Claims:1. A kneading method for preparation of a solid dispersion composition of Lafutidine comprising the steps of:
(a) blending Lafutidine and polyvinyl pyrollidone K-30 to give a uniform blend;
(b) adding Poloxamer 407 and Gelucire 50/13 to the blend to give a mix;
(c) triturating the mix with an hydro-alcoholic solvent system to produce a paste; and
(d) kneading followed by drying the paste to give the solid dispersion composition.
2. The method as claimed in claim 1, wherein Lafutidine is present in a range of 13% w/w to 14% w/w of the composition.
3. The method as claimed in claim 1, wherein polyvinyl pyrollidone K-30 is present in a range of 13% w/w to 14% w/w of the composition.
4. The method as claimed in claim 1, wherein Poloxamer 407 is present in a range of 16% w/w to 17% w/w of the composition.
5. The method as claimed in claim 1, wherein Gelucire 50/13 is present in a range of 57% w/w to 58% w/w of the composition.
6. The method as claimed in claim 1, wherein the hydro-alcoholic solvent system is a mixture of an alcohol and water.
7. The method as claimed in claim 6, wherein the alcohol is selected from ethanol, 2-propanol, propanol, or methanol.
8. The method as claimed in claim 6, wherein the weight ratio of alcohol to water is in the range of 3:1 to 1:3.
9. The method as claimed in claim 1, wherein the hydro-alcoholic solvent system is ethanol : water in a weight ratio of 1:1.
10. The method as claimed in claim 1, wherein the solid dispersion composition is self-emulsifying.
11. A solid dispersion composition prepared by kneading comprising of Lafutidine, polyvinyl pyrollidone K-30, Poloxamer 407 and Gelucire 50/13.
12. The composition as claimed in claim 11, wherein Lafutidine is present in the range of 13% w/w to 14% w/w of the composition.
13. The composition as claimed in claim 11, wherein polyvinyl pyrollidone K-30 is present in the range of 13% w/w to 14% w/w of the composition.
14. The composition as claimed in claim 11, wherein Poloxamer 407 is present in the range of 16% w/w to 17% w/w of the composition.
15. The composition as claimed in claim 11, wherein Gelucire 50/13 is present in the range of 57% w/w to 58% w/w of the composition.
16. The composition as claimed in claim 11, wherein the composition is self-emulsifying.

Description:FIELD OF THE INVENTION
[0001] The present disclosure relates generally to pharmaceuticals. More specifically, the disclosure is directed to a kneading method of preparing solid dispersion compositions comprising insoluble drug Lafutidine.

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] Most of the active pharmaceutical ingredients have low bioavailability at the target site owing to low levels of solubility of these ingredients in water. Poorly water soluble drugs end up being consumed in larger quantities than required to overcome the loss of drug due to insolubility and to reach the desired therapeutic plasma concentration. Thus, increasingly scientists are focusing on ways to prepare compositions of insoluble active pharmaceuticals to improve drug delivery. Solid dispersions are one such solution to overcome insolubility. Solid dispersions refer to compositions wherein a hydrophobic drug is dispersed in a hydrophilic carrier or environment.
[0004] Conventionally solid dispersions have been produced primarily by melt processing, or solvent evaporation techniques. In melt processing, the drug and carriers are heated to melting point to produce fine colloidal dispersion followed by rapid cooling, and subsequent milling to produce solid dispersion. However, melt processing has numerous drawbacks such as immiscibility of drug/carrier causing non-homogeneous mixing and thermal instability. In solvent evaporation technique, the drug and carriers are dissolved in small quantity of organic solvent followed by solvent evaporation and milling to generate solid dispersion. This process also has several shortcomings for instance, complexity in eliminating traces of solvent from product, explosion hazard, diffusion of solvent into space to produce environment pollution and the prospective for drug re-crystallization. Stability of these conventional solid dispersions is challenging.
[0005] Lafutidine is an alkyl-aryl ether that is essentially an H2 receptor agonist and is used for treatment of stomach and gastric disorders including stomach ulcers, and gastric reflux. Lafutidine is insoluble in water. The inventors of the present disclosure overcome the deficiencies of known methods of preparation of solid dispersions and provide a kneading method of preparation of a solid dispersion composition of Lafutidine.

