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The work aims to formulate pentoxifylline extended release matrix tablet of hydrophilic polymer. HPMC K15M and hydrophobic polymer MCC 101 combination ...
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FORMULATION, DEVELOPMENT AND EVALUATION OF EXTENDED RELEASE TABLET OF PENTOXIFYLLINE

Mahesh W. Thube1*, S. R. Shahi1, B. S. Gulecha1, I. Tadvee1, N. Zadbuke1, V. G. Somani2 1

Government College of Pharmacy, Aurangabad. Maharashtra (INDIA).

Mahesh Thube

2

Themis Laboratories Ltd, Mumbai. Maharashtra, INDIA. Email: [email protected]

ABSTRACT

The work aims to formulate pentoxifylline extended release matrix tablet of hydrophilic polymer HPMC K15M and hydrophobic polymer MCC 101 combination using 32 factorial designs. Pentoxifylline is the hemorrheologic agent, lowering blood viscosity, and improving erythrocyte flexibility. It is having half life 0.4 - 0.8 hours (1-1.6 hours for active metabolite) with the usual oral dose is 400 mg three times daily. Nine formulations were prepared and dissolution studies were performed. The dissolution data obtained were fitted to the PCP disso version 3 software. Linear regression analysis and model fitting depicted that the formulations followed Peppas-Korsmeyer Equation suggesting “Anomalous Transport” release mechanism. The two formulation variables were found to be significant for the release properties (P < 0.05). The quadratic mathematical model developed could be used to further predict formulations with desirable release. The similarity factor f2 was found to be 55.75 for the developed formulation indicating the release was similar to that of the marketed formulation (Trental®). Thus, a combination of HPMC K4M and MCC 101 extends the release for a period of 24 hrs. Key Words: HPMC, Matrix Tablet, Extended Release, Pentoxifylline, Experimental Design

INTRODUCTION Pentoxifylline is a tri-substituted xanthine derivative designated chemically as 1(5-oxohexyl)-3, 7-dimethylxanthine that, unlike

theophylline, is a hemorrheologic agent, i.e. an agent that affects blood viscosity. Pentoxifylline is soluble in water and ethanol, and sparingly soluble in toluene.i

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Pentoxifylline is a xanthine derivative used in the treatment of peripheral vascular disease. Although often classified as a vasodilator, its primary action seems to be a reduction in blood viscosity, probably by effects on erythrocyte deformability and platelet adhesion and aggregation. It is reported to increase blood flow to ischemic tissues and improve tissue oxygenation in patients with peripheral vascular disease and to increase oxygen tension in the cerebral cortex and in the cerebrospinal fluid; it has been used in cerebrovascular disorders. Pentoxifylline also inhibits production of the cytokine, tumor necrosis factor alpha (TNFα), and this property is under investigation in a number of diseases.ii Bioavailability is nearly 100% for oral dosing. Metabolism is through Hepatic and via erythrocytesiii. It is having half life 0.4 - 0.8 hours (1-1.6 hours for active metabolite) with the usual oral dose is 400 mg three times daily.iv So there is need to formulate the modified release dosage form of pentoxifylline to improve the patient compliance and cost effective pharmacotherapy. Hydroxy propyl methylcellulose (HPMC) has been extensively used since the early 1960s as a rate-controlling polymer in oral extendedrelease dosage forms. This popularity can be attributed to the polymer’s non-toxic nature, its availability in different chemical substitution and hydration rates (for example, USP Type 2208 (Methocel K), 2910 (Methocel E), 2906 (Methocel F)) and viscosity grades (100, 4000 and 15 000 cps), good compressibility, and extensive studies to identify formulation/ processing variables. These types of HPMC differ by various degrees of substitution of hydroxy-propyl (hydrophilic) and methoxy (hydrophobic) groups and hence its versatility to retard drug release of various solubilities. Two aspects of HPMC govern its performance in an extended-release matrix system. The rapid formation of a viscous gel layer upon hydration

