Transient oil-in-simethicone emulsion

Abstract

A transient oil-in-simethicone emulsion for oral administration wherein 5 simethicone is present from 50% to 80% by weight of the emulsion. Also described is the process for the preparation of the transient oil-in-simethicone emulsion and capsule dosage form.

Description

[0001] TRANSIENT OIL-IN-SIMETHICONE EMULSION

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a transient oil-in-simethicone emulsion for oral administration for the treatment of gastrointestinal disorders. The invention also provides a process for the preparations of such transient emulsion and oral pharmaceutical compositions comprising such emulsion. The emulsion may comprise one of more additional active ingredient.

[0004] BACKGROUND OF THE INVENTION

[0005] Emulsified formulations have been used as a delivery system for the administration of drugs having poor water solubility due to their ability to increase the absorption of poor water-soluble drugs. Emulsions are dispersed systems consisting of two or more mutually insoluble or sparingly soluble liquids. One of the liquids is usually present in excess and is termed the continuous or external phase, while the liquid dispersed in it is termed the dispersed, discontinuous, or internal phase. If two immiscible oils are emulsified with each other, the term oil-in-oil (O / O) emulsion is used. The oil-in-oil (0 / 0) emulsion usually comprise surfactants or emulsifiers to facilitate the emulsification process.

[0006] Simethicone is a silicone compound used for the management of flatulence and bloating. It relieves the discomfort produced by the presence of excess gas in the gastrointestinal tract. Simethicone has been utilized in a variety of therapeutic liquid and solid dosage forms such as tablets, capsules, chewable films, and liquid. There are several formulations of simethicone available in combination with other drugs such as antacids, antidiarrheals, antiperistaltics and H2 blockers, however it was found that the dissolution rate of the antidiarrheals, antiperistaltics and H2 blockers was adversely effected in the presence of simethicone.

[0007] In view of the above problem, U.S. Patent No. 5,980,944 (“US ‘944”) discloses a solid oral dosage form simethicone are separated from other active ingredients by a barrier coat on the granules, which is substantially impermeable to simethicone. This solid oral dosage form comprises granules of active ingredients used in gastrointestinal disorders which may be diphenoxylate, loperamide, loperamide-N-oxide, pharmaceutically acceptable salts thereof or combinations thereof, and a therapeutically effective amount of simethicone.

[0008] Similarly, U.S. Patent No. 6,024,980 (“US ‘980”) discloses a pharmaceutical product containing loperamide hydrochloride and simethicone. An intimate mixture of loperamide hydrochloride and simethicone results in deleterious effects on the loperamide hydrochloride dissolution profile. In order to provide an immediate release profile, this pharmaceutical product is formed from two phases, which are disposed in discrete regions and have at least one interface with each other. However, this formulation pose a concern to the formulation scientist at large scale due to the requirement for two distinct phases in the formulation at plant scale level.

[0009] U.S. Patent No. 5,248,505 (“US ‘505”) features an effective amount of simethicone and loperamide, among others such as attapulgite, bismuth subsalicylate, diphenoxylate HC1, polycarbophil, calcium polycarbophil and mixtures thereof. One of the embodiments of the same contains purified water q.s. to lOOmL denoting an oil-in-water emulsion.

[0010] A fixed dose combination of loperamide hydrochloride and simethicone is available in certain solid forms (Imodium® Multi-Symptom Relief caplets and Imodium® Duo caplets and chewable tablets - 2 mg of loperamide, 125 mg of simethicone from Johnson & Johnson Consumer Inc). Despite having fixed-dose combinations of loperamide and simethicone in tablet dosage form and having loperamide softgels and simethicone softgels as individual ingredients, there is no marketed product comprising fixed-dose combinations of loperamide and simethicone in softgel capsule dosage form.

