Drug Delivery, 12:133–139, 2005 Copyright c Taylor & Francis Inc. ISSN: 1071-7544 print / 1521-0464 online DOI: 10.1080/10717540590925726 Formulation, Characterization, and Evaluation of Ketorolac Tromethamine-Loaded Biodegradable Microspheres Vivek Ranjan Sinha and Aman Trehan University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India Ketorolac tromethamine has to be given every 6 hr intramus- cularly in patients for acute pain, so to avoid frequent dosing and patient inconvenience we found it to be a suitable candidate for parenteral controlled delivery by biodegradable microspheres for the present study. Ketorolac tromethamine-loaded microspheres were prepared by o/w emulsion solvent evaporation technique using different polymers: polycaprolactone, poly lactic-co-glycolic acid (PLGA 65/35), and poly lactic-co-glycolic acid (PLGA 85/15). To tailor the release profile of drug for several days, blends of PLGA 65/35 and PLGA 85/15 were prepared with polycaprolactone (PCL) in different ratios. The results revealed that microspheres made with 1:3 (PLGA65/35: PCL) blend released 97% of the drug in 5 days as compared with 97% in 30 days in with pure PLGA65/35 microspheres. Microspheres made with 1:1 (PLGA65/35:PCL) and 3:1 (PLGA65/35:PCL released 98% of the drug in 30 days. In mi- crospheres made with 1:3 (PLGA85/15:PCL), almost the entire drug was released in a week whereas in batches made with pure PLGA85/15 and 3:1 (PLGA 85/15:PCL) more than 80% of the drug was released in 60 days as compared with 96% in 60 days in 1:1 (PLGA85/15:PCL). Higher encapsulation efficiency was ob- tained with microspheres made with pure PLGA 65/35. These for- mulations were characterized for particle size analysis by Malvern mastersizer that revealed particle size in range of 12–15 micron and 12–22 micron for microspheres made with polymer blends of PLGA 65/35:PCL and PLGA85/15:PCL, respectively. In with pure PLGA65/35 and PLGA85/15, particle size was 28 micron and 8 micron, respectively. Surface topography was studied by scan- ning electron microscopy that revealed a spherical shape of micro- spheres. From our study it we concluded that with careful selection of different polymers and their combinations, we can tailor the release of ketorolac tromethamine for long periods. Keywords Microspheres, Polycaprolactone (PCL), Poly Lactic-Co- Glycolic Acid (PLGA) Since its emergence, the field of controlled drug delivery has grown immensely. Interest in controlled-release technology has Received 25 May 2004; accepted 24 August 2004. We are most grateful to the University Grants Commission (UGC) for providing financial assistance. Address correspondence to Vivek Ranjan Sinha, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India. E-mail: vr [email protected]increased steadily throughout the past few decades. Because of the time and cost involved in developing a new molecule ($800 million to $1 billion when factoring all postlaunch activities, such as marketing, advertising, education, and training), there is great focus on developing novel or innovative drug delivery technologies that are intelligent enough to navigate the therapeu- tic molecule to the desired site and that can be developed much quicker and more economically ($20 to $50 million and 3–4 years). These cutting edge technologies are needed to deliver drugs, proteins, and other genetically engineered pharmaceu- ticals to their site of action so that their delivery is accurate, modulated, and effective. Despite the competition from alternative modalities, demand for controlled release parenteral drug delivery systems is rising 9.5% annually and expected to reach almost $20 billion in 2005. Parenteral drug administration, especially intravenous infusion, leads to easy and complete absorption of drug in systemic circu- lation, eliciting a prompt drug response. But this requires direct medical supervision and hospitalization of the patient. Parenteral drug administration via the intramuscular route or the subcuta- neous route has a fairly rapid onset of action followed by a rapid decline in the blood–drug level leading to relatively short dura- tion of therapeutic response. To amelionatethe above problems associated with different seems modes of drug administration, injectable depot formula- tion to provide the solution. Parenteral depot formulations can control drug release over a predetermined time span usually in days to weeks to months (Okada et al. 1994; Okada et al. 1989). There are various means of formulating prolonged release prepa- rations and the use of biodegradable microspheres is one of them (Cruaud, Benita, and Benoit 1999; Bozdag et al. 2001; Li et al. 2001; Thies and Bissery 1984). Microspheres of biodegradable and nonbiodegradable poly- mers have been investigated for sustained release depending on their final application. Nonbiodegradable polymers pose prob- lems of toxicity, difficulty in removal, and of a now constant rate of drug release from controlled release devices using these poly- mers (Herman and Bodmeier 1995). To overcome these prob- lems, concept of biodegradable polymers for sustained release parenteral drug delivery systems began to develop in the early 133 Drug Delivery Downloaded from informahealthcare.com by Laurentian University on 09/14/13 For personal use only.
