WO2016046847A1 - Metal embedded hydrophilic polymer for drug delivery applications - Google Patents

Metal embedded hydrophilic polymer for drug delivery applications Download PDF

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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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PCT/IN2015/050118
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French (fr)
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Nayaku Nivrati Chavan
Surendra PONRATHNAM
Sachin Tanaji MANE
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Council Of Scientific & Industrial Research
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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.

Abstract

The present invention discloses a porous polymer for drug delivery application comprising poly(acrylic acid-co-trimethylolpropane triacrylate) supported gold or poly(methacrylic acid- co-pentaerythritol triacrylate) supported silver/copper for controlled and selective in vitro drug delivery.

Description

METAL EMBEDDED HYDROPHILIC POLYMER FOR DRUG DELIVERY
APPLICATIONS
FIELD OF THE INVENTION:
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.
BACKGROUND AND PRIOR ART:
In recent years, there has been significant increase in gold nanoparticles (nps) research belonging to biomedical applications. Gold stabilized porous as well as hydrophilic polymers are an attractive area. Because of much more electronegativity of gold than any other transition metal has outstanding results in drug adsorption-desorption. Other factors attributes to better results are porosity, particle size, surface area, as well as reactivity of polymer. Polymer supported gold are currently used in biomedical applications especially it has immense potential interest in drug delivery. Out of transition metals Au, Ag, Fe, Zn, Cu, Co, and Ni have shown great promise in biomedical applications. Polymer supported metals have been recently received great attention due to interesting properties and wide applicability. Properties of polymers are highly tunable changing physico- chemical parameters. 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.
In the last decade, considerable attention has been devoted to the synthesis of polymer supported metal because of their interesting properties and wide applications in optical, electronic, catalytic, and magnetic materials. 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. Article titled "Smart delivery and controlled drug release with gold nanoparticles: new frontiers in nanomedicine" by Valerio Voliani et al. published in Recent Patents on Nanomedicine, 2012, Volume 2, No. 1 reports smart delivery and controlled drug release with gold nanoparticles. Article titled "Acrylic acid copolymer nanoparticles for drug delivery: structural characterization of nanoparticles by small-angle x-ray scattering" by J. J. Miiller et al. published in Colloid and Polymer Science, 1994, 272(7), pp 755-769 reports copolymer nanoparticles of acrylic acid, acrylic amide, acrylic butylester, and methacrylic methylester (CAA) dispersed in water and in 0.15 M NaCl-solution were investigated by small-angle x-ray scattering (SAXS) experiments.
Article titled "Gold and iron oxide nanoparticle-based ethylcellulose nanocapsules for cisplatin drug delivery" by Kannaiyan Sathish Kumar et al. published in Iranian Journal of Pharmaceutical Research, 2011 ; 10(3), pp 415-424 reports the drug release for gold nanoparticles/anticancer drug (Au-cis) incorporated ethylcellulose nanocapsules was controlled and slow compared to iron oxide nanoparticles -cisplatin incorporated ethylcellulose nanocapsules. Hence, gold nanoparticles act as good trapping agents which slow down the rate of drug release from nanocapsules. Article titled "Porous carriers for controlled/modulated drug delivery" by G. Ahuja et al. published in Indian Journal of Pharmaceutical Research, 2009, 71(6), pp 599-607 reports pharmaceutically exploited porous adsorbents includes, silica (mesoporous), ethylene vinyl acetate (macroporous), polypropylene foam powder (microporous), titanium dioxide (nanoporous). 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.
Book titled "Advances in polymeric matrices and drug particle engineering Chapter- 1" by Sonke Svenson published in 2006 reports polymeric matrices were used for drug delivery applications, when loaded with silver particles, can be utilized in antimicrobial coatings. Loading a polymer coating with a small amount of silver nanoparticles (10 μg/cm2) had shown to completely inhibit growth of the Gram-positive bacterium Staphylococcus aure.
Article titled "The separation power of nanotubes in membranes: a review" by Bart Van der Bruggen published in International Scholarly Research Network 2012 reports electro-sensitive drug delivery system triggered by MWCNTs in a matrix of polyethylene oxide (PEO) and pentaerythritol triacrylate.
