Entrapment of Drugs within Metallic Platinum and their Delivery - ACS

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Controlled Release and Delivery Systems

Entrapment of Drugs within Metallic Platinum and their Delivery Barak Menagen, and David Avnir ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.9b00379 • Publication Date (Web): 03 Apr 2019 Downloaded from http://pubs.acs.org on April 16, 2019

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ACS Biomaterials Science & Engineering

Entrapment of Drugs within Metallic Platinum and their Delivery Barak Menagen and David Avnir Institute of Chemistry and the Center for Nanoscience and Nanotechnology, the Hebrew University of Jerusalem, Jerusalem, 9190401, Israel [email protected]

Abstract Platinum has been a widely used metal for a variety of implanted medical devices, because of its inertness, low corrosion rate, high biocompatibility, high electric conductivity and good mechanical stability. A highly desirable property still in need to be addressed, is the tailoring of drug-delivery ability to that metal. This is needed in order to treat infections due to the process of implanting, to treat post-operation pain, and to prevention of blood clotting. Can Pt itself serve as a delivery matrix? A review on metallic implants (cited below) proposes that “Metals themselves can be used for delivering pharmaceutics” but adds that “there has been no current research into [that] possibility” despite its advantages. Here we present a solution to that challenge, and show a new method of using an inert metal as a 3D matrix from within which entrapped drug molecules are released. This new type of drug-delivery system is fabricated by the molecular metals entrapment methodology, resulting in various drugs@Pt. Specifically the following drugs have been entrapped and released: the pain-killer and platelet – inhibitor NSAIDs ibuprofen and naproxen, the antibiotics ciprofloxacin, and the antiseptic chlorhexidine. The delivery profiles of all biocomposites are were studied in two forms – powders and pressed discs showing, in general, fast followed by slow first order release profiles. It is shown that the delivery kinetics can be tailored by changing the entrapment process, by applying different pressures in the disc preparation, and by changing the delivery temperature. The latter was also used to determine the activation energy for the release. Full characterization of the metallic biomaterials is provided, including XRD, SEM, EDAX, TGA and surface area/porosity analysis.

Keywords Platinum, Drug-delivery, Activation energy, Implants, Sustained release

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Introduction Metallic platinum and its alloys have been a widely used for almost seven decades now for a variety of implanted medical1,2 . A 2010 study estimated an annual use of a staggering 255,000 oz. (7 tons) for these purposes and predicted an increase following the population growth and its aging3. Pt implants include guidewires for cardiac rhythm devices, middle ear implants, neuromodulation devices, catheters, fillers to treat aneurysm, stents, and more2,4–7. The properties of Pt that gave rise to its use as implantable metal are chemical inertness and low corrosion rate, high biocompatibility and very low toxicity2,7, high electric conductivity and good mechanical stability. In addition, it is also radiopaque rendering it is clearly visible in X-ray images, which allows easy monitoring of the position of the device during treatment2,8,9. Lacking in this list is the highly desirable property of tailoring of drug-delivery ability to that metal. Treatment of infections due to the process of implanting, treatment of associated post-operation pain, and prevention of blood clotting are some of the drug-treated conditions that always have been on the wish-list for this metal. Contaminations and pains following surgical implanting procedures, cause not only serious unwanted clinical situations but have also an unwanted medial economic cost10–13. We also recall that, in general, delivery of drugs from a matrix enables the drug to reach slowly and locally target sites, and that it has important advantages including higher efficiency, lower toxicity, and lower side effects, compared to an oral or intravenous treatment14–16. The existing arsenal of materials used for delivery of drugs includes polymers and biopolymers, ceramic and glassy matrices, soft carriers such as liposomes, and more13,14,17–19. It comes as a surprise that while the release from coated metallic surfaces (such as stents) is known13, the use of an inert metal as a three-dimensional volumetric carrier of drugs, has not been explored. In a review on “Metallic implant drug/device combinations for controlled drug release” Birbilis et al write about restorable metals13: “Metals themselves can be used for delivering pharmaceutics …However to the best of our knowledge there has been no current research into [that] possibility… This concept provides advantages as the implant can provide mechanical support, controlled (local) drug delivery, [and] serve the functional implant role” - all of this holds for bio-inert metals: A solution to this need, focusing on Pt, is the topic of our report. The approach we use is based on a general materials methodology we developed and which enables the entrapment of molecules (including polymers and proteins) within metals is still in its infancy20–26. In brief, the mechanism of the entrapment is the following: A solution containing a soluble metal salt and the molecules to be entrapped, are treated with a carefully selected