Formulation, Characterization, and Evaluation of KetorolacTromethamine-Loaded Biodegradable Microspheres
Vivek Ranjan Sinha and Aman TrehanUniversity Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
Ketorolac tromethamine has to be given every 6 hr intramus-cularly in patients for acute pain, so to avoid frequent dosing andpatient inconvenience we found it to be a suitable candidate forparenteral controlled delivery by biodegradable microspheres forthe present study. Ketorolac tromethamine-loaded microsphereswere prepared by o/w emulsion solvent evaporation technique usingdifferent polymers: polycaprolactone, poly lactic-co-glycolic acid(PLGA 65/35), and poly lactic-co-glycolic acid (PLGA 85/15). Totailor the release profile of drug for several days, blends of PLGA65/35 and PLGA 85/15 were prepared with polycaprolactone (PCL)in different ratios. The results revealed that microspheres madewith 1:3 (PLGA65/35: PCL) blend released 97% of the drug in5 days as compared with 97% in 30 days in with pure PLGA65/35microspheres. Microspheres made with 1:1 (PLGA65/35:PCL) and3:1 (PLGA65/35:PCL released 98% of the drug in 30 days. In mi-crospheres made with 1:3 (PLGA85/15:PCL), almost the entiredrug was released in a week whereas in batches made with purePLGA85/15 and 3:1 (PLGA 85/15:PCL) more than 80% of thedrug was released in 60 days as compared with 96% in 60 daysin 1:1 (PLGA85/15:PCL). Higher encapsulation efficiency was ob-tained with microspheres made with pure PLGA 65/35. These for-mulations were characterized for particle size analysis by Malvernmastersizer that revealed particle size in range of 12–15 micronand 12–22 micron for microspheres made with polymer blendsof PLGA 65/35:PCL and PLGA85/15:PCL, respectively. In withpure PLGA65/35 and PLGA85/15, particle size was 28 micron and8 micron, respectively. Surface topography was studied by scan-ning electron microscopy that revealed a spherical shape of micro-spheres. From our study it we concluded that with careful selectionof different polymers and their combinations, we can tailor therelease of ketorolac tromethamine for long periods.
Since its emergence, the field of controlled drug delivery hasgrown immensely. Interest in controlled-release technology has
Received 25 May 2004; accepted 24 August 2004.We are most grateful to the University Grants Commission (UGC)
for providing financial assistance.Address correspondence to Vivek Ranjan Sinha, University Institute
of Pharmaceutical Sciences, Panjab University, Chandigarh-160014,India. E-mail: vr [email protected]
increased steadily throughout the past few decades. Because ofthe time and cost involved in developing a new molecule ($800million to $1 billion when factoring all postlaunch activities,such as marketing, advertising, education, and training), thereis great focus on developing novel or innovative drug deliverytechnologies that are intelligent enough to navigate the therapeu-tic molecule to the desired site and that can be developed muchquicker and more economically ($20 to $50 million and 3–4years). These cutting edge technologies are needed to deliverdrugs, proteins, and other genetically engineered pharmaceu-ticals to their site of action so that their delivery is accurate,modulated, and effective.
