Research Article

Design, characterization, and in vitro evaluation of zaltoprofen solid dispersion as a hollow-type rectal suppository Shaimaa Nazar Abd Alhammid*, Manar Adnan Tamer, Mais Abd-Alridha Abbod

ABSTRACT

Aim: The present study aims to improve the poor water solubility of zaltoprofen which is a non-steroidal anti-inflammatory drug (NSAIDs) with a potent analgesic effect using solid dispersion then formulate it as a hollow type suppository to be more convenient for geriatric patients. Materials and Method: Zaltoprofen solid dispersions were prepared by solvent evaporation technique in different zaltoprofen: Soluplus® ratios. Results: Among the formulations tested, zaltoprofen solid dispersion preparation using 1:5 (zaltoprofen: Soluplus®) ratio showed the highest solubility and selected for further investigation. Solid dispersion characterization was evaluated by differential scanning calorimetry (DSC), X-ray diffraction study (XRD) and Fourier transformation infrared spectroscopy (FTIR). DSC and XRD analysis showed a complete transformation of zaltoprofen in the solid dispersion from a crystalline state to amorphous state. The selected zaltoprofen solid dispersion was further incorporated into hollow type suppositories using witepsol H 35 as a suppositories base. The hollow type suppositories were evaluated for hardness test (breaking strength), melting time, softening time and in vitro drug dissolution rate. Formula F8 containing zaltoprofen solid dispersion in the whole of hollow type suppository showed the shortest and significantly the highest dissolution rate profile (100% within 15 min) compared to other hollow type suppository formulas prepared that contain zaltoprofen powder in its whole. Conclusion: It is concluded that the development of zaltoprofen solid dispersions using Soluplus® as hollow-type suppositories could be used as a promising approach for improving the solubility of poorly water-soluble drugs. KEY WORDS: Hollow-type suppositories, Solid dispersions, Soluplus, Witepsol H 35, Zaltoprofen

INTRODUCTION and tranquilizer therapy.[3,4] Hollow-type suppositories are superior to conventional suppositories in that they Suppositories are solid dosage forms, intended for were found to be less influenced by the kind of the insertion into body cavities where they melt, soften base material then were the conventional types.[5] [1] or dissolve, and exert their local or systemic effects. Furthermore, it can carry either powdered or solution forms of drugs in addition to the elimination of the The rectal absorption occurs mainly by passive effect of the heating process on the nature of the drug diffusion, and the drug release from a suppository during the preparation of the suppository.[6] At the is likely to be an essential factor in determining the same time, they are expected to eliminate interaction drug concentration in the rectal fluids and hence its between drugs and base materials since the two absorption rate. This means, both the drug solubility are separated.[7] On the other hand, hollow-type and the excipients characteristics play a crucial role in suppository showed more rapid drugs release with the rate of drug absorption.[2] efficient absorption than conventional suppositories.[8] A hollow-type suppository is a suppository which has Zaltoprofen (ZLP) is nonsteroidal anti-inflammatory a hollow cavity in the middle to accommodate drugs drugs (NSAIDs) with potent analgesic effect. NSAIDs in various forms such as powders or solutions, is very are sort out according to their chemical structure and effective as a rapid pain reliever or in an anxiolytic their selective inhibition of cyclooxygenase (COX)-1 and COX-2.[9] Access this article online ZLP is one of the NSAIDS advised for patients who Website: jprsolutions.info ISSN: 0975-7619 have rheumatoid arthritis as well as to relieve pain

Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq

*Corresponding author: Shaimaa Nazar Abd Alhammid, Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq. Phone: +91-9647703951999. E-mail: [email protected]

