Description:FIELD OF THE INVENTION
[0001] The present disclosure relates generally to pharmaceutical formulations of Lafutidine. More specifically, the disclosure is directed to a microemulsion formulation for management of gastric ulcer comprising Lafutidine and virgin coconut oil.

BACKGROUND OF THE INVENTION
[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] Lafutidine (LAFT) a newly developed anti-ulcer drug which is a histamine H2-receptor antagonist and indicates reduced postprandial as well as night-time gastric acid secretion in clinical investigations. Lafutidine has a receptor binding affinity which is 2-80 times higher than other similar category drugs such as famotidine, ranitidine and cimetidine. It is practically insoluble in water i.e. 0.243 mg/ml which impairs its dissolution in upper gastric fluid; delaying the absorption rate and therefore, has low bioavailability. Literature reports usually revealed that drugs with a very low aqueous solubility will demonstrate low dissolution rates, limited absorption and therefore poor bioavailability. Improvement of drug dissolution in such cases is a significant parameter to augment therapeutic efficacy.
[0004] Improving the dissolution levels of aqueous insoluble drugs and minimizing the drug's first-pass effect remains the most challenging issues for production scientists to provide industrial applicability as well as increased clinical effectiveness. The improved dissolution rates can enhance the drug oral bioavailability. Use of lipids and surfactant mixture-based delivery systems have been designed for boosting drug dissolution, for avoiding the first-pass effect and thereby, augmenting the oral bioavailability of poorly aqueous-soluble drugs. However, improved drug delivery systems specifically for Lafutidine have not been discovered and the existing systems have scope for improvement.
[0005] There is a need in the art to develop improved formulations of Lafutidine which demonstrate increased dissolution rates and oral bioavailability.

OBJECTS OF THE INVENTION
[0006] An object of the present disclosure is to provide a microemulsion formulation of Lafutidine.
[0007] An object of the present disclosure is to provide a microemulsion formulation of Lafutidine with improved dissolution rates and oral bioavailability.
[0008] Another object of the present disclosure is to provide a process of preparing a microemulsion formulation of Lafutidine.

