Formulation and Evaluation of Extended Release Trihexyphenidyl Hydrochloride Hard Gelatin Capsules

Transcription

1 Vinay Kumar et al: Formulation and Evaluation of Extended Release Trihexyphenidyl Hydrochloride 1359 Research Paper International Journal of Pharmaceutical Sciences and Nanotechnology Volume 4 Issue 1 April June 2011 Formulation and Evaluation of Extended Release Trihexyphenidyl Hydrochloride Hard Gelatin Capsules K. Vinay Kumar, S. Jagan Mohan, V. Kiran Kumar, and Y. Madhusudan Rao* Centre for Biopharmaceutics and Pharmacokinetics, University College of Pharmaceutical Sciences, KakatiyaUniversity, Warangal , Andhra Pradesh, India. ABSTRACT: This work aims at investigating different types and levels of hydrophilic high molecular weight matrix agents, (including HPMC K15M, Metalose-60 SH, Metalose-65 SH and Metalose-90SH-SR), hydrophobic diluent (Talc) and formulation methods (Non-aqueous granulation and direct filling by simple mere mixture) in an attempt to formulate hard gelatin extended release matrix capsules containing Trihexyphenidyl HCl (Benzhexol). The drug release from all the extended release matrix capsules show polymer as well as talc concentration dependent retardation affect. The Metalose 90SH-SR concentration was optimized to approximately 27 %w/w of total capsule net content weight. The hydrophobic diluent s talc concentration was optimized and the useful concentration was approximately 17.45%w/w of the total net capsule content weight. The lactose concentration was also optimized and the effective concentration was found to be approximately 48.36% w/w. The prepared hard gelatin extended release capsules were evaluated for weight variation, Average net content, locked length, content uniformity, assay (drug content) and in-vitro drug release studies. From the invitro release studies of the prepared formulations, one formula was optimized from each method. All the formulations showed linear release profiles and extended the release of trihexyphenidyl HCl (Benzhexol) over h. The release profiles of extended release matrix capsules of trihexyphenidyl HCl (THP HCl) from the selected formulations were close to zero order and follow diffusion dependent release. The prepared extended release matrix capsules of trihexyphenidyl HCl (Benzhexol) produced from the optimized formulations SR-5 and DB SR-4 complied with the USP XXVII specifications. The difference factor (f1) and similarity factor (f2) was calculated for all these formulations and found to the below 15 and above 50. Irrespective of the formulation method type and its procedure, the prepared hydrophilic extended release matrix capsules showed non-fickian anomalous transport (coupled diffusion in the hydrated matrix and polymer relaxation) as the values of release exponent (n) are in between 0.50 and Finally it was clear that it is possible to design a formulation with any of the above two methods giving the desired drug release profile suggesting that nonaqueous granulation, Direct filling were good methods for preparing extended release matrix capsules of trihexyphenidyl HCl (Benzhexol). KEYWORDS: Trihexyphenidyl HCl (THP HCl, Benzhexol); HPMC K4M; Metalose-60 SH; Metalose-65 SH, Metalose-90SH-SR, Talc, Extended Release Capsules Introduction Extended Release dosage forms are formulated in such a manner as to make the contained drug available over an extended period of time following administration. Expressions such as controlled-release, prolonged-release, repeat-action and sustained-release have also been used to describe such dosage forms. A typical controlled release * For correspondence: yamasani123@gmail.com ymrao123@yahoo.com system is designed to provide constant or nearly constant drug levels in plasma with reduced fluctuations via slow release over an extended period of time. In practical terms, an oral controlled release dosage form should allow a reduction in dosing frequency as compared to when the same drug is presented as conventional dosage form (Qiu and Zhang 2000). Advanced polymers of the genre METOLOSE, METOLOSE-SR (USP. Metalose SR), METHOCEL, KOLLIDON, KLUCEL are the major part of the formularies of the modified release product development in formulation research departments. 1359

