TECHNICAL FIELD
[0001] The present disclosure relates generally to the field of Pharmaceuticals. Particularly, the present disclosure provides solid dispersion formulation of Lamotrigine. Aspects of the present disclosure also relates to a method of preparation of solid dispersion formulation of Lamotrigine.
BACKGROUND
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Given the increasing percentage of drug candidates with poor aqueous solubility, with up to 90% of NCE (New Chemical Entity) candidates belonging to either BCS category II or IV, one significant focus of formulation scientists over the past 15 years has been to develop formulations which enable the delivery of the resulting drugs at a reasonable rate and extent of oral bioavailability. This has led to the successful market introduction of a notable number of drugs based on various advanced drug delivery technologies, including: formation of solid dispersions, nanocrystal formation via media milling, and the creation of self-emulsifying drug delivery systems. Building on the significant progress achieved in the four mentioned domains, (absorption process understanding, developability of new chemical entities (NCEs), formulation/drug delivery system design, and patient-centered drug design), there is still opportunity for additional advancement of the broader area of oral drug delivery, which can be achieved in particular by more seamlessly integrating development activities across the four domains. Many of the new drugs/compounds emanating from drug discovery pipelines are poorly water-soluble, as defined by the Biopharmaceutics Classification System. In fact, it is estimated that up to 80% of new small molecule drugs in development can be regarded as poorly soluble. Pharmaceutical scientists are therefore often under pressure to improve the solubility of these challenging compounds in order to maximize exposure and reduced variability. Examples of the successful application of these technologies towards novel medicines include drugs like Kaletra®(ritonavir, lopinavir), Sporanox® (itraconazole), Emend® (aprepipant), and Fortovase® (saquinavir). 2
[0004] Solid dispersion technology can be used to improve the in-vitro and in-vivo dissolution properties of slightly water-soluble drugs and to control dissolution rate of slightly water-soluble drugs. Solid dispersion is a product formed by converting a fluid drug carrier combination into solid state. Solid dispersion systems have been considered over last 25 years as a means of increasing the solubility, dissolution and absorption of poorly water-soluble drugs. This method typically involves formulation of eutectic mixtures of drugs with water soluble carriers by the melting their physical mixtures. The mechanism suggested for enhanced solubility and rapid dissolution of dispersion is - when the dispersion is exposed to water, the soluble carrier dissolves rapidly leaving the insoluble drug in a state of microcrystalline dispersion of very fine particles.
[0005] Lamotrigine, an antiepileptic drug (AED) belonging to the phenyltriazine class, is chemically unrelated to existing antiepileptic drugs. Lamotrigine displays a broader therapeutic profile than earlier antiepileptic drugs with significant efficacy against absence seizures. Lamotrigine is rapidly and completely absorbed and plasma protein binding is 55% in-vitro. Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N- glucuronide conjugate. However, solubility of Lamotrigine in water is only 0.17mg/mL at 25ºC, Lamotrigine is slightly soluble in anhydrous ethanol, the minimum solubility of Lamotrigine is 0.1 mg/mL in pH 7.4 phosphate buffer. Accordingly, there remains a need in the art of formulation of Lamotrigine that improves the solubility profile thereof and hence, improves its bioavailability. Need is also felt of a method of preparation of formulation of Lamotrigine that improves the solubility profile thereof and in turn improves its bioavailability.
[0006] The present disclosure satisfies the existing needs, inter alia, others and provides a solid dispersion formulation of Lamotrigine. Aspects of the present disclosure also provide a method of preparation of a solid dispersion formulation of Lamotrigine.
OBJECTS OF THE INVENTION
[0007] An object of the present disclosure is to provide a formulation of Lamotrigine.
[0008] Another object of the present disclosure is to provide a formulation of Lamotrigine that improves equilibrium solubility of Lamotrigine.
[0009] Another object of the present disclosure is to provide a formulation of Lamotrigine that improves the bioavailability of Lamotrigine.
[0010] Another object of the present disclosure is to provide a method of preparation of formulation of Lamotrigine. 3
[0011] Another object of the present disclosure is to provide a solid dispersion formulation of Lamotrigine.
[0012] Another object of the present disclosure is to provide a method of preparation of a solid dispersion formulation of Lamotrigine.
[0013] Further object of the present disclosure is to provide a solid dispersion formulation of Lamotrigine that exhibits better dissolution characteristics of Lamotrigine as compared to pure Lamotrigine.
[0014] Still further aspect of the present disclosure is to provide a solid dispersion formulation of Lamotrigine that exhibits same therapeutic efficacy at lower dose of Lamotrigine.