Received on: 21-08-2018; Revised on: 25-09-2018; Accepted on: 27-10-2018

Drug Invention Today | Vol 12 • Issue 1 • 2019 83 Shaimaa Nazar Abd Alhammid, et al. and inflammation after surgery, injury, and tooth Preparation of ZLP-Soluplus solid dispersions extraction.[10] It is freely soluble in acetone, soluble Solvent evaporation method in ethanol and methanol, and practically soluble in It is a commonly used method to prepare solid water.[11-13] The bioavailability of the drug is about 70% dispersions in small scale and involves the when given orally due to the first pass metabolism.[14] solubilization of API and carriers in a volatile solvent. In this method, thermal degradation of API Solid dispersion is considered as one of the most or polymers can be prevented since the process can effective approaches to improve water solubility and be performed without extensive heating. The basic the dissolution rate consequently the bioavailability process of solvent evaporation method involves two [15] of poorly water-soluble drugs. Soluplus which is steps: a combination of polyvinyl caprolactam-polyvinyl 1. Dissolving the physical mixture of API and carrier acetate-polyethylene glycol [PEG] graft copolymer) in a common solvent or solvent mixture. is a novel polymer that has amphiphilic properties, 2. Removing the solvent to obtain the solid mass and designed and developed for solid solutions. the resulting solid mass is afterward pulverized and milled.[18] Unlike traditional solubilizers such as Cremophor RH40 and Solutol HS15, Soluplus with its Characterization of optimized solid dispersion multifunctional features of a polymer for solid Differential scanning calorimetric (DSC) studies solutions with excellent stability and an active Thermograms for ZLP plain powder, Soluplus plain solubilizer by micelle formation in water, also, can powder, and the selected solid dispersion formulation be considered as a member of the fourth generation were obtained. The samples were sealed in aluminum [16] of solid dispersions. Soluplus shows enormous pans and analyzed using a Shimadzu DSC-60 (Kyoto, solubilizing properties for Biopharmaceutics Japan). The samples were heated in an atmosphere of Classification System Class II drugs and offers the nitrogen and thermograms were obtained by heating possibility of producing solid solutions of several at a constant heating rate of 10°C/min in the range of drugs of the poor water solubility using extrusion 20–350°C. techniques.[17] Powder X-ray diffraction (XRD) The primary objective of this study was done to Diffraction patterns of ZLP plain powder, Soluplus formulate ZLP solid dispersion as hollow-type plain powder, and the selected solid dispersion suppositories for rectal administration to achieve a formulation were determined in a Scintag XRD meter rapid and complete release of the drug. (USA) using Cu K α radiation with a nickel filter, a voltage of 45 kV, and a current of 40 mA. MATERIALS AND METHODS Fourier transformation-infrared (FT-IR) spectroscopy Materials FT-IR spectra were obtained using FTIR spectrometer ZLP powder was purchased from Hangzhou Hyper which was employed to characterize the possible Chemicals Limited, China. Witepsol H35 was supplied by interactions between the drug and the carrier in the Samara’s Drug Industry, while cocoa butter, theobroma solid state. Samples of about 2 mg were lightly ground oil, and PEG 1000, PEG 4000, and PEG 6000 were and mixed with IR grade dry potassium bromide and synthesized in BDH Chemicals, Ltd., India. On the other then compressed at 10 tones in a hydraulic press hand the poly ethylene glycol (PEG 400) was provided for 5 min to form discs. The spectra of ZLP plain from Searle Company, Hopkin and Williams [England]). powder, Soluplus plain powder, and the selected Soluplus® was provided by BASF, Germany. All other solid dispersion formulation were scanned over a chemicals were of analytical grade. frequency range of 4000–500 cm−1 with a resolution of 4 cm−1.[19] Methods Preparation of ZLP-Soluplus solid dispersions Preparation of suppositories Phase solubility studies Hollow-type suppositories were prepared by fusion An excess amount of ZLP was added to the aqueous method [Table 1] in which the suppository base solutions of Soluplus in water containing increasing (Witepsol 35, cocoa butter, and PEG) was melted at concentrations of Soluplus (1:1, 1:3, and 1:5 of their appropriate temperature; then, the melted bases ZLP:Soluplus). The vials were sealed then shaked at were poured into 2 g suppository mold equipped by 37 ± 0.5°C for 48 h in a thermostatically controlled cylindrical tube in the center and allowed to stand for water bath, and the samples were filtered through a 2 h at room temperature to solidify. After construction 0.45 μm membrane filter. The filtrate was diluted, of a hollow cavity in the solidified bases, 10 mg ZLP and the concentration in the solution was determined powder mixed with lactose powder (used as filler) in a spectrophotometrically at λmax 243 nm. ratio (1:0.5) was added to the cavity.[20]