2 1360 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 4 Issue 1 April-June 2011 A typical extended release system is designed to provide constant or nearly constant drug levels in plasma with reduced dose, frequency of administration and fluctuations in plasma concentrations via slow release over an extended period of time (Reza et. al., 2003). A matrix device consists of drug dispersed homogenously throughout a polymer matrix. Two major types of materials are used in the preparation of matrix devices (Bala Remesh Chary 2000), which include hydrophobic carriers like glyceryl tristearate, fatty alcohols, fatty acids, waxes; carnauba wax, methyl methacrylate, polyvinyl chloride, polyethylene, ethyl cellulose and hydrophilic polymers like, sodium carboxy methyl cellulose, hydroxyl propyl methyl cellulose, sodium alginate, xanthan gum, polyethylene oxide and carbopols. Matrix systems offer several advantages relative to other extended release dosage form like easy to manufacture, versatile, effective, and low cost and can be made to release high molecular weight compounds (Krishna Veni et al., 2001). Since the drug is dispersed in the matrix system, accidental leakage of the total drug component is less likely to occur, although occasionally, cracking of the matrix material can cause unwanted release THP HCl (Benzhexol), (1 RS)-1-Cyclohexyl-1-phenyl- 3-(piperidin-1-yl) propan-1-ol hydrochloride is a white, crystalline powder sparingly soluble in water, soluble in chloroform and methanol, sparingly soluble in methylene chloride (Ashwin Patel et al., 2009). The drug is used as an anticholinergic agent and in the treatment of drug induced extra pyramidal symptoms, used as adjunct in the treatment of all forms of Parkinsonism, (Post encephalitic, arteriosclerotic, and idiopathic), Treatment of trigeminal neuralgia, for the treatment of nicotine poisoning and anti spasmodic. Its mode of action is by preventing the effects of acetyl choline (ACh) by blocking its binding to muscarinic cholinergic receptors at neuroeffector sites on smooth muscle, cardiac muscle, and gland cells; in peripheral ganglia; and in the central nervous system (Hadidi 2004). Experimental Materials Trihexyphenidyl HCl was obtained from Venkar labs, Hyderabad, India. Polymers HPMC K15M, Metalose-60 SH, Metalose-65 SH, Metalose-90SH-SR, were obtained from Colorcon limited, U.K. Excipients like Talc, lactose, aerosol, magnesium stearate were procured from the DANMED Pharmaceuticals Pvt. Ltd, Hyderabad, India. All other chemicals and reagents used were of analytical grade except for those used in HPLC analysis, which were HPLC grade. Methods Drug excipient compatibility The simple physical mixtures of THP HCl with all the polymers and other excipients used in the formulations were taken in glass vials and observed every week to make sure that there is no drug excipient interaction. Micromeritics Static angle of repose, compressibility index, Hausner ratio, poured (or fluff) bulk and tapped bulk densities were determined according to the fixed funnel and freestanding cone method reported by (Raghuram et al., 2003). Preparation of Hard Gelatin Capsules Two methods were used for preparing THP HCl hard gelatin capsules they are 1) Non-aqueous Granulation (NAG) 2) Direct filling (DB) Formulations K15, M60-SH, M65- SH, and SR 1-5, DB DB SR: 1-4 were prepared using HPMC K15M and Metalose. Non-aqueous Granulation (NAG): Lactose and talc were used as the fillers, Magnesium stearate was used as lubricant where as talc and aerosil were glidants. All the ingredients were weighed and sifted through # 40 mesh. Then all the ingredients were mixed in a poly bag for 10 min. Binder solution was prepared by using Povidone K 30 in IPA & DCM (1:1). The blend was granulated by using binder solution. Then the wet mass was passed through #10 mesh and dried at room temperature for 45 minutes. Dried granules were passed through #30 mesh and lubricants were added. (Metalose, talc, aerosil, magnesium stearate). Finally granules were filled in size 2 hard gelatin capsules using capsule hand filling machine. The composition of the capsules prepared under various trials with HPMC K15M and Metalose were given in the table 1. Direct filling (DB): All the formulation ingredients, except the lubricant and glidant, were sifted through #40 mesh and mixed in a polybag and shaken by hand for about min. The lubricant and glidant were added to the powder mixture and mixed for another 2 3 min by hand. Finally granules were filled in size 2 hard gelatin capsules using capsule hand filling machine. The composition of the Capsules prepared under various trials with Metalose-90SH-SR by direct filling was given in the table 2.