OBJECTS OF THE INVENTION
[0006] An object of the present disclosure is to provide a method of preparing a solid dispersion composition to improve the solubility of Lafutidine.
[0007] An object of the present disclosure is to provide a method of preparing a solid dispersion composition of Lafutidine employing kneading method.
[0008] An object of the present disclosure is to provide a kneading method of preparing a solid dispersion composition of Lafutidine employing appropriate surfactants.
[0009] Another object of the present disclosure is to provide a solid dispersion composition of Lafutidine with enhanced solubility and self-emulsifying nature.

SUMMARY OF THE INVENTION
[0010] 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.
[0011] The present disclosure relates to a kneading method of preparation of solid dispersion composition comprising molecular dispersions of practically water insoluble drug Lafutidine (LFD) in a polymeric composition comprising of an amorphous polymer polyvinyl pyrollidone K-30 (PVP K-30) and emulsifying polymers poloxamer 407 & gelucire 50/13.
[0012] In an aspect, the present disclosure relates to a kneading method for preparation of a solid dispersion composition of Lafutidine comprising the steps of:
(a) blending Lafutidine and polyvinyl pyrollidone K-30 (PVP K-30) to give a uniform blend;
(b) adding Poloxamer 407 and Gelucire 50/13 to the blend to give a mix;
(c) triturating the mix with an hydro-alcoholic solvent system to produce a paste; and
(d) kneading followed by drying the paste to give the solid dispersion composition.
[0013] In another aspect, the present disclosure relates to a solid dispersion composition comprising of Lafutidine, polyvinyl pyrollidone K-30, Poloxamer 407 and Gelucire 50/13.
[0014] In another aspect, the present disclosure relates to a solid dispersion composition prepared by kneading comprising of Lafutidine, polyvinyl pyrollidone K-30, Poloxamer 407 and Gelucire 50/13.
[0015] In still another aspect, the present disclosure relates to a method of treatment, amelioration or prevention of gastric disorders in a subject by administering a therapeutically effective amount of the solid dispersion composition of Lafutidine.
[0016] In yet another aspect, the present disclosure relates to use of the solid dispersion composition of Lafutidine for treatment, amelioration or prevention of gastric disorders in a subject.
[0017] 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
[0018] 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: is a Contour plot (2D) showing the effect of independent variables on solubility (µg/ml) (Y1) of LFD in the solid dispersion composition as per an embodiment of the present disclosure
Figure 2: is a Response surface plot (3D) showing the effect of independent variables on solubility (µg/ml) (Y1) of LFD in the solid dispersion composition as per an embodiment of the present disclosure
Figure 3: is a Contour plot (2D) showing the desirability function of LFD in the solid dispersion composition as per an embodiment of the present disclosure
Figure 4: is a Response surface plot (3D) showing the desirability function of LFD in the solid dispersion composition as per an embodiment of the present disclosure