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and the second aspect is the viscosity of the rate controlling polymer used. Once the gel layer is formed, viscosity of the gel layer regulates the overall rate of drug release.vThe mechanism of drug release from hydrophilic matrix tablets after ingestion is complex but it is based on diffusion of the drug through, and erosion of, the outer hydrated polymer on the surface of the matrix. Typically, when the matrix tablet is exposed to an aqueous solution or gastrointestinal fluids, the surface of the tablet is wetted and the polymer hydrates to form a gelly-like structure around the matrix, which is referred to as the “gel layer”. The process is also termed as the glassy to rubbery state transition of the (surface layer) polymer. This leads to relaxation and swelling of the matrix which also contributes to the mechanism of drug releasevi. The need for fast hydrating polymer is particularly critical when formulating a water-soluble drug such as pentoxifylline. Section 1.01 Overall drug release mechanism from HPMC-based systemsvii: The overall drug release mechanism from HPMC based pharmaceutical devices strongly depends on the design (composition and geometry) of the particular delivery system. The following phenomena are involved. 1. At the beginning of the process, steep water concentration gradients are formed at the polymer/water interface resulting in water imbibitions into the matrix. To describe this process adequately, it is important to consider (a) The exact geometry of the device; (b) In case of cylinders, both, axial and radial direction of the mass transport; and (c) The significant dependence of the water diffusion coefficient on the matrix swelling ratio. In dry systems the diffusion coefficient is very low, whereas in highly swollen gels it is of the same order of magnitude as in pure water. Water acts as a plasticizer and reduces the 2

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glass transition temperature (Tg) of the system. Once the Tg equals the temperature of the system, the polymer chains undergo the transition from the glassy to the rubbery state. 2. Due to the imbibitions of water HPMC swells, resulting in dramatic changes of polymer and drug concentrations, and increasing dimensions of the system. 3. Upon contact with water the drug dissolves and (due to concentration gradients) diffuses out of the device.

mathematical modeling of drug release from HPMC-based systems, one must identify the most important transport phenomenon for the investigated device and neglect the other processes; otherwise the mathematical model becomes too complex for facile use. The present work aims to formulate pentoxifylline extended release matrix tablet of hydrophilic polymer HPMC K15M and hydrophobic polymer MCC 101 combination for extending the release for the period of 24hrs. Article II.

4. With increasing water content the diffusion coefficient of the drug increases substantially. 5. In the case of poor water-solubility, dissolved and non-dissolved drug coexist within the polymer matrix. Non-dissolved drug is not available for diffusion. 6. In the case of high initial drug loadings, the inner structure of the matrix changes significantly during drug release, becoming more porous and less restrictive for diffusion upon drug depletion. 7. Depending on the chain length and degree of substitution of the HPMC type used, the polymer itself dissolves more or less rapidly. As a result of conditions 1, 2, 3, 4 and 7 the mathematical description of the diffusional processes requires strongly time-dependent terms. From the aforementioned possible phenomena it is obvious that there is no universal drug release mechanism that is valid for all kinds of HPMC-based systems. In contrast, there are many devices that exhibit various mechanisms that control drug release, mechanisms such as polymer swelling, drug dissolution, drug diffusion or combinations of the above. The physicochemical characteristics and geometry of each device determine the resulting governing processes. Concerning the

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2. Materials:

Pentoxifylline was kindly supplied by Shreya Life Sciences (Aurangabad, M.S, India). Hydroxy propyl methyl cellulose (HPMC) K15M was obtained as gift sample from Colorcon India Ltd. (Goa, India), Micro Crystalline Cellulose (Avicel PH 101) was supplied by Signet Chem. The commercially available pentoxifylline tablets chosen were Trental®. All other chemicals used were of reagent grade and were used without further purification. Article III.