Article titled "Preparation of glycerol dimethacrylate -based polymer monolith with unusual porous properties achieved via viscoelastic phase separation induced by monodisperse ultra high molecular weight poly(styrene) as a porogen" by Aoki H et al. published in Journal of Chromatogr A, 2006, 1119(1-2) pp 66-79 reports preparation of polymer -based monolith capillary was examined by the use of glycerol dimethacrylate (GDMA) as a monomer and monodisperse standard polystyrene (PS) solution in chlorobenzene as a porogen.
Metal stabilized by highly porous, crosslinked, and more hydrophilic polymer developing has been considerable attraction in drug profiling (adsorption-desorption). In general, nps ranged between 10-1000 nm have the disadvantages of aggregation or agglomeration over micron sized particles during application time. OBJECTIVE OF THE INVENTION:
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.
Still another objective of present invention is to provide selective metal efficiency in drug delivery under controlled parameters such as pH, contact time as well as drug desorption efficacy. Still another object of the invention is to determine efficiency of Cu/Ag based poly(MA-co-PETA).
SUMMARY OF THE INVENTION:
Accordingly, 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 m2/g with particle size in the range of 15-30 μπι.
In an embodiment of present invention the metal embedded hydrophilic porous polymer are useful in drug delivery wherein drug loading is in the range of 80-90%.
In another embodiment, present invention provides a process for preparation of metal embedded hydrophilic porous polymer comprising the steps of:
a) carrying the suspension polymerization wherein oil phase comprising monomer, crosslinker, initiator, and porogen by adding to the suspension reactor containing 1 wt% of poly(vinylpyrrolidone) dissolved in distilled water with constant stirring speed at 70 °C for 3 h to afford a mixture;
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.
In yet another embodiment, present invention provides a process wherein said monomer is selected from acryclic acid or methacrylic acid.
In yet another embodiment, present invention provides a process wherein said porogen is selected from chlorobenzene or 1,2-dichlorobenezene.
In yet another embodiment, present invention provides a process wherein said cross linker is selected from trimethylolpropane triacrylate or pentaerythritol triacrylate.
In yet another embodiment, 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.
In yet another embodiment, present invention provides the composition, wherein said drug is selected from pantoprazole sodium, chloroquine, and salbutamol.
In yet another embodiment, 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. BRIEF DESCRIPTION OF THE DRAWINGS
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.
The following abbreviations are used in present invention:
g : gms
Mol : Moles
AA : Acrylic acid
MA : Methacrylic acid
CLD : Crosslink density
PSM : Polymer supported metal
TMPTA : Trimethylolpropane triacrylate
PETA : Pentaerythritol triacrylate
PVP : Poly(vinylpyrrolidone)
AIBN : Azobisisobutyronitrile
SOL porogen : Solvating porogen
Poly(AA-co-TMPTA): Poly(acrylic acid-co-trimethylolpropane triacrylate) Poly(MA-co-PETA) : Poly(methacrylic acid-co-pentaerythritol triacrylate) ATCB : Acrylic acid-trimethylolpropane triacrylate -chlorobenzene
ATCBAU : Acrylic acid-trimethylolpropane triacrylate-chlorobenzene-gold
MPDC : Methyl methacrylate-pentaerythritol triacrylate- 1,2- dichlorobenzene
MPDCCU : Methyl methacrylate-pentaerythritol triacrylate- 1,2- dichlorobenzene: copper chloride
MPDCSN : Methyl methacrylate-pentaerythritol triacrylate- 1,2- dichlorobenzene: silver nitrate
PSG : Polymer supported gold
nps : nanoparticles
DETAILED DESCRIPTION OF THE INVENTION
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 m2/g, preferably in the range of 100-150 m2/g, and particle size in the range of 15-30 μπι, 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.
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%.
In an aspect, 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.