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reducing agent. The metal cations are reduced to metal atoms of zero valency, which begin to aggregate into embryonic nanocrystals. The molecules of the compound to be entrapped collide with these growing crystallites, and reversibly adsorb on them. If the residence time of the adsorbed state is longer than the rate of reduction of the metallic cations and further metal particles precipitation, then the adsorbed molecules are entrapped, and become part of the composite material (see ref.’s 24 and 25 for schemes of that process). The interaction between the entrapped molecule and the surrounding metallic cage, depend very much on the moieties which the molecules has. It can span from weak van-der-Vaals interactions, in which the entrapped molecules is physically held in the cage, and up to strong interactions such as between the metal and the lone pair of electrons of nitrogen, oxygen and sulfur atoms which are part of the entrapped molecule. It should be emphasized that adsorption, a 2D molecular configuration and entrapment, a 3D architecture, involve completely different processes and end-materials. For instance, simple washing can remove an adsorbent, while such water soluble drug molecules are removed from the matrix slow enough to make it a release matrix. Finally, previous studies with doped metals have shown that the stability of the entrapped molecules, increases, as a result of the entrapment 24,25 – this property is also useful in the context of this study on the entrapment of drugs. A wide variety of applications of these new composited have been reported27–35, and of relevance to our report are a series of antibacterial composites based on the entrapment of antibacterial agents within antibacterial metals – the slowly dissolving silver and copper- aimed at wound treatment: Strong synergism between the two components – the metal and the drug - was observed, creating powerful broad-scope biocidal activity, enhancing the residual antibacterial activity of several analgesic agents, and offering dual medical functionality20–23. Following the above described needs, we have selected to develop entrapment and release procedures for the following drugs, which are known in delivery applications (Fig. 1): naproxen (nap), a widely used NSAID drug used for sustained release applications due to its pain relief and anti-inflammatory properties36–38; ibuprofen (ibu), an NSAID drug with similar properties and application

38–40,

which is also anticoagulation drug41; chlorhexidine (chd), an efficient antiseptic

agent of general medical uses42–44; and ciprofloxacin (cip), a wide-spectrum antibiotic45,46. The four drugs structures are presented in figure 1. Full characterization of the new composites, their release profiles and three types of manipulations that influence on their release kinetics are presented below. Finally, also of relevance to this introduction is to cite the reports on molecular



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entrapment within Pt-Cu alloy47, and the fabrication of chiral electrochemical deposited thin Pt films by the use of chiral molecules48,49. O

(1)

(2)

OH

OH

O

F

OH

O

O

O

(3)

H

N

N

Cl- +H2N

(4)

H N

Cl

H N NH

H N NH2+ Cl-

Cl

Cl- NH2+ NH N H

N H

N H

Figure 1. The structures of the drugs in their delivered forms: (1) ibuprofen (ibu), (2) naproxen (nap), (3) ciprofloxacin (cip)50 and (4) chlorhexidine (chd).

Experimental Details Chemicals: Sodium ibuprofen, chlorhexidine (free amine), chlorhexidine digluconate (20%w in water), chlorhexidine dihydrochloride, D-gluconic acid (45-50%w in water) and hydrazine hydrate (50-60%w in water) were purchased from Sigma Aldrich. Ibuprofen (the acid form) and sodium naproxen were purchased from Acros Organics. Potassium tetrachloroplatinate(II) was purchased from Alfa Aesar. Ciprofloxacin was purchased from TCL. Caution: Hydrazine solution is toxic and should be carried with care – please consult the MSDS first. Excess hydrazine can be safely removed by washing with water. Syntheses: Ibuprofen@Pt: 0.645 g (1.00×10-3 moles) of potassium tetrachloroplatinate was dissolved in 1890 L of NaOH 1M diluted with 630 L of double-distilled water (DDW) and stirred for 5 min at 60°C and 300 rounds per minutes (RPM). Prior to the reduction, the hydrazine solution was diluted X10 by taking 50 L of the reducing agent solution and diluting it with 450 L of DDW within an Eppendorf. Then, the 500 L diluted hydrazine solution was added to the palatinate solution as follows: 30 L was added every 30 seconds seven times followed by two additions of 60 L at an interval of 30 seconds, and finally 75 L was added two times in the same interval of time, 480 L