3. Method:

Section 3.01 3.1 Compatibility Study between Drug and Polymers: The drug pentoxifylline and polymers HPMC K15M and MCC PH 101 are taken in 1:1:1 proportion respectively, and placed in the stability chamber at 40◦C and 75% RH for the period of 1 month and the mixture was analyzed by DSC thermogram, Figures 1 and 2. Section 3.02 3.2 Formulation of Extended Release matrix tablet of Pentoxifylline: The Drug, HPMC (Methocel K15M), and MCC (Avicel PH 101) were mixed and moistened with a binder solution. The binder solution consists of Poly Vinyl Pyrrolidone K30 in Isopropyl alcohol. The wet mass was forced through a 22 3

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mesh sieve. The granules were dried 1 hr at 600C, and then calibrated through the same sieve. The other excipients include Talcum as glidant and Magnesium stearate as lubricating agent of specified quantity as shown in table 1 (all quantities are in mg). The final mixture was compressed by a single rotary press tablet machine with 14mm diameter punches. The compressed tablets possessed hardness between 6.5 to 8 kg/cm2. (Table : 1)

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The mechanism of drug release was analyzed using PCP disso version 3 software. The release profiles were also analyzed for f2 (similarity) factor values to assess the similarity or difference in the release profiles. The marketed formulation Trental® was used to compare release profile and similarity factor. The data also fitted to the Design Expert® Software ver.7.1.6 for statistical analysis. Section 3.05 3.5 Optimization Data Analysis:

Section 3.03 3.3 Physical characterization of the tablets: Formulated tablets were subjected to different physical characterization studies. The drug content of each batch of the formulated tablets was determined in triplicate. The weight variation was determined on 20 tablets using electronic balance. Tablet hardness was determined for minimum 6 tablets of each batch using Monsanto (Standard type) tablet hardness tester. Friability was determined with 20 tablets in a electronic friabilator for 4min at 25rpm. Section 3.04 3.4 In Vitro Drug release Profile Determinationviii: All drug release experiments were carried out using a USP dissolution apparatus. The USP 30 (XXX) specified the monograph for the ‘Pentoxifylline extended release tablets’ with different ten dissolution test and specification. If the formulated product compiles with the any of dissolution test specification in the USP, then the labeling may be indicated to meet USP dissolution test. So the dissolution parameters were set according to USP dissolution test-4. It included 900mL deionized water as the dissolution media, maintained at 37±1◦C at 50 rpm. At predetermined time intervals, 5 ml samples were replaced with fresh medium when withdrawn and the amount of drug released was determined spectrophotometrically at 274.4 nm table.

Various RSM computations for the current optimization study were performed employing Design Expert software (Design Expert License version7.0.3 State-Ease Inc, Minneapolis, MN). Polynomial models including interaction and quadratic terms were generated for all the response variables using multiple linear regression analysis (MLRA) approach. The general form of the model is represented as the following equation: y = β0 + β1x1 + β2x2 + β3x1x2 + β4x21 + β5x22 + β6x1x22 + β7x21x2 Where, β0 is the intercept representing the arithmetic average of all quantitative outcomes of runs; β1 to β7 experimental response values of Y; and X1 and X2 are the coded levels of the independent variable(s). The terms X1X2 and X2i (i= 1to2) represent the interaction and quadratic terms, respectively. Statistical validity of the polynomials was established on the basis of ANOVA provision in the Design Expert Software. Three-dimensional (3-D) contour plots were constructed based on the model polynomial functions. These plots were useful to see interaction effects on the factors on the responses.

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Article IV.

4. Results and discussions

Section 4.01 4.1 Compatibility Study between Drug and Polymers:

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software. The kinetic models used were zero order, first order, Korsmeyer and Peppas, Hixson Crowell, Higuchi equationx.

After the 1 month no visual changes were observed in the physical mixture. The DSC thermogram showed no change in the melting range of the drug, figure.1

To investigate the mechanism of in vitro drug release and to compare the release profile differences among these matrix formulations, the percent drug released versus time profiles were plotted.

Section 4.02 4.2 Formulation of Extended Release matrix tablet of Pentoxifylline:

Data corresponding to release were fitted using the equation proposed Korsmeyer-Peppas.