SUMMARY
[0015] The present disclosure relates generally to the field of Pharmaceuticals. Particularly, the present disclosure provides solid dispersion formulation of Lamotrigine. Aspects of the present disclosure also relates to a method of preparation of solid dispersion formulation of Lamotrigine.
[0016] The present disclosure is on a premise that a solid dispersion formulation of Lamotrigine, said formulation comprising Lamotrigine and modified locust bean gum in a weight ratio ranging from 1:1 to 1:7 surprisingly improves the equilibrium solubility of Lamotrigine by about 2.5 times as compared to that of the Lamotrigine.
[0017] Accordingly, an aspect of the present disclosure provides a solid dispersion formulation of Lamotrigine, said formulation comprising Lamotrigine and modified locust bean gum in a weight ratio ranging from 1:1 to 1:7. In an embodiment, the formulation exhibits equilibrium solubility of Lamotrigine more than 420.00 μg/ml when determined in 0.1 N HCl at 37±0.5ºC. In an embodiment, the formulation comprises modified locust bean gum in amorphous form. In an embodiment, the formulation comprises Lamotrigine in amorphous form. In an embodiment, FTIR spectrum of the modified locust bean gum exhibits peaks at 3448 cm-1, 2928 cm-1, 1647 cm-1, 1431 cm-1 and 1026 cm-1. In an embodiment, the formulation comprises Lamotrigine and modified locust bean gum in a weight ratio of 1:3. In an embodiment, the formulation exhibits broad peaks at diffraction angle (2θ) 9.5282, 11.5302, 12.4514, 16.9594, 17.9348, 19.4634, 20.4359, 22.8476, 25.5305, 26.6542, 28.8402 and 31.7301 in XRD spectrum. In an embodiment, the formulation exhibits absence of any or a combination of peaks at diffraction angle (2θ) 12.4514, 17.9348, 22.8476, 26.6542 in XRD spectrum. In an embodiment, the formulation exhibits endothermic peak at 4
216.88oC with enthalapy of fusion 22.87 J/g and endothermic peak at 66.58oC with enthalapy of fusion 114.07 J/g. In an embodiment, the formulation comprises Lamotrigine and modified locust bean gum in a weight ratio of 1:5. In an embodiment, the formulation is prepared using a solvent evaporation process.
[0018] Another aspect of the present disclosure provides a method of preparation of solid dispersion formulation of Lamotrigine, said method comprising the steps of: taking Lamotrigine and modified locust bean gum in a weight ratio ranging from 1:1 to 1:7; contacting said Lamotrigine and modified locust bean gum with an organic solvent; and effecting evaporation of said organic solvent to realize solid dispersion formulation of Lamotrigine. In an embodiment, the solid dispersion formulation comprises modified locust bean gum in amorphous form. In an embodiment, the solid dispersion formulation comprises Lamotrigine in amorphous form. In an embodiment, FTIR spectrum of the modified locust bean gum exhibits peaks at 3448 cm-1, 2928 cm-1, 1647 cm-1, 1431 cm-1 and 1026 cm-1. In an embodiment, the formulation comprises Lamotrigine and modified locust bean gum in a weight ratio of 1:3. In an embodiment, the formulation exhibits absence of any or a combination of peaks at diffraction angle (2θ) 12.4514, 17.9348, 22.8476, 26.6542 in XRD spectrum. In an embodiment, the formulation exhibits endothermic peak at 216.88oC with enthalapy of fusion 22.87 J/g and endothermic peak at 66.58oC with enthalapy of fusion 114.07 J/g.
[0019] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like components.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] The accompanying drawings are included to provide a further understanding of the present disclosure, and are incorporated in and constitute a part of this specification. The drawings illustrate exemplary embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure.
[0021] FIG. 1A, 1B and 1C illustrate exemplary FT-IR spectra of Lamotrigine, Modified Locust Bean Gum (MLBG) and a solid dispersion formulation of Lamotrigine, in accordance with embodiments of the present disclosure. 5
[0022] FIG. 2A, 2B and 2C illustrate exemplary Powder X-Ray Diffraction patterns of Lamotrigine, Modified Locust Bean Gum (MLBG) and a solid dispersion formulation of Lamotrigine, in accordance with embodiments of the present disclosure.
[0023] FIG. 3 illustrates an exemplary overlay of Differential Scanning Calorimetry (DSC) of Lamotrigine, Modified Locust Bean Gum (MLBG) and a solid dispersion formulation of Lamotrigine, in accordance with embodiments of the present disclosure.
[0024] FIG. 4A, 4B and 4C illustrate exemplary Scanning Electron Microscopy (SEM) images of Lamotrigine, Modified Locust Bean Gum (MLBG) and a solid dispersion formulation of Lamotrigine, in accordance with embodiments of the present disclosure.