[0011] PCT application No. 2019 / 165420 (“WO ‘420”) discloses a pharmaceutical dosage form comprises a capsule shell and a fill composition, wherein the fill composition comprises an emulsion of (a) simethicone, (b) loperamide or a pharmaceutically acceptable salt thereof, and (c) at least two surfactants, wherein the emulsion has a hydrophilic lipophilic balance ranging from about 8 to about 12. However, what is claimed in this application is a complex mixture of at least two surfactants which include at least one hydrophilic surfactant [selected from group consisting of polyethylene glycol (PEG) fatty acid esters, PEG esters, PEG ethers, PEG glycerides, saturated polyglycolized glycerides, and combinations thereof] and at least one lipophilic surfactant (selected from the group consisting of macrogolglycerides, sorbitan esters, mono- and diglycerides, glycol mono and diesters, glyceryl esters, PEG esters, propylene glycol laurate, glyceryl monooleate, sorbitan monooleate, medium chain mono- and diglycerides, and combinations thereof). In an embodiment of this application, Simethicone is diluted in solvent before being included in the emulsion. Solvents for this purpose may include, but not limited to low polarity solvents including aliphatic esters such as isopropyl myristate. The complexity of the emulsion system presented in this invention is for the purpose of having a physically stable emulsion, which by traditional definition is an emulsion where no phase separation is observed throughout the shelf-life. Exemplary embodiment presented is said to be “stable . . . [with] no noticeable separation. In addition, no separation was observed in final capsules for over 18 months.”

[0012] PCT Publication No. WO 2017 / 180567 (“WO ‘567”) discloses a silicone emulsion that is free of both surfactants and emulsifiers. It further discloses that the emulsion comprises a dispersed oil phase containing a polyorganosiloxane with one or more hydroxyl groups, suspended in a continuous phase consisting of either an aqueous medium or an anhydrous organic diol, which also includes an anionic polymer.

[0013] PCT Publication No. WO 2015 / 104176 (“WO ‘ 176”) discloses a surfactant-free water-in-oil (W / O) invert emulsion, where the emulsion comprises: (a) 5 to 95 parts by weight of self-emulsifying organopolysiloxanes with specific formulae. These organopolysiloxanes contain at least one of the groups Rl, R2, and R3 in the branched organopolysiloxane structure; and (b) water.

[0014] PCT Publication No. WO 2014 / 130763 (“WO ‘763”) discloses a particle-stabilized oil-in-polar (o / p) emulsion, comprising: a) A dispersed oil phase; b) A continuous polar phase substantially free of water; and c) A particulate solid (e.g., silica particles with surface silanol groups) that stabilize the emulsion. The emulsion is substantially free of emulsifiers or surfactants.

[0015] Continuous polar phase of this invention includes diols (ethane- 1,2-diol, propane- 1,3 -diol, propane- 1 ,2-diol, butane- 1,4-diol), polyethylene glycol, ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol. The non-patent reference entitled Oil-in-oil emulsions stabilised solely by solid particles (“Binks Paper”) discusses the stabilization of emulsions between two immiscible oils, specifically, the use of fumed silica particles coated with either hydrocarbon or fluorocarbon groups to act as stabilizers of emulsions of various vegetable oils with linear silicone oils (PDMS) of different viscosities. The different types of oil used in the paper (i.e., olive, sunflower, rapeseed, among others) are partnered with silicone oil. The two oils are immiscible and the goal was to create a stable composition for at least one year.

[0016] SUMMARY OF THE INVENTION

[0017] US ‘944 discloses an oral dosage form of simethicone that is separated from other active ingredients by a barrier coat on the granules. On the other hand, the present invention describes an oral dosage form of simethicone and other active ingredient in liquid form which is thereafter encapsulated into a capsule.

[0018] US ‘980 features two phases, each containing a semi-solid fill material. These semisolid fill materials used in both phases are sufficiently viscous so that an appreciable amount, less than about 1, preferably less than 0.5 gram, cannot be expelled at room temperature with a syringe having a 16 gauge or smaller needle. The present invention does not comprise a semi-solid fill material but instead, liquid emulsion. In this regard, it therefore also follows that the composition of the present invention does not share the viscosity requirement of US ‘980 such that US 980’s semi-solid fill materials cannot be expelled at room temperature with a syringe having a 16 gauge or smaller needle. Further, US ‘980 likewise contains simethicone in one of its preferred embodiments. However, it must be noted that it is stated in US ‘980 that the two phases are each disposed in discrete regions of the soft gelatin capsules, thereby preventing contact. The composition of the present invention is therefore outside the coverage of US 980’s disclosures because the present invention describes an emulsion where an external or continuous phase is intimately in contact with an internal or dispersed phase.