SUMMARY OF THE INVENTION
[0009] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in Detailed Description section. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
[0010] Aspects of the present disclosure provide a microemulsion formulation of Lafutidine comprising the drug, an oil phase, a surfactant and a co-surfactant.
[0011] In an aspect, the present disclosure provides a microemulsion formulation for management of gastric ulcer comprising Lafutidine or pharmaceutically acceptable salts thereof, an oil phase consisting of virgin coconut oil, a surfactant consisting of a polysorbate, and a co-surfactant consisting of propylene glycol.
[0012] In an embodiment, the formulation further comprises an aqueous phase consisting of water.
[0013] In an embodiment, the polysorbate may be selected from polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monolaurate or combinations thereof.
[0014] In an embodiment, the surfactant may be present in a weight ratio of about 2:1 with respect to the co-surfactant.
[0015] In an aspect, the present disclosure provides a process of preparing the microemulsion formulation comprising the steps of: (a) mixing the surfactant and the co-surfactant together to give a surfactant mixture; (b) adding and vortexing the oil phase in the surfactant mixture; (c) mixing Lafutidine to the mixture of step (b) and (d) adding gradually the aqueous phase with stirring to give the microemulsion formulation.
[0016] Other aspects of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learnt by the practice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS
[0017] The following drawings form part of the present specification and are included to further illustrate aspects of the present disclosure. The disclosure may be better understood by reference to the drawings in combination with the detailed description of the specific embodiments presented herein.
Figure 1 provides a contour plot (2D) showing the effect of independent variables - Smix (mg) and oil (mg) on Q90 (percentage drug released in 90 minutes) (Y1) of the microemulsion formulation as per an embodiment of the present disclosure.
Figure 2 provides a contour plot (2D) showing the effect of independent variables - Water (mg) and oil (mg) on Q90 (Y1) of the microemulsion formulation as per an embodiment of the present disclosure.
Figure 3 provides a contour plot (2D) showing the effect of independent variables - Water (mg) and Smix (mg) on Q90 (Y1) of the microemulsion formulation as per an embodiment of the present disclosure.
Figure 4 provides a response surface plot (3D) showing the effect of independent variables - Smix (mg) and oil (mg) on Q90 (Y1) of the microemulsion formulation as per an embodiment of the present disclosure.
Figure 5 provides a response surface plot (3D) showing the effect of independent variables - Water (mg) and oil (mg) on Q90 (Y1) of the microemulsion formulation as per an embodiment of the present disclosure.
Figure 6 provides a response surface plot (3D) showing the effect of independent variables - Smix (mg) and Water (mg) on Q90 (Y1) of the microemulsion formulation as per an embodiment of the present disclosure.
Figure 7 provides a contour plot (2D) showing the effect of independent variables - Smix (mg) and oil (mg) on drug content (Y2) of the microemulsion formulation as per an embodiment of the present disclosure.
Figure 8 provides a contour plot (2D) showing the effect of independent variables - Water (mg) and oil (mg) on drug content (Y2) of the microemulsion formulation as per an embodiment of the present disclosure.
Figure 9 provides a contour plot (2D) showing the effect of independent variables - Water (mg) and Smix (mg) on drug content (Y2) of the microemulsion formulation as per an embodiment of the present disclosure.
Figure 10 provides a response surface plot (3D) showing the effect of independent variables - Smix (mg) and oil (mg) on drug content (Y2) of the microemulsion formulation as per an embodiment of the present disclosure.
Figure 11 provides a response surface plot (3D) showing the effect of independent variables - Water (mg) and oil (mg) on drug content (Y2) of the microemulsion formulation as per an embodiment of the present disclosure.
Figure 12 provides a response surface plot (3D) showing the effect of independent variables - Smix (mg) and Water (mg) on drug content (Y2) of the microemulsion formulation as per an embodiment of the present disclosure.
Figure 13 provides a contour plot of desirability function of the microemulsion formulation as per an embodiment of the present disclosure.
Figure 14 provides a response surface plot of desirability function of the microemulsion formulation as per an embodiment of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION
[0018] The following is a detailed description of embodiments of the disclosure. 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.
[0019] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[0020] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0021] In some embodiments, numbers have been used for quantifying weights, percentages, ratios, and so forth, to describe and claim certain embodiments of the invention and are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0022] 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.
[0023] 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.
[0024] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[0025] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[0026] 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 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.
[0027] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified.
[0028] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[0029] It should also be appreciated that the present disclosure can be implemented in numerous ways, including as a system, a method or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
[0030] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0031] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[0032] As described herein, the term ‘effective amount’ refers to the amount of the formulation required to bring about a change or improvement in a subject without side effects or overdosing.
[0033] The term ‘management’ as used herein refers to treatment, alleviation, amelioration or prevention of gastric ulcer in a subject.
[0034] The term, "subject" as used herein refers to an animal, preferably a mammal, and most preferably a human. The term "mammal" used herein refers to warm-blooded vertebrate animals of the class 'mammalia' , including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young, the term mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
[0035] Aspects of the present disclosure provide a microemulsion formulation of Lafutidine, an oil or lipid phase, a surfactant and a co-surfactant.
[0036] In an embodiment, the present disclosure provides a microemulsion formulation for management of gastric ulcer comprising Lafutidine or pharmaceutically acceptable salts thereof, an oil phase consisting of virgin coconut oil, a surfactant consisting of a polysorbate, and a co-surfactant consisting of propylene glycol.
[0037] In an embodiment, the formulation further comprises an aqueous phase consisting of water.
[0038] In an embodiment, Lafutidine or pharmaceutically acceptable salts thereof may be present in the formulation in a weight percentage range of about 1% w/w to about 2% w/w of the formulation. In a preferred embodiment, Lafutidine may be present in the formulation in a weight percentage of about 1% w/w of the formulation.