[0025] FIG. 5 illustrates an exemplary graph depicting In vitro drug release profile of pure drug (Lamotrigine) and various solid dispersions (SD1, SD3, SD5, SD7), realized in accordance with embodiments of the present disclosure.
DETAILED DESCRIPTION
[0026] The following is a detailed description of embodiments of the disclosure depicted in the accompanying drawings. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0027] Each of the appended claims defines a separate invention, which for infringement purposes is recognized as including equivalents to the various elements or limitations specified in the claims. Depending on the context, all references below to the “invention” may in some cases refer to certain specific embodiments only. In other cases it will be recognized that references to the “invention” will refer to subject matter recited in one or more, but not necessarily all, of the claims.
[0028] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[0029] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a 6
limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0030] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0031] The present disclosure relates generally to the field of Pharmaceuticals. Particularly, the present disclosure provides solid dispersion formulation of Lamotrigine. Aspects of the present disclosure also relates to a method of preparation of solid dispersion formulation of Lamotrigine.
[0032] The present disclosure is on a premise that a solid dispersion formulation of Lamotrigine, said formulation comprising Lamotrigine and modified locust bean gum in a weight ratio ranging from 1:1 to 1:7 surprisingly improves the equilibrium solubility of Lamotrigine by about 2.5 times as compared to that of the Lamotrigine.
[0033] An aspect of the present disclosure provides a solid dispersion formulation of Lamotrigine, said formulation comprising Lamotrigine and modified locust bean gum in a weight ratio ranging from 1:1 to 1:7. In an embodiment, the formulation exhibits mean equilibrium solubility of Lamotrigine more than 420.00 μg/ml when determined in 0.1 N HCl at 37±0.5ºC. In an embodiment, the formulation comprises modified locust bean gum in amorphous form. In an embodiment, the formulation comprises Lamotrigine in amorphous form. In an embodiment, FTIR spectrum of the modified locust bean gum exhibits peaks at 3448 cm-1, 2928 cm-1, 1647 cm-1, 1431 cm-1 and 1026 cm-1. In an embodiment, the formulation comprises Lamotrigine and modified locust bean gum in a weight ratio of 1:3. In an embodiment, the formulation exhibits broad peaks at diffraction angle (2θ) 9.5282, 11.5302, 12.4514, 16.9594, 17.9348, 19.4634, 20.4359, 22.8476, 25.5305, 26.6542, 28.8402 and 31.7301 in XRD spectrum. In an embodiment, the formulation exhibits absence of any or a combination of peaks at diffraction angle (2θ) 12.4514, 17.9348, 22.8476, 26.6542 in XRD spectrum. In an embodiment, the formulation exhibits endothermic peak at 216.88oC with enthalapy of fusion 22.87 J/g and endothermic peak at 66.58oC with enthalapy of fusion 114.07 J/g. In an embodiment, the formulation comprises Lamotrigine and modified locust bean gum in a weight ratio of 1:5. In an embodiment, the formulation is prepared using a solvent evaporation process. 7
[0034] The modified locust bean gum (alternatively and synonymously termed herein as MLBG) utilized in the present invention can be prepared by heating it at an elevated temperature for a predetermined time period, preferably with intermittent or continuous stirring to preclude charring thereof. In accordance with an embodiment, locust bean gum is placed in a porcelain dish and heated on sand bath for about 2 hours. The polymer was stirred continuously with spatula in order to avoid the charring of the polymer. The temperature of the sand bath is kept at 120°C. The prepared modified locust bean gum (MLBG) is then sieved through the 80 # mesh and kept in air tight container away from moisture at room temperature. However, it should be appreciated that the MLBG can be prepared by any other method as known to or appreciated by a person skilled in the pertinent art without departing from the scope and spirit of the present invention.
[0035] FTIR spectrum of the MLBG, realized in accordance with an embodiment of the present disclosure, exhibits peaks at 3448 cm-1 due to O-H stretching, 2928 cm-1 due to C-H stretching, 1647 cm-1 due to C=C stretching, 1431 cm-1 due to CH2 bend and 1026 cm-1 due to C-O stretching, as can be seen from FIG. 1B. DSC (Differential Scanning Calorimetry) of the MLBG, realized in accordance with an embodiment of the present disclosure, exhibits endothermic peak at 79.87oC with enthalapy of fusion 245.77 J/g and another endothermic peak at 242.42 oC with enthalpy of fusion 44.722 J/g. SEM (Scanning Electron Microscopy) of the MLBG, realized in accordance with an embodiment of the present disclosure, is illustrated in FIG. 3B.