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(~0.85×10-3 mole hydrazine) in total. Visually, in the reduction reaction, the red Pt complex solution, turns into a black suspension of the formed metallic Pt. Ibuprofen was entrapped by adding at once 17.8 mg (0.078 mmol) of sodium ibuprofen, two minutes after starting the gradual addition of the reducing agent solution (31% of the reducing agent). After adding the drug, the addition of the reducing agent solution (the rest of the 69%) continued as described above, and the reaction mixture was stirred for additional 55 minutes, a total of 60 minutes from the reduction start. The resulting suspension was filtered, washed with 3 portions of 5 mL DDW and vacuum-dried overnight. After 1 day of storage, the resulting powder was crushed and homogenized. The Pt reduction yield was 292 mg (97%). The weight percentages of the entrapped drug (in its free acid form) was determined by extracting it and measuring the concentration by the well accepted analytical method of uv-vis spectroscopy (see below), from a known amount of the ibu@Pt composite with DDW, and was found to be 1.8%, reflecting entrapment yield of 30%, respectively. For comparison purposes, pure Pt was made in a similar way, but without the drug, yielding 295 mg (98% reduction yield). For successful entrapment, the reaction started under basic conditions (eq. 1 below) but with an equimolar shortage of base, so that at the end of the reduction the conditions were acidic (eq.2). An alternative entrapment procedure was tested for ibuprofen only, in which the drug was added to the platinum salt solution described above, prior to the reduction step. We denote this early entrapment product as EE-ibu@Pt. The weight percentage of the entrapped drug in this case was found to be 3.0% reflecting entrapment yield of 49%, respectively. Naproxen@Pt: Naproxen was entrapped similarly, using 19.65 (0.078 mmol) of sodium naproxen. The Pt reduction yield was 298 (99%) and the entrapped percentage (in the non-ionized form) was 3.0 % (46 % entrapment yield). Ciprofloxacin@Pt: The drug was first converted to its sodium salt form by dissolving 2.5 mg (0.0075 mmoles) of ciprofloxacin in 490 L of DDW and 10 L of sodium hydroxide 1M, vortexing for few minutes in order to accelerate the dissolution. Then 0.215 g (0.52 ×10-3 moles) of potassium tetrachloroplatinate was dissolved in 2 mL of DDW by stirring at 500 RPM and at 30°C for 5 minutes. 180 L of the previously described diluted hydrazine solution was added at once to the palatinate solution, and after 30 seconds the ciprofloxacin solution was added as well. The reduction reaction in this case is only eq. 2. The reaction was carried out for 15 minutes, after which the resulting suspension was filtered, washed with 5 mL of DDW and vacuum-dried overnight. After 1 day of storage, the resulting powder was crushed and homogenized. Pure Pt



was made by the same method only without dissolving the drug within the Eppendorf. The reduction yield was 91 mg (91%) and 89 mg (89%) for the pure Pt which was prepared similarly for comparative purposes. The entrapped weight percentage was 0.5% (20% entrapment yield). Chlorhexidine@Pt: 0.215 g (0.52 ×10-3 moles) of potassium tetrachloroplatinate was dissolved in 840 L of sodium hydroxide 1 M and 1660 L of DDW, as described above. 200 L of the diluted hydrazine solution described above was added at once to the palatinate solution, and after 10 seconds 40 L of the chlorhexidine digluconate solution (20% by weight) was added as well. The entrapment reaction was carried out for 10 minutes. The product was processed and cleaned as described above. Pure Pt was made similarly, except that 40 L DDW was added instead of the chlorhexidine solution. The Pt reduction yields for the composite and for the pure Pt yields were 96 mg (96%) and 90 mg (90%) respectively. The entrapped weight percentage was 3% (34% entrapment yield). Compressed discs Formation: All powders were also compressed to 13 mm diameter and 0.5 mm thickness discs by using an infra-red pellets press follows: 200 mg of the composite was subjected to pressures in the range of 500-10,000 psi for 3 minutes. Then the pressure was released and immediately the composite was pressed again, for 6 cycles. Delivery measurements: UV-vis concentration calibration curves were prepared for all drugs by standard procedure (see Supplementary Materials, SM). The analytical wavelengths and optimized amounts taken for the release experiment are collected in Table S1 and Fig. S1a-d. Kinetics of release was determined by shaking a water suspension of the desired amount of the composites powder or disc with an incubator shaker at 100 RPM at 30°C. At specific times, samples of 2.5 ml were taken and measured, and then immediately back transferred to the tested suspension. In the release kinetics profile, 100% is the maximum extractable amount as determined by absorbance spectroscopy. Release activation energy measurements were carried out similarly at a range of temperatures: 30, 35, 40, 45, 50 and 60°C. Instrumentation: Thermogravimetric analysis (TGA) was carried out with a Mettler-Toledo TGA/SDTA 851e, from 50 to 800 °C, at a heating rate of 10 °C per minute under air atmosphere. Density measurements were carried out with a Micromeritics AccuPyc 1340 instrument using helium as the displacing gas. UV – Vis absorbance spectroscopy was carried out with HewlettPackard 8452A diode-array UV-vis spectrophotometer. Scanning electron microscope (SEM) and energy-dispersive X-ray spectroscopy analysis (EDAX) were carried out on a Sirion (FEI) high