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Evaluation of the prepared ZLP suppositories the physical properties of the prepared hollow-type Hardness test (breaking strength) suppositories. Hardness was determined at room temperature using Erweka hardness tester. A good result is at Effects of the types of lipophilic base least 1.8–2 kg pressure. The purpose of this test is to Formulas F4 and F5 were prepared using lipophilic verify that the suppository can be transported under bases which are cocoa butter and Witepsol H35 to normal conditions and administered to the patient. investigate their effect on the physical properties of The suppository was placed into the holding device the prepared hollow-type suppositories. with the tip upward, and the test chamber was then Effect of the types of suppository base and mode of ZLP closed with a glass plate. At this point, the initial load F2 (PEG 400:4000 in a ratio 70:30) that was contained which was given by the entire suspended block was hydrophilic bases and 80 mg of ZLP powder and F5 600 g. After 1 min, a disc of 200 g was added, and this (Witepsol H 35) that was contained a lipophilic base weight addition was continued every minute until the and 80 mg of ZLP powder to investigate the effect suppository collapse. of the nature of the suppository base on the physical properties and the in vitro release of ZLP from the If the suppository collapsed within 20–40 s of placing prepared suppositories. the last disk, then half of this mass was used in the calculation, i.e., 100 g. Effect of ZLP-Soluplus solid dispersions ratios Formulas F6, F7, and F8 were prepared from different If the suppository remained uncrushed for more than ratios of ZLP-Soluplus solid dispersions (1:1, 1:3, and [21] 40 s, then all the mass was used in the calculation. 1:5 of ZLP:Soluplus) to investigate the effect of solid Determination of the melting time dispersions ZLP-Soluplus on the physical properties The suppositories were placed into a glass tube (2.5 cm and the in vitro release of ZLP from the prepared diameter); 2 ml of a phosphate buffer ± solution of pH 7.4 suppositories. was then added. The tube was placed in a water bath at 37°C ± 0.5°C. The time required for each suppository to RESULTS AND DISCUSSION melt entirely and disintegrate was determined.[20] ZLP-Soluplus Solid Dispersions Softening time determination Phase solubility studies The softening time test was performed for lipophilic ZLP aqueous solubility was calculated to bases suppositories, and it indicates how long specific be 0.0135 mg/mL; therefore, ZLP can be defined as a preparation takes to lose its physical structure. The practically insoluble drug according to the United States softening time was done by inserting the suppository Pharmacopeia. Therefore, the solubility of ZLP alone in the spiral-shaped glass basket of the test tube. and in the presence of serial dilutions of Soluplus is A thermostat connected to the tester provided circulating represented in Table 2. The solubility of ZLP increased distilled water inside the test tube at a temperature of as a function of Soluplus concentrations due to micellar 37°C and constant rate flow. The time required for the first drop of the suppository base to appear floating on the surface was considered as the softening.[22] Table 1: Composition of ZLP hollow‑type suppositories In vitro drug release Formulas ZLP quantities (mg) Type of base In vitro release test was carried out using USP rotating F1 80 powder PEG 400:6000 (70:30) basket dissolution apparatus. Each suppository was F2 80 powder PEG 400:4000 (70:30) placed in a basket and lowered into a flask containing F3 80 powder PEG 400:1000 (70:30) 900 ml of phosphate buffer solution (pH 7.4). The F4 80 powder Cocoa butter F5 80 powder Witepsol H 35 basket rotated at 50 rpm at a constant temperature of F6 80 powder: (1:1) SD Witepsol H 35 37°C ± 0.5°C.[10] At appropriate time intervals (0, 5, 10, F7 80 powder: (1:3) SD Witepsol H 35 15, 20, 25, 30, 40, 50, and 60 min), 5 ml samples were F8 80 powder: (1:5) SD Witepsol H 35 withdrawn through syringe millipore filter, the volume PEG: Polyethylene glycol, SD: Solid dispersion, ZLP: Zaltoprofen of the dissolution medium was kept constant by replacing the withdrawn volume of the sample with an Table 2: The aqueous solubility of different equal volume of fresh dissolution medium maintained ZLP‑Soluplus solid dispersion ratios prepared by the at the same temperature. ZLP samples analyzed using solvent evaporation method presented in mg/ml an ultraviolet spectrophotometric method.[23] ZLP‑Soluplus® solid dispersion Aqueous solubility ratios Factors affecting formulations 1:1 0.018 Effects of the type of PEG 1:3 0.2 Formulas (F1, F2, and F3) were prepared to study 1:5 2.4 the effect of a mixture of different PEG types on ZLP: Zaltoprofen

