6.0
7.0
8.0 / BRIEF RESUME OF THE INTENDED WORK
ENCLOSURE – I
6.1 Need for the study
The oral route remains the preferred route of drug administration due to its convenience, good patient compliance and low medicine production costs. In order for a drug to be absorbed into the systemic circulation following oral administration, the drug must be dissolved in the gastric fluids. The active pharmaceutical ingredient in a solid dosage form must undergo dissolution before it is available for absorption from the gastrointestinal tract1.
The development of meaningful dissolution procedure for drug product with limited water solubility has been a challenge to both the pharmaceutical industry and the agencies that regulate them. These challenges include developing and validating the test methods, ensuring the method is appropriate discriminatory and addressing the potential for In vivo –In vitro studies2.
Solubility behavior of a drug is one of the key determinants of its oral bioavailability. In recent years, the number of poorly soluble drug candidates has increased tremendously. The formulation of poorly soluble drugs for oral delivery presents a challenge to the formulation scientists. Oxicam derivatives of non-steroidal anti-inflammatory drugs (NSAID’S). The major drawback of these drugs is its low aqueous solubility that delays its absorption from the gastrointestinal tract 3, 4, 5, 6.
Several techniques already exists, to enhance dissolution like particle size reduction via micronization or nano suspensions, conversion of a crystalline molecule to its amorphous state, complexation with suitable complexing agents, solid dispersions of drug in suitable carriers etc., for poorly soluble drugs. Apart from these techniques liquisolid compact technique is a feasible and novel approach to improve the dissolution of poorly soluble drugs by its immediate release dosage form3.
The present study is to improve the dissolution of poorly soluble drug and to be released at gastric pH relevant to fed state by using the liquisolid compact technique. The USFDA, CDER guidelines, states that the use of USP – II paddle apparatus at 75 RPM stirring speed using pH 7.4 phosphate buffer at 37 ± 0.50C up to 60 minutes prescribed for poorly soluble NSAID’S drugs. In this present study an attempt was made to study the drug release at pH 5 (Fed State condition). Hence, it is aimed to formulate Immediate release solid dosage form by adopting Liquisolid technique6, 7.
ENCLOSURE – II
6.2 Review of the literature
  1. Jennifer D, et al., suggested that development of dissolution methods for new chemical entities as per industry perspective8.
  2. Robert AR, et al., suggested on dissolution test method development should consider the design and matrix (cohesive properties of formulated drug) of the dosage form as well as the physicochemical (intrinsic) properties of the active pharmaceutical ingredient. The dissolution test media selection should be justified for pH (recommended range pH 1.2–7.5) as well as surfactant type (ionic versus non-ionic) and level. By using in vitro dissolution tests, the industry generally seeks to establish In vivo–In vitro relationships9.
  3. Ali N, et al.,worked on liquisolid (LS) technique for dissolution rate enhancement of a high dose water-insoluble drug. Different LS formulations of Carbamazepine were accomplished by dissolving the drug in the non-toxic hydrophilic liquids and adsorbing the solution onto the surface of silica. The USP paddle method was used for all the In vitro dissolution studies. The rate of stirring was 100±2 rpm. The dosage forms were placed in 900 ml of distilled water containing 1% (w/v) sodium lauryl sulfate (SLS) and
maintained at 37 ± 0.50C. The formulations containing poly vinyl pyrrolidone (PVP) as additive has a betterdissolution rate in comparison with conventional direct compressed tablet (DCT) 10.
  1. Rania HF, et al.,investigated the In vitro andIn vivo performance of the prepared liquisolid tablets containing Famotidine. It is held within the powder substrate in a solubilized, almost molecularly dispersed state, which contributed to the enhanced drug dissolution properties. All the tested liquisolid tablet formulations showed higher drug dissolution rate than the conventional, directly compressed tablets. In addition, the selected optimal formula released 78.36%. Further, the bioavailability study indicated that the prepared optimal liquisolid formula did not differ significantly from the marketed Famotidine tablets concerning Cmax, Tmax, and AUC(0–8) at P < 0.0511.