3 Vinay Kumar et al: Formulation and Evaluation of Extended Release Trihexyphenidyl Hydrochloride 1361 Table 1 Composition of trihexyphenidyl HCl (Benzhexol) 2 mg extended release capsule formulations nonaqueous granulation. Composition K15M M60-SH M65-SH Formulations SR-1 SR-2 SR-3 SR-4 SR-5 Trihexyphenidyl Talc Lactose HPMCK4M Metalose 60SH Metalose 65 SH Metalose 90 SH-SR Povidone IPA+Methylene chloride(1:1) q.s q.s q.s q.s q.s q.s q.s q.s Metalose 60SH Metalose 65 SH Metalose 90 SH-SR Talc Aerosil Magnesium stearate Table 2 Composition of trihexyphenidyl HCl (Benzhexol) 2 mg extended release capsule formulations direct blending. Composition Formulations DB SR-1 DB SR-2 DB SR-3 DB SR-4 Trihexyphenidyl Talc Lactose Metalose-90-SR Talc Aerosil Magnesium stearate Metalose-90-SR Total Dissolution studies All the capsules prepared were subjected to dissolution studies using Labindia Dissolution test apparatus (Modified USP type I) equipped with an auto sampler and fraction collector for collection and replenishment of samples and dissolution medium respectively. Dissolution medium used was water. Temperature and rpm were 37 ±0.5 C and 100 respectively. Samples were taken at intervals 1, 2, 3 4, 6, 8 and 12 hrs and analyzed for Trihexyphenidyl HCl by HPLC at 210nm. Chromatographic apparatus and conditions Chromatographic separation of THP HCl was performed on a Shimadzu HPLC System (Japan) equipped with UV- Visible detector using C18 column, (150mm X 4.6 I.D, 5μ). The mobile phase used was mixed buffer, methanol & acetonitrile in the ratio of 50:20:30. Standard solution and dissolution samples were analyzed at 210 nm using UV detector. The mobile phase was pumped at a flow rate of 1.0 ml/min with an injector valve fitted to a 100 μl volume sample loop.

4 1362 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 4 Issue 1 April-June 2011 Release Kinetics (Ritger and Peppas 1987) Different kinetic equations (zero-order, first-order, and Higuchi s equation) were applied to interpret the release rate of the drug from matrix systems. The best fit with higher correlation (r 2 > 0.99) was found with Higuchi s equation for all the formulations. Two factors, however, diminish the applicability of Higuchi s equation to matrix systems. This model fails to allow for the influence of swelling of the matrix (upon hydration) and gradual erosion of the matrix. Therefore, the dissolution data was also fitted according to the well-known exponential Korsmeyer- Peppas equation (Korsmeyer, et al., 1983), which is often used to describe drug release behavior from polymeric systems: Mt/ M = ktn Mt/ M is the fraction of drug release at time t, and k is the kinetic constant; n is the release exponent (indicating the general operating release mechanism). n value between 0.43 and 0.5 indicates Fickian (case I) diffusion-mediated release. Non-Fickian (anomalous) release, coupled diffusion, and polymer matrix relaxation occurs if 0.5 < n < 0.89, purely matrix relaxation or erosion-mediated release occurs for n = 1 (zero-order kinetics), and super case II type of release occurs for n > 0.89 (Peppas 1985). Stability study The optimized formulations in triplicate were prepared and kept for stability studies at 25 ± 2 C / 60 ± 5% RH, 40 ± 2 C / 75 ± 5% RH and in photo stability chambers. The drug content in the tablets was determined after 30,90and 180 days. A long term and accelerated stability study was conducted by storing capsules in HDPE containers at 25 ± 2 C / 60% ± 5% RH and 40 ± 2 C / 75% ± 5%RH. The content of the drug from the capsules were tested monthly for six months. Photo stability: Samples should were exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter to allow direct comparisons to be made between the drug substance and drug product. The content of the drug from the capsules were tested. Results and Discussion Drug excipient interaction study The results of drug excipient interaction study clearly indicated that there is no drug excipient interaction at 40 ± 2 C / 75% ± 5% RH after 4 & 8weeks. By using this study prototype formulations were developed with some selected excipients. The results of