A METHOD OF ENHANCING PROPERTIES OF ATORVASTATIN CALCIUM DRUG

Abstract

To improve dissolution and bioavailability of practically insoluble lipid lowering drug Atorvastatin calcium using liquisolid technique. Method: Liquisolid compacts were prepared by using various carriers and a mathematical model for calculating the required quantities of powder and liquid ingredient to produce an acceptably flow and a compressible admixture. Micro crystalline cellulose, Lactose monohydrate, Hydroxy propyl methyl cellulose, Dicalcium phosphate, Silicon dioxide, Crosscarmellulose were employed as carrier, coating material and super disintegrant respectively. The prepared liquisolid compacts were evaluated for their micromeritic properties and drug-excipient interactions by FTIR. The liquisolid tablets were prepared and evaluated for their tableting properties.Results: The liquisolid systems showed acceptable micromeritic properties, the FTIR studies states that there is no chemical interaction between the drug and the excipients. The tableting properties of the liquisolid compacts were within the accepted limits. The release rate of Atorvastatin calcium was higher when compared to the marketed Atorvastatin calcium. Conclusion: In the present research work, the potential of liquisolid systems to enhance the dissolution properties of Atorvastatin calcium was investigated. In case of Atorvastatin calcium liquisolid tablets thereby revealing enhanced dissolution rate than marketed tablets. Thus the objective of incorporating Atorvastatin calcium into liquisolid system to achieve faster dissolution rates was met with success.

Specification

Description:FIELD OF THE INVENTION
[0001] The present invention is related to improve dissolution and bioavailability of atorvastatin calcium more particularly using liquisolid technique.

BACKGROUND
[0002] The liquisolid process is a novel and effective approach to improving solubility. Bioavailability relies on drug solubility. With the evolution of modern pharmaceutical products, solubility is a big problem for the pharmaceutical industry. One of the most daunting aspects of drug production remains the enhancement of oral bioavailability of poorly water-soluble drugs. A newer methodology "powdered solution technology" or "liquisolid technology", has been applied to prepare water-insoluble drugs into rapid-release solid dosage forms. This method is efficient, economic, viable for industrial production, also useful in control drug delivery system. Hence due to above reasons liquisolid technique is most efficient and novel approach for solubility enhancement. To prepare water insoluble drugs into rapid-release solid dosage forms, 'powdered solution technology' or 'liquisolid technology' has been applied. This approach is reliable, cost-effective, viable for industrial production, and also useful in the drug delivery control system. Therefore, liquisolid technique is the most effective and novel method for enhancing solubility due to the above factors.

[0003] The lipophilic are poorly water-soluble. Enhancing the dissolution and bioavailability of these drugs is a major challenge for the pharmaceutical industry. Liquisolid technique, which is based on the conversion of the drug in liquid state into an apparently dry, non-adherent, free flowing and compressible powder, is a novel and advanced approach to tackle the issue. The objective of this article is to present an overview of liquisolid technique and summarize the progress of its applications in pharmaceutics. Low cost, simple processing and great potentials in industrial production are main advantages of this approach. In addition to the enhancement of dissolution rate of poorly water-soluble drugs, this technique is also a fairly new technique to effectively retard drug release. Furthermore, liquisolid technique has been investigated as a tool to minimize the effect of pH variation on drug release and as a promising alternative to conventional coating for the improvement of drug photostability in solid dosage forms. Overall, liquisolid technique is a newly developed and promising tool for enhancing drug dissolution and sustaining drug release, and its potential applications in pharmaceutics are still being broadened.