[0039] In an embodiment, the oil phase may be present in the formulation in a weight percentage range of about 6% w/w to about 18% w/w of the formulation. In a preferred embodiment, the oil phase may be present in the formulation in a weight percentage of about 18% w/w of the formulation.
[0040] In an embodiment, the surfactant may be present in the formulation in a weight percentage range of about 16% w/w to about 32% w/w of the formulation. In a preferred embodiment, the surfactant may be present in the formulation in a weight percentage of about 26% w/w of the formulation.
[0041] In an embodiment, the co-surfactant may be present in the formulation in a weight percentage range of about 8% w/w to about 16% w/w of the formulation. In a preferred embodiment, the co-surfactant may be present in the formulation in a weight percentage of about 13% w/w of the formulation.
[0042] In an embodiment, the aqueous phase may be present in the formulation in a weight percentage range of about 42% w/w to about 83% w/w of the formulation. In a preferred embodiment, the aqueous phase may be present in the formulation in a weight percentage of about 43% w/w of the formulation.
[0043] In an embodiment, the surfactant may be present in a weight ratio of about 2:1 with respect to the co-surfactant. In an embodiment, the polysorbate and propylene glycol may be present in a weight ratio of about 2:1.
[0044] In an embodiment, total of surfactant and co-surfactant may be present in a weight ratio of about 9:1 to 1:9 with respect to the oil phase.
[0045] In an embodiment, the polysorbate may be selected from polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monolaurate or combinations thereof. In a preferred embodiment, the polysorbate may be polyoxyethylene sorbitan monooleate.
[0046] In an embodiment, the pharmaceutically acceptable salts includes Lafutidine hydrochloride.
[0047] In an embodiment, the formulation may further comprise a pharmaceutically acceptable excipient. The excipient may be added to increase stability or biocompatibility.
[0048] In an embodiment, the pharmaceutically acceptable excipient may be selected from a preservative, buffer, vehicle, antioxidant, flavoring agent, coloring agent, or combinations thereof.
[0049] In an embodiment, the excipient may be selected from isopropanol, glycerol, PEG 400, anhydrous ethanol, ethanediol, 1,2-propanediol, caramel, tocopherol, methanol, ethanol, sodium sulfite, sodium bisulfate, phosphate buffer, spearmint oil, cinnamon oil, mint flavor, or combinations thereof. However, it may be appreciated that any other excipient well known in the art may be employed within the spirit and scope of the invention.
[0050] In an embodiment, the formulation may be in the form of a liquid, or semi-solid. In an embodiment, the formulation may be an aerosol, semi-solid, paste, syrup, gel, spray, suspension, or solution.
[0051] In an embodiment, the formulation may be administered orally, intravenously, transmucosally, parenterally, topically, or combinations thereof.
[0052] Virgin coconut oil also possesses inherent anti-ulcer activity. In an embodiment, the formulation demonstrates synergistic anti-ulcer activity.
[0053] In an embodiment, the formulation synergistically enhances the aqueous solubility of the drug Lafutidine.
[0054] In an embodiment, the formulation shows improved percentage cumulative drug release and higher drug content in the physiological environment. This enhances the drug’s oral bioavailability.
[0055] In an embodiment, the percentage cumulative drug release of the formulation is synergistically influenced by amount of the surfactant and co-surfactant, while it is antagonistically influenced by the amount of oil phase and aqueous phase. In an embodiment, the drug content of the formulation is synergistically influenced by amount of the surfactant and co-surfactant and the amount of the oil phase, while it is antagonistically influenced by the amount of the aqueous phase.
[0056] In an embodiment, the percentage cumulative drug release of the formulation may be over 90%. In some embodiments, the formulation shows a 3.15-fold amplification in in-vitro drug release compared to the pure drug Lafutidine.
[0057] In an embodiment, the formulation is capable of giving drug content of up to 10 mg/mL.
[0058] In an embodiment, the formulation synergistically overcomes the first-pass effect thereby, augmenting the oral bioavailability of Lafutidine.
[0059] In an embodiment, the formulations show storage stability. In a preferred embodiment, the formulation that is refrigerated has long shelf-life.
[0060] In an embodiment, the present disclosure provides a process of preparing the microemulsion formulation comprising the steps of: (a) mixing the surfactant and the co-surfactant together to give a surfactant mixture; (b) adding and vortexing the oil phase in the surfactant mixture; (c) mixing Lafutidine to the mixture of step (b); and (d) adding gradually the aqueous phase with stirring to give the microemulsion formulation.
[0061] In an embodiment, the microemulsion may be prepared at room temperature.
[0062] In an embodiment, the microemulsion may be prepared at a pH range of about 6 to about 7.
[0063] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure 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
[0064] The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and formulations, the exemplary methods, devices and materials are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary.
[0065] The optimized formulation for the present disclosure was determined using Box-Behnken design.
Example 1: Preliminary experiments for selection of levels of factors (X1-X3)
[0066] During the preliminary studies, levels of X1 [virgin coconut oil (mg)], X2 [surfactant mix (Smix) (mg)]( which is a mixture of tween 80 and propylene glycol), and water were determined through titration method. Virgin coconut oil (VCO) and Smix were mixed in varied weight ratios from 9:1 to 1:9 (% w/w) and diluted with distilled water to get micro-emulsion. Experiments were performed at various ratios of Smix (tween 80: propylene glycol) [1:2, 1:1, 1:0, 2:1]. Each weight ratio was visually checked for clear and easily flow-able micro-emulsions, and turbidity was noted as the end point of the titration. During preliminary experimentation, it was found that Smix (tween 80: propylene glycol in 2:1) was optimum for microemulsion formation.
Experimental design
[0067] Microemulsion formulation of Lafutidine and Box-Behnken design (BBD) layout for its production, have been depicted in Tables 1 & 2, respectively.
Table 1: Independent and response variables for the formulation
Independent variables -1 (Low) 0 (Medium) +1 (High)
X1= Oil (mg) 50 100 150
X2 = *Smix (mg) 200 300 400
X3 = Water (mg) 400 550 700
Response variables Constraint
Y1 = Q90 Maximize
Y2 = Drug content (mg/ml) Maximize
*Smix (mg) is mixture of surfactant (tween 80) and co-surfactant (propylene glycol) in 2:1; Q90 is percentage cumulative drug release in 90 minutes.
Table 2 : Box-Behnkendesign (BBD) layout for the formulation
Batch X1 [Oil (mg)] X2 [Smix (mg)] X3 [Water (mg)]
1 -1 -1 0
2 1 -1 0
3 -1 1 0
4 1 1 0
5 -1 0 -1
6 1 0 -1
7 -1 0 1
8 1 0 1
9 0 -1 -1
10 0 1 -1
11 0 -1 1
12 0 1 1
13 0 0 0
14 0 0 0
15 0 0 0
16 0 0 0
17 0 0 0

