene (porogen) were added to the suspension reactor containing 1 wt% of poly(vinylpyrrolidone) as a protective colloid dissolved in 200 mL of distilled water with constant stirring speed of 500 rotations per min.
  • the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerization.
  • the product obtained in the form of beads was cooled, filtered, and washed several times with water, methanol, and dried in oven at 60 °C under reduced pressure for 8 h.
  • Invention provides polymer supported gold for drug delivery that provides long term delivery.
  • Polymer supported gold micron particles selectively show more efficiency for more polar drugs
  • pantoprazole sodium unlike less polar drugs (chloroquine).
  • pantoprazole sodium Owing to long term drug delivery of pantoprazole sodium becomes more economical, effective, and non-wastage of drugs over conventional oral drug delivery.

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Abstract

La présente invention concerne un polymère poreux utilisable en vue de l'administration de médicaments comprenant de l'or supporté par du poly(acide acrylique-co-triacrylate de triméthylolpropane) ou de l'argent/cuivre supporté par du poly(acide méthacrylique-co-triacrylate de pentaérythritol) pour l'administration contrôlée et sélective de médicaments in vitro.
PCT/IN2015/050118 2014-09-23 2015-09-23 Polymère hydrophile à inclusions métalliques utilisable en vue de l'administration de médicaments Ceased WO2016046847A1 (fr)

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WO2017180991A1 (fr) * 2016-04-14 2017-10-19 Board Of Trustees Of The University Of Arkansas Support de greffe à activité plasmonique, et ses procédés de fabrication et d'utilisation
WO2019060989A1 (fr) * 2017-09-26 2019-04-04 National Research Council Of Canada Fabrication assistée par microfluidique de composites microparticules polymères-nanoparticules métalliques
US20200223999A1 (en) * 2017-09-26 2020-07-16 National Research Council Of Canada Polymer film-metal composites

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017180991A1 (fr) * 2016-04-14 2017-10-19 Board Of Trustees Of The University Of Arkansas Support de greffe à activité plasmonique, et ses procédés de fabrication et d'utilisation
US10390927B2 (en) 2016-04-14 2019-08-27 Board Of Trustees Of The Univeristy Of Arkansas Graft scaffold with plasmonic activity, and methods of making and using same
WO2019060989A1 (fr) * 2017-09-26 2019-04-04 National Research Council Of Canada Fabrication assistée par microfluidique de composites microparticules polymères-nanoparticules métalliques
US20200223999A1 (en) * 2017-09-26 2020-07-16 National Research Council Of Canada Polymer film-metal composites
US11661469B2 (en) * 2017-09-26 2023-05-30 National Research Council Of Canada Polymer film-metal composites
US11753485B2 (en) 2017-09-26 2023-09-12 National Research Council Of Canada Microfluidic assisted fabrication of polymer microparticle-metal nanoparticle composites

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