[0004] The solubility and dissolution properties of any drug are vital determinants of its oral bioavailability. The dissolution rate of poorly soluble, highly permeable (BCS-II) drugs, such as atorvastatin calcium, can be improved by application of the liquisolid (LS) technique. Methods: Different liquisolid compacts were prepared using a mathematical model for calculating required quantities of powder and liquid ingredients to produce an acceptably flowable and compressible admixture. Avicel PH 102, aerosil 200 and explotab were employed as carrier, coating material and disintegrant, respectively. The prepared liquisolid systems were evaluated for their micromeritic properties and possible drug-excipient interactions by Infrared spectra (IR) analysis, differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). Liquisolid compacts were prepared and evaluated for their tableting properties. Results: The liquisolid system showed acceptable micromeritic properties. The IR and DSC studies ruled out any significant interaction between the drug and excipients. The XRPD analysis confirmed formation of a solid solution inside the compact matrix. The tabletting properties of the liquisolid compacts were within the acceptable limits. The release rates of liquisolid compacts were markedly higher compared with directly compressed tablets, due to increasing wetting properties and surface area of the drug. From the obtained pharmacokinetic parameters, such as the AUC, tmax and Cmax, the liquisolid compacts demonstrated better bioavailability compared with their conventional formulation. Conclusion: This study shows that the liquisolid technique is a promising alternative for improvement of the dissolution and oral bioavailability of water insoluble drugs a confirmed by estimating the pharmacokinetic parameters in vivo in rabbits.

SUMMARY
[0005] The potential of liquisolid systems to enhance the dissolution properties of Atorvastatin calcium was investigated. It was found that there is a relationship between the carrier to coating material ratio (R value) and the in vitro release of Atorvastatin calcium from liquisolid tablets. An increased R value associated with enhanced wicking, disintegration and thus, enhanced drug release. The optimized formulation F-8 revealed a percentage cumulative drug release (CDR) of 86.7% at the end of 45 min, while marketed tablets (lipvas) revealed a % CDR value of 82.6%. In case of Atorvastatin calcium direct compressible tablets thereby revealing enhanced dissolution rate. Thus, the objective of incorporating Atorvastatin calcium into liquisolid system to achieve faster dissolution rates was met with success.

DESCRIPTION OF THE FIGURES:
[0006] Figure 1: illustrates λmax of atorvastatin calcium.

[0007] Figure 2: illustrates calibration curve of atorvastatin calcium in pH6.8 PBS.

[0008] Figure 3: illustrates FT-IR spectra for the pure atorvastatin calcium.

[0009] Figure 4: illustrates FT- IR Spectra for atorvastatin calcium + formulation excipients.

[0010] Table 1: illustrates formulation of atorvastatin calcium LST`s

[0011] Table-2: illustrates precompression parameters of all the formulations F1 - F8.

[0012] Table-3: illustrates post compression parameters of atorvastatin calcium LST`s.

[0013] Figure-5: illustrates comparison of wetting time of formulations F1 - F8.

[0014] Figure- 6: illustrates comparison of disintegration time of formulations F1 - F8.

[0015] Table-4: illustrates comparative dissolution profiles of the formulations F1-F8.

[0016] Figure-7: illustrates comparative dissolution profiles of F8 & Marketed Tablets.

DETAILED DESCRIPTION OF THE INVENTION:
[0017] Atorvastatin calcium purchased from Yarrow Chem Products, Mumbai, Micro crystalline cellulose, Di calcium phosphate, Crosscarmellulose sodium, Lactose and HPMC were obtained from Loba chemie, Mumbai, Propylene glycol, Tween 40 & 80, Span 80 were obtained from S.D. Fine Chem. Ltd, Mumbai and all the other chemicals were used as Analytical grade.

[0018] Determination of λmax: An accurately weighed 10 mg of Atorvastatin calcium was transferred in a 100ml volumetric flask. To flask phosphate buffer was added in small proportion so as to dissolve Atorvastatin calcium. The volume was made up to 100 ml with phosphate buffer pH 6.8 to get a concentration of 100 µg/ml. 20 µg/ml solution of Atorvastatin calcium was prepared in dilution. The resulting solution was scanned in UV-Vis sepectrophotometer from 400-200 nm to determine theλmax.