[0019] The present invention departs from WO ‘420 as the liquid fill of the present invention does not need at least two surfactants which include at least one hydrophilic surfactant [selected from group consisting of polyethylene glycol (PEG) fatty acid esters, PEG esters, PEG ethers, PEG glycerides, saturated polyglycolized glycerides, and combinations thereof] and at least one lipophilic surfactant (selected from the group consisting of macrogolglycerides, sorbitan esters, mono- and diglycerides, glycol mono and diesters, glyceryl esters, PEG esters, propylene glycol laurate, glyceryl monooleate, sorbitan monooleate, medium chain mono- and diglycerides, and combinations thereof). The liquid fill is also intentionally made to be transient, such that the once homogeneous liquid fill will separate into phases after encapsulation.

[0020] Prior arts which feature dimethicone or simethicone in stabilizing surfactant-free emulsions, as well as the utilization of silicon dioxide particles in stabilizing emulsion compositions are largely restricted to oil-in-water or water-in-oil emulsions, with no clear evidence extending to oil-in-oil emulsions, which is a distinguishing feature of the subject technology. WO ‘567 discloses an oil-in-water emulsion that is free of both surfactants and emulsifiers, which also includes an anionic polymer. WO ‘ 176 discloses a surfactant- free water-in-oil invert emulsion, where the emulsion comprises water dispersed in selfemulsifying organopolysiloxanes. WO ‘763 discloses a particle-stabilized oil-in-polar (o / p) emulsion, comprising dispersed oil phase and a continuous polar phase which includes diols (ethane- 1 ,2-diol, propane- 1,3 -diol, propane- 1,2-diol, butane- 1,4-diol), polyethylene glycol, ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol. The present invention departs from these prior art since the composition of the present invention involves oil-in- oil emulsion. Water is neither the dispersed nor the continuous phase in the present invention. Further, none of the mentioned polar components of WO ‘763 is used in the present invention as the dispersed or the continuous phase.

[0021] The non-patent prior art reference Binks Paper mentions an oil-in-oil emulsion generally composed of silicone oil and a type of vegetable oil (i.e., olive, sunflower and rapeseed). However, the goal of the experiments in the Binks Paper, as can be gleaned from the test results, is to create a stable emulsion which can last for at least one year. It does not disclose use of the compositions in pharmaceutical dosage forms such as capsules, supporting the novelty of the subject technology in this context. Furthermore, the present invention, although oil-in-oil, is intentionally designed to be a transient emulsion.

[0022] US ‘505 discloses an oil-in-water emulsion where simethicone is present as 30% simethicone emulsion, combined with other excipients like sucrose, sorbitol, propylene glycol, and glycerin. This composition is mixed and adjusted with a sodium hydroxide solution to stabilize the emulsion. However, the prior art does not disclose the subject technology based on its focus on oil-in-oil emulsions and transient emulsions involving simethicone.

[0023] Oil-in-water and water-in-oil emulsions are fundamentally different from an oil-in- oil emulsion. The mechanisms of stabilizing the dispersed phase (oil-in-water vs. oil-in-oil) are distinct. Oil- in-oil emulsions, such as those discussed in the Binks paper, involve a more complex interaction between immiscible oils, and stabilizing these emulsions requires specific considerations, such as the use of silicon dioxide particles, as opposed to stabilizing oil with an aqueous phase. A person ordinarily skilled in the art would not automatically consider the transition from oil-in-water or water-in-oil emulsions to oil- in-oil emulsions.

[0024] There is no clear motivation that would lead one to combine the teachings in US ‘505 and the Binks Paper because they operate in distinct fields with different objectives. A person skilled in the art working on gastrointestinal treatments using oil-in-water emulsion would not have an immediate reason to apply the principles of oil- in-oil emulsions from the Binks paper, which addresses a different technical challenge (long-term stability of immiscible oils). There is no clear indication or suggestion in either reference that would lead to the use of an oil-in-oil emulsion stabilized with fumed silica in a pharmaceutical formulation. Even moreso, to a transient oil-in-oil emulsion.