Despite the competition from alternative modalities, demandfor controlled release parenteral drug delivery systems is rising9.5% annually and expected to reach almost $20 billion in 2005.Parenteral drug administration, especially intravenous infusion,leads to easy and complete absorption of drug in systemic circu-lation, eliciting a prompt drug response. But this requires directmedical supervision and hospitalization of the patient. Parenteraldrug administration via the intramuscular route or the subcuta-neous route has a fairly rapid onset of action followed by a rapiddecline in the blood–drug level leading to relatively short dura-tion of therapeutic response.
To amelionatethe above problems associated with differentseems modes of drug administration, injectable depot formula-tion to provide the solution. Parenteral depot formulations cancontrol drug release over a predetermined time span usually indays to weeks to months (Okada et al. 1994; Okada et al. 1989).There are various means of formulating prolonged release prepa-rations and the use of biodegradable microspheres is one of them(Cruaud, Benita, and Benoit 1999; Bozdag et al. 2001; Li et al.2001; Thies and Bissery 1984).
Microspheres of biodegradable and nonbiodegradable poly-mers have been investigated for sustained release depending ontheir final application. Nonbiodegradable polymers pose prob-lems of toxicity, difficulty in removal, and of a now constant rateof drug release from controlled release devices using these poly-mers (Herman and Bodmeier 1995). To overcome these prob-lems, concept of biodegradable polymers for sustained releaseparenteral drug delivery systems began to develop in the early
133
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134 V. R. SINHA AND A. TREHAN
1970s. Thus, interest in biodegradable polymers developed fortwo reasons: first, surgical removal of a drug-depleted deliverysystem of nonbiodegradable polymers is difficult and nonre-moval may pose toxicological problems; second, diffusion con-trolled delivery systems, though excellent means of achievingpredetermined rates of drug delivery, are limited by polymerpermeability and characteristics of the drug. Because the ba-sic mechanism in nondegradable devices is diffusion, drugs thathave either high molecular weight or poor solubility in polymerare not amenable to diffusion-controlled release.
Yolles, Eldridge and Woodland (1971) were one of the firstgroup to report the use of polypeptides in parenteral drug deliv-ery systems. Thus in the past decade, commercial developmentsusing these polymers have taken place, the most notable beingprostate cancer treatment where a single once-a-month injec-tion has replaced 30 daily injections. Additional promising treat-ments for cancer, viral and bacterial infections, birth control andAIDS are being investigated (Sanders et al. 1985; Rogers andOwnsu-Ababio 1993; Brannon-Peppas, Grosvenor, and Smith1994; Fujita et al. 1992; Cowsar et al. 1985; Eldridge et al.1993). Various FDA-approved controlled release parenteral for-mulations based on these biodegradable microspheres are avail-able in the market includeing Lupron Depot
MATERIALS AND METHODSBiodegradable polymers PLGA 65:35 (inherent viscosity:
0.61 dl/g) and PLGA 85/15 (inherent viscosity: 0.66 dl/g) wereprocured from Birmingham Polymers (USA); polycaprolactone(m wt 10,000) from Fluka; ketorolac tromethamine from SunPharma (Ahemdabad, India); methocel from Panacea Biotech(Lalru, India); and dichloromethane from Qualigens Fine Chem-icals (India).
Preparation of MicrospheresKetorolac tromethamine-loaded microspheres were prepared
by o/w solvent evaporation technique. Ketorolac tromethamine(25 mg) was dispersed in 10 ml of dichloromethane containing500 mg of polymer (in case of blends, the amount of 500 mgwas divided according to ratios e.g., 1:1–250 mg of PLGA and250 mg of PCL). This dispersion was then added to an acidicaqueous phase (50 ml) containing 0.5% of HPMC while stirringto form o/w emulsion. The stirring was continued until completeevaporation of the solvent. The resulting microspheres were fil-tered, washed with excess of water to remove any unentrappeddrug, and finally dried.