[0036] Another aspect of the present disclosure provides a method of preparation of solid dispersion formulation of Lamotrigine, said method comprising the steps of: taking Lamotrigine and modified locust bean gum in a weight ratio ranging from 1:1 to 1:7; contacting said Lamotrigine and modified locust bean gum with an organic solvent; and effecting evaporation of said organic solvent to realize solid dispersion formulation of Lamotrigine. In an embodiment, the solid dispersion formulation comprises modified locust bean gum in amorphous form. In an embodiment, the solid dispersion formulation comprises Lamotrigine in amorphous form. In an embodiment, FTIR spectrum of the modified locust bean gum exhibits peaks at 3448 cm-1, 2928 cm-1, 1647 cm-1, 1431 cm-1 and 1026 cm-1. In an embodiment, the formulation comprises Lamotrigine and modified locust bean gum in a weight ratio of 1:3. In an embodiment, the formulation exhibits absence of any or a combination of peaks at diffraction angle (2θ) 12.4514, 17.9348, 22.8476, 26.6542 in XRD spectrum. In an embodiment, the formulation exhibits endothermic peak at 216.88oC with 8
enthalapy of fusion 22.87 J/g and endothermic peak at 66.58oC with enthalapy of fusion 114.07 J/g.
[0037] In an embodiment, the solid dispersion formulation of Lamotrigine is prepared by solvent evaporation method, wherein Lamotrigine and MLBG are mixed in a ratio ranging from 1:1 to 1:7 and then passed through 80# mesh sieve. The mixture resulting therefrom is then mixed with 25 ml of solvent in a round bottom flask. In an embodiment, the solvent is an organic solvent. In an exemplary embodiment, the organic solvent is ethanol. However, any other organic solvent or a combination/mixture of organic solvents or a combination/mixture of aqueous solvent and organic solvent, as known to or appreciated by a person skilled in the pertinent art, can be used in the present invention to serve its intended purpose without departing from scope and spirit of the present disclosure. In an embodiment, the solvent is removed from the said mixture to realize the solid dispersion formulation of Lamotrigine. In an embodiment, the solvent is removed by vacuum evaporation at a elevated temperature, preferably using a rotary evaporator and maintaining temperature ranging from 40-60°C and under vacuum below 200 mmHg. In an embodiment, the resultant solid dispersion is allowed to dry at room temperature. Optionally, the resultant solid dispersion is sieved through 80# mesh.
[0038] In an embodiment, the solid dispersion formulation of Lamotrigine comprises Lamotrigine and modified locust bean gum in a weight ratio of about 1:3. In an embodiment, the formulation exhibits mean equilibrium solubility of Lamotrigine of about 653.429 ± 8.54 μg/ml when determined in 0.1 N HCl at 37±0.5ºC. In an embodiment, the formulation comprises modified locust bean gum in amorphous form. In an embodiment, the formulation comprises Lamotrigine in amorphous form. In an embodiment, the formulation exhibits broad peaks at diffraction angle (2θ) 9.5282, 11.5302, 12.4514, 16.9594, 17.9348, 19.4634, 20.4359, 22.8476, 25.5305, 26.6542, 28.8402 and 31.7301 in XRD spectrum. In an embodiment, the formulation exhibits broader peaks of the diffraction angle of 2θ at 9.5282, 11.5302, 12.4514, 16.9594, 17.9348, 19.4634, 20.4359, 22.8476, 25.5305, 26.6542, 28.8402, 31.7301 with peak intensities of 46.25, 13.08, 42.70, 40.58, 35.29, 60.61, 46.57, 16.06, 36.08, 36.57, 23.39, 22.44 and the decreased areas of 32.83, 22.29, 30.31, 23.04, 40.08, 34.42, 66.11, 8.29, 51.22, 31.15, 9.96 and 38.23, respectively. In an embodiment, the formulation exhibits absence of any or a combination of peaks at diffraction angle (2θ) 12.4514, 17.9348, 22.8476, 26.6542 in XRD spectrum, indicating conversion of crystalline form of Lamotrigine to amorphous form. In an embodiment, the formulation exhibits endothermic peak at 216.88oC with enthalapy of fusion 22.87 J/g and endothermic peak at 66.58oC with enthalapy 9
of fusion 114.07 J/g. In an embodiment, FTIR spectrum of the formulation exhibits most of the characteristic peaks of Lamotrigine, which indicates no interaction of Lamotrigine with MLBG.
[0039] Solid dispersions of Lamotrigine, in accordance with embodiments of the present disclosure, using modified locust bean gum (MLBG) is a potential carrier systems leading to enhanced solubilization and therefore, better dissolution characteristics of Lamotrigine. Modified form of locust bean gum, realized in accordance with an embodiment of the present disclosure, exhibits excellent flow properties and aids in formulation development. The mixing of drug with MLBG leads to enhanced wetting of drug particles, size reduction are responsible for improved solubility of Lamotrigine. Further, enhanced in-vivo efficacy of solid dispersion formulation of Lamotrigine in comparison to pure drug (Lamotrigine) can afford complete protection against seizures. Accordingly, Lamotrigine may be used at low doses and thereby reduces drug related side effects.