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resolution (HR) SEM instrument. X-ray powder diffraction measurements were performed on a D8 Advance diffractometer (Bruker AXS, Karlsruhe, Germany) with a secondary Graphite monochromator, 2° Sollers slits and 0.2 mm receiving slit. The powder samples were placed on low background quartz sample holders. X-ray diffraction (XRD) patterns from 5° to 85° 2θ were recorded at room temperature using CuKα radiation (λ = 0.15418 nm) with the following measurement conditions: tube voltage of 40 kV, tube current of 40 mA, step scan mode with a step size of 0.02° 2θ and a counting time of 1 s per step. The Pt crystallite size was determined from the experimental XRD data using Scherrer equation. The instrumental broadening was determined using LaB6 powder (NIST SRM 660). Surface area analyses were determined by adsorption-desorption N2-BET isotherms analysis obtained from Micromeritics ASAP-2000 physisorption instrument.

Results and discussion Developing the drugs entrapment protocols The list of challenges that had to be solved in developing the optimal procedures for the entrapment of the drugs, was rather demanding: Conditions should be such that creation of a stable metallic sol of nanoparticles be avoided to enable the formation of bulk powders and discs; that the resulting doped metal will not decompose after its formation, but will have mechanical stability for the delivery experiments; that the drug is not reduced under the conditions that reduce the Pt salt and that oxidized form of the reducing agent will be easily washed away (Fig. S1); that the desired final form of the drug (salt or non-ionized), suitable for the relevant durations of release time, is obtained in the final product; that the porosity of the formed Pt and the drug-entrapping Pt cages are such that the majority of the entrapped drug will be released, and at relevant rates. The latter is particularly a challenge, because most of the previous molecular entrapment methodologies were develop for minimal or even zero-leaching of the dopant (such as entrapped catalysts27,51,52). The charge of the drug molecules at the initial entrapment stages and particularly at the end of it – anions in the case of acids, cations in case of the amines, as well as the uncharged species -were found to be crucial for the challenges mentioned. All of these required selection of the right reducing agent, tailoring a pH-controlled profile along the entrapping process, and finding the right sequence of addition of the reaction components and the rates of their additions. The procedures described in the Experimental details, based on the reduction of K2PtCl4 with hydrazine solution are the result of these