In another aspect, the present invention provides a process for the synthesis of porous polymer comprising the steps of:
a) carrying the suspension polymerization wherein oil phase comprising monomer, crosslinker, initiator, and porogen by adding to the suspension reactor containing 1 wt% of poly(vinylpyrrolidone) dissolved in distilled water with constant stirring speed to afford a mixture; and
b) heating the reactor to complete the polymerization work-up to afford the desired product in the form of beads.
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 synthesis of copolymers and its metal modification is depicted in Schemes 1 and 3 whereas their applications represented in Schemes 2 and 4.
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.
Figure imgf000010_0001
Pantoprazole sodium Chloroquine
In an aspect, 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.
The pharmaceutical 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. Accordingly, 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.
Pharmaceutical 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.
Examples
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.
Example 1
a) Suspension polymerization
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. After complete addition of the oil phase to the aqueous phase, the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerisation. On completion of the reaction time, 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)
Figure imgf000012_0001
Reaction conditions:
Batch size - 16 mL, AIBN - 2.5 mol%, stirring speed - 500 rpm, reaction time - 3 h, reaction temperature - 70 °C, outer phase - H20, protective colloid - poly(vinylpyrrolidone), concentration of protective colloid - 1 wt%, porogen - chlorobenzene/l,2-dichlorobenzene, porogen concentration - 48 mL (1 :3 v/v)
b) Synthesis of polymer supported metal (PSM)
A 200 mg of chloroauric acid (HAuCl4) was dissolved in 5 mL of deionised water. Aqueous metal solution was added to 2 g of 10% crosslinked polymer. This mixture was placed for 30 h for uniform adsorption of chloroauric acid at room temperature. Sodium borohydride (500 mg) was dissolved in 3 mL of deionised water and this aqueous solution was added dropwise to the polymer -chloroauric acid solution for reduction under nitrogen atmosphere at room temperature till effervescence stop completely. Mixture was placed under shaking for 5 h. Subsequently, polymer mixture was filtered and washed with deionised water. Synthesis of polymer supported gold and plausible adsorption mechanism is shown in Schemes 1 and 2, respectively.
c) Fourier transform infrared spectroscopy
Fourier transform infrared spectroscopy (FT-IR) was used to confirm the synthesis of polymer as well as polymer supported metal. FT-IR (KBr) spectroscopy of poly(AA-co- TMPTA) base polymer and PSG were carried out to confirm the synthesis of base polymer and covalent binding of metal with carboxylic acid. FT-IR (KBr, cm"1) spectroscopy of poly(AA- co-TMPTA) illustrates the peak at 1722 related to the carboxylic acid functionality, 2983 assigned to -CH2- vib., 1171 and 963 assigned to C-O-C str. and C-OH vib., respectively whereas broad peak at 3415 for labile hydroxyl group of carboxylic acid. 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.
FT-IR (KBr, cm 1) spectroscopy of poly(MA-co-PETA) and PSM Cu/Ag confirms the covalent binding of metal with carboxylic acid. Poly(MA -co -PET A) shows that, broad peak at 3419 corresponds to -C-OH group. Then, -C-O-C str. assigned by 1178 whereas 979 corresponds to -C-OH vib. The peaks at 845, 1679, 2984, and 1452 corresponds to C-O-C sym. str., -C=0, -C-H str. and -CH2- viz., respectively. Subsequently, polymer supported copper revealed a peak at 1738 for -COO- indicated shifting of carboxylic acid peak due to metal modification. Similarly, polymer supported silver shift the acid peak towards 1730. It must be pointed out that, broad absorbance peak at 3400-3500 is due to -C-OH which was significantly diminished in polymer embedded metal. Still further there is small 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.
d) Surface area determination
Surface area of poly(AA-co-TMPTA) was evaluated at different CLD. Surface area of base polymer and PSM gold was evaluated for 10 and 25% CLD. The base polymer has surface area of 85.67 and 287.71 m2/g for 10 and 25% CLD, respectively. In addition, PSM gold revealed the surface area of 78.87 m2/g for 10% CLD. Besides, increase in CLD increases the surface area. In addition, PSG revealed the decrease in surface area due to covalent exchange of gold metal with acid functionality for 10% CLD.
