0001
`
`PSG2006
`Catalent Pharma Solutions v. Patheon Softgels
`IPR2018-00422
`
`

`

`Journal of BIOMATERIAL$ SCIENCE
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`0002
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`

`

`J. Biomater. Sci. Polymer Edn, Vol. 6, No. 2, pp. 141-147 (1994)
`© VSP 1994.
`
`Pharmacokinetic results on naproxen prodrugs based on
`poly( ethyleneglycol)s
`
`, L. SARTORE1
`E. RANUCCI 1
`and P. FERRUTI 1
`1Dipartimento di Ingegneria Meccanica, Universitii di Brescia, via Branze 38, 25133 Brescia, Italy
`2Istituto di Ricerche Farmacologiche M. Negri, via Eritrea 62, 20157 Milano, Italy
`
`, R. LATINe, R. BERNASCONI2
`
`, I. PERONI 1
`
`Received 15 January 1993; accepted 17 June 1993
`
`Abstract-Five prodrugs of S( + )-2-(6-methoxy-2-naphthyl)propionic acid (naproxen), in which the drug
`was bound by ester linkages to diethyleneglycol (1), triethyleneglycol (II), octanediol (III), butyl(cid:173)
`triethyleneglycol (IV), and butyl-tetraethyleneglycol (V), respectively, were prepared and tested for their
`pharmacokinetic properties after oral administration. It was found that bioavailabilities decreased in the
`order, and in all cases were lower than that of the free drug.
`
`Key words: S( + )-2-(6-methoxy-2-naphthyl)propionic acid; naproxen pharmacokinetics; oligomeric
`prodrugs; oligomeric poly(ethyleneglycol)s.
`
`INTRODUCTION
`By analogy with conventional prodrugs [1], an oligomeric prodrug can be defined as
`an oligomeric substance that, once administered, gives rise to an active drug, as a
`consequence of a chemical transformation occurring within the body [2] . Typically,
`an oligomeric prodrug is composed of two parts: an oligomeric carrier promoiety;
`and a drug moiety linked by a chemical bond cleavable under physiological condi(cid:173)
`tions. The oligomeric prodrug approach, using poly(ethyleneglycol)s (PEGs), has
`been followed in the past with excellent results, with the purpose of increasing
`bioavailability and reducing toxicity of pyromidic acids, 4-isobutylphenyl-2-
`propionic acid (ibuprofen) [3] and ursodeoxycholic acid [4, 5] . Similar derivatives
`with other families of drugs also show interesting properties.
`In this paper, we thought it interesting to report on a new set of derivatives all con(cid:173)
`taining the same drug moiety, coupled with ester bond with oligomers having different
`molecular size and a different hydrophilic-lipophilic balance (HLB). As a drug we have
`selected S( + )-2-(6-methoxy-2-naphthyl)propionic acid (naproxen) which has the advan(cid:173)
`tage of being very easily detectable in the blood stream, and of having, as a free drug,
`very good pharmacokinetic characteristics and high bioavailability after oral adminis(cid:173)
`tration. Naproxen does not undergo first pass metabolism in the liver [6]. The aim of
`this paper was to study the effect of the promoiety on pharmacokinetic properties of
`oligomeric derivatives in which the drug moiety is highly hydrophobic, and the bond is
`of the ester type, without interferences by a protection towards liver inactivation.
`
`EXPERIMENTAL
`Materials and methods
`Infrared spectra were obtained with an FT-IR Jasco 5600 spectrophotometer from
`KBr pellets for naproxen and from casted films for its ester derivatives . 1H NMR
`
`0003
`
`