optimizations, which included also temperature and even stirring speed. Hydrazine was selected as a reducing agent after testing a number of reductants because it was found to achieve high yields, and because no impurities of its oxidized products are left in the final product (eq.’s 1 and 2). Another example of parameters considerations is the tailoring of the pH: It was found that starting from basic environment increases the reduction yield, probably due to the inhibition of the protonation of the nitrogen atoms of the hydrazine. On the other hand, in order to entrap the NSAID carboxylic drugs, it was necessary to end the entrapment process in the acidic environment in order to diminish the solubility the sodium salts by converting them to the non-ionized acids. For that reason, the entrapment reaction of ibu and nap started under basic conditions (eq. 1) but with less base than needed to complete the reduction, so that when the base is consumed, eq.2 enters into operations, acidifying the environment to a low pH of about 1, so that the entrapped species is the non-ionized acid: (1) N2H4 + 4NaOH + 2K2PtCl4  2Pt + N2 + 4H2O + 4K+ +4Na+ + 8Cl(2) N2H4 + 2K2PtCl4  2Pt + N2 + 4K+ + 4H+ 8ClSpecial optimizations of entrapment conditions were also needed to be developed for the next two drugs. In order to entrap ciprofloxacin the free acid was first converted to the sodium salt (preferred over conversion of the amine group to the HCl salt) – this conversion ensures homogeneous distribution of the dopant. The entrapment was carried out according to eq. (2) so that the entrapped final species is the ammonium chloride salt. Homogeneity in the entrapment of CH was challenging because of the low solubility of the free base under basic conditions and because of the low solubility of most of its salts. The best conditions, described under Experimental conditions were found to add CH as a digluconate salt, start the entrapment according to eq. 1, and continuing it according to eq. 2, as in the case of the two NSAID drugs. The final acidic conditions and the excess of the formed HCl end the entrapment as a dichloride salt of CH. In this case the entrapped CH is partially aggregated but this aggregation is no limit for obtaining good release profiles from the metallic Pt (see below). Materials characterization XRD measurements (Fig. 2a) show that the nanocrystals which build the aggregated porous structures are of cubic elemental platinum. Scherrer analysis of these spectra indicates that for the composites and for pure Pt synthesized under the basic conditions (ibu@Pt, nap@Pt, chd@Pt and Pt) the average crystallite size is around 64 nm (see Table S2), while for the neutral starting


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conditions used for cip@pt (and its Pt reference) the crystallite size is smaller, around 45 nm. EDAX elemental analysis confirms the hybrid nature of these biomaterials, namely the presence of Pt along with elements typical for each drug (Fig. 2b,c and S2) including carbon, oxygen and nitrogen (for the relevant drugs- cip and chd). In the EDAX of cip@Pt, one detects some Cl, indicating that the drug is entrapped in its chloride salt form.

a

d

b

e

keV

f

c

keV

Figure 2. Representative XRD and EDAX spectra and TGA profiles of drug@Pt: (a) XRD of (from (1) to (8)- EE-ibu@Pt (dark purple), ibu@Pt (dark green), nap@Pt (brown) and Pt prepared under similar conditions (purple), cip@Pt (green) and Pt prepared under similar conditions (blue),



CH@Pt (red) and Pt prepared under similar conditions (black). Red lines: lit. data53. EDAX of (b) ibu@Pt and of (c) cip@Pt. For additional EDAX spectra, see Fig. S1. (d) TGA profiles of ibu@Pt (black, left axis), Pt prepared under similar conditions (green, left axis), sodium ibu (blue, right axis), ibu (red, right axis). (e): TGA profiles of cip@Pt (black, left axis), Pt prepared under similar conditions (green, left axis), cip (blue, right axis), cip chloride (red, right axis). (f) The weight loss first derivative graphs versus temperature of ibu@Pt and the pure components: ibu@Pt (black line, left axis), Pt (green line, left axis), sodium ibuprofen (blue line, right axis), ibuprofen (red line, right axis). For additional TGA analysis and the first derivative graphs, see Fig. S2c and S3a-f. Direct indications of the existence of the organic components within the composites, along with quantitative evaluation of the amount of the entrapped drugs, were obtained by TGA (Fig. 2d-f, Fig. S2 c and S3 a-f) and by spectrophotometric analysis of the water extracts of the entrapped drugs (Table 1). The latter method was also used to confirm that the drug is not reduced in the entrapment process (see fig S1a-d). While TGA reports the total amount of organic matter in the composite, extraction experiments provide information on the population of molecules that are accessible for release. This population is smaller than the total amount, because of the existence of a sub-population that is totally enclosed within the metallic cages or resides within bottle-neck cages. The standard in reporting loading and release of drugs from various supports is to use units of %-weight, and it is seen that the extractable amount is in the range of 0.5 – 4.0 w%. However, since Pt is a heavy atom, it is helpful to get a feeling about that amount with other units; let us take EE-ibu@Pt as an example: 3.7 w% is equivalent to a 3.6 mol%, and since each drug molecule contains 33 non-metallic atoms, this means that in this composite the ratio of metallic to non-metallic atoms is about 1:1. One can also estimate that in this case, each drug molecule is surrounded on the average by 96 Pt atoms (see the Supplementary Material for the details of the estimation). This molar ratio represents a “solvation shell” of a sphere of ~ 100 Pt atoms, the diameter of which - ~1.4 nm – surrounding one drug molecule which is coincidentally of a similar size – ~1.2 nm. The metal-organic hybrid nature of the composite is clearly evident by using yet another unit, namely the ratio between the number of non-metallic atoms and the number of the metal atoms; in this case it turns out that the 3.7w% means a non-metal:metal atomic ratio of 1.17! A central observation in the TGA profiles is that the decomposition temperatures are shifted to lower temperatures (see for instance, the 40°C shift in the case of ibu@Pt (Fig. 2d and 2f). These shifts – which serve as an additional proof of entrapment – are due to the catalytic effect of the metal on the oxidation of the organic molecule54,55. In other words, these shifts indicate that the NSAID molecules interact directly with the walls of the metallic cage. Similar TGA-catalytic effects were observed for