DETAILED DESCRIPTION OF THE INVENTION
[0019] 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.
[0020] 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.
[0021] 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.
[0022] 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.
[0023] 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.
[0024] 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.
[0025] 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.”
[0026] 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.
[0027] 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.
[0028] 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.
[0029] 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.
[0030] 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.
[0031] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0032] 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.
[0033] The term, "pharmaceutically acceptable" as used herein refers to a carrier comprised of a material that is not biologically or otherwise undesirable.
[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] The term “therapeutically effective amount” refers to the amount determined by a medical professional that treats, prevents or ameliorates the condition of a subject without causing any side effects.
[0036] Lafutidine is an insoluble drug for treatment of problems associated with stomach including ulcers, reflux etc. Stability of conventional solid dispersions is a problem and they generally re-crystallize when prepared by solvent evaporation or melt processing. Re-crystallization problem generally encountered with these production technologies can be prevented with use of surfactants Gelucire 50/13 and Poloxamer 188. The disclosed technique is industrially scalable with minimum use of solvents.
[0037] Gelucire 50/13 is a water dispersible surfactant, solubilizer, and bioavailability enhancer. Gelucire belongs to a family of vehicles that are derived from mixtures of mono-, di-, and triglycerides and polyethylene glycol fatty acid esters. Poloxamer 407 (PXM) is a triblock polymer with low melting point (56-57°C), non-ionic surfactant characteristics, and possesses oral safety. PVP is a homo-polymer of N-vinylpyrrolidone. Polyvinyl pyrollidone K-30 or PVP-30 or K-30 is a hygroscopic, adhesive and amorphous polymer frequently employed in pharmaceutical industry for formation of films.
[0038] In an embodiment, the present disclosure relates to a kneading method for preparation of a solid dispersion composition of Lafutidine comprising the steps of:
(a) blending Lafutidine and polyvinyl pyrollidone K-30 (PVP K-30) to give a uniform blend;
(b) adding Poloxamer 407 and Gelucire 50/13 to the blend to give a mix;
(c) triturating the mix with an hydro-alcoholic solvent system to produce a paste; and
(d) kneading followed by drying the paste to give the solid dispersion composition.
[0039] In an embodiment, Lafutidine may be present in a range of about 13% w/w to about 14% w/w of the composition. Lafutidine includes its pharmaceutically acceptable salts and derivatives thereof.
[0040] In an embodiment, polyvinyl pyrollidone K-30 may be present in a range of about 13% w/w to about 14% w/w of the composition.
[0041] In an embodiment, Poloxamer 407 may be present in a range of about 16% w/w to about 17% w/w of the composition.
[0042] In an embodiment, Gelucire 50/13 may be present in a range of about 57% w/w to about 58% w/w of the composition.
[0043] In an embodiment, blending of Lafutidine and polyvinyl pyrollidone K-30 may be performed using mortar and pestle, blender, batch mixer extruder, continuous dry-mixer, high shear/impact mixer, ribbon screw mixer, conical paddle mixer, conical screw mixer, high speed paddle mixer, high impact mixer, or combinations thereof.
[0044] In an embodiment, the hydro-alcoholic solvent system is a mixture of an alcohol and water. Alternatively it may be acetic acid or dimethyl sulfoxide (DMSO).
[0045] In an embodiment, the alcohol may be selected from ethanol, propanol, 2-propanol, or methanol.
[0046] In an embodiment, the weight ratio of alcohol to water may be in the range of about 3:1 to about 1:3. In a preferred embodiment, the hydro-alcoholic solvent system is ethanol: water in a weight ratio of about 1:1.
[0047] In an embodiment, drying may be carried out in an oven, vacuum desiccator or combination thereof. In an embodiment, the composition may be sifted before and after drying in a vacuum desiccator.
[0048] In an embodiment, the method does not involve heating which avoids any thermal degradation of the drug or polymer components.
[0049] In an embodiment, the method is simple, industrially scalable, commercially realistic and cost-effective for preparation of solid dispersions.
[0050] In another embodiment, the present disclosure relates to a solid dispersion composition comprising of Lafutidine, polyvinyl pyrollidone K-30, Poloxamer 407 and Gelucire 50/13.
[0051] In an embodiment, the components together possess a synergistic effect to produce solid dispersions with high solubility which a pure drug-Lafutidine does not possess.
[0052] In an embodiment, the composition has enhanced solubility which increases the solubility of the Lafutidine and makes it available at the site of action. Thus, the composition also increases the bioavailability of the drug.
[0053] In an embodiment, the composition is self-emulsifying and does not re-crystallize. In an embodiment, the solid dispersion composition forms fine milky emulsion within about two minutes.
[0054] Self-emulsifying solid dispersion forms fine relatively stable oil-in-water (o/w) micro-emulsions upon aqueous dilution (gastrointestinal fluids) and gentle agitation. Dispersed microemulsion globules in the GI tract have a broad surface area and facilitate the rapid diffusion of the dissolved form of the pharmaceutical product and/or the mixed form of micelles comprising the drug substance, and therefore may be responsible for carrying the medication to the GI membrane for diffusion via the unstirred water layer. Furthermore, another significant contributor to greater bioavailability is lymphatic transport. By stimulating lipoprotein formation and intestinal lymphatic liquid flux, the lipid composition of self-emulsifying solid dispersion promotes the level of lymphatic drug transport.
[0055] In an embodiment, the LFD in the above solid dispersion composition has a solubility in the range of about 500 to about 2500 µg/mL.
[0056] In yet another embodiment, the present disclosure relates to a solid dispersion composition prepared by kneading comprising of Lafutidine, polyvinyl pyrollidone K-30, Poloxamer 407 and Gelucire 50/13.
[0057] In an embodiment, Lafutidine may be present in the range of about 13% w/w to about 14% w/w of the composition.
[0058] In an embodiment, polyvinyl pyrollidone K-30 may be present in the range of about 13% w/w to about 14% w/w of the composition.
[0059] In an embodiment, Poloxamer 407 may be present in the range of about 16% w/w to about 17% w/w of the composition.
[0060] In an embodiment, Gelucire 50/13 may be present in the range of about 57% w/w to about 58% w/w of the composition.
[0061] In an embodiment, the composition may be prepared in a solid dosage form. Said composition may be further formulated into a pharmaceutically useful product including tablets, powders, lozenges, capsules, pellets, granules, extrudate and sachets. Suitable excipients may be added to prepare such formulations. Said excipients may be selected from surfactant, plasticizer, disintegrants, lubricant, glidant, binder, pH agents, coloring agents, flavoring agents, or combinations thereof.
[0062] In still another embodiment, the present disclosure relates to a method of treatment, amelioration or prevention of gastric disorders in a subject by administering a therapeutically effective amount of the solid dispersion composition of Lafutidine.
[0063] In an embodiment, the amount of solid dispersion administered may be determined by a medical professional based on the subject’s health, medical history and other conditions.
[0064] In yet another embodiment, the present disclosure relates to use of the solid dispersion composition of Lafutidine for treatment, amelioration or prevention of gastric disorders in a subject.
[0065] In an embodiment, the solid dispersion may suitably be administered to a subject with acidity, gastric ulcers, duodenal ulcers, colonic ulcers, gastroesophageal reflux and gastritis, as well as wounds in the lining of the stomach associated with acute gastritis and acute exacerbation of chronic gastritis.
[0066] 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.
[0067] 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. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, 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.
EXAMPLE 1:
Experimental design
[0068] Solid dispersion compositions of LFD and quality by design (QbD) central composite design (CCD) layout for production of these solid dispersions has been depicted below in Tables 1 & 2, respectively.