`

`142
`
`E. Ranucci et al.
`
`spectra were run on a 60 MHz 360A Varian spectrometer, in CDC13 solutions, using
`TMS as internal reference. Elemental analyses were performed by Redox Labora(cid:173)
`tory (Cologno Monzese-Milano). TLC were run on Merck silica gel layers using
`chloroform/isopropanol 4: 1 as eluent.
`1,8-
`n-butanol,
`tetraethyleneglycol,
`Diethyleneglycol,
`triethyleneglycol,
`octanediol, 1, 1'-carbonyldiimidazole and S( + )-2-(6-methoxy-2-naphthyl)-propionic
`acid (naproxen) were purchased from Fluka and used without further purification.
`Naproxen
`imidazolide-naproxen (14.00 g, 60.80 mmol) was dissolved
`in
`alcohol-free chloroform (100 ml). N,N'-carbonyldiimidazole (19.71 g, 121.6 mmol)
`was added at once, under inert atmosphere, and the solution was ·maintained
`under stirring for 30 min. The reactive solution was used as such in the following
`reactions.
`Diethyleneglycol-naproxen adduct (1)-diethyleneglycol (2 g, 18.85 mmol) was
`dissolved in alcohol-free chloroform (10 ml) and dried over calcium hydride. The
`chloroform solution was then filtered off and added to the naproxen imidazolide
`solution previously prepared. The reaction mixture was maintained in anhydrous
`conditions, at 60°C for 24 h. After this time it was diluted with chloroform,
`extracted with 0.1 sodium hydroxide aqueous solution (2 x 20 ml), then with water
`(5 x 20 ml), and dried over desiccator. The solvent was then evaporated under
`reduced pressure. The crude product obtained was purified by column chromatog(cid:173)
`raphy (silica gel, chloroform/isopropanol 4: 1 as eluent). Yield = 5.150 g (850Jo ).
`Elemental: experimental C% 67.82, HOJo 7.07; and calculated C% 67.94, H% 6.92.
`IR (cm- 1
`): 2820-2960 (vC-H); 1730 (vC=O); 1600 (vC=C); and 1140 (vC-0).
`1H NMR (<:5, ppm): 0.8 (3H, d, CH 3-C); 3.95-4.33 (13H, m, CH2 -0, H -0,
`CH 3-0, CH2 -0-CO, CH-Ar); and 6.1-6.8 (6H, m, aromatic H).
`Triethyleneglycol-naproxen (II), and octanediol-naproxen adduct (Ill) were
`prepared with the same procedure as that for diethyleneglycol, by substituting
`equivalent amounts (on a molar base) of the above diols for diethyleneglycol.
`The products were characterized as follows: (II) Elemental: experimental:
`C% 66.02, HOJo 7.89; and calculated C% 66.31, H% 7.18. IR (cm- 1
`): 2820-2960
`(v C- H); 1730 (v C=O); 1600 (v C=C); 1500 (v C=C); and 1140 (v C-0).
`1H NMR
`(<:5, ppm): 0.8 (3H, d, CH 3-C); 3.95-4.33 (17H, m, CH2 -0,
`CH 2 -0-CO, CH 2 -0, CH-Ar, H-0); and 6.1-6.8 (6H, m, aromatic H).
`(Ill) Elemental: experimental C% 71.07, H% 7.69; and calculated C% 71.54;
`
`H% 7.28. IR (cm- 1): 2820-2960 (v C-H); 1730 (v C=O); 1600 (v C=C); and 1140
`(v C-0). 1H NMR (<:5, ppm): 0.8 (3H, d, CH 3-C); 0.89-1.30 (12H, m, CH2 -C);
`3.95-4.33 (9H, m, CH3-0, CH 2 -0-CO, CH-Ar, C-CH2 -0, H-0); and
`6.1-6.8 (6H, m, aromatic H).
`Butyl-triethyleneglycol adduct: butanol (2 g, 27 mmol was dissolved in alcohol(cid:173)
`free chloroform (50 ml). N,N'-carbonyldiimidazole (8.858 g, 54.6 mmol) was added
`at once, under inert atmosphere, and the solution was maintained under stirring for
`30 min. Anhydrous triethyleneglycol (4.057 g, 27.0 mmol), was added to the reac(cid:173)
`tion mixture, and it was maintained overnight under stirring at 60°C. After this time
`it was diluted with chloroform, extracted several times with water, and dried over
`desiccator. The
`solvent was
`then evaporated under
`reduced pressure.
`Yield = 6.808 g (100%). IR (cm- 1
`): 2860 (v C- H); 1742 (v C=O); and 1140
`(v C-0). 1H NMR (<:5, ppm): 0.85 (3H, t, CH 3-C); 1.0-1.4 (4H, m, CH 2 -C); and
`3.95-4.33 (15H, m, CH 2 -0-CO, CH2 -0, H -0).
`
`0004
`
`