drug excipient compatibility studies were presented in the Table 3. No excipient was found to be incompatible with Trihexyphenidyl HCl. Table 3 Compatibility study of Trihexyphenidyl with excipients at condition 2-8 C, 25 C/60%RH, 40 C/75%RH and photostability. Material Ratio (D: E) Observation Week1 Week2 Week3 Week4 Drug 1:0 White to off white powder NC NC NC NC D + HPMC 1:5 Off-white, FF-powder NC NC NC NC D + Metalose 1:5 Off-white, FF-powder NC NC NC NC D + IPA 1:5 Liquid NC NC NC NC D + M. Starch 1:5 Off-white, FF-powder NC NC NC NC D + M.Stearate 20:1 Off-white, FF-powder NC NC NC NC D + Aerosil 20:1 Off-white, FF-powder NC NC NC NC D + Talc 1:5 Off-white, FF-powder NC NC NC NC D+ DCM 1:5 Liquid NC NC NC NC D+MCC 1:5 Off-white, FF-powder NC NC NC NC D+Lactose 1:5 Off-white, FF-powder NC NC NC NC D+Povidone 1:5 Yellowish white, FF-powder NC NC NC NC NC = No Change; W=White; FF = Free Flowing; P = Powder; D = Trihexyphenidyl hydrochloride. DCM = dichloromethane E = Excipients

5 Vinay Kumar et al: Formulation and Evaluation of Extended Release Trihexyphenidyl Hydrochloride 1363 Micromeritics The various micromeritic properties like bulk density, tapped density, and compressibility index (%), angle of repose and hausner ratio were determined for Trihexyphenidyl HCl and various formulations were given in the table 4 & 5. The compressibility index, hausner ratio and angle of repose indicated poor flow characteristics. So it was improved by inclusion of suitable amounts of lubricants and glidants. Table 4 Micromeritic properties of drug (trihexyphenidyl HCl). S.No Parameter THP HCl 1 LOD Bulk density (g/ml) Tapped density (g/ml) Compressibility index 25 5 Hausner ratio 1.81 The prepared capsules were subjected to weight variation, average net content, locked length, drug content, content uniformity and the results were given in the table 6 and all these results were found to be in the permissible limits. Dissolution studies The release profiles of Trihexyphenidyl HCl by direct filling in all the formulations were very close to each other. The drug was releasing for 12 hrs and follow near zero order release. The drug release rate from Metalose-90SH- SR based matrix capsules decreased with the increase in the polymer level and talc. This effect might be ascribed to an increase in the extent of gel formation in the diffusion layer (Alderman, 1984). The drug release from all the matrix capsules shows polymer as well as talc concentration dependent retardant affect. The results of in-vitro release from HPMC K15M, Metalose-60 SH, and Metalose-65 SH matrix Capsules were shown in figures 1. All the formulations were not complying with the USP specifications of the THP HCL extended release capsules and the release profile was fast as the extent of polymer was not sufficient enough to retard the drug release profile for 12 hrs due to low viscosity grade polymer The formulation Metalose-90SH-SR released more than 90% of the drug in 12 hrs. However at various time intervals the cumulative % drug release is very close to zero order. Hence the formulation SR 5 prepared with metalose-90sh-sr was selected as optimized formulation. The results of in-vitro release from Metalose-90SH-SR matrix capsules were shown in figure 2. Formulations SR 1 & 4 released less than 85% of drug with in12 hrs due to higher concentration of polymer & talc. Table 5 Physical characteristics of THP HCl granules. Formulation code % LOD w/w Bulk Density Tapped Density Hausner Ratio Angle of Repose K15M M60-SH M65-SH SR SR SR SR SR DB SR DB SR DB SR DB SR

6 1364 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 4 Issue 1 April-June 2011 Table 6 Weight variation, locking length, drug content and content uniformity of prepared capsules. Formula code Weight variation (mg) Average net content (mg) Locked length (mm) Drug Content (%) (Assay) Content Uniformity (%) (CU) K15M ± M60-SH ± M65-SH ± SR ± SR ± SR ± SR ± SR ± DB SR ± DB SR ± DB SR ± DB SR ± Drug Release Profiles with different polymers 100 %Drug Release Time (hrs) K15M M60-SH M65-SH Fig. 1 In-vitro drug release profiles of THP HCl ER capsules with different polymers (NAG).