Encapsulation Efficiency and Percentage YieldKetorolac tromethamine-containing microsphres (10 mg)
were mixed with 1 ml of dichloromethane, and then 10 ml ofwater was added into solution for the extraction of ketorolac
tromethamine. The solution was mixed by vortex mixer, clari-fied by standing for few minutes, and then upper layer (water)was analyzed for ketorolac trometha mine spectrophotometri-cally at 323 nm. The encapsulation efficiency and precent yieldwere calculated using the following formula.
%EE = Mass of incorporated drug
Mass of drug used for microsphere preparation× 100
%Yield = [1]Weight of microsphres obtained
Weight of drug and polymer used for microsphere preparation× 100
[2]
In Vitro Release Profile StudiesMicrospheres (15 mg) were suspended in 1.5 ml of PBS
(phosphate buffered saline; pH 7.4) in eppendorf tubes andplaced in an incubator-shaker (37◦C) at 50 rpm. At predeter-mined time intervals, samples were centrifuged and supernatantswere withdrawn and replaced by fresh PBS. The process wascontinued until the completion of the dissolution study. Concen-tration of ketorolac tromethamine in supernatants was analyzedspectrophotometrically at 323 nm.
Scanning Electron MicroscopyThe surface topography of microspheres was investigated us-
ing scanning electron microscope (JSM 6100 JEOL, Tokyo,Japan). Microspheres samples were mounted onto stubs us-ing double-sided adhesive tape. The stubs were then vacuumcoated with gold using fine coat ion sputter JFC 1100 (JEOLJapan). Then the microspheres were examined with SEM (JEOLJSM 6100, Tokyo, Japan).
Size Distribution AnalysisThe mean diameter and particle size distribution were exam-
ined by laser diffractometry using Malvern Mastersizer 2000. Incase of laser diffraction measurements, microspheres were sus-pended in distilled water, that was continuously homogenizedat 12,000 rpm and sonicated for 90 sec prior to particle sizedetermination.
In Vivo Pharmacodynamic StudiesThe pharmacodynamic studies were performed using tail
flick method. An analgesiometer (Popular India Ltd.) was usedto measure tail flick response. The tail-withdrawal from the heatsource was taken as the end point. A cut-off of 12 sec was ob-served to prevent damage to the tail. Normal laca mice weighing18–25 g were divided into three groups. Each group consistedof minimum of 6 mice. Blank microspheres, drug solution, anddrug-loaded microspheres (pure PLGA65/35) were injected sub-cutaneously to Groups I, II, and III, respectively. Percent anal-gesic effect (Shu-Yang Yen et al. 2001) was measured as follows:
RESULTS AND DISCUSSIONScanning electron micrographs of PLGA (65:35), PLGA
(85:15), PLGA (65:35): PCL, and PLGA (85:15): PCL mi-crospheres loaded with ketorolac tromethamine are shown inFigures 1–4, respectively. Micropheres of all the polymers werefound to be spherical in nature. As evident from Figure 1, the mi-crospheres prepared from the pure PLGA (65:35) were smooth,spherical, nonporous, with some depressions on the surface. Thesurface topography of microspheres prepared from blend of PCLand PLGA (65:35) in the ratio of 1:1 as depicted in Figure 2revealed a slightly porous surface with few depressions on sur-face. The surface topography of microspheres prepared fromPLGA (85:15) is shown in Figure 3. The microsphres of PLGA(85:15) were smooth and spherical in nature with some minutepores on their surface, whreas the microspheres prepared withblend of PCL and PLGA (85:15) in the ratio of 1:1 (as shownin Figure 4) were spherical and highly porous in nature. Thishighly porous nature was attributed to a faster rate of salting outand precipitation of high molecular weight polymer during sol-vent evaporation compared with those of the lower molecularweight polymer (Elkheshen 1996; Wang, Sato, and Horikoshi1997).