[0019] Calibration Curve: 100 mg of Atorvastatin calcium transferred into 100 ml volumetric flask and makeup the final volume with pH 6.8 phosphate buffer. From this stick solution different concentration 5 - 40 µg/ml was made up with pH 6.8 phosphate buffer. From each concentration sample was taken & the absportion was measured at 242 nm by using UV spectrophotometer by using pH 6.8 phosphate buffer as a blank. The graph was plotted by taking concentration on X-axis and absorption on Y-axis.

[0020] Drug Excipients Compatibility Studies: Compatibility study was performed by the KBr pellet method using the fourier transform infared spectrophotometer5. Abaseline correction was made using dired potassium bromide, and then the spectra of Atorvastatin calcium, carrier and coating materials were obtained6.

[0021] Solubility Analysis: Saturated solution were prepared by adding excess amount of Atorvastatin calcium to appropriate solvents like propylene glycol, Tween-80, Tween-40 and Span-80, then shaking on orbital shaker for 48hrs at 25 rpm under constant vibrations. The solution were filtered through 0.45micron filter, diluted suitably and analyzed by UV-visible spectrophotometer at 242 nm7.

[0022] Determination of Flowable Liquid-Retention Potential (Ø-value): The admixture containing nonvolatile solvent and carrier or coating material were mixed using motor and pestle. In constant weight of nonvolatile solvent (Tween-40), increasing carrier or coating material (MCC, HPMC, DCP, Lactose and collidial silicondioxide) was incorporated and on each addition, an angle of repose was determined. The flowable liquid retention potentional (Ø-value) of each liquid/powder admixture was calculated using the following equation8.
Øvalue= weight of liquid/weight of solid

[0023] Determination of Liquid Load Factors (LF) &Carrier and Coating ratio(R Value):
The maximum amount of liquid load on carrier/coating material, termed "load factor" (LF). Appropirte amounts carrier and coating materials used to procedure an acceptable flowing and compactiable powder were calculated using following equation9.
Lf = ØCA + ØCO(1/R)-----1
Where, ØCA and ØCO are flowable liquid retention potential value of carrier and coating material. Liquid load factor (Lf) is defined as ratio of the weight of liquid medication (W) over the weight of the carrier powder (Q) in liquisolid system, which should be possessd by an acceptably flowing and compressible system.
Lf = W/Q-------2
R is calculated by using following equation
R = Q/q------3
R represents the ratio between the weights of carrier (Q) and coating material (q) present in the formulation. where, Q-Weight of carrier material, q-weight of coating material.

[0024] PREPARATION OF TELMISARTAN LIQUISOLID COMPACT: Required quantity of Atorvastatin calcium was initially dispersed in nonvolatile solvent (Span-80) termed as liquid vehicle. Then a mixture of carrier and coating materials was added to the above liquid by continuous mixing for a period 10 to 20 minutes in motor10. The amount of carrier and coating materials are taken depends on above equations.

[0025] FORMULATION OF TELMISARTAN LIQUISOLID TABLETS: Different formulation (F1-F8) of tablets were prepared by direct compression method10.To above binary mixture (liquisolid compact) disintegrant like Crosscarmellulose sodium and another remaining additive like magnesium sterate were mixed in mortar. The final mixture was directly compressed into tablets to achieve into tablet hardness or encapsulation. Tablet hardness was kept within range of 3-4kg/cm2.

[0026] PRECOMPRESSION PARAMETERS: Before the compression the prepared blend was evaluated for the following parameters11. Bulk Density: Apparent bulk density was determined by pouring the 5 gm of powder into 100 ml measuring cylinder. The bulk volume (V) of the poured drug was determined and bulk density was calculated using the formula.
Db = M/Vb
Where; Db is bulk density, M is weight of powder and Vb is bulk volume of powder.
Tapped Density: Determined by 5 gm of powder placed in 100 ml measuring cylinder and tapped for 100 times. The minimum volume (Vt) occupied was measured. The tapped density was calculated using following formula.
Dt = M/Vt
Where; M is mass of powder and Vt is tapped volume of powder
Carr's Index: It indicates powder flow properties. It is expressed in percentage
I = Dt - Db/Dt *100
Where; Dt is tapped density and Db is bulk density of powder.