  2. Spiro S, et al., worked on enhancement of Prednisolone dissolution properties using liquisolid (LS) compacts. The In-vitro release characteristics of Prednisolone, a very slightly water soluble glucocorticoid. The potential of liquisolid systems to improve the dissolution properties of water-insoluble agents was investigated using Prednisolone as the model drug. LS compacts demonstrated significantly higher drug release rates, in different dissolution media and volumes, compared to tablets prepared by the direct compression method 12.
  3. Amal AE, et al., carried out liquisolid Systems to improve the dissolution of Furosemide. This study was to enhance the in vitro dissolution properties of the practically water insoluble loop diuretic Furosemide, by utilizing liquisolid technique. The results shown that all formulations exhibited higher percentage of drug dissolved in water compared to that at acidic medium. Liquisolid compacts containing synperonic PE/L 81 demonstrated higher release rate at the different pH values 13.
  1. Amrit BK, et al., carried on improve Fenofibrate dissolution through its formulation into liquisolid tablets and then to investigate In vitro performance of prepared liquisolid systems. Enhanced drug release profiles due to increased wetting properties and surface of drug available for dissolution was obtained in case of liquisolid tablets 14.
  2. Sanjeev G, et al., worked on In vitro dissolution property of slightly water soluble Bromhexine hydrochloride was improved by exploring the potential of Liquisolid (LS) system. The In vitro release pattern of LS compacts and directly compressed tablets were studied using USP-II apparatus. The drug release shows significant benefit of LS in increasing wetting properties and surface area of drug available for dissolution. From this study it concludes that the LS technique is a promising alternative approach for improvement of dissolution property of water-insoluble drugs 15.
  3. Ali N, et al., worked on potential of liquisolid systems to improve the dissolution properties of a water-insoluble agent (Indomethacin) was investigated. Propylene glycol as vehicle produced higher dissolution rates in comparison with other formulation containing PEG 400 or Tween 80 of the same concentration 16.
ENCLOSURE – III
6.3 Objectives of the study
The specific objective of this study is to formulate and evaluate the liquisolid tablet of oxicam derivative with an aim.
  1. To increase the solubility of poorly soluble drugs.
  2. Simplicity of preparation and low cost.
  3. To minimize excipients in formulation compare with other formulations.
  4. To increase the therapeutic efficacy of drug.
  5. Novel, feasible and promising approach in tablet technology.
  6. Study the statistical significance of the evaluation parameters.
MATERIALS AND METHODS
Materials:
Drug : One of the NSAID’s (oxicamderivatives) such as Meloxicam,
Piroxicam, Tenoxicam and Lornoxicam etc.
Liquid Solvents : Non – Toxic Hydrophilic solvents like PEG (Poly Ethylene
Glycol) -200, 400, Propylene Glycol, Glycerin and Tweens etc.
Carriers : MCC (Microcrystalline Cellulose), Lactoseetc.
Coating agents : Silica (Amorphous) etc.
Additives : PVP (Poly Vinyl Pyrrolidine), HPMC ( Hydroxy Propyl
Methyl Cellulose) etc.
Superdisintegrants : Crospovidone, sodium starch glycolate, Croscaramellose etc.
Method:
To develop liquisolid tablets on the basis of optimized loading factor, the drug is first dissolved in non – toxic hydrophilic liquids and then absorbed on suitable carrier. Further mass is coated with silica and compressed into tablets by direct compression method.
Evaluation:
  1. Compatibility study by Fourier Transform Infra Red (FTIR)
  2. Phase solubility studies as per FDA guidelines.
  3. Surface Morphology of liquisolid compact by Scanning Electron Microscopy (SEM)
  4. Solid state by Differential Scanning Calorimetry (DSC)/ Powder X – ray Diffraction (PXRD)
  5. To evaluate pre compressionparameters such as flow property, drug content uniformity, bulk density, tapped density, hausener’s ratio and post compression parameters such as Hardness, weight variation, friability and disintegration.