7 Vinay Kumar et al: Formulation and Evaluation of Extended Release Trihexyphenidyl Hydrochloride 1365 Release profile of THP HCl %Drug Release SR-1 SR-2 SR-3 SR-4 SR Time (hrs) Fig. 2 In-vitro Dissolution profiles of THP HCl ER Capsules with in Metalose-90SH-SR (MSR-1 to MSR -5) by non-aqueous granulation. Release Profile of THP HCl %Drug Release DB SR-1 DB SR-2 DB SR-3 DB SR-4 Time (hrs) Fig. 3 In-vitro Dissolution profiles of THP HCl ER Capsules with in Metalose-90SH-SR (MDB-1 to MDB-4) by direct blending. The formulations SR 2 & 3 released more than 80% of the drug within 6 hrs due to lower concentration of polymer. The formulation SR 5 exhibited a release profile close to first order with a drug release more than 90% within 12 hrs. Hence this SR 5 was considered as the optimized formulation. From the above experiments it was observed that the drug release profile from different grades of polymers is as follows: HPMC K15M < Metalose -60SH < Metolose-65SH < Metalose 90SH-SR

8 1366 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 4 Issue 1 April-June 2011 HPMC K15M-based matrices exhibited significantly lower drug release-retarding efficiency than the Metalose- 60SH, Metolose-65SH and Metalose 90SH-SR. These results might be attributed to the relatively low swellability and rapid dilution and erosion of the diffusion gel layer (Erni and Held 1987). The results of in-vitro release from DB SR: 1-4 matrix tablets were shown in figures 3. All the formulations except DB SR: 4 released less than 85% of drug within12 hrs due to higher concentration of polymer & talc. The formulation DB SR: 4 released more than 90% of the drug within 12 hrs. The formulation DB SR: 4 showed a cumulative % drug release close to zero order. Hence the DC-4 formula was found to be optimized. Selection of optimized formulation based on dissolution data models The optimized formulation was selected based on the dissolution profiles of the formulations when compared with the USP Specification as there was no standard reference extended release product of THP HCl was available. f1 and f2 calculation by using USP Specification For the comparison of release profiles of initial and stability samples, ''difference factor'' f1 and ''similarity factor'' f2 Were calculated (Moore and Flanner 1996). The difference factor (f1) measures the percent error between the two curves over all time points. The two release profiles are considered to be similar, if f1 value is lower than 15 (between 0 and15). The similarity factor (f2) is a logarithmic transformation of the sum of squared error of differences between the test and the reference product. The two dissolution profiles are considered to be similar, if f2 value is more than 50 (between 50 and 100). f1 and f2 values are calculated by using suitable mathematical equations and reported in table 7. Table 7 f 1 and f 2 factors of the optimized formulations. Formulation code f 1 f 2 SR DB SR Release kinetics The values of release exponent (n) and correlation coefficients (r 2 ) of all the optimized formulations are given in the table 8. Upon comparison of correlation co-efficient values (r 2 ) of all the optimized formulations, it was found that the release profiles of Trihexyphenidyl HCl are close to zero order in the case of Metalose 90SH-SR. The prepared hydrophilic matrix Capsules showed non-fickian anomalous transport (Coupled diffusion in the hydrated matrix and polymer relaxation) as the values of release exponent (n) are in between 0.50 and Stability studies The stability results of best formulae after 30,90, 180 days were compared with their initial results it was found that there was no significant difference in the drug content between control and the formulations stored at 25 ± 2 C / 60 ± 5% RH, 40 ± 2 C / 75% ± 5%RH and photo stability. The drug content values of stability studies of all the optimized formulations are given in the table 9. The products were found to be stable. Formulation Code Table 8 Release kinetics of different optimized formulations. r 2 value Zero order First order Higuchi Korsmeyer- Peppas Release Exponent (n) SR DB SR Formulation Code Table 9 Stability results: Drug content of the optimized formulations for Trihexyphenidyl HCl (N=3). Initial 25 C/60%RH Exposed Conditions 40 C/75%RH 90 days 180 days 30 days 90 days 180 days Photo stability SR DB SR