[0027] Hausner Ratio: Hausner ratio is an indirect index of ease of powder flow. Hausner ratio is the ratio of tapped density to bulk density. Lower the value of hausner ratio better is the flow property. Powder with hausner ratio less than 1.18, 1.19, 1.25, 1.3-1.5 and greater the 1.5 indicate excellent, good, possible and very poor, respectively. It was calculated by the following formula12.
Hausner ratio = Dt/Db
Where, Dt is tapped density and Db is bulk density
Angle of repose: The angle of repose was determined by using funnel method.
Ɵ = Tan-1(h/r)
Where, Ɵ = angle of repose, h = height of cone, r = radius of cone

[0028] POST FORMULATION STUDIES: Weight Variation: Twenty tablets were taken and then weight was determined individually and collectively on a digital weighing balance. The average weight of a tablet was determined from collective weight13. Thickness: Tablet thickness can be measured using a simple procedure 5 tablet was taken and their thickness was measured using Vernier calipers. Hardness: It is force required breaking a tablet by compression in radial direction, it is an important parameter in formulation of ODTs because excessive crushing strength significantly reduces the disintegration time. In the present study crushing strength of tablet was measured using Pfizer hardness testers.

[0029] Disintegration time: One tablet in each 6 tubes of basket was placed and the apparatus subjected to run. The assembly should be raised and lowered between 50 cycles per minute. The time in second taken for complete disintegration of tablet with no palpable mass remaining in the apparatus was measured and recorded14.
Friability Test: Friability of tablets was determined using Roche friability.
% Friability = initial weight - final weight *100
initial weight

[0030] Initial weight: Drug Content Uniformity: The tablets were weighed and powdered. An amount of powder equivalent to 40 mg of Atorvastatin calcium was dissolved in 100 ml of phosphate buffer pH 6.8, filtered, diluted suitably and analysed for drug content at 242 nm using UV-Visible spectrophotometer. From absorbance value, amount of drug present in given tablet was calculated15.

[0031] Wetting Time: Determined by placed five circular tissue papers in a petri dish containing 10 cm diameter. Ten millimetres of water-containing Eosin, water-soluble dye, is added to Petri dish. A tablet was carefully placed on surface of tissue paper. The time required for water to reach upper surface of tablet was noted as a wetting time16.

[0032]Dissolution Studies: In vitro drug release studies for liquisolid tablets of Atorvastatin calcium (which differ in carrier concentration & Rvalue ) marketed tablets was studied using dissolution test apparatus (USP - II model) paddle type, for fabricated batches with rotation speed of 50 rpm using phosphate buffer pH 6.8 as dissolution medium maintained at room temperature of 37+- 0.5°C. Samples were withdrawn at predetermined time interval and filtered through wattman filter paper, diluted suitably and analysed at 242 nm for cumulative drug release using double beam visible spectrophotometer. The dissolution experiments were conducted in triplicate17.

[0033] Determination of λmax: The 20 μg/ml Atorvastatin calcium solution was scanned in UV-Vis spectrophotometer from 400- 200 nm to determine the λmax. The λmax was found to be at 242 nm, so the calibration curve of Atorvastatin calcium was developed at this wavelength.

[0034] Calibration Curve of Atorvastatin calcium: The standard graph of Atorvastatin calcium in pH 6.8 PBS was constructed by making the concentration range 5 - 40 µg/ml solutions. The absorbance of solutions was examined under UV- spectrophotometer at an absorption maximum of 242 nm. The curve obeyed Beer-Lambert's law and the correlation coefficient value (R2) of buffer was0.975.

[0035] Solubility of Atorvastatin calcium: The solubility is an important aspect in liquisolid systems, as the higher solubility of the drug in the non-volatile solvent can lead to higher dissolution rates since the drug will be more molecularly dispersed and more surface of a drug will be exposed to the dissolution medium. Atorvastatin calcium appears to be more soluble in span-80 than other solvents propylene glycol, Tween-80 and Tween-40. So, span-80 was the appropriate solvent in the preparation of Atorvastatin calcium liquisolid tablets.