`

`Naproxen prodrugs based on poly(ethyleneglycol)s
`
`143
`
`Butyl-triethyleneglycol-naproxen adduct: (IV): butyl-triethyleneglycol (5 .00 g,
`19.82 mmol) was dissolved in alcohol free chloroform (20 ml) and dried over
`calcium hydride. The chloroform solution was then filtered off and added to the
`naproxen imidazolide solutiOJl prepared as previously described. The reaction
`mixture was maintained in anhydrous conditions, at 60°C for 24 h. After this time
`it was diluted with chloroform, extracted several times with water, and dried over a
`desiccator. The solvent was then evaporated under reduced pressure. The crude
`product obtained was purified by column chromatography (silica gel, chloro(cid:173)
`form/ isopropanol 4: 1 as eluent). Yield = 7.466 g (900Jo ). Elemental: experimental
`C% 67.82, H% 7.07; and calculated C% 67.94, H% 6.92. IR (cm- 1
`): 2960
`(vC -H); 1740 (vC=O); 1600 (vC=C); 1500 (vC=C); and 1140 (vC-0).
`1H NMR (£5, ppm): 0.80-0.85 (6H, m, CH 3-C); 1.0-1.4 (4H, m, CH2 -C);
`3.95-4.33 (18H, m, CH 3-0, CH 2 -0-CO, CH-Ar, CH2 -0); and 6.1-6.8 (6H,
`m, aromatic H).
`Butyl-tetraethyleneglycol-naproxen adduct (V) was prepared with the same proce(cid:173)
`dure as triethyleneglycol one, by substituting equivalent amounts (on a molar base)
`of tetraethyleneglycol for triethyleneglycol. The product was characterized as
`follows: IR (cm- 1
`): 2860-2960 (v C- H); 1730 (v C=O); 1600 (v C=C); 1500
`(v C=C); and 1140 (v C-0). 1H NMR (£5, ppm): 0.80-0.85 (6H, m, CH3-C);
`1.0-1.4 (4H, m, CH2 -C); 3.95-4.33 (22H, m, CH 3-0, CH2 -0-CO, CH-Ar,
`CH2 -0); and 6.1-6.8 (6H, m, aromatic H).
`
`Pharmacokinetic studies
`
`Male CD Sprague Dawley rats (Charles River, Italy), 333 =f= 90 g (S.D.) body weight
`were used. A silicone catheter (1.19 mm outer diameter, Silastic, Dow Corning) was
`inserted in the right jugular vein under light ether anaesthesia 24 h before drug treat(cid:173)
`ment [7]. Overall, 21 rats were utilized for the analysis. Naproxen hydrochloride was
`used as a reference standard for pharmacokinetic comparisons. It was administered
`by gavage to nine rats (20 mg kg - 11 body weight).
`Naproxen derivatives were given by gavage to twelve rats, at a dose of 20 mg kg- 1
`body weight of naproxen equivalent. All compounds for oral administration were
`suspended in corn oil. The presence of underivatized naproxen in corn oil suspen(cid:173)
`sions of derivatives was checked by HPLC. Blood samples of 0.8 ml were collected
`at serial times, up to 30 h, after oral (gavage) administration, and immediately cen(cid:173)
`trifuged. Plasma samples (about 0.4 ml) were stored at -20°C until extraction.
`To the 0.3 ml of rat plasma, 10 f.J,g of 6-methoxy-2-naphthylacetic acid (6-MNA)
`(50 ,ul of 200 f.J,g/ml solution), as internal standard, and 20 f.J,l of HCl 0.1 M were
`added. After addition of 5 ml of diethylether the tubes were shaken horizontally for
`15 min and centrifuged for 5 min at 600 g. The organic phase was transferred and
`evaporated at room temperature under a stream of nitrogen. The residue was redis(cid:173)
`solved in 200 f.J,l of acetonitrile and 20 f.J,l as injected into an HPLC [8]. The mobile
`phase was acetonitrile-phosphate buffer (H2P04 /HPO~-) 20 mM 60:40 vollvol
`(pH 6.20), delivered at 1 ml min- 1 (Beckman 112 solvent delivery module). The
`column effluent was monitored at 280 nm (Beckman 160 UV Absorbance Detector)
`and the concentration of each compound was calculated using a standard calibration
`curve, run with each assay.
`
`0005
`
`