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molecularly doped silver51,56. Due to the acidic conditions of the entrapment process, the NSAID drugs are entrapped in their non-dissociated carboxylic form. Indeed, it is seen that the TGA profiles of the NSAID@Pt are different from the free sodium salt form but similar to the free acidic TGA profile form (Fig. 2d,f, S2a-d). Table 1. Amount (%-w) of the entrapped drugs. Composite Drug TGA decline (a) Extraction (a) Without

nap@Pt

ibu@Pt

cip@Pt

chd@Pt EE-ibu@Pt

3.6

2.1

1.0

4.0

3.7

3.0

1.9

0.5

3.0

3.0

the decline in pure Pt of 1.2%-w

The porous nature of the Pt matrix needed for its function as a releasing matrix was determined by microscopy, by analysis of the nitrogen adsorption-desorption isotherms data, and by density measurements. It can be seen – ibu@Pt, Fig. 3 – that the powdered material (Fig. 3a) is characterized by a hierarchical aggregated structure, from large aggregates of tens of microns which form the powder (Fig. 3b) to smaller aggregates in the microns range (Fig. 3c), to smaller units of about 200-300 nm (Fig. 3d), to nanocrystallite grains of few tens of nm, seen also by Scherrer analysis of the XRD data. Fig. 3g and 3h are special as it provides direct visual proof of the entrapment: The energy electrons cause the dopant to ooze out and decompose, leaving behind the darkened square. Delivery experiments were carries out from both the powder and from pressed discs – see Fig. 3e for the apparent tighter porosity, which indeed affects the release rate (next section). Surface areas and densities are lower, as expected, than pure Pt prepared under similar conditions; the values are typical of microporous - mesoporous materials (Table S2, SI) – for sake of brevity the surface area and porosity studies are described in the Supplementary Information.



a

e

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b

c

d

f

g

h

Figure 3. (a) ibu@Pt composite powder. (b) – (d): SE-SEM images of ibu@Pt representing the hierarchical structure of the composites. (b) bar – 10 μm, (c) bar – 3 μm, (d) bar - 500 nm. (e) The surface of a pressed disc of ibu@Pt (bar – 2 μm). (f) – (g) SE-SEM images of cip@Pt. (f) bar - 2 μm, (g) bar – 1 μm. Note the dark square marked with an arrow, which indicates the oozing of organic material due to the highly focused electron beam. (h) A typical aggregate of ibu@Pt after (bar -50 microns) – note again the black square caused by the beam. For additional images, see Fig.’s S3. Delivery kinetics profiles All composites show successful delivery of the entrapped drugs from the metallic Pt matrix, either from the powder form or from the pressed discs form – see Fig. 4. In general, we found two types of release kinetics, which are based on the common first order release kinetics, and which can be unified under the umbrella equation 3: (3)

(

( )) + m (1 ― exp ( ― )) t

m(t) = mb + mf 1 ― exp ― τf

s

t τs

where mb is an initial fast burst release, mf is a fast first order released component with a time constant of τf, and ms is a first order slow-release component with a time constant of τs. The various entrapped drugs obey release profiles which have a slow ms component with either burst mb or fast release mf populations (but not with both) – see Table 2 (down to the thick separator), which summarizes the drugs release kinetics parameters of all composites powders and discs.


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a

b

c

d

Figure 4. Drug delivery profiles. The bottom minutes axis and the black squares refer to the powders; the upper hours axis and the red dots refer to 10,000 PSI pressed discs. Note the long time break in the axes. (a) nap; (b) ibu; (c) chd; (d) cip.