[0040] While the foregoing describes various embodiments of the invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
EXAMPLES
[0041] MODIFICATION OF LOCUST BEAN GUM (LBG)
[0042] Locust bean gum was placed in porcelain dish and heated on sand bath for 2 h. The polymer was stirred continuously with spatula in order to avoid the charring of the polymer. The temperature of the sand bath was kept at 120°C. The prepared modified locust bean gum (MLBG) was sieved through the 80 # mesh and kept in air tight container away from moisture at room temperature.
[0043] FORMULATION OF BATCHES OF SOLID DISPERSION FORMULATION OF LAMOTRIGINE
[0044] Solid dispersions were prepared by solvent evaporation method. In this method, the drug (Lamotrigine) and the polymer (MLBG) were mixed in the ratios of 1:1, 1:3, 1:5, and 1:7 and passed through the 80 # mesh sieve. The drug and polymer was mixed in the 25 ml of solvent (ethanol) in the round bottom flask of rotary evaporator. The assembly was set and the solvent was removed by using rotary evaporator. Temperature of the bath was kept at 10
45-50°C and under vacuum below 200 mm of Hg. The resultant solid dispersions were allowed to dry at room temperature. Finally, the solid dispersions were sieved through 80 # mesh and stored in air tight containers at room temperature. Solid Dispersions resulting therefrom are termed as SD1 (wherein Lamotrigine and MLBG were mixed in weight ratio of 1:1), SD3 (wherein Lamotrigine and MLBG were mixed in weight ratio of 1:3), SD5 (wherein Lamotrigine and MLBG were mixed in weight ratio of 1:5), and SD7 (wherein Lamotrigine and MLBG were mixed in weight ratio of 1:7).
[0045] EQUILIBRIUM SOLUBILITY STUDIES
[0046] The equilibrium solubility of pure drug (Lamotrigine) and each of the solid dispersions (SD1, SD3, SD5, SD7) were determined in 0.1 N HCl at 37±0.5ºC. For each preparation, an equivalent of 25 mg of drug was added to 25 ml of 0.1 N HCl in 250ml conical flasks. The flasks were kept in shaking incubator for 48 h at 37±0.5°C. Then, the solution was filtered and the filtrate was assayed spectrophotometrically at 267nm.
[0047] Table 1 below illustrates Equilibrium Solubility of Pure drug (Lamotrigine) and Various Solid Dispersions (SDs).
Formulation
Equilibrium Solubility (μg/ml)
(Mean±SD), n=3
Pure Drug (Lamotrigine)
262.815 ± 5.78
SD1
425.992 ± 4.57
SD3
653.429 ± 8.54
SD5
688.086 ± 7.64
SD7
539.350 ± 8.11
[0048] Equilibrium solubility of the pure drug (Lamotrigine) in 0.1 N HCl was found to be 262.815 ± 5.78 μg/ml. Mixing of drug with locust bean gum in solid dispersion surprisingly led to significant increase (~2.6 times) in drug solubility (SD1, SD3, SD5, and SD7). The increase in drug solubility may be due to increased wettability by the gum and reduced particle size during formulation of mixtures. Equilibrium solubility increased with increase in the concentration of MLBG up to 1:5 ratio of drug and MLBG.
[0049] FOURIER TRANSFORM INFRARED (FT-IR) SPECTROSCOPY 11
[0050] About 10 mg of the sample was mixed with dried potassium bromide of equal weight. The mixture was properly ground using pestle and mortar. Pellets were formed by compressing the mixture by using hydraulic press. Transparent pellets formed in this way were scanned. The spectra were scanned over a frequency range 0f 4000-400 cm-1. Infrared absorption spectra of pure Lamotrigine, MLBG and Solid Dispersion (SD3) were obtained using potassium bromide disks, under static air using FTIR spectrophotometer.
[0051] FTIR spectra of samples were recorded using FTIR as to ascertain the presence of different functional groups. FTIR spectrum of pure drug showed characteristic peaks at 3743 due to NH2 stretching, at 3212 due to CH2 stretching, 1440 due to C-H stretching, 1292 due to C=N stretching, 1023 due to Aromatic C-H in plane bending, 756 due to C–N=C stretching and at 570 C-Cl stretching. FTIR spectrum of MLBG showed peaks at 3448 due to O-H stretching, 2928 due to C-H stretching, 1647 due to C=C stretching, 1431 due to CH2 bend and 1026 due to C-O stretching. FTIR spectrum of SD3 showed most of the characteristic peaks of drug which indicates no interaction of drug with polymer. FIG. 1A, 1B and 1C illustrate exemplary FT-IR spectra of Lamotrigine, Modified Locust Bean Gum (MLBG) and a solid dispersion formulation of Lamotrigine (SD3), respectively.