Surface area of poly(MA-co-PETA) was evaluated at different CLD. Porogen is a crucial parameter which intensively affects to the surface area. However, 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 m2/g for 5 and 25% CLD, respectively. In addition, PSM copper revealed the surface area of 57 m2/g whereas PSM silver has the surface area of 65 m2/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.
e) Particle size distribution
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 μιη 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 μιη) 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.
g) Differential thermogravimetric analysis
Thermal stability of synthesized and modified copolymer was evaluated. Differential thermal analysis of copolymer at different CLD was performed by simultaneous thermal analysis (Perkin Elmer) from 50-800 °C temperature under nitrogen atmosphere at heating rate of 10 °C/min. Differential thermogravimetry (DTG) of base polymer (ATCB) for 10 and 25% CLD was studied. DTG curve elucidated that, Tmax of base polymer (ATCB) was 446 and 442 °C for 10 and 25% CLD, respectively. In addition, PSG displayed the Tmax at 398 °C for 10% CLD. Overall, if hydrogen of carboxylic acid functionality replaced by gold that decreases Tmax. Crosslinker has the flexible property. Thus, owing to more concentration of flexible crosslinker for 25% CLD in base polymer showed decrease in Tmax.
Furthermore, 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) was studied. In addition, DTG of PSM Cu and Ag for 5 and 25% CLD were also studied. 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. On the other hand, PSM Ag displayed Tmax of 371 and 351 °C for 5 and 25% CLD, respectively. Overall, if hydrogen of carboxylic acid functionality exchanged by copper that attenuates Tmax whereas hydrogen exchanged by silver there is further attenuation in Tmax. Crosslinker has the flexible property. Thus, owing to more concentration of flexible crosslinker at 25% CLD in base as well as PSM both showed the decrease in Tmax for 25% CLD than 5% CLD.
h) Differential scanning calorimetry
The base polymer (ATCB) revealed the glass transition temp (Tg) of 228 and 223 °C for 10 and 25% CLD, respectively. Moreover, PSG (ATCBAU) displayed Tg of 217 °C for 10% CLD. The reason of difference in Tg of base polymer and PSG as well as CLD is same as aforementioned in DTG.
The base polymer (MPDC) demonstrated the Tg of 290 and 286 °C for 5 and 25% CLD, respectively. Moreover, 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. i) Scanning electron microscopy
Scanning electron microscopy (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. In addition, 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.
j) EDX analysis
It was observed that base polymer (ATCB) contains carbon and oxygen only. In addition, 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. The elemental composition of base
and modified polymer is presented in Table 2. Table 2. EDX analysis of base polymer (ATCB-10, 25) and PSM (ATCBAU-10)
Figure imgf000016_0001
In addition, it was observed that, base polymer (MPDC) 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. Similarly, PSM silver revealed the presence of carbon, oxygen along with silver (6.02, 3.05 wt%) for 5 and 25% CLD, respectively. Interestingly, 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.
Table 3. EDX analysis of base polymer (MPDC) and PSM (MPDCCU and MPDCSN) in wt% for 5 and 25% CLD
Figure imgf000016_0002
k) Drug release study by spectrometric method
In order to investigate the effect of polarity, drugs with different polarity was selected for adsorption-desorption profile. Different drug concentration was prepared in deionised water to analyze the absorbance for calibration curve. Calibration was carried out by analyzing the absorbance of different drug concentration in ppm. -Regression coefficient (R2) observed was 0.999 and 0.998 for pantoprazole sodium and chloroquine, respectively.