It is generally seen that while the release profiles of the powders have characteristic times (𝜏) and half-lives (t1/2) in the minutes up to one hour range, the characteristic times of the pressed composites are up to a few days. The powders have a significant fast component (of the order of half of the released materials), which upon compression is dramatically reduced, giving more weight to the long time release in the discs. Applying Pressure on the powder creates tighter metal cages surrounding the drug molecules, slowing therefore their release. The existence of two



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populations represents the fact that there is a distribution in the openings and accessibilities of the entrapping cages and pores. One should note that even the fast components represent entrapment and not simple adsorption; adsorbed molecules are easily washed away in the cleaning process of the material. The variations between the various drugs are due to their different functional moieties and their ionization states. For instance, compared with the two NSAID drugs, ibu and nap which have a non-ionized carboxylic acid group and therefore show a similar kinetic behavior, chd, which has two amine protonated groups, has a very rapid release in the first few minutes.

Table 2. The kinetic parameters of the drugs release kinetics Composite

Form (a)

mb (%)

mf (%)

𝜏f

t1/2-f

ms (%)

𝜏s

t1/2-s

R2

nap@Pt

powder

-

74±2

-

9 ±1

ibu@Pt

powder

-

45±2

ibu@Pt

disc

2.9±0.7

cip@Pt

powder

-

73±7

cip@Pt

disc

-

17±1

chd@Pt

powder

48±2

chd@Pt

disc

nap@Pt

73±15 (min) 52±1 (hrs) 57±4 (min) 7.6±0.2 (hrs) 13±4 (min) 10.1±0.2 (hrs) 3.8±0.2 (min) 3.0±0.1 (hrs) 26±1 (hrs) 33±1 (hrs) 82±6 (min) 13.9±0.4 (hrs)

51±10 (min) 36±1 (hrs) 40±3 (min) 5.3±0.1 (hrs) 9±3 (min) 7.0±0.1 (hrs) 2.6±0.1 (min) 2.1±0.1 (hrs) 18±1 (hrs) 23±1 (hrs) 57±4 (min) 9.6±0.3 (hrs)

0.997

disc

4.5±0.2 (min) 0.6±0.2 (hrs) 3.9±0.2 (min)

26±3

nap@Pt

6.5±0.3 (min) 0.8±0.3 (hrs) 5.6±0.3 (min)

91.3±0.8 55±2 98.0±0.8

1.9±0.2 (min) 0.9±0.1 (hrs) -

26±7

-

2.7±0.3 (min) 1.2±0.1 (hrs) -

5.4±0.7

-

-

-

96±1

-

8±1

-

5±1

-

44±1

EE ibu@Pt

disc

2.6±0.2

-

0.6±0.4 (hrs) 0.6±0.3 (hrs) 5.0±0.2 (min) -

0.5±0.3 (hrs) 0.5±0.2 (hrs) 3.5±0.1 (min) -

93±1

EE ibu@Pt

disc (500 PSI) disc (6,000 PSI) powder

nap@Pt

(a)

81±1 51±2

96±1 55±1 102±2

Discs were prepared at a press pressure of 10,000 PSI, unless otherwise indicated

Affecting the release profiles The observed release profiles reflect the synthetic conditions of the preparation of the composites, and the conditions used to release the drug from it. It is expected – and now will be


0.999 0.998 0.997 0.994 0.999 0.993 0.995 0.999 0.999 0.998 0.998

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shown – that variability in these parameters can be used to control and fine tune the release kinetics. For instance, ibu was entrapped by two procedures – the standard procedure used for all drugs in which the drug was added to the reaction mixture after starting the reduction of the metal cation – and by a procedure in which the ibu was added to the Pt precursor prior to the reduction (early entrapment, EE-ibu@Pt). Is there an effect of this procedural change? As seen in Table 1 and Table 2 (compare ibu@Pt EE-ibu@Pt) and in Fig. 5a (compare with Fig. 4b), some parameters remain un-affected (the proportions of the fast and slow populations and the kinetics of the fast components), others change: First it is seen that the EE procedure almost doubles the amount entrapped (Table 1); and that the rate of release of the long-term component, becomes even longer in the EE procedure. This is particularly evident in the disc format, where the characteristic time, doubles. However, the EE was not use as a standard procedure, because in other cases it led to platinum micron or nano particles stabilized by the organic molecules in the medium. Physical parameters can also be used to affect the release characteristics. The observation that applying a pressure of 10,000 PSI affects the release profile so dramatically, points to the possibility of using the pressure of the disc preparation as a control parameter of the release characteristics. Indeed, as seen in Table 2 (bottom) and in Fig. 5b, when nap@Pt discs are prepared at various pressures, gradual variability that follows the increase of pressure from zero (powder), to 500, 6000, and 10000 PSI, is obtained, providing control of t1/2 from minutes to 36 hrs, particularly in the slow ms component. a