The results of percentage yield, percent encapsulation ef-ficiency (EE), and particle size analysis are listed in Table 1.Yield was reasonably good in all batches. Microencapsulationof highly water-soluble drugs like ketorolac tromethamine byo/w emulsion solvent evaporation technique results in quite lowentrapment efficiency because of the solubility of drug in theouter phase. So to increase encapsulation efficiency, pH of theexternal phase was adjusted toward the acidic side to minimizethe solubility of the drug in external phase. Higher encapsulationefficiency was obtained in batch made with pure PLGA 65:35,which was 58% as compared with its blends in which it variedfrom 40–50%. This significant difference in percent EE as com-
FIG. 1. Scanning electron micrograph of ketorolac tromethamine-loadedPLGA 65/35 microspheres.
FIG. 2. Scanning electron micrograph of ketorolac tromethamine-loadedPCL: PLGA 65/35 (1:1) microspheres.
pared with its blends might be attributed to the higher intrinsicviscosity of the pure polymer solution, which prevented the re-lease or leakage of drug from the inner phase to outer phase andhence resulted in increased entrapment efficiency.
Moreover, encapsulation efficiency also depended on the lac-tide/glycolide ratio of the polymer i.e., higher the lactide ratio,higher the encapsulation efficiency (Jeon et al. 2000). Anotherreason for higher encapsulation efficiency in pure PLGA65/35polymer as compared with its blends was bigger particle size(28 µ) as compared with its blends in which it varied from 13–16 µ. In the case of pure PLGA85/15 and its blends, there wasno significant difference in encapsulation efficiencyal, thoughthe encapsulation efficiency was on the higher side in the caseof pure PLGA85/15; i.e., 49% as compared with its blends (41–45%) which was due to the same reason as cited above. Lowerencapsulation efficiency in pure PLGA85/15 as compared with
FIG. 3. Scanning electron micrograph of ketorolac tromethamine-loadedPLGA 85/15 microspheres.
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136 V. R. SINHA AND A. TREHAN
FIG. 4. Scanning electron micrograph of ketorolac tromethamine-loadedPCL: PLGA 85/15 (1:1) microspheres.
pure PLGA65/35 despite having higher molecular weight wasdue to very small particle size (4 µ) in pure PLGA85/15, whichwas in accordance with previous reports (Bozdag et al. 2001).In general, low encapsulation efficiency in batches could beattributed to high water solubility of ketorolac tromethamine,which partitions into the continuous aqueous phase during themanufacturing process (Selek et al. 2003).
The release profile of different batches of microspheres isshown in Figure 5 (PLGA 65/35 and its blends with PCL) andFigure 6 (PLGA 85/15 and its blends with PCL). Release profilesindicated lower burst effect of ∼18% in pure PLGA 65/35 ascompared with approximately 30% in 1:1 (PLGA65/35:PCL)and 3:1 (PLGA65/35: PCL) blends. About 50% of the drugwas released in 24 hr in pure PLGA 65/35 in contrast to 6hr in 1:1 (PLGA65/35:PCL), 8 hr in 3:1 (PLGA65/35:PCL),
FIG. 5. Release profile of ketorolac tromethamine from PLGA 65/35 microspheres and its blends with PCL.
TABLE 1Percentage (%) yield, encapsulation efficiency (EE) andparticle size data of PLGA 65/35, PLGA85/15, and their
blends with PCL
Batch Mean particlecode Batch specification % Yield % EE size (µ)
and 45 min in 1:3 (PLGA65/35: PCL). The results revealedthat microspheres made with 1:3 (PLGA65/35: PCL) blend re-leased 97% of the drug in 5 days compared with 98% in 14days, 98% and 97% in 30 days in 1:1 (PLGA65/35:PCL), 3:1(PLGA65/35:PCL), and pure PLGA65/35 microspheres, respec-tively. In batches made with PLGA 85/15 and its blends, bursteffect ranged from 16–20%. About 50% of the drug was re-leased in 5 days in pure PLGA 85/15 in contrast to 8 hr in1:1 (PLGA85/15:PCL), 2 days in 3:1 (PLGA85/15:PCL), and6 hr in 1:3 (PLGA85/15: PCL). Microspheres made with 1:3(PLGA85/15:PCL) released almost the entire drug in 1 week,whereas in batches made with pure PLGA85/15 and 3:1 (PLGA85/15:PCL) more than 80% of the drug was released in 60days as compared with 96% in 60 days in 1:1 (PLGA85/15:PCL).