`

`144
`
`E. Ranucci et al.
`
`The assay allowed a complete separation of derivatives from naproxen and
`detected concentrations as low as 100 ng ml- 1 of naproxen in plasma. The terminal
`elimination rate constant (ft) was estimated by linear regression of the terminal phase
`of the log plasma concentration vs time curve. The half-life (t 112 ) was calculated as
`In 2/ fl. The area under the plasma concentration-time curve was calculated by the
`trapezoidal rule, truncated at 30 h (AUC0_30 h). Clearance (Cl) after the intravenous
`dose was calculated as dose/ AUC and the relative oral bioavailability (F) was calcu(cid:173)
`lated as AUCcterivative/ AUCnaproxen ·
`
`RESULTS AND DISCUSSION
`
`Synthesis of naproxen derivatives
`
`The naproxen derivatives 1-V prepared in this investigation were all obtained by
`condensation of S( + )-2-(6-methoxy-2-naphthyl)propionic acid with the . proper
`hydroxylic compounds, using 1,1 '-carbonyldiimidazole as a coupling agent, in
`anhydrous, alcohol-free chloroform. Therefore, in all cases, the chemical linkage
`
`0
`~H3 II
`~CH-C-OH +
`;V\}J
`
`N
`O
`N
`~ II F\:J
`N-C-N -
`
`1)
`
`CH 0
`3
`
`N
`Fl
`HN"=J
`
`2)
`
`+
`
`HO-R
`
`CHCl
`
`3
`
`N
`Fl
`HN"=J
`
`0
`~H3 II
`~CH-C-0-R
`
`;V\}J
`
`CH 0
`3
`
`I: R = HO-CH2CH 20-CH2CH 2 -
`II: R = HO-(CH 2CH20)z-CH2CH 2 -
`III: R = HO-(CH2CH2CH 2CH 2)z-
`IV: R = CH3(CH2)z-CH20CO-CH2CH 2 -(0CH2CH2)z(cid:173)
`V: R = CH 3(CH2)z-CH20CO-CH2CH 2 -(0CH2CH2h-
`
`Scheme 1.
`
`0006
`
`

`

`Naproxen prodrugs based on poly(ethyleneglycol)s
`
`145
`
`between the drug and the promoiety is an ester bond. The reaction pathway followed
`to prepare products I-IV consists of two steps. Firstly, an activated derivative of
`naproxen, namely naproxen-imidazolide was prepared. Secondly, the activated
`derivative was reacted at 60°C, and under anhydrous conditions with a large excess
`(derivative I-III) or a small excess (derivative IV and V) of the proper hydroxylated
`compound (see Scheme 1) . .
`Particular care must be taken, in the second step, to work with excess naproxen(cid:173)
`imidazolide in respect to the hydroxy compounds, in order to avoid the presence of
`unreacted alcoholic moieties, which are very difficult to separate from their ester(cid:173)
`derivative. On the contrary, residual naproxen imidazolide can be easily eliminated
`from the reaction mixture by simply repeatedly washing the organic solution with
`aqueous sodium hydroxide.
`In the case of derivatives IV and V, the hydroxylated compounds they are based
`on were in turn prepared by reacting n-butanol with CDI, thus obtaining butyl(cid:173)
`imidazolyl formate, and then with a large excess of triethylene and tetraethylene
`glycol, respectively (Scheme 2).
`Reaction times were prolonged, due to the exceptional stability of naproxen(cid:173)
`imidazolide to nucleophilic attack. The kinetics of condensation reactions were fol(cid:173)
`lowed by HPLC analysis for every product, up to complete conversion. Purification
`
`CH (CH ) OH
`3
`2 4
`
`+
`
`CHCl
`3
`
`N Fi
`
`HNCJ
`
`0
`II FN
`(CH ) O-C-N1 -~
`CJ-
`
`2 4
`
`CH
`3
`
`+
`
`HO- ( CH CH 0) -OH
`2
`2
`n
`
`CHCl
`
`3
`
`N Fl
`HNCJ
`
`0
`II
`CH (CH )CH 0-C-O(CH CH 0)-0H
`3
`2: 2
`2
`2
`n
`
`n
`
`3, 4
`
`Scheme 2.
`
`0007
`
`