Example 2: Preparation of microemulsion
[0068] For the preparation of the formulation, the amount of Lafutidine (10 mg/ml of microemulsion) was kept constant. The oil and Smix were weighed in different weight ratios separately (Table 1 and Table 2) and mixed using vortexing (Remi, India). Lafutidine was mixed with the oil-Smix mixture. The aqueous phase was transferred gradually to the previously prepared mixture with continuous stirring using magnetic stirrer at room temperature (Remi, India) to give the formulation.
Example 3: Dissolution and bioavailability studies of the formulation
3.1 In vitro dissolution studies for determination of Q90 (Y1)
[0069] The in-vitro dissolution studies were performed using USP dissolution apparatus type-II in phosphate buffer, pH-6.8 as dissolution media. The pure Lafutidine and the microemulsion formulation (equivalent to 10 mg of pure Lafutidine) were evaluated at 50 rpm at 37 ±0.5 °C. Aliquots were taken at different time intervals with replacement method (to maintain the dissolution volume) and drug concentration was determined using UV spectrophotometer at 279 nm. Cumulative percent drug release was plotted as a function of time. Q90 (percentage drug released in 90 minutes) was determined.
Statistical and response surface analysis of Q90 (Y1) by Design-Expert software
[0070] The R², F-value and p-value for Q90 (Y1) were 0.9692, 92.87 and < 0.0001. Therefore, second order polynomial model was generated by multiple regression analysis using Design-Expert software (Trial Version 12.0.9.0, Stat-Ease Inc., MN) suggested. Q90 (Y1) of the microemulsions was synergistically influenced by Smix(mg) (X2) while antagonistically influenced by oil (mg) (X1) and water (mg) (X3) which can be elucidated by following polynomial quadratic equation:
[0071] Y1 = 82.09 - 0.5575X1 + 8.09X2 - 0.0462X3 + 3.24X1X2 - 1.62X1X3 + 0.8225X2X3 + 2.62X1² - 1.29X2² + 2.28X3²
Table 3: Model Summary Statistics
Source Std. Dev. R² Adjusted R² Predicted R² PRESS
Linear 3.02 0.8161 0.7736 0.6382 233.47
2FI 2.52 0.9018 0.8429 0.5918 263.38
Quadratic 0.8750 0.9917 0.9810 0.8918 69.83 Suggested
Cubic 0.5250 0.9983 0.9932 *Aliased