Drug Invention Today | Vol 12 • Issue 1 • 2019 85 Shaimaa Nazar Abd Alhammid, et al. solubilization. On the other hand, the solubility of ZLP were investigated using powder XRD figures as shown was increased up to 2.4 mg/mL corresponding to 177.8- in Figures 4-6. The diffractogram of ZLP revealed fold increase, indicating an excellent affinity between its crystalline nature as indicated that ZLP has a high ZLP and Soluplus to form a molecular dispersion. melting point (139.5°C), which is an indication of the Soluplus is a polymeric solubilizer with an amphiphilic strong crystal lattice energy. This high melting point chemical structure, having a large number of hydroxyl is one of the factors responsible for its poor aqueous groups which make it a good solubilizer for poorly solubility.[26] Therefore, any approach which disrupts soluble drugs in aqueous media. Phase solubility the crystalline nature and/or results in lowering the showed an increase in drug solubility with increasing crystal lattice energy would improve the aqueous polymer concentration.[24] solubility of the drug. Therefore, the crystalline nature of the drug can be disrupted by solid-state dispersion DSC studies of the drug into water-soluble carrier molecules which DSC was employed to evaluate the phase of replace the drug molecule in the crystal lattice. This transformation of ZLP during the formation of solid results in a partial or total loss of drug crystallinity, dispersions. As illustrated in Figures 1 and 2, the free resulting in a significant increase in its solubility. drug was characterized by a single, sharp melting As a water-soluble polymer, the Soluplus has been endothermic peak of 138.4°C corresponding to the demonstrated to retard and inhibit the crystallization melting point of ZLP confirming its crystallinity. of drugs, giving amorphous solid dispersions with Soluplus showed broad endothermic peaks at increased drug dissolution rate and solubility.[27] 77.52°C. The optimized solid dispersion formulation did not show the endothermic melting peak of ZLP, FTIR spectroscopy suggesting a complete conversion of the crystalline To study the possibility of the interaction between drug into its amorphous form as shown in Figure 3.[25] ZLP and Soluplus in the solid state, the spectra of

Powder XRD For further examination for the physical form of the drug in the solid dispersion, a pure ZLP, physical mixture, and the optimized solid dispersion formulation F8

Figure 3: Differential scanning calorimetric studies for the selected formula F8

Figure 1: Differential scanning calorimetric studies of zaltoprofen

Figure 4: X-ray diffraction of zaltoprofen pure drug

Figure 5: X-ray diffraction of the physical mixture

Figure 2: Differential scanning calorimetric studies of the physical mixture Figure 6: X-ray diffraction of selected formula (F8)

86 Drug Invention Today | Vol 12 • Issue 1 • 2019 Shaimaa Nazar Abd Alhammid, et al. pure ZLP powder, physical mixture, and that of the facts which are: There was band wavelength at 3057 selected lyophilized tablet (F8) shown in Figures 7-9 and 3059 cm−1 which represented the O-H stretching that displayed no significant shifting in the position of (standard freq. =3000–3200) cm−1 in both the pure the characteristic peaks of the main functional groups. drug, physical mixture, and the selected formula. The previous evaluation was based on the following There were band wavelengths at 1703 and 1705 cm−1 which represented the –C=O stretching (standard Table 3: Physical properties of hollow‑type freq. = 1680–1880) cm−1 in both the pure drug, suppositories of ZLP physical mixture, and the selected formula. There was Formulas Hardness (kg) Melting Softening band wavelength at 926 cm−1 which represented the time (min) time (min) –C-S-C stretching (standard freq. = 800–1000) cm−1 in F1 2.6 28 ‑ both the pure drug, physical mixture, and the selected F2 2.5 26 ‑ formula. Furthermore, there was band wavelength F3 ‑ ‑ ‑ F4 2.6 29 at 1284 cm−1 which represented the C-H bending in F5 2.7 32 7 the plane of the benzene ring (standard freq. =1300– F6 2.9 33 7.5 −1 F7 2.8 32 8 1000) cm in both the pure drug, physical mixture, F8 2.7 31 8 and the selected formula. There was band wavelength ZLP: Zaltoprofen at 696 and 665 cm−1 which represented the C-C ring