`

`146
`
`E. Ranucci et al.
`
`4o A
`
`4o B
`
`30
`
`30 ~\
`E2o ~ 0>
`E.
`c
`0
`~ a+-~~~~~~~~~
`c Q)
`§
`
`10
`
`0
`
`12
`
`18
`
`24
`
`30
`
`36
`
`()
`
`40
`
`D
`
`4o E
`
`40 c
`
`30
`
`20 r\
`'o~
`
`10
`
`0+-~~~~~~~~~-,
`0
`12
`18
`24
`30
`36
`
`40 F
`
`30
`
`20
`
`10
`
`()
`
`(/)
`
`3o
`
`C'Cl E
`C'Cl a. 20
`
`10 / \
`.
`o+-~~~~~~~~~FT~~
`12
`18
`24
`30
`36
`0
`
`0+-~~~~~~~~~ o~~~~~~n-~~~
`12
`18
`24
`30
`0
`12
`18
`24
`0
`36
`30
`36
`
`time (h)
`
`Figure 1. Time course of plasma concentrations in rats who received 20 mg kg- 1 body weight by gavage:
`A = naproxen, B = I, C = II, D = IV, E = V, F = III.
`
`of raw products was performed by gel filtration chromatography (silica gel, chloro(cid:173)
`form/isopropanol 4: 1). All adducts were characterized by IR and NMR spec(cid:173)
`troscopy. Results are in full agreement with proposed structures. Their purity was
`checked by HPLC.
`
`Pharmacokinetic results
`
`Average plasma concentrations of naproxen, after oral administration to rats of
`naproxen and five derivatives, are shown in Fig. 1. Underivatized naproxen gave rise
`to the highest AUC from time 0 to 30 h: 409 mg 1- 1 h. Relative bioavailabilities of
`derivatives I to V are reported in Table 1. Derivatives I and II showed the highest
`relative bioavailability of the group. Plasma half-lives of the active moiety were
`similar for all derivatives, but slightly longer for underivatized naproxen. This is not
`expected; in fact the chemical species measured is always the same, i.e. naproxen.
`The higher t 112 found after underivatized naproxen can be explained by the higher
`plasma concentrations which always made it possible to identify the slow terminal
`component. For other derivatives, the last time point was not always measurable,
`thus giving rise to possible underestimation of the terminal t 112 • A slow component
`
`Table 1.
`Pharmacokinetic data on prodrugs 1-V.
`
`Compound
`
`t 1/2 (h)
`
`AUC0 _30 h (mg 1- 1 h)
`
`Frel (o/o)
`
`Naproxen
`I
`II
`III
`IV
`v
`
`9.5 =t= 4.7
`4.8 =t= 1.3
`5.2 =t= 2.2
`4.1 =t= 1.3
`5.4 =t= 1.4
`3.8
`
`410 'F 100
`256 'F 168
`350=t=112
`47 =t= 10
`94 =t= 80
`214
`
`100
`62.4
`85.4
`11.5
`22.9
`52.2
`
`0008
`
`

`

`Naproxen prodrugs based on poly(ethyleneglycol)s
`
`147
`
`of the elimination was apparent from about 20 h thereafter. It may be observed that
`naproxen was always undetectable in corn oil suspensions for oral administration,
`indicating that all the naproxen measured in plasma comes from in vivo cleavage of
`drug-promoiety linkage.
`In all cases, all the new naproxen derivatives described in this paper show
`bioavailability lower than that of the free drug. This is in contrast with previous
`results obtained with other hydrophobic carboxylated drugs [4, 5], and might be
`related to the fact that naproxen is not inactivated by liver, and therefore there is not
`a protective effect in this direction owing to the prodrug approach. However, the
`early plasma peak and the relatively reproducible, even if lower, bioavailability of
`the derivatives offer the possibility of searching for less gastrolesive NSAID
`molecules among this group.
`
`CONCLUSIONS
`
`The five derivatives selected for this study were of comparable molecular size, but
`differed in terms of hydrophilicity of the promoiety in three of them, in fact, namely
`I-II, the promoieties were typically amphiphilic, while in derivative III the promoi(cid:173)
`ety was hydrophobic, and in derivatives IV and V the promoieties have an inter(cid:173)
`mediate HLB. The pharmacokinetic results clearly demonstrate that derivative III
`has the lowest bioavailability. All the other derivatives have bioavailabilities which,
`although not dramatically different from each other, can be arranged in the order
`II > I > V > IV. It is evident from these considerations that, either the absorption
`through the gastrointestinal tract, or the hydrolytical stability of the drug-promoiety
`linkage, responsible for the detection of the free drug in the blood stream, or both,
`are strictly related to the overall hydrophilic- lypophilic balance of the prodrug
`molecule. In fact, the bioavailability of naproxen adducts is comparable with the
`oligoethyleneoxides-based prodrugs, but abruptly decreases when the drug is bound
`to the residue with the longest hydrocarbon chain, and finally it reaches intermediate
`values when the promoiety is a compromise between the two situations. We think
`that the same trend will be probably followed by most derivatives obtained from
`drugs with the same physico-chemical properties.
`
`Acknowledgements
`
`This work has been supported by the Italian CNR, Progetto Finalizzato Chimica
`Fine. R. Bernasconi is fellow of Banca Popolare di Milano.
`
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