[0036] Drug Excipients Compatibility Studies: The interaction studies were performed to find any kind of interaction between drug and excipients used in liquisolid tablets. FT-IR spectroscopy was used to determine the functional group present in the pure drug sample. The FTIR spectrum of pure Atorvastatin calcium was showed the characteristic peak at 1316.80 cm-1(C-N - stretching), 1650.71 cm-1 (C=O - stretching am idic group), 3152.09 cm-1 (N-H - stretching), 1650.71 cm-1 (C=C - bending), 746.50 cm-1, 691.35 cm-1 (C-F- stretching), 1159.08 cm-1 (O-H- bending).

[0037]: The FTIR spectra of the Atorvastatin calcium and formulation excipients were shown in Figures. The spectra of drug and excipients employed were showed a broad peak at the same place of the peak observed at the spectrum of pure Atorvastatin calcium has been observed, which indicated that there was no chemical interaction with the formulation excipients.

[0038] Determination of Flowable Liquid-Retention Potential (Φ -value): The liquisolid mixtures containing varying amount of carrier (MCC, HPMC, Lactose and DCP) were prepared according to method described previously. Thereafter, angle of repose of these liquisolid mixtures were determined. The liquid/solid mass ratio (m/m) of blends with angle of slide corresponding to ≤30 was taken as the -value for Φ calculation.

[0039] Determination of Liquid Load Factors (Lf) & Carrier and Coating Ratio (R): Mathematical model equation for carrier and coating material in Span-80 can be given according to values of (ΦCA) and (ΦCO) as given as follow:
Lf = ΦCA + ΦCO (1 / R) … (1)
Based on this equation, Lf is calculated by using different R values and based on value of W (liquid medication), amount of carrier can be calculated according to equation (2), and then amount of coating can be calculated by applying equation (3) depending on R value. The liquisolid tablets were formulated.

[0040] PREPARATION OF ATORVASTATIN CALCIUM LIQUISOLID COMPACT: Liquisolid compacts were prepared by using eight different carriers to coating ratio i.e F1 (MCC: silicon dioxide - 97.90/19.19), F2 (MCC: silicon dioxide - 111.1/18.7), F3 (HPMC: silicon dioxide - 112/18.9), F4 (HPMC: silicon dioxide - 126/19.1), F5 (DCP: silicon dioxide - 125/18.9), F6 (DCP: silicon dioxide - 140/18.9). F7 (Lactose: silicon dioxide - 87.5/19.8), F8 (Lactose: silicon dioxide - 96.5/18.6), Liquisolid blend was formulated as represented in Table 1.

[0041] FORMULATION OF ATORVASTATIN CALCIUM LIQUISOLID TABLETS: Eight tablet formulations (F1 - F8) were prepared by direct compression method. To the liquisolid compacts crosscarmellulose sodium, magnesium stearate and talc were added and compressed into tablets. Atorvastatin calcium liquisolid tablets were formulated as represented following table.

[0042] Precompression Parameters: The powdered blends of all the formulations were evaluated for bulk density and tapped density by using bulk density apparatus and the results were shown in Table. The bulk density was found in the range of 0.336±0.02 - 0.550±0.03 gm/cm3. The tapped density ranged between 0.393±0.03 - 0.620±0.04 gm/cm3. Which indicate that powder is loosely packed. These values were further used for calculating Carr's index and Hausner ratio to check its flow ability of powder. The Compressibility index and Hausner's ratio values of all the formulations indicate that the prepared blends possessed minimum interparticulate interactions and good flow property which is preliminary requirement for formulating the tablets. The prepared powder blends of all the formulations were evaluated for the flow properties. The angle of repose of all the formulations was within the range of 280 - 420. These values indicate that the powder blend F7 & F8 had excellent flow properties; F4, F5 & F6 had good flow properties, and F1, F2 & F3 had exhibited poor flow properties.