9 Vinay Kumar et al: Formulation and Evaluation of Extended Release Trihexyphenidyl Hydrochloride 1367 Conclusions The drug release from all matrix Capsules showed a polymer concentration dependent retardation effect as well as hydrophobic diluent (talc) concentration dependent retardant affect. The Metalose 90SH-SR concentration was optimized to approximately 27 % w/w of total capsule net content weight. The hydrophobic diluent talc concentration was optimized and the useful concentration is approximately 17.45% of the total net capsule content weight. The in-vitro drug release profiles of all formulations revealed efficient control of drug release was zero order with non-fickian diffusion anomalous transport mechanism. Though the dissolution profiles of all the optimized formulations were close to the zero order, MSR-5 was not considered to be advantageous as the DB SR:4 used in this formulation IPA & DCM are organic solvents and the residual solvent limits are required as per the ICH guidelines. DB SR: 4 was found to be advantageous due to their method of formulation i.e. direct blending which was very easy, feasible, fast and economical. No significant difference in the drug content between initial and the formulations stored at 25 C/60%, 40 C/75%RH and photo stability. The drug release profile is satisfactory with Metalose 90SH-SR polymer. The drug release profile from different grades of polymers is as follows: HPMC K15 < Metalose -60SH < Metolose-65SH < Metalose 90SH-SR Acknowledgements The authors are thankful to DANMED pharmaceuticals Pvt. Ltd, Cherlapally, Hyderabad, India for their support and cooperation in carrying out the research work. References Alderman, D.A. (1984) A review of cellulose ethers in hydrophilic matrices for oral controlled release dosage forms. Int J Pharm Technol Prod Manuf. 5: 1Y9. Ashwin Patel, Alankar Shrivastava, Anurekha Jain and GK singh. (2009) Method development and validation for estimating of trihexyphenidyl hydrochloride in tablet dosage form. Bala Ramesh Chary, R., and Madhusudan Rao, Y. (2000) Formulation and evaluation of methocel K15M bioadhesive matrix tablets. Drug Development and Industrial Pharmacy, 26(8). Erni, W., and Held, K. (1987) The hydrodynamically balanced system: a novel principle of controlled drug release. Eur Neurol. 27:21Y27. Kamal A. Hadidi. (2004) Development of screening method for most commonly abused anticholinergic drugs in Jordan; trihexyphenidyl, procyclidine and biperidin. Korsmeyer, R.W., Gurny, R., Doelker, E.,Buri, P., and Peppas, N.A. (1983) Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm.15: 25Y35. Krishna Veni, Jayasagar, G. and Madhusudan Rao, Y. (2001) Formulation and evaluation of diclofenac sodium, usinghydrophilic matrices. Drug Development and Industrial Pharmacy, 27(8): Moore JW, Flanner HH Mathematical com- parison of curves with an emphasis on in-vitro dissolution profiles. Pharm Technol 20: Peppas, N. A. (1985) Analysis of Fickian and Non-Fickian Drug Release from polymers. Pharm. Acta. Helv. 60, Qiu, Y., Zhang, G., (2000) Research and Development Aspects of Oral Controlled-Release Dosage Forms in Handbook of Pharmaceutical Controlled Release Technology (Wise, D. L. Edt), Marcel Dekker Inc. Raghuram, R.K., Srinivas, M., and Srinivas, R. (2003) Oncedaily sustainedrelease matrix tablets of nicorandil: formulation and in-vitro evaluation.aaps PharmSciTech [serial online]. 4:E61. Reza, M.S., Abdul Quadir, M., and Haider, S.S. (2003) Comparative evaluation of plastic, hydrophobic and hydrophilic polymers as matrices for controlled-release drug delivery. J Pharm Pharm Sci.6: 282Y291. Ritger, P.L., and Peppas, N.A. (1987) A simple equation for description of solute release, II: Fickian and anomalous release from swellable devices. J Control Release.5:37Y42. USP. Metalose SR (Hypermellose), Sustained release agent for matrix systems.