Table 1: Independent and response variables for the solid dispersions
Independent variables -1.41 (Axial) -1 (Low) 0 (Medium) +1
(High) +1.41 (Axial)
X1= Poloxamer 407 (mg) 5.9 10 20 30 34.1
X2= Gelucire 50/13 (mg) 15.9 20 30 40 44.1
Response variables Constraint Importance
Y = Solubility (µg/ml) Maximize +++

Table 2: Central composite design (CCD) layout for solid dispersions
Batch X1 [Poloxamer 407 (mg)] X2 [Gelucire 50/13 (mg)]
1 -1 -1
2 1 -1
3 -1 1
4 1 1
5 -1.41421 0
6 1.41421 0
7 0 -1.41421
8 0 1.41421
9 0 0
10 0 0
11 0 0
12 0 0
13 0 0

EXAMPLE 2:
Production methodology
[0069] Solid dispersion compositions LFD were manufactured by kneading technique using an amorphous polymer PVP K-30 and emulsifying polymers poloxamer 407 & gelucire 50/13. 10 mg of LFD was blended with 10 mg of PVP K-30 in a mortar and pestle followed by addition of accurately weighed amount of emulsifying polymers as indicated in Table 1 for manufacturing different batches of solid dispersions. Physical mixtures were triturated with ethanol-water (1:1) solution to produce thick paste, which was successfully kneaded for 30 minutes. Thick paste was oven dried at 45°C; dried mass was pulverized, sieved through # 30 sieves, stored in vacuum desiccators for 48 h, sieved through # 60 sieves again and stored in airtight container.
EXAMPLE 3:
Determination of aqueous solubility (µg/ml) of LFD and solid dispersions of LFD (Y1)
[0070] LFD (10 mg) and solid dispersions of Example 2 equivalent to 10 mg LFD were transferred to 10 ml of distilled water in screw-capped glass vials, sealed, and placed 24 hours in orbital shaker (Remi, India) at 37°C. The withdrawn aliquots were subsequently centrifuged, washed, diluted and the UV-spectrophotometer was used to measure the LFD concentration by recording absorbance at 286 nm. The aqueous solubility of LFD was found to be 209 µg/ml while LFD-solid dispersion solubility for prepared batches ranged from 578-2435 µg/ml.
Statistical analysis of solubility (µg/ml)(Y1)data of LFD-solid dispersions by QbD
[0071] On the basis of regression coefficient (R²), F-value and p-value calculated by Design-Expert software (Trial Version 12.0.9.0, Stat-Ease Inc., MN), quadratic model was suggested for Y1. From statistical analysis of solubility data, R², adjusted R² and predicted R² for quadratic model were found to be 0.9991, 0.9985 and 0.9946 (p < 0.0001) (Table 3). The predicted R² of 0.9946 is in reasonable agreement with the adjusted R² of 0.9985; i.e. the difference is less than 0.2. Therefore, statistical analysis of Y1 can be used to navigate the design space. From lack of fit test, F-value and p-value for quadratic model was found to be 6.05 and 0.0573 (p>0.05), respectively (Table 4). Lack of fit p-value > 0.05 implies best fitting of model. Insignificant lack of fit is good for data fitting. Therefore, quadratic model was selected for further analysis and second order polynomial model was generated by multiple regression analysis using Design-Expert software. The model F-value of 1589.22 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 (Table 5). Solubility (µg/ml) (Y1) of LFD-solid dispersions was synergistically influenced by poloxamer 407 (X1) and gelucire 50/13 (X2) which can be elucidated by following polynomial quadratic equation:
Y1 = 1526.80 + 447.55X1 + 461.65X2 - 115.00X1X2 + 32.04X1² + 71.29X2²