  6. In – Vitro release & Release kinetic studies at gastric pH 5 (fed state condition).
  7. Validation of the developed dissolution method.
  8. Study the statistical significance of the evaluation parameters.
ENCLOSURE –IV
7.1 Source of data
1. Library: Bharathi college of pharmacy
  1. E-library: Bharathi college of pharmacy
  2. Practical data’s are obtained from laboratory-based studies.
ENCLOSURE-V
7.2 Method of collection of data
Data on drug was collected through literature survey and from physicochemical data base such as solubility in various solvents, pH of the drug solution and compatibility of the drug with various excipients.
A) Preparation:
Preparation of liquisolid tablets by direct compression method.
B) Characterization:
Compatibility study by FTIR andcharacterization of formulation by surface morphology
by SEM, solid state by DSC/ PXRD.
  1. Prepared powder mass will be evaluated for
a)Flow property
b)Drug content uniformity
c)Bulk density
d)Tapped density
e)Hausener’s ratio
  1. Prepared liquisolid tablets will be evaluated for
a)Hardness
b)Weight variation
c)Friability
d)Disintegration
e)In - vitro dissolution studies at fed state pH
f)Validation of the developed dissolution method
ENCLOSURE-VI
7.3 Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please mention briefly.
-NOT APPLICABLE-
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
-NOT APPLICABLE-
ENCLOSURE – VII
LIST OF REFERENCES
  1. Venkat BY, Adhikrao VY. Enhancement of solubility and dissolution rate of bcs class II pharmaceuticals by nonaquious granulation technique. Int J Pharm Res Dev2010;1(12):08–20.
  2. Gowthamarajan K, Sachin KS. Dissolution testing for poorly soluble drugs: a continuing Perspective. Dissolution Technol2010;17(2):24–32.
  3. Amal AE, Ngiik T. Effects of liquisolid formulations on dissolution of Naproxen. Eur J Pharm Biopharm 2009;73:373-84.
  4. Yadav VB, Yadav AV. Liquisolid granulation technique for tablet manufacturing: an overview. J Pharm Res 2009;2(4):670-4.
  5. list.com
  6. www. wikiapedia.com
  7. US FDA Dissolution methods for drug products,[
cder/dissolution/dsp_SearchResults_Dissolutions.cf]
  1. Jennifer D, Johannes K. Pharmaceutical Dissolution Testing. United States of America: Taylor & Francis Group; 2005. p. 69 - 93.
  2. Robert AR, Cynthia KB, Hitesh PC, Beverly N, Brian RR. Acceptable analytical practices for dissolution testing of poorly soluble compounds. Pharm Tech 2004;28(12):56-65.
  1. Ali N, Yousef J, Baharak JN. Liquisolid technique for dissolution rate enhancement of a high dose water-insoluble drug (carbamazepine). Int J Pharm 2007;341:26–34.
  2. Rania HF, Mohammed AK. Enhancement of famotidine dissolution rate through liquisolid tablets formulation: In vitro and in vivo evaluation. Eur J Pharm Biopharm 2008;69:993–1003.
  3. Spiro S, Srinivas S. Enhancement of prednisolone dissolution properties using liquisolid compacts. Int J Pharm 1998;166:177–88.
  4. Amal AE, Babatunde A,Ebtessam AE and Sahar E. Liquisolid Systems to Improve the
dissolution of furosemide. Sci Pharm 2010;78:325–44.
  1. Amrit BK, Indrajeet DG, Avinash HH, Pandurang ND and satish BB. Dissolution rate enhancement of fenofibrate using liquisolid tablet technique. Lat Am J Pharm 2009;28(2):219-25.
  2. Sanjeev G, Ravindra J. Liquisolid technique for enhancement of dissolution properties of bromhexine hydrochloride. Res J Pharm Tech 2009;2(2):382–6.
  3. Ali N, Yousef J, Mohammad RS, Solmaz A. Liquisolid technique as a tool for enhancement of poorly water-soluble drugs and evaluation of their physicochemical properties. Acta Pharm 2007;57:99-109.