[0052] POWDER X-RAY DIFFRACTION STUDY
[0053] Powder X-Ray Diffraction patterns were traced employing X-ray diffractometer for the samples using Ni filtered Cu (K-α) radiations, a voltage of 45 kV, a current of 40 mA. The samples were analyzed over 2θ range of 0-50° with scan step size of 0.0170o (2θ) and scan step time 25 s. The presence or absence of crystallinity of drug and polymer was determined by X-Ray diffraction studies by comparing some representative peak heights in the diffraction pattern of the solid dispersions with that of pure drug Lamotrigine. Lamotrigine showed sharp peaks of the diffraction angle of 2θ at 9.882, 11.5203, 12.5498, 16.7575, 18.0759, 19.6679, 20.6704, 22.9946, 25.5965, 26.8499, 28.9782, 31.7771 with peak intensities of 10.43, 16.49, 100.00, 35.84, 46.60, 25.00, 20.95, 11.22, 28.58, 71.57, 47.53, 13.05 and the area of 16.05, 38.08, 256.52, 64.36, 119.54, 57.72, 42.99, 28.77, 72.51, 302.63, 200.95 and 38.62 respectively. Diffraction patterns of MLBG showed amorphous nature of polymer. Diffraction patterns of solid dispersion batch SD3 showed broader peaks of the diffraction angle of 2θ at 9.5282, 11.5302, 12.4514, 16.9594, 17.9348, 19.4634, 20.4359, 22.8476, 25.5305, 26.6542, 28.8402, 31.7301 with peak intensities of 46.25, 13.08, 42.70, 40.58, 35.29, 60.61, 46.57, 16.06, 36.08, 36.57, 23.39, 22.44 and the decreased areas of 32.83, 22.29, 30.31, 23.04, 40.08, 34.42, 66.11, 8.29, 51.22, 31.15, 9.96 and 38.23 respectively. Absence of some characteristic peaks and the decreased area of some characteristic peaks of 12
diffraction angle of 2θ at 12.4514, 17.9348, 22.8476, 26.6542 of drug in solid dispersion batch SD3 indicated conversion of crystalline form of drug to amorphous form. FIG. 2A, 2B and 2C illustrate exemplary Powder X-Ray Diffraction patterns of Lamotrigine, Modified Locust Bean Gum (MLBG) and a solid dispersion formulation of Lamotrigine (SD3), respectively.
[0054] DIFFERENTIAL SCANNING CALORIMETRY STUDY
[0055] Thermal properties of pure drug (Lamotrigine), MLBG, and Solid Dispersions (SD3) were analysed by Differential Scanning Calorimetry (DSC 821e Mettler Toledo, USA). The sample was sealed in aluminium pan and scanned from 30 to 300°C at a heating rate of 10°C/min in nitrogen atmosphere. DSC thermogram of Pure Drug (Lamotrigine) showed sharp endothermic peak at 218.53oC with enthalapy of fusion 134.65 J/g corresponding to its melting point, which indicates its crystalline nature. DSC thermogram of MLBG showed endothermic peak at 79.87oC with enthalapy of fusion 245.77 J/g & another endothermic peak at 242.42 oC with enthalpy of fusion 44.722 J/g.
[0056] DSC thermogram of solid dispersions batch SD3 showed endothermic peak at 216.88oC with enthalapy of fusion 22.87 J/g (indicated pure drug) and endothermic peak at 66.58 oC with enthalapy of fusion 114.07 J/g (indicated MLBG). DSC studies of SD3 revealed that their is no significant shift in the endothermic peak of the drug in SD3 but the intensity of peak is reduced remarkably. This suggest the conversion of crystalline drug into amorphous form. The exothermic peak in the SD3 can not be justified. FIG. 3 illustrates an exemplary overlay of Differential Scanning Calorimetry (DSC) of Lamotrigine, Modified Locust Bean Gum (MLBG) and a solid dispersion formulation of Lamotrigine (SD3), respectively.