Figure 7: Fourier transformation infrared of zaltoprofen (ZLP) pure ZLP

Figure 8: Fourier transformation infrared of the physical mixture

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Figure 9: Fourier transformation infrared of the selected formula F8 bending out of the plane of the benzene ring in both the pure drug, physical mixture, and the selected formula.

From all above, principle peaks of pure ZLP were also detected in the physical mixture, and the selected formula F8, which can indicate that there was no interaction found.[28]

Evaluation of suppositories Effects of the type and ratio of PEG Table 2 summarizes the effects of changing the type and ratio of PEGs on the physical properties of the Figure 10: In vitro dissolution profiles of zaltoprofen hollow-type suppositories. The results indicated that from different hollow-type suppositories formulations in the melting time increases in the order (F2>F1), while phosphate buffer 7.4 and 37°C temperature F3 was melted at room temperature. This may be related mainly to the fact that the melting point and the hardness of PEGs increase as a function of increasing were attributed to the high melting point of the bases the polymerization of the polymer used that may while PEG bases have a lower melting point, and increase with increasing the molecular weight used.[29] their water-soluble properties made them easy to Furthermore, F2 was selected as the best formula dissolve.[31] The effect of the type of suppository base among the hydrophilic base suppositories and used for on the release of ZLP is shown in Figure 10. Ranking further investigation. the tested formulas in descending order, according to the percentage of drug release along the dissolution Effect of the types of suppository base and mode of ZLP period was as follows: F2> F4>F5. It was found that Three formulas were selected for this study. It was the release rate was significantly higher (P < 0.05) for found that the melting time and hardness for lipophilic suppositories prepared from hydrophilic bases (F5) bases (Witepsol H 35) were to be longer compared (PEG 400–4000 [70:30]) than that from those prepared to that of hydrophilic bases (PEG 4000:400 [70:30]) from oleaginous bases F4 to F5. The increase in the [Table 3]. This is because the melting time and hardness release of the drug may attribute that the presences of of PEG increase as a function of polymerization of the PEG, which increase the dissolution rate of the drug polymer used that increases with the increase of the from the suppository.[32] molecular weight used.[30] The rapid melting of PEG 400–4000 (70:30) about Besides to that, the hardness of the oleaginous bases 3 min and the presence of lactose powder, which (Witepsol H 35) was found to be higher than that used as a filler, in a ratio of 1:0.5 lead to enhance for the water-soluble base which may be due to the the drug powder dissolution, so allowed the rapid high values of the oil-soluble suppositories which release of ZLP. The faster release of ZLP from mixed

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PEG bases may be due to the low affinity of ZLP to ZLP-Soluplus solid dispersion compared with the the bases and the water solubility of the base, which suppositories that formulated with ZLP powder using allows ZLP to be released by both diffusion and different suppository base. Hence, the hollow-type erosion mechanisms.[8] suppositories are useful as a promising approach for a fast drug release, and it is a more convenient dosage Drug partitioning is a function of the nature of the form for the geriatric patients. base, and it corresponds to the affinity of the drug toward bases. When there is a low affinity between the REFERENCES drug and the base, the release rate of the substances having high solubility in aqueous media is expected 1. Ansell H, Allen L, Popovich N. Pharmaceutical Dosage form th [32] and Drug Delivery System. 8 ed. Baltimore: Lippincott to be high. Williams and Wilkins; 2005. p. 316-30. 2. Shegokar R, Kamalinder RK. 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