Table 4: Lack of Fit Tests
Source Sum of Squares df Mean Square F-value p-value
Linear 117.56 9 13.06 47.38 0.0010
2FI 62.24 6 10.37 37.63 0.0018
Quadratic 4.26 3 1.42 5.15 0.0737 Suggested
Cubic 0.0000 0 Aliased
Pure Error 1.10 4 0.2757

Table 5: ANOVA for Quadratic model for Q90 (Y1) of the microemulsion formulation
Source Sum of Squares df Mean Square F-value p-value
Model 639.88 9 71.10 92.87 < 0.0001 significant
A 2.49 1 2.49 3.25 0.1145
B 524.07 1 524.07 684.53 < 0.0001
C 0.0171 1 0.0171 0.0224 0.8854
AB 42.12 1 42.12 55.02 0.0001
AC 10.50 1 10.50 13.71 0.0076
BC 2.71 1 2.71 3.53 0.1022
A² 28.96 1 28.96 37.83 0.0005
B² 7.06 1 7.06 9.22 0.0189
C² 21.80 1 21.80 28.47 0.0011
Residual 5.36 7 0.7656
Lack of Fit 4.26 3 1.42 5.15 0.0737 not significant
Pure Error 1.10 4 0.2757
Cor Total 645.24 16

[0072] The Model F-value of 92.87 (in Table 5) implies the model is significant. There is only a 0.01% chance that an F-value this large could occur due to noise. P-values less than 0.0500 indicate model terms are significant. The lack of fit F-value of 5.15 and lack of fit P-value > 0.05 implies best fitting of model. The predicted R² (in Table 3) of 0.8918 is in reasonable agreement with the Adjusted R² of 0.9810 (in Table 3); i.e. the difference is less than 0.2. Therefore, statistical analysis of Y1 can be used to navigate the design space. The contour and response surface plots showing the effect of the variables- Smix(mg), oil (mg) and water (mg) on the cumulative percentage drug released in 90 minutes Q90 (Y1) for the microemulsion are provided in Figures 1-6. Through in-vitro drug release study, it was found that Q90 of Lafutidine increased from 29.12% in pure drug to 91.84% for the microemulsion formulation of Lafutidine which confirms 3.15-fold increase in percentage drug release.
3.2 Determination of drug content (mg/ml)(Y2)
[0073] Drug content in the microemulsion was estimated by diluting the microemulsion with methanol. Briefly, 0.2 mL of microemulsion was diluted up to 10 mL with methanol. Furthermore, an aliquot of this solution was appropriately diluted with methanol and analyzed by UV spectrophotometer (Labindia) at 279 nm.
Statistical and response surface analysis of drug content (mg/mL) (Y2)
[0074] The R², F-value and p-value for drug content (Y2) were 0.9811, 40.48 and < 0.0001. Therefore, second order polynomial model was generated by multiple regression analysis using Design-Expert software. Drug content (mg/mL) (Y2) of the formulation was synergistically influenced by oil (mg) (X1) and Smix (mg) (X2) while antagonistically influenced by water (mg) (X3) which can be elucidated by following polynomial quadratic equation:
Y2 = 9.35 + 0.1838X1 + 0.4613X2 - 0.5775X3 + 0.23X1X2 + 0.1025X1X3 - 0.1975X2X3 - 0.1115X1² - 0.5165X2² - 0.054X3²
Table 6: Model Summary Statistics
Source Std. Dev. R² Adjusted R² Predicted R² PRESS
Linear 0.3688 0.7241 0.6604 0.5038 3.18
2FI 0.3686 0.7880 0.6608 0.2493 4.81
Quadratic 0.1314 0.9811 0.9569 0.7576 1.55 Suggested
Cubic 0.0811 0.9959 0.9836 *Aliased

Table 7: Lack of Fit Tests
Source Sum of Squares df Mean Square F-value p-value
Linear 1.74 9 0.1936 29.46 0.0026
2FI 1.33 6 0.2221 33.80 0.0022
Quadratic 0.0945 3 0.0315 4.80 0.0820 Suggested
Cubic 0.0000 0 Aliased
Pure Error 0.0263 4 0.0066