[0057] SCANNING ELECTRON MICROSCOPY STUDY
[0058] Samples of pure drug, MLBG and solid dispersions (SD3) formulations were mounted onto the stubs using double sided adhesive tape and then coated with gold palladium alloy (150-200 A°) using fine coat ion sputter (Joel, fine coat ion sputter, JFC-1100). The samples were subsequently analyzed under the scanning electron microscope for external morphology. The drug (Lamotrigine) appeared as discrete rectangular crystalline structure while topological changes (slight porous) are observed in solid dispersion. FIG. 4A, 4B and 4C illustrate exemplary Scanning Electron Microscopy (SEM) images of Lamotrigine, Modified Locust Bean Gum (MLBG) and a solid dispersion formulation of Lamotrigine (SD3), respectively.
[0059] IN VITRO DISSOLUTION STUDIES OF SOLID DISPERSIONS AND PURE DRUG 13
[0060] In vitro dissolution studies of various solid dispersions (SD1, SD2, SD3, SD4) and pure drug (Lamotrigine) were carried out in 900ml of 0.1 N HCl at 37±0.5°C with the stirrer rotation speed of 50 rpm using USP dissolution apparatus using a paddle stirrer (Type II). A 5ml aliquot of dissolution medium was withdrawn at 5, 15, 30, 45, 60, 90, and 120 minutes with the pipette. The samples were suitably diluted and assayed spectrophotometrically at 267 nm. The study was done in triplicate.
[0061] In vitro drug release profile of pure drug (Lamotrigine) and various solid dispersions (SD1, SD3, SD5, SD7) is shown in FIG. 5. Pure drug (referred as PD in the graph) exhibited 27% release in 15 min whereas SD1 batch exhibited 42% release in 15 min. Maximum dissolution (54% in 15 min & 100% in 60 min) was observed in SD3 batch (in comparison to pure dug) indicating that 1:3 ratio of drug to polymer was the optimum batch. The increased wettability of drug along with change in crystallinity in solid dispersions mixture is responsible for improved dissolution of drug. Increased amounts of polymer (1:5 & 1:7) may lead to the formation of viscous plugs which may hinder the drug release. Higher amount of gum created a viscous mesh around drug particles. Drug release in 1:5 was decreased in comparison to 1:3 which did not comply with the solubility results.
[0062] IN VIVO PHARMACODYNAMICS STUDIES
[0063] Male inbred Swiss albino mice were used in the study and experimental protocol was duly approved by Institutional Animal Ethics Committee (1181/PO/ReBi/S/08/CPCSEA). Male inbred Swiss albino mice weighing 25±2g maintained on standard laboratory diet (Ashirwad Pvt. Ltd., Chandigarh, India) having free access to tap water were employed in the present study. They were housed in the departmental animal house and were exposed to 12 hr cycle of light and dark. The experiments were conducted in a semi-sound proof laboratory. The experimental protocol was approved by the institutional animal ethics committee. Care of the experimental animals was carried out as per the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Ministry of Environment and Forest, Government of India.
[0064] Drugs and chemicals used for In Vivo Study: Pentylenetetrazole (Sigma, St. Louis, USA) was dissolved in normal saline (which served as a vehicle for preparing all the drug solutions/dilutions). All drug solutions were freshly prepared before use.
[0065] Induction of the pentylenetetrazole kindled model of epilepsy in mice: In this study, the animals were divided into 3 groups each comprising 6 animals (Disease Control, Lamotrigine Pure drug (25 mg/kg p.o), Solid dispersion Lamotrigine treated (25 mg/kg p.o) groups. Lamotrigine and optimized formulation of Lamotrigine were administered 30 min 14
before the administration of Pentylenetetrazole (PTZ) (80 mg/kg) by subcutaneous route. The animals were observed for 30 min by placing in a separate cage.
[0066] Statistical Analysis: Data obtained from the study was statistically analyzed using one-way ANOVA followed by Turkey’s multiple range test as post-hoc analysis. Moreover, analysis of the time-course data of the study was also done using two-way ANOVA. A value of p<0.05 was considered to be statistically significant. The mice treated with PTZ have shown convulsions after 117.2±5.23 sec of PTZ administration and all mice died after onset of seizures. The optimized formulation of Lamotrigine have shown 100% protection against PTZ induced convulsions whereas pure Lamotrigine have shown 83.33% protection with onset of Convulsions after 574±2.23 sec. Results are shown in Table 2 below.
Table 2: Latency Period of Seizures Induced in Mice
Treatment
No of animal used
Onset of Convulsions (SEC)
Number of animal convulsed
% Of convulsions
% Animal Surviving
PTZ Control
80 mg/kg, (s.c.)
06
117.2±5.23
06
100
0.00
Lamotrigine Pure drug (25 mg/kg, p.o)
06
574±2.23
06
50
83.33
Lamotrigine Solid dispersion (25 mg/kg, p.o)
06
0.00±0.00
00
0.00
100
[0067] The results obtained herein showed that optimized formulation of Lamotrigine surprising attenuates the PTZ induced seizures and provide complete protection as compared to pure Lamotrigine. Hence, formulated Lamotrigine solid dispersions were found to be potent as compared to pure drug Lamotrigine for the treatment of epileptogenesis.