[0025] The inventors of the present invention have developed an improved oil-in-oil, specifically an oil-in-simethicone emulsion for oral administration comprising one or more additional active ingredients. The inventors have identified that transient emulsion provides an advantage that there is no phase separation in the emulsion when the emulsion is being prepared and filled into the pharmaceutical composition, thereby ensuring content uniformity. On the other hand, once the emulsion is filled into capsule, the two or more phases separate after a specific time lapse. This ensures that the hydrophobic nature of simethicone does not affect the dissolution of the other active ingredient, thereby its bioavailability. Such liquid fill may be encapsulated i.e. contained in a capsule shell made of any material suitable for use in pharmaceutical capsule dosage forms. The inventors of the present invention have also developed a soft capsule of a fixed- dose combination of loperamide and simethicone, wherein the composition has a smaller size as compared to the marketed tablet of the loperamide and simethicone and the said composition is bioequivalent to the commercially available loperamide plus simethicone product.

[0026] The present specification relates to a transient oil-in-simethicone emulsion for oral administration wherein the amount of simethicone is about 50% to about 80% by weight of the emulsion.

[0027] According to the first aspect, the present invention relates to a transient oil-in- simethicone emulsion for oral administration wherein the amount of simethicone is about 50% to about 80% by weight of the emulsion.

[0028] According to another aspect, the present invention relates to a capsule dosage form comprising transient oil-in-simethicone emulsion for oral administration wherein the simethicone about 50% to about 80% by weight of the emulsion.

[0029] According to the second aspect, the present invention relates to a transient oil-in- simethicone emulsion for oral administration comprising one or more additional active ingredients wherein simethicone is present from about 50% to about 80% by weight of the emulsion.

[0030] According to yet another aspect, the present invention relates to a capsule dosage form comprising a transient oil-in-simethicone emulsion for oral administration, the capsule comprises: a. A capsule shell, and b. An transient emulsion fill composition comprising simethicone and one or more additional active ingredient, wherein simethicone is present in amount of about 50% to about 80% by weight based on the weight of the emulsion.

[0031] According to one of the embodiment, the transient oil-in-simethicone emulsion is used in treatment of gastrointestinal disorders. According to one embodiment, transient oil-in-simethicone emulsion for oral administration comprising an external phase and an internal phase, and wherein the external phase comprises an active ingredient, and the internal phase comprises one or more additional active ingredients.

[0032] According to one embodiment, the active ingredient in external phase is simethicone that is present from 50% to 80% by weight of the emulsion.

[0033] According to one of the embodiment, the active ingredients in the internal phase are selected from the group consisting of antidiarrheal agent, anticholinergic or antispasmodic agent, prokinetic agent, proton pump inhibitor, histamine h2 blockers, antacid, dopamine antagonist and combination thereof.

[0034] According to one of the embodiment, active ingredient in the internal phase is loperamide, domperidone, otilonium, hyoscine, dicyclomine, pinaverium, cisapride, pharmaceutically acceptable salts thereof and combination thereof.

[0035] According to one of the embodiment, the droplet size of the emulsion is less than 70 pm.

[0036] According to one of the embodiment, the emulsion needs only one type of surfactant. Most preferably from the lipophilic class.

[0037] According to one of the embodiment, the emulsion contains no surfactant.

[0038] According to one of the embodiment, the length of the capsule is about 3 mm to about 20 mm.

[0039] According to one of the embodiment, the ratio of internal phase to external phase is 1 : 1.

[0040] According to one of the embodiment, the ratio of internal phase to external phase is 4:5.

[0041] According to one of the embodiment, the ratio of internal phase to external phase is 2:3. According to one of the embodiment, the ratio of internal phase to external phase is

[0042] 1 :2.

[0043] According to one of the embodiment, the ratio of internal phase to external phase is 25:64.

[0044] According to one of the embodiment, the ratio of internal phase to external phase is 1 :4.

[0045] According to yet another aspect, the present invention relates to a process for the preparation of a capsule dosage form comprising a transient oil-in-simethicone emulsion for oral administration, the process comprises the steps of: a. Dissolving an active ingredient into an oil and optionally other pharmaceutically acceptable ingredients, b. Blending simethicone with the blend of step a), c. Homogenizing the blend of step b) into an emulsion, and d. Filing the emulsion into capsules; wherein simethicone is present in amount of about 50% to about 80% by weight based on the weight of the emulsion.

[0046] In yet another aspect, the present invention relates to a capsule dosage form for oral administration of simethicone and loperamide comprising a transient oil-in-oil emulsion wherein dissolution of loperamide in the capsule in fasted-state simulated gastric fluid within acceptable range or is comparable or improved than the dissolution of loperamide in Imodium® Liqui-Gel capsules.