[0043] Postcompression Parameters: All the formulations were prepared under similar conditions and the tablets exibited white color, convex in shape with smooth surface. The characteristics of prepared LST`s of Atorvastatin calcium are discussed below. The hardness for the tablets of all formulations was adjusted to 3-5 Kg/cm2 so that the effect of carrier on the dissolution rate could be evaluated accurately. The friability of all the formulated tablets was within 1%, which is an indication of good mechanical resistance of the tablet. The drug content varied between 95.93±0.46 to 98.51±0.18 for all the formulations. The thickness was measured for the tablets of all formulations and was found to be within the acceptable range. The variation in weight was within the range of ± 5% complying with pharmacopoeial specification.

[0044] Wetting Time: For all the formulations, with increase in the carrier concentration, the wetting time was decreased accordingly. It is clear from the results that the formulation containing MCC & HPMC had shown more wetting time than lactose and DCP. This may be due to the fact that MCC & HPMC is disintegrated by swelling mechanism leading to longer wetting time and lesser water absorption ratio. The formulations that contain lactose have the shortest wetting time, which may be attributed to the strong wicking action of this carrier. The wetting time was in the range of 25 seconds to 88 seconds and the formulation F8 showed minimum wetting time of 25.3 seconds.

[0045] DISINTEGRATION TIME: The in vitro disintegration time of prepared tablets (F1 - F8) was present between 3.1 to 7.7 minutes. Out of eight formulations, the tablets prepared using 96.5 mg of lactose showed rapid disintegration in 3.1 min. It was clear that the disintegration time of lactose containing tablets were comparatively lower than tablets containing MCC, HPMC and DCP. This may be due to its rapid capillary activity and hydration when comes in contact with buffer and water.

[0046] EVALUATION OF INVITRO RELEASE STUDIES: The cumulative percentage release in pH 6.8 PBS for all the formulations was recorded and the formulation F2, F4, F6 and F8 showed higher drug release than compared to F1, F3, F5 and F7. It was found that there is a relationship between the carrier to coating material ratio (R value) and the in vitro release of Atorvastatin calcium from liquisolid tablets. An increased increase R value associated with enhanced wicking, disintegration and thus, enhanced drug release. The tablets formulated with lactose showed greater rate of dissolution when compared to the tablets formulated with MCC, HPMC and DCP. In formulation F8 containing 96.5 mg of lactose along with 10 mg of Crosscarmellulose sodium showed better dissolution rate than those of all other formulations. This might be because of its high disintegrating nature. The dissolution study of an optimized formulation (F-8) compared with marketed tablets (Lipvas - 40 mg) and it was found that F-8 showed significant higher drug release rate than marketed tablet.
, Claims:CLAIMS:
I/WE CLAIM:
A method of evaluation of atorvastatin calcium liquisolid tablets and comparing the dissolution
data with marketed tablet, comprising:
a 10 mg of atorvastatin calcium was transferred in a 100ml volumetric flask;
whereby to flask phosphate buffer was added in small proportion so as to dissolve atorvastatin
calcium;
the volume was made up to 100 ml with phosphate buffer pH 6.8 to get a concentration of 100 μg/ml;
a 20 μg/ml solution of atorvastatin calcium was prepared in dilution;
whereby the resulting solution was scanned in uv-vis spectrophotometer from 400-200 nm to determine the λ max;
a 100 mg of atorvastatin calcium transferred into 100 ml volumetric flask and makeup the final volume with pH 6.8 phosphate buffer;
whereby from this stick solution different concentration 5-40 μg/ml was made up with pH 6.8 phosphate buffer;
whereby from each concentration sample was taken and the absorption was measured at 242 nm by using uv spectrophotometer by using ph 6.8 phosphate buffer as a blank;
wherein required quantity of atorvastatin calcium was initially dispersed in nonvolatile solvent (span-80) termed as liquid vehicle;
a mixture of carrier and coating materials was added to the above liquid by continuous mixing for a period 10 to 20 minutes in motor; and
different formulation (f1-f8) of tablets were prepared by direct compression method.

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