b



Figure 5. Effects of procedure variations. (a) Effect of changing the entrapment protocol – early entrapment (EE) of ibu – see Experimental Details. Inset– Fig. 4b: ibu, regular protocol. (b) Discs pressure preparation effect: nap@Pt. Inset: Release from the powder. The temperature of release is expected to affect the kinetics, because it increases the rate of diffusion and accelerates also the detachment of the drug molecules from their interactions with the surfaces of the metallic. The question was, what is the sensitivity to variations in this parameter? This question was tested with nap@Pt disc, and the results - Fig. 6a and the figure table – show that again the slow component is affected most: 𝜏s is accelerated from 52 to 12 hrs, upon raising the temperature from 30 to 50°C. Temperature analysis also leads to the possibility of evaluating the activation energy for releasing the drug from the matrix, 𝐸𝑎, by applying Arrhenius analysis, 𝐸𝑎

(4)

𝑘 = 𝐴𝑒

― 𝑅𝑇

,

Where k is the release rate for each temperature, A is the pre factor and reflects the specific structure of the metal matrix, R is the gas constant and T is the temperature (in Kalvin). The Arrhenius analysis is shown in Fig. 6b, and it is seen that the compliance with Arrhenius behavior is good (R2 = 0.97) with an activation energy 14.2 kcal/mol and a pre-factor of 0.004 mol/sec. The observed activation energy is within the known range of general release activation energies 57,58, and almost twice as much as higher compared to the reported activation energy of nap released from poloxamer gel59, which is in fact expected, taking into account the flexibility of the gel, compared to the rigidity of the metallic matrix.


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Temperature 30°C

mf (w%) 9.4±0.7

𝜏f (hrs) 0.8±0.3

ms (w%) 91.3±0.8

𝜏s (hrs) 52±1

35°C 40°C 50°C

4±1 12±1 15±1

0.5±0.4 0.5±0.2 0.5±0.2

96±1 88±1 85±1

33±1 29±2 12±1

a

b

Figure 6. (a) Delivery of nap from nap@Pt discs at different temperatures. Table: The kinetic parameters of the release. (b) An Arrhenius analysis of the release of nap from nap@Pt discs.

Conclusion and outlook The use of an inert implantable metal – Pt – as a drug delivery matrix was developed and demonstrated in this study. In general, it was found that the release has two modes – an initial rapid release, followed by a slow mode, both obeying first order kinetics. This was observed both in powders and in pressed discs. From the practical point of view, two components release is a wanted profile in many medical protocols, where an initial fast dose is desired, to be followed by a slow maintenance low dose period60. Also from the practical point of view, both the compressed item and the powder are of potential use. We have used a disc shape, but the powder can be compressed to any of the many shapes that implanted Pt assumes (see ref. 2 for examples). In any event mechanical stability of theses composites after compression will need to be investigated at



first. Powders on the other hand can be used as injectable bioactive fillers, as components of biopolymers, and as components of medical plastic devices. The drugs we have selected are relevant to conditions which may appear after the implanting surgery. For example, a major concern is infection which follows the surgery, for which chd@Pt and cip@Pt were developed, and where fast release kinetics with a duration of up to 24 H is needed in order to prevent the biofilm creation12. Orthopedic implanted medical devices representing a fast growing worldwide multi-billion dollars market. Such devices maintain a functional quality of life for millions of individuals each year by improving significantly patient health, tolerance of impaired conditions and mobility10,61. This is the broader aspect of our drugs@metals studies.

Acknowledgements This work was supported by the Israel Science Foundation (grant no. 703/12) and by the FTA program of the Israel Ministry of Commerce and Industry. B. M. thanks The Israel Ministry of Science of Israel for a PhD scholarship. Special thanks are due to the staff of the Center of Nanoscience and Nanotechnology at the Hebrew University.

Supporting Information Supporting Information is available at Supporting Information from the paper library or from the author.

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Entrapment of Drugs within Metallic Platinum and their Delivery Barak Menagen and David Avnir For Table of Contents Use Only:


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82x44mm (300 x 300 DPI)


Entrapment of Drugs within Metallic Platinum and their Delivery - ACS

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