[0047] In yet another aspect, the present invention relates to a capsule dosage form for oral administration of simethicone and loperamide comprising a transient oil-in-oil emulsion wherein the loperamide in the capsule is bioequivalent to loperamide in Imodium® Multisymptom Relief Tablet.

[0048] In yet another aspect, the present invention relates to a capsule dosage form for oral administration of simethicone and loperamide comprising a transient oil-in-oil emulsion wherein the loperamide in the capsule is bioequivalent to loperamide in Imodium® Liqui- Gel capsules. In yet another aspect, the present invention relates to a capsule comprising simethicone and loperamide, which when administered to a fasting human at a dose of 2 x 2 mg of loperamide exhibits: a. a Cmax of about 1.000 to about 1.720 ng / mL; and b. an AUC of about 17.000 to about 27.000 h.ng / mL;

[0049] BRIEF DESCRIPTION OF THE DRAWINGS

[0050] FIG. 1 shows the multimedia dissolution profile for loperamide and simethicone capsule vis-a-vis reference product Imodium® Liqui-Gel Capsules.

[0051] FIG. 2 shows the multimedia dissolution profile for loperamide and simethicone capsule vis-a-vis reference product Imodium® Multi-symptom Relief Tablet.

[0052] FIG. 3 shows in vivo comparative pharmacokinetic profile of Test (Example 26) vs. Reference Product (Imodium® Liqui-Gel Capsules).

[0053] FIG. 4 shows in vivo comparative pharmacokinetic profile of Test (Example 26) vs. Reference Product (Imodium® Multi-symptom Relief Tablet).

[0054] DETAILED DESCRIPTION OF THE INVENTION

[0055] As used herein, the term "oral pharmaceutical composition" refers to capsules including hard and soft capsules which can either be gelatin or non-gelatin capsules. The preferred oral pharmaceutical composition is soft capsules, which can either be gelatin or non-gelatin soft capsules. The transient emulsion liquid fill is filled into the capsule shell and sealed.

[0056] By “transient emulsion” it is intended that the emulsion does not coalesce during the time period starting from when it is prepared to when it is filled into the composition. This time period may be on the order of days but not more than a week. Upon encapsulation, the transient emulsion is designed to separate into two or more phases. The composition is otherwise stable during the entire shelflife in context of other parameters such as chemical stability, appearance of the capsule shell, dissolution, disintegration etc., as given in the examples below. The stability of the dosage form was checked at 30°C and 75% RH for a period of two years. The capsules of the exemplary embodiment were found to be stable in the above specified conditions during the entire shelf life. The phrase “contains less than two surfactants” differentiates the current invention from prior art such that the current invention does not need at least two surfactants which include at least one hydrophilic surfactant [selected from group consisting of polyethylene glycol (PEG) fatty acid esters, PEG esters, PEG ethers, PEG glycerides, saturated polyglycolized glycerides, and combinations thereof] and at least one lipophilic surfactant (selected from the group consisting of macrogolglycerides, sorbitan esters, mono- and diglycerides, glycol mono and diesters, glyceryl esters, PEG esters, propylene glycol laurate, glyceryl monooleate, sorbitan monooleate, medium chain mono- and diglycerides, and combinations thereof).” Furthermore, it means that:

[0057] (1) Only one class of these substances is present in the emulsion. Most preferably from the lipophilic class. However, it would not depart from the spirit of the invention to include surfactant / s from the other class that is / are present as impurity / impurities, for example less than 0.5% by weight based on the total weight of the emulsion, preferably, in order of increasing preference, less than 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, and 0.01% by weight.

[0058] (2) The emulsion does not contain any surfactant listed above. However, it would not depart from the spirit of the invention to include surfactant / s that occur / s as impurity / impurities, for example less than 0.5% by weight based on the total weight of the emulsion, preferably, in order of increasing preference, less than 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, and 0.01% by weight.

[0059] SIMETHICONE AND SILICON DIOXIDE SURFACE CHARACTERIZATION

[0060] Simethicone is a mixture of a. polydimethylsiloxane or fully methylated linear siloxane polymers containing repeating units of the formula [-(CH3)2SiO-]n, stabilized with trimethylsiloxy end-blocking units of the formula

[0061] [-(CH3)3SiO-], and b. silicon dioxide.