Table 3: Model summary statistics for solubility (µg/ml) (Y1)
Source Sequential p-value Lack of Fit p-value R² Adjusted R² Predicted R²
Linear < 0.0001 0.0002 0.9721 0.9665 0.9447
2FI 0.0083 0.0007 0.9877 0.9835 0.9743
Quadratic < 0.0001 0.0573 0.9991 0.9985 0.9946 Suggested
Cubic 0.0886 0.1039 0.9997 0.9992 0.9886 Aliased

Table 4: Lack of fit tests solubility (µg/ml) (Y1)
Source Sum of Squares df Mean Square F-value p-value
Linear 94365.39 6 15727.57 116.33 0.0002
2FI 41465.39 5 8293.08 61.34 0.0007
Quadratic 2453.74 3 817.91 6.05 0.0573 Suggested
Cubic 595.13 1 595.13 4.40 0.1039 Aliased

Table 5: ANOVA for quadratic model for solubility (µg/ml) (Y1)
Source Sum of Squares df Mean Square F-value p-value
Model 3.399E+06 5 6.799E+05 1589.22 < 0.0001 Significant
A-Poloxamer 407 (mg) 1.602E+06 1 1.602E+06 3745.79 < 0.0001
B-Gelucire 50/13 (mg) 1.705E+06 1 1.705E+06 3985.43 < 0.0001
AB 52900.00 1 52900.00 123.66 < 0.0001
A² 7140.18 1 7140.18 16.69 0.0047
B² 35352.40 1 35352.40 82.64 < 0.0001
Residual 2994.54 7 427.79
Lack of Fit 2453.74 3 817.91 6.05 0.0573 Not significant

Optimized formulation of LFD-solid dispersions
[0072] Optimized LFD comprises of 12.36 mg of poloxamer 407 and 44.1 mg of gelucire 50/13 which has solubility of 2120 µg/ml and desirability function of 0.815 (refer Figures 1-4).
[0073] Thus, LFD-solid dispersion compositions were successfully synthesized as per central composite design (CCD) layout using kneading technique. Response surface analysis of solubility (µg/ml) (Y1) of LFD-solid dispersions by Design-Expert software (Trial Version 12.0.9.0, Stat-Ease Inc., MN) showed that solubility (µg/ml) (Y1) of LFD-solid dispersions was synergistically influenced by poloxamer 407 (X1) and gelucire 50/13 (X2). Aqueous solubility of LFD in LFD-solid dispersions increased from 209µg/ml to 2120 µg/ml, which demonstrated a 10.14-fold amplification in solubility.
[0074] The foregoing embodiments are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.

ADVANTAGES OF THE PRESENT INVENTION
[0075] The present disclosure provides an easy, cost effective, and environmentally safe kneading method of preparing solid dispersions of Lafutidine.
[0076] The present disclosure provides a method of preparing solid dispersion composition of Lafutidine which increases its solubility in water up to 10-folds.
[0077] The present disclosure provides a method of preparing solid dispersion composition of Lafutidine which does not involve any melting process and thus avoids thermal disintegration of the components.
[0078] The present disclosure provides a method of preparing solid dispersion composition of Lafutidine without solvent evaporation techniques which leave residual solvents or diffuse solvents into the environment.
[0079] The present disclosure provides a method of preparing solid dispersion composition of Lafutidine which is industrially scalable with minimum usage of solvents.