In order to obtain calibration curve, different concentration of salbutamol drug was prepared. Drug solution of 5, 10, 15, 20, and 25 ppm concentration was prepared in deionised water and absorbance was analyzed by UV spectrometer. Plot of absorbance versus concentration was in good agreement (R2=0.988) with studied parameter. 1) Effect of pH on drug adsorption selectivity
The pH extensively affect on adsorption capacity as well as selectivity of drug profiling. Buffer solution of different pH (3, 4, 5, and 6) was prepared using acetic acid (0.1 M) and sodium acetate (0.1 M). Experiment was carried out in 30 mL of glass vial wherein 20 mg of PSG was added to glass vial containing 20 mL (25 ppm) of drug solution at different pH. Vials were placed under shaking at room temperature. Sample was analyzed after 20 h by measuring UV absorbance. It was observed that, pantoprazole sodium adsorbed in greater amount than chloroquine. This may be because of covalent adsorption of pantoprazole sodium and co-ordinate adsorption of chloroquine with PSG. Pantoprazole sodium adsorbed 84% while chloroquine adsorbed 63% with PSG. This adsorption was attenuated for higher pH. At pH 6, pantoprazole sodium adsorption was attenuated to 62% whereas chloroquine adsorption attenuates to 40%. Thus, higher selectivity was obtained for pantoprazole sodium compared to chloroquine. The results of pH effect on drug adsorption are depicted in Fig. 6.
Metal selectivity with respect to drug adsorption was also carried out. 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. On the other hand, adsorption decreases to 45 and 49% at pH 6 for PSM Cu (MPDCCU) and PSM Ag (MPDCSN), respectively. Thus, it was concluded that PSM Ag has better adsorption capacity than PSM Cu. Effect of pH on adsorption of salbutamol is shown in Fig. 7.
m) Contact time effect on drug adsorption selectivity
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 of pantoprazole sodium and chloroquine was carried out using ATCBAU-10 to obtain maximum adsorption of drugs. Drug adsorption was carried out at room temperature using 20 mg of PSG and 20 mL (50 ppm) solution of both drugs at pH 3. Experimental procedure and conditions were similar as aforementioned in contact time. The sample solution of drugs was removed at 30 h. Equilibrium adsorption was studied using 50 ppm of pantoprazole sodium and chloroquine drug for 30 h at pH 3. The maximum adsorption of pantoprazole sodium and chloroquine was 16.53 and 13.06 mg/g, respectively.
In addition to this, contact time study of salbutamol adsorption was also analyzed. A 20 mg of PSM Cu/Ag was added separately to 30 mL glass vials containing 20 mL (25 ppm) of drug solution in pH 3 buffer at room temperature and were placed under shaking. Sample was removed after certain interval of time for absorbance analysis. Results revealed that, maximum 83 and 85% of drug adsorption was obtained in 30 h for PSM Cu and Ag, respectively. Moreover, PSM silver demonstrated higher adsorption property compared to PSM copper. Both, PSM Cu and Ag showed the gradual increase in adsorption rate instead of exponential. Effect of contact time on salbutamol adsorption is shown in Fig. 9.
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.
n) Selectivity in desorption of pantoprazole sodium and chloroquine
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. Moreover, 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 CJqe 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.
Langmuir adsorption isotherm was also carried out for salbutamol drug with respect to copper and silver at pH 3 and room temperature. The adsorption isotherm was fitted to linearly transformed Langmuir adsorption isotherm. The plot of Langmuir adsorption isotherm of salbutamol for PSM Cu and Ag is in good agreement with parameter studied. Thus, results confirm that the salbutamol adsorption was monolayer for both metals. The Langmuir adsorption isotherm (C/qe versus Ce) is depicted in Fig. 13.
EXAMPLE 2
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. After complete addition of the oil phase to the aqueous phase, the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerisation. On completion of the reaction time, 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.
EXAMPLE 3:
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. After complete addition of the oil phase to the aqueous phase, the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerisation. On completion of the reaction time, 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.
EXAMPLE 4
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. After complete addition of the oil phase to the aqueous phase, the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerisation. On completion of the reaction time, 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.
EXAMPLE 5
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. After complete addition of the oil phase to the aqueous phase, the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerization. On completion of the reaction time, 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.
EXAMPLE 6
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. After complete addition of the oil phase to the aqueous phase, the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerization. On completion of the reaction time, 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.
EXAMPLE 7
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. After complete addition of the oil phase to the aqueous phase, the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerization. On completion of the reaction time, 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.
EXAMPLE 8
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. After complete addition of the oil phase to the aqueous phase, the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerization. On completion of the reaction time, 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.
EXAMPLE 9
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. After complete addition of the oil phase to the aqueous phase, the temperature of the reactor was raised to 70 °C and maintained for 3 h to carry out the polymerization. On completion of the reaction time, 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.