[0062] Simethicone used in the composition complies to the USP monograph definition of NLT 90.5% and NMT 99.0% of polydimethylsiloxane ([-(CH3)2SiO-]n), and NLT 4.0% and NMT 7.0% of silicon dioxide.

[0063] There are various commercially available simethicones. Simethicones, as described in this application may be one of these commercially available simethicone or combinations thereof. Similary, simethicones can be prepared by mixing polydimethylsiloxane and silicon dioxide with or without different surface modifications. Moreover, silicon dioxide with different surface modifications can be added to already existing commercially available simethicones without exceeding the USP definition limit of NMT 7.0% of silicon dioxide.

[0064] The general term “silicon dioxide” is used to refer to hydrophilic silicon dioxide (without surface modification) or hydrophobic silicon dioxide with different surface modifications.

[0065] It is surprisingly found that not all simethicones will be able to produce the desired transient oil-in-simethicone emulsion. The differences between the simethicones lie on the surface characteristics of the silicon dioxide incorporated in the said active ingredient.

[0066] The surface characteristics of the silicon dioxide can be described quantitatively using Fourier Transform Infrared (FTIR) Spectrophotometry. The FTIR Absorbance of the silicon dioxide’s total free and vicinal silanol and alkylsilyl moiety (both normalized against Si-0 Absorbance) can be determined. These values are calculated by extracting the silicon dioxide from the simethicone with subsequent FTIR analyses using the procedure outlined below.

[0067] SILICON DIOXIDE SURFACE CHARACTERIZATION:

[0068] Extraction of Silicon Dioxide

[0069] 1. Load Simethicone fluid into centrifuge tubes. Securely cap each tube.

[0070] 2. Centrifuge for at least 60 minutes at 3500 RPM.

[0071] 3. Decant the supernatant fluid leaving mostly solid residues (crude silicon dioxides) at the bottom of the centrifuge tube.

[0072] 4. Add toluene into the centrifuge tubes containing the crude silicon dioxides. Securely cap each tube.

[0073] 5. Sonicate the mixture for at least 60 minutes at room temperature.

[0074] 6. Decant the supernatant fluid leaving mostly solid residues (crude silicon dioxides) at the bottom of the centrifuge tube.

[0075] * Repeat steps 4 to 6 two more times 7. Add hexanes into the centrifuge tubes containing the crude silicon dioxides. Securely cap each tube.

[0076] 8. Sonicate the mixture for at least 60 minutes at room temperature.

[0077] 9. Centrifuge for at least 60 minutes at 3500 RPM.

[0078] 10. Decant the supernatant fluid leaving mostly solid residues (crude silicon dioxides) at the bottom of the centrifuge tube.

[0079] * Repeat steps 7-10 two more times

[0080] 11. Evaporate the residual hexanes in an oven set at 80°C until there is no characteristic hexane smell.

[0081] 12. Analyze using FTIR.

[0082] FTIR Analysis

[0083] The procedure was adapted from NAFTA - PIS TEST METHOD of Evonik Industries for Determination of Silanol Density by FTIR; Document No: PA NAFTA-PIS- Silica-ANA 1200, Date: January 24, 2018, Revision: 00.

[0084] 1. The silicon dioxide sample to be analyzed is mounted in between clean and polished NaCl windows.

[0085] 2. The FTIR spectrophotometer (i.e. Thermo Nicolet 6700 FTIR), is set-up by entering the following parameters:

[0086] Number of Scans 32

[0087] Resolution 2

[0088] Final Format Absorbance

[0089] Correction None

[0090] Collect Background after 60 minutes

[0091] Sample Compartment Main

[0092] Detector DTGS KBr

[0093] Beamsplitter CsI

[0094] Source IR

[0095] Accessory Transmission E.S.P

[0096] Window None

[0097] Max Range Limit 4000

[0098] Min Range Limit 1400

[0099] Gain: 8 Autogain

[0100] Optical Velocity 0.6329

[0101] Aperture 34

[0102] Zero Filling None

[0103] Apodization Triangular

[0104] Phase Correction Mertz

[0105] 3. Run background using air as blank. 4. Clamp the two NaCl windows with silicon dioxide sample into the sample holder. Place the sample holder into the instrument and the close sample chamber.

[0106] 5. Run the FTIR analysis.