[0068] Although the subject matter has been described herein with reference to certain preferred embodiments thereof, other embodiments are possible. As such, the spirit and scope of the appended claims should not be limited to the description of the preferred embodiment contained therein. Furthermore, precise and systematic details on all above aspects are 15
currently being made. Work is still underway on this invention. It will be obvious to those skilled in the art to make various changes, modifications and alterations to the invention described herein. To the extent that these various changes, modifications and alterations do not depart from the scope of the present invention, they are intended to be encompassed therein.
ADVANTAGES OF THE INVENTION
[0069] The present disclosure provides a formulation of Lamotrigine that improves equilibrium solubility of Lamotrigine.
[0070] The present disclosure provides a formulation of Lamotrigine that improves the bioavailability of Lamotrigine.
[0071] The present disclosure provides a solid dispersion formulation of Lamotrigine that exhibits better dissolution characteristics of Lamotrigine as compared to pure Lamotrigine.
[0072] The present disclosure provides a solid dispersion formulation of Lamotrigine that exhibits same therapeutic efficacy at lower dose of Lamotrigine.

We Claim:
1. A solid dispersion formulation of Lamotrigine, said formulation comprising Lamotrigine and modified locust bean gum in a weight ratio ranging from 1:1 to 1:7.
2. The formulation as claimed in claim 1, wherein said formulation exhibits mean equilibrium solubility of Lamotrigine of more than 420.00 μg/ml, when determined in 0.1 N HCl at 37±0.5ºC.
3. The formulation as claimed in claim 1, wherein said formulation comprises modified locust bean gum in amorphous form.
4. The formulation as claimed in claim 1, wherein said formulation comprises Lamotrigine in amorphous form.
5. The formulation as claimed in claim 1, wherein FTIR spectrum of the modified locust bean gum exhibits peaks at 3448 cm-1, 2928 cm-1, 1647 cm-1, 1431 cm-1 and 1026 cm-1.
6. The formulation as claimed in claim 1, wherein said formulation comprises Lamotrigine and modified locust bean gum in a weight ratio of 1:3.
7. The formulation as claimed in claim 6, wherein said formulation exhibits broad peaks at diffraction angle (2θ) 9.5282, 11.5302, 12.4514, 16.9594, 17.9348, 19.4634, 20.4359, 22.8476, 25.5305, 26.6542, 28.8402 and 31.7301 in XRD spectrum.
8. The formulation as claimed in claim 6, wherein said formulation exhibits absence of any or a combination of peaks at diffraction angle (2θ) 12.4514, 17.9348, 22.8476, 26.6542 in XRD spectrum.
9. The formulation as claimed in claim 6, wherein formulation exhibits endothermic peak at 216.88oC with enthalapy of fusion 22.87 J/g and endothermic peak at 66.58oC with enthalapy of fusion 114.07 J/g.
10. The formulation as claimed in claim 1, wherein said formulation comprises Lamotrigine and modified locust bean gum in a weight ratio of 1:5. 17
11. The formulation as claimed in claim 1, wherein said formulation is prepared using a solvent evaporation process.
12. A method of preparation of solid dispersion formulation of Lamotrigine, said method comprising the steps of:
taking Lamotrigine and modified locust bean gum in a weight ratio ranging from 1:1 to 1:7;
contacting said Lamotrigine and modified locust bean gum with an organic solvent; and
effecting evaporation of said organic solvent to realize solid dispersion formulation of Lamotrigine.
13. The method as claimed in claim 12, wherein said solid dispersion formulation comprises modified locust bean gum in amorphous form.
14. The method as claimed in claim 12, wherein said solid dispersion formulation comprises Lamotrigine in amorphous form.
15. The method as claimed in claim 12, wherein FTIR spectrum of the modified locust bean gum exhibits peaks at 3448 cm-1, 2928 cm-1, 1647 cm-1, 1431 cm-1 and 1026 cm-1.
16. The method as claimed in claim 12, wherein said formulation comprises Lamotrigine and modified locust bean gum in a weight ratio of 1:3 and wherein said formulation exhibits absence of any or a combination of peaks at diffraction angle (2θ) 12.4514, 17.9348, 22.8476, 26.6542 in XRD spectrum.
17. The method as claimed in claim 12, wherein said formulation exhibits endothermic peak at 216.88oC with enthalapy of fusion 22.87 J/g and endothermic peak at 66.58oC with enthalapy of fusion 114.07 J/g.