EXAMPLE 10
In 20 mL of deionized water, 5 g of silver nitrate (AgN03) was dissolved. In a stopper conical flask, 10 g of 5% of crosslinked polymer was added. To this, 10 mL of AgN03 in deionized water was added. This mixture was placed for 30 h to obtain uniform adsorption of silver salt. Sodium borohydride (1 g) was dissolved in 5 mL of deionised water and this aqueous solution was added to the polymer supported silver nitrate salt for reduction under nitrogen atmosphere at room temperature till effervescence stop completely. Mixture was stirred for 5 h. Subsequently, polymer mixture was filtered and washed with deionised water till neutral pH of filtrate. Synthesis and applications of Ag embedded polymer are shown in Schemes 3 and 4.
EXAMPLE 11
In 20 mL of deionized water, 5 g of cupric chloride dihydrate (CuCl2.2H20) was dissolved. In a stopper conical flask, 10 g of 5% of crosslinked polymer was added. To this, 10 mL of CuCl2.2H20 in deionized water was added. This mixture was placed for 30 h to obtain uniform adsorption of copper salt. Sodium borohydride (1 g) was dissolved in 5 mL of deionised water and this aqueous solution was added dropwise to the polymer-copper chloride dihydrate solution for reduction under nitrogen atmosphere at room temperature till effervescence stop completely. Mixture was stirred for 5 h. Subsequently, polymer mixture was filtered and washed with deionised water till neutral pH of filtrate. Synthesis and applications of
Cu embedded polymer are shown in Schemes 3 and 4, respectively.
ADVANTAGES OF THE INVENTION
a. Invention provides polymer supported gold for drug delivery that provides long term delivery.b. Polymer supported gold micron particles selectively show more efficiency for more polar drugs
(pantoprazole sodium) unlike less polar drugs (chloroquine).
c. Provides drug delivery selective to polymer supported Cu/Ag micron particles. Hydrophilic property of polymer supported gold favorable to adsorb drug effectively from an aqueous solution.
d. Much higher selectivity is obtained with drugs in the form of salt (pantoprazole sodium) than drug in the form of polar (chloroquine) or non-polar in adsorption profile,
e. Owing to long term drug delivery of pantoprazole sodium becomes more economical, effective, and non-wastage of drugs over conventional oral drug delivery.

Claims

CLAIM:
1. 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 m2/g with particle size in the range of 15-30 μπι.
2. The metal embedded hydrophilic porous polymer as claimed in claim 1, wherein said polymer is useful in drug delivery wherein drug loading is in the range of 80-90%.
3. A process for the preparation of metal embedded hydrophilic porous polymer comprising the steps of:
a) carrying the suspension polymerization wherein oil phase comprising monomer, crosslinker, initiator, and porogen by adding to the suspension reactor containing 1 wt% of poly(vinylpyrrolidone) dissolved in distilled water with constant stirring speed at 70 °C for 3 h to afford a mixture;
b) heating the reactor to complete the polymerization work-up to obtain beaded polymer; and c) modifying beaded polymer as obtained in step (b) with metal by aqueous reduction method to obtain Metal embedded hydrophilic porous polymer.
4. The process as claimed in claim 3, wherein said monomer is selected from acryclic acid or methacrylic acid.
5. The process as claimed in claim 3, wherein said porogen is selected from chlorobenzene or 1,2- dichlorobenezene.
6. The process as claimed in claim 3, wherein said cross linker is selected from trimethylolpropane triacrylate or pentaerythritol triacrylate.
7. A composition comprising a drug and the metal embedded hydrophilic porous polymer as claimed in claim 1, wherein release of the drug is extended up to 30 h independent of the solubility, polarity, hydrophilicity or hydrophobicity of the drug.
8. The composition as claimed in claim 7, wherein said drug is selected from pantoprazole sodium, chloroquine, and salbutamol.
9. The composition as claimed in claim 7, wherein the adsorption and desorption of the drugs is in the range of 68 to 93% and 25 to 95% respectively.
5
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