[0107] 6. Export the data into a spreadsheet format.

[0108] * Repeat steps 1 to 6 until 10 measurements have been performed Calculation

[0109] 1. Establish a baseline in the resulting spectrum where a line is drawn in the range from approximately 3800 to 2800 cm1.

[0110] 2. A second baseline is then drawn in the range from approximately 2100 to 1750 cm’1.

[0111] 3. Using the established baseline in step 1, measure the peak height in mm in the following wavenumbers: a. 3750 cm'1corresponding to free silanol (Si-OH) b. 3660 cm'1corresponding to bridged or vicinal silanol c. Most intensive band ranging from 2900 cm'1to 3000 cm1; e.g. 2970 cm-1corresponding to alkylsilyl moeity Si-CHs

[0112] 4. Using the established baseline in step 2, measure the peak height in mm in 1870 cm'1corresponding to vibrations of Si-O.

[0113] 5. Calculate the following values: a. FTIR Absorbance of free and vicinal silanol normalized against Si-0 =

[0114] Peak Height at 3750 cm-1Peak Height at 3660 cm-1

[0115] Peak Height at 1870 cm-1Peak Height at 1870 cm-1b. FTIR Absorbance of alkylsilyl normalized against Si-0 =

[0116] Peak Height at2970 cm-1

[0117] Peak Height at 1870 cm-1

[0118] It was surprisingly observed by the inventors that only simethicones having certain range of a. FTIR Absorbance of free and vicinal silanol normalized against Si- O, and b. FTIR Absorbance of alkylsilyl normalized against Si-0 were particularly useful for the preparation of transient emulsion. It is preferred that silicon dioxide present in simethicone has FTIR Absorbance of total free and vicinal silanol normalized against Si-0 greater than or equal to 1.1, preferably 1.1 to 4.1 and FTIR Absorbance of alkylsilyl normalized against Si-0 greater than or equal to 1.3, preferably 3.6 to 24.9. The weight percentage of simethicone in the emulsion fill composition ranges from about 50% w / w to about 80% w / w, in particular about 60% w / w to about 70% w / w of the emulsion.

[0119] OTHER ACTIVE INGREDIENTS

[0120] The pharmaceutical composition comprises one or more active ingredient other than simethicone which are effective in treating gastrointestinal distress. The other active ingredient may be selected from the group consisting of antidiarrheal agent, anticholinergic or antispasmodic agent, prokinetic agent, proton pump inhibitor, histamine h2 blockers, antacid, dopamine antagonist and combination thereof. Antidiarrheal agent is selected from, for example, loperamide, attapulgite, bismuth subsalicylate, diphenoxylate, polycarbophil, racecadotril or pharmaceutically acceptable salt thereof. Anticholinergic or antispasmodic agent is selected from, for example, atropine, hyoscine, dicyclomine, fesoterodine, hyoscyamine, ipratropium, methscopolamine, pinaverium, otilonium, mebeverine or pharmaceutically acceptable salt thereof. Prokinetic agent is selected from, for example, domperidone, cisapride, metoclopramide, itopride or pharmaceutically acceptable salt thereof. Proton pump inhibitor agent is selected from, for example, omeprazole, pantoprazole, lansoprazole, esomeprazole, tenatoprazole, and rabeprazole or pharmaceutically acceptable salt thereof. Histamine H2 agent is selected from, for example, ranitidine, famotidine, cimetidine, and nizatidine or pharmaceutically acceptable salt thereof. Antacids agent is selected from, for example, aluminum hydroxide, magnesium hydroxide, aluminum carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, hydrotalcite, and magaldrate. The active ingredients listed above may be combined with other active ingredients to provide multi- relief from various gastrointestinal disorders. The active ingredient / s may be present in the simethicone phase or the oil phase, depending the solubility or miscibility in a particular oil or simethicone.