Table 8: ANOVA for Quadratic model for drug content (mg/ml) (Y2) of the microemulsion formulation
Source Sum of Squares df Mean Square F-value p-value
Model 6.29 9 0.6986 40.48 < 0.0001 Significant
A 0.2701 1 0.2701 15.65 0.0055
B 1.70 1 1.70 98.62 < 0.0001
C 2.67 1 2.67 154.60 < 0.0001
AB 0.2116 1 0.2116 12.26 0.0100
AC 0.0420 1 0.0420 2.44 0.1626
BC 0.1560 1 0.1560 9.04 0.0198
A² 0.0523 1 0.0523 3.03 0.1251
B² 1.12 1 1.12 65.09 < 0.0001
C² 0.0123 1 0.0123 0.7114 0.4268
Residual 0.1208 7 0.0173
Lack of Fit 0.0945 3 0.0315 4.80 0.0820 not significant
Pure Error 0.0263 4 0.0066
Cor Total 6.41 16

[0075] The Model F-value of 40.48 (in Table 6) implies the model is significant. There is only a 0.01% chance that an F-value this large could occur due to noise. P-values less than 0.0500 indicate model terms are significant. The lack of fit F-value of 4.80 and lack of fit P-value > 0.05 implies best fitting of model. The Predicted R² of 0.7576 (in Table 6) is in reasonable agreement with the Adjusted R² of 0.9569 (in Table 6); i.e. the difference is less than 0.2. Therefore, statistical analysis of Y2 can be used to navigate the design space. The contour and response surface plots showing the effect of the variables- Smix(mg), oil (mg) and water (mg) on the drug content (mg/mL)(Y2) for the microemulsion are provided in Figures 7-12.
Example 4: Desirability function of the Formulation
[0076] The optimized microemulsion consisted of 150 mg virgin coconut oil, 325 mg Smix and 360 mg water, which has Q90 and drug content of 91.84% and 10.094 mg/mL, respectively with desirability function of 0.852. The contour plot and response surface plot of desirability with respect to Smix and oil have been plotted in Figures 13-14. Through in-vitro drug release study, it was found that Q90 of Lafutidine increased from 29.12% to 91.84% in the microemulsion formulation which is about 3.15-folds increase in percentage drug release.
[0077] From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein merely for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention and should not be construed so as to limit the scope of the invention or the appended claims in any way.

ADVANTAGES OF THE PRESENT INVENTION
[0078] The present disclosure provides a microemulsion formulation which increases the bioavailability of Lafutidine.
[0079] The formulation of the present disclosure provides over 3-folds increase in percentage cumulative drug release compared to pure drug Lafutidine.
[0080] The formulation of the present disclosure avoids first-pass effect thereby, augmenting the oral bioavailability of Lafutidine.

We Claims:

1. A microemulsion formulation for management of gastric ulcer comprising Lafutidine or pharmaceutically acceptable salts thereof, an oil phase consisting of virgin coconut oil, a surfactant consisting of a polysorbate, and a co-surfactant consisting of propylene glycol.
2. The formulation as claimed in claim 1, wherein the formulation further comprises an aqueous phase consisting of water.
3. The formulation as claimed in claim 1, wherein Lafutidine or pharmaceutically acceptable salts thereof is present in the formulation in a weight percentage range of 1% w/w to 2% w/w of the formulation.
4. The formulation as claimed in claim 1, wherein the oil phase is present in the formulation in a weight percentage range of 6% w/w to 18% w/w of the formulation.
5. The formulation as claimed in claim 1, wherein the surfactant is present in the formulation in a weight percentage range of 16% w/w to 32% w/w of the formulation.
6. The formulation as claimed in claim 1, wherein the co-surfactant is present in the formulation in a weight percentage range of 8% w/w to 16% w/w of the formulation.
7. The formulation as claimed in claims 1-2, wherein the aqueous phase is present in the formulation in a weight percentage range of 42% w/w to 83% w/w of the formulation.
8. The formulation as claimed in claims 1, wherein the surfactant is present in a weight ratio of 2:1 with respect to the co-surfactant.
9. The formulation as claimed in claim 1, wherein the polysorbate is selected from polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monolaurate or combinations thereof.
10. A process of preparing the microemulsion formulation as claimed in claims 1-9, wherein the process comprises the steps of: (a) mixing the surfactant and the co-surfactant together to give a surfactant mixture; (b) adding and vortexing the oil phase in the surfactant mixture; (c) mixing Lafutidine to the mixture of step (b); and (d) adding gradually the aqueous phase with stirring to give the microemulsion formulation.