As the wet granulation enhances fluidity and compactibility of high-dose drugs with poor flow and/or compactibilityix, also non-aqueous granulation with IPA found to provide better quality tablets with higher viscosity HPMC, so the solution of PVP K30 in Isopropyl alcohol is used as the binder. The formulations prepared thus found to have good physicochemical properties and found to control the drug release for both the drugs when in vitro release studies were carried out. As the drug doses were high, no attempt was made to incorporate the excipients (such as lactose, dicalcium phosphate, etc.) other than polymers into the tablet matrices to increase the bulk further or to improve the granule properties. Section 4.03 4.3 Physical characterization of the tablets: The tablets were evaluated for appearance, hardness, friability, weight variation, and drug content uniformity. The results are reported in Tables 2. Section 4.04 4.4 In Vitro Drug release Profile: The formulations were formulated as per the composition given in Table1. The formulations were evaluated for in-vitro dissolution studies and the samples were analyzed spectrophotometrically at 274.4nm. The data obtained were fitted to disso calculation

Mt = kt M ∞

n

Where, Mt/M∞ is the fraction of drug released at time t, k the kinetic constant, and n the release exponent that characterizes the mechanism of drug release. For matrix tablets, n = 0.5 indicated pure diffusion controlled drug release and n = 1 indicated swelling-controlled drug release or Case II transport. Other values for n indicated anomalous transport kinetics, i.e. a combined mechanism of pure diffusion and Case II transport. The special case with n = 0.5 in above equation represents the Higuchi model. (Table 3) The USP specifies the limits according to Dissolution test-4 as, in 1st hr up to 20 % release; within 8 hr 35 to 60 % release and at the end of 24 hrs more than 80 % drug should be released. The formulation combination with HPMC K15M 150 mg and MCC PH101 40 mg showed about 85.41 % release over 24 hrs. To know the mechanism of drug release from the formulations, the data were treated with PCP disso version 3 software. The formulations followed “Peppas-Korsmeyer model”. If n value is near to 0.5 it indicates diffusion control release, and the n value of near 1.0 indicates erosion or relaxation control. Intermediate values suggest that diffusion and erosion 5

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contribute to overall mechanism. For the present study the results revealed “Anomalous Transport” mechanism, suggesting that the mechanism is not well known or more than one type of release phenomenon is involved.

+1 level as in shown in the formulations F1-F2F3; the Q24 obtained was 66.82, 66.39, and 69.23 % respectively. There is no significant change in the release profile and the tablets possessed poor matrix integrity.

Total amount of drug released from all the formulations up to 24 hrs ranged between 61.25 and 85.41% indicating incomplete drug release at higher concentration of HPMC K15M as well as MCC PH101. Rate of drug release until 24 hrs tended to decrease with increase in the content of HPMC. This is complimentary to the literature that the viscosity of the gel layer around the tablet increases with increase in the hydrogel concentration, thus limiting the release of active ingredient.The similarity factor f2 was found to be 55.75 for the developed formulation indicating the release was similar to that of the marketed formulation (Trental®).

The formulations F4, F5 and F6 had been formulated with 0 levels of HPMC K15M and MCC 101 were used from -1 level to +1 level; the cumulative release obtained is 77.96, 83.43 and 85.41%, respectively. The release data suggests that the drug release from matrix increased as a function of MCC 101.