[0121] COMPONENTS, ATTRIBUTES, AND PREPARATION OF LIQUID FILL

[0122] The emulsion further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of oil, co-solvent, antioxidants, colorants, and opacifiers. As explained above, the two oils are immiscible in an oil-in-oil emulsion, as one of the oil is simethicone, the characteristic of the other oil should be that it is immiscible with simethicone and at the same time emulsifiable with simethicone. Although some of these oils can be considered surfactants as they were identified in prior art, depending on use, their purpose in this invention is mainly just to dissolve one or more active ingredient / s and nothing else. The examples of oil suitable for the composition include free fatty acids such as oleic acid, lauric acid, capric acid, caprylic acid; propylene glycol mono- and di- esters such as propylene glycol dicaprate, propylene glycol moncaprylate, propylene glycol dicaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol dilaurate, propylene glycol dioleate, propylene glycol laurate, propylene glycol myristate, propylene glycol oleate; and glycerol mono- and di-esters such as glycerol monostearate, glycerol monolaurate, glycerol monooleate, glycerol dilaurate; and mixtures thereof. With simethicone being the external or continuous phase, the transient emulsification is accomplished by the silicon dioxide component of the simethicone and not these oils. The oils may be present in an amount from about 5% to about 50% by weight of the emulsion. In case of oil-in-simethicone, oil forms the internal phase and simethicone forms the external phase.

[0123] Even though the emulsion is oil-in-oil type, the composition may comprise water in an amount less than 5% by weight of the emulsion. The small quantity water in the oil-in- oil emulsion can help in dissolving the active ingredient and / or excipients such as colorants, preservatives that need to be incorporated into the mixture.

[0124] Quality attributes such as appearance, and stability of emulsion are strongly influenced by another critical parameter: the droplet size of the emulsion. The droplet size is measured by microscopy. In particular, the droplets are less than 70 pm, in particular 5- 50 pm when measured by microscopy.

[0125] The emulsion fill composition may comprise one or more antioxidants such as DL- a- tocopherol, butylhydroxy toluene (BHT) and butylhydroxy anisole (BHA).

[0126] The emulsion fill comprises one or more co-solvents such as propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, butane-l,3-diol, pentane- 1,5-diol and 1 -methyl-2,4-pentadiol. The co-solvent may vary from about 0.5% to about 10% w / w of the emulsion, such as from about 1% to about 5% w / w.

[0127] The amount of fill composition ranges from about 150 mg to about 1000 mg, in particular from about 170 mg to about 500 mg.

[0128] The fill composition, i.e., transient emulsion, is made using known emulsification methods. A transient emulsion suitable for use in the present invention can be effectively made with a high shear homogenizer at 3000 to 15000 RPM.

[0129] COMPONENTS, ATTRIBUTES, AND PREPARATION OF CAPSULE

[0130] Capsules including hard and soft capsules can either be gelatin or non-gelatin capsules. The preferred oral pharmaceutical composition is soft capsules, which can either be gelatin or non-gelatin soft capsules. The transient emulsion liquid fill is filled into the capsule shell and sealed.

[0131] The outer shell of the capsules comprises excipients selected from the group consisting of film-forming agent, plasticizer, water as solvent, opacifiers, preservatives, colorants, and antioxidants.

[0132] The plasticizers in capsule shell may be selected from glycerin, sorbitol-sorbitan solution, sorbitol, maltitol, and polypropylene glycol or mixtures thereof. The concentration of the plasticizer may vary from 20% to 40% by weight of the capsule shell, in particular 25% to 30% by weight of the capsule shell.

[0133] In the case of soft gelatin capsules, the water content of the gelatin solution used to produce a capsule shell may range between 0.7 and 1.3 parts of water to each part of dry gelatin. After the capsule is formed, most of the water was removed by drying. The finished capsules contain water in amount of 2% to 10 % w / w based on the weight of the capsule shell, in particular 2% to 6 % w / w.

[0134] The capsule shell may also comprise preservatives to prevent the growth of bacteria and mold in the capsule base solution during storage. Potassium sorbate, sorbic acid, sodium benzoate, benzoic acid, and methyl-, ethyl-, and propyl hydroxybenzoate may be used as preservatives.

[0135] Capsule shell and liquid fill in the capsule may also comprise colorant and / or opacifier (e.g., titanium dioxide, pharmaceutically acceptable natural and synthetic dyes) added for the visual appeal.

[0136] The size of the capsule shell ranges from about 3 mm to about 20 mm, in particular from about 3 mm to about 18 mm, and preferably from about 6 mm to about 15 mm. PREPARATION OF PHARMACEUTICAL COMPOSITIONS

[0137] The pharmaceutical composition is useful for the treatment of gastrointestinal disorders which includes but are not limited to diarrhea including travelers’ diarrhea