Two processes govern the release of drug from biodegradablepolymers: initially the release is diffusion controlled and later on
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TAB
LE
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roup
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75.1
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∗ Sig
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Sign
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137
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138 V. R. SINHA AND A. TREHAN
FIG. 6. Release profile of ketorolac tromethamine from PLGA 85/15 microspheres and its blends with PCL.
a major part of drug, bound to polymeric matrix, is released bymatrix erosion mechanism (Selek et al. 2003). Faster release inPLGA65/35 batches as compared with PLGA85/15 batches wasdue to higher molecular weight of that latter as higher molecularweight polymers degrade slowly. Rate of hydration of polymericmaterials also depends on water uptake of the polymer. Lacticacid polymer because of methyl group is more hydrophobic thanglycolide polymer (Lewis 1990). So there was less water uptakein comparison to other polymers like polyglycolic acid. The wa-ter uptake increases as the glycolide ratio in copolymer increases(Gilding and Reed 1979) and hence PLGA65/35 showed fasterrelease compared with PLGA 85/15. Greater hydrophobicity ofthe polymer also leads to less water uptake and hence slower re-lease of drug. Release from pure polymers was slower than theircorresponding blends due to semicrystalline nature of PCL. Asa result, water can penetrate easily into the amorphous part ofpolymer facilitating the release of drug by diffusion through thepores.
The data of in vivo pharmacological response (percent anal-gesic effect) versus time for mice is shown in Table 2. Resultsrevealed that a significant difference in percent analgesic re-sponse between control and drug solution up to 9 hr. After thatthere was no significant difference that might be due to a de-crease in therapeutic level of pure drug solution in the bloodin. Significant difference was observed in analgesic responsebetween control and microspheres at all time points, except at504 hr that may be attributed to degradation of drug in plasma.In a comparison between drug solution and microspheres, per-cent analgesic response was observed for 7 days in drug-loadedmicrospheres compared with drug solution in which responselasted for 3 hr only. Significant difference in analgesic responsewas observed at all points except at 6 hr and 9 hr, which mightbe due to slow release of drug from microspheres. This also issupported by in vitro release of drug from microspheres.
As can be seen from in vitro data at 6 hr and 9 hr, percent drugrelease was just 36% and 39%, which might be low enough toproduce the desired pharmacodynamic response. But after that,especially at 3–5 days, there was a significant increase in drugrelease that might be sufficient enough for the drug to cross theminimum effective level and hence result in significant anal-gesic response. Although the drug release was obtained up to 30days in in vitro studies, in vivo percent analgesic response wasobserved for 7 days only. This may be attributed to the balancebetween percent drug released and simultaneous degradation ofdrug in plasma. After 7 days the percent drug released may notbe significant enough to strike a balance with drug degradationin plasma, resulting in plasma drug level below the therapeu-tic window and hence no significant analgesic response wasobserved.
CONCLUSIONSStudies revealed that with pure PLGA 65/35 and pure
PLGA85/15 the release of drug was sustained for up to 30 daysand 60 days, respectively. When these polymers were blendedwith PCL in different ratios, drug release could be tailored from5 days to 60 days. From the study we concluded that withcareful selection of different polymers and their blending withPCL in appropriate ratios, release of ketorolac tromethaminecan be tailored from several hours to several days. Ketorolactromethamine is widely used in the treatment of moderate to se-vere postoperative or postsurgery pains, acute musculo-skeletalpain, chronic pain states, postpartum or labor pains, and post-traumatic pain. The treatment protocol involves 2–3 injectionsper day. Thus, by following this approach of encapsulating it inbiodegradable microspheres using different polymers, levels ofketorolac tromethamine can be maintained for long periods inthe body, which can obviate painful injections given a numberof times per day.
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KETOROLAC TROMETHAMINE-LOADED MICROSPHERES 139
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