The data was interpreted using Design expert 7.1.4 software. The ANOVA data as shown in Table: 4 The quadratic model for the percentage drug release at 24 hr was found to be significant. The increase in the polymer concentration causes in the increase in the density of swollen hydrogel network, which is a hindrance to the drug diffusion and consequently decrease the release rate. Final Equation in Terms of Coded Factors: Q =84.10-0.755X1+1.558 X2-0.73X1X2-14.64 (X1) 2-4.11 (X2) 2 Final Equation in Terms of Actual Factors: Q =84.10-0.755HPMC+1.558MCC0.73HPMC*MCC-14.64(HPMC) 2-4.11(MCC) 2 The relationship between the variables further elucidated using response surface plot. If X1 i.e. HPMC K15M is kept at a lower level and X2 i.e. MCC 101 was increased from -1 level to

The further increase in level of matrix forming polymer HPMC K15M to +1 level resulted in further retardation of release in formulation batches F7, F8 and F9. The model F-value 10.49 implies that the model is significant (Table: 4). There is only a 0.38 % chance that a "Model F-Value" this large could occur due to noise. A negative "Pred RSquared" implies that the overall mean is a better predictor of response than the current model. "Adeq Precision" measures the signal to noise ratio. A ratio greater than 4 is desirable. The ratio of 7.168 indicates an adequate signal. This model can be used to navigate the design space. The P-value is 0.0038; Values of "Prob > F" less than 0.0500 indicate model terms are significant. In this case X2 are significant model terms. Values greater than 0.1000 indicate the model terms are not significant Article V.

5. Conclusion:

The study reveals successful application of factorial design and optimization technique for the development of extended release tablet of Pentoxifylline providing release for the period of 24 Hrs. The statistical approach for formulation optimization is a useful tool, particularly when two or more variables are to be evaluated simultaneously. The variables HPMC K15M and MCC PH101 (Avicel 101) involved in the study 6

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exhibited significant effect on the responses i.e. release profile. Overall, an extended release Pentoxifylline formulation has been developed using the 32 factorial designs. The formulation F6 shows promising response and complied with USP dissolution Test-4.

Article VI.

6. Acknowledgement:

The authors would like to thanks the Colorcon India Pvt. Ltd. for providing gift samples of HPMC grades and also Signet Chem Ltd. for providing gift sample of Avicel 101 7. References 1) www.drugs.com/pro/pentoxifylline.html 2) Sweetman S.C. (Ed), Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Electronic version. 3) Pentoxifylline - Wikipedia, the free encyclopedia

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4) Pentoxifylline Drug Information Provided by Lexi-Comp Merck Manual Professional 5) Using METHOCEL Cellulose Ethers for Controlled Release of Drugs in Hydrophilic Matrix Systems, Dow Product Boucher 6) Kewal K. Jain, Drug Delivery Systems, Extended-Release Oral Drug Delivery Technologies, 2008, Humana Press, 223239 7) J. Siepmanna, N.A. Peppas, Modeling of drug release from delivery systems based on 8) Hydroxy propyl methyl cellulose (HPMC), Advanced Drug Delivery Reviews, 48 (2001) 139–157 9) United States Pharmacopoeia, United States Pharmacopoeia Convention, USP30-NF-25, pg:2902 10) James Swarbrick, Encyclopedia of Pharmaceutical Technology, Tablet Formulation, Third Edi, Vol 6, Informa Healthcare USA, 3646. 11) Anant Ketkar and et al, PCP Disso software, User Guide.

Tables and Figures: Table 1: Formulation Batches CODE

PENTOXIFYLLINE

F1 F2 F3 F4 F5 F6 F7 F8 F9

400 400 400 400 400 400 400 400 400

HPMC K15M 100 100 100 150 150 150 200 200 200

MCC PH101 30 35 40 30 35 40 30 35 40

PVP K30 24 24 24 24 24 24 24 24 24

TALC 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5

Mg. TAB.WT STEARATE (mg) 4.2 564.7 4.2 569.7 4.2 574.7 4.2 614.7 4.2 619.7 4.2 624.7 4.2 664.7 4.2 669.7 4.2 674.7

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Table 2: Physical Characterization of Tablets. Formulation Batches F1 F2 F3 F4 F5 F6 F7 F8 F9

Hardness (n=3) kg/cm2±S.D. 6.5±0.8 7.2±0.8 6.8±0.4 6.6±0.8 7.2±0.5 7.8±0.4 7.4±0.3 8.1±0.4 7.9±0.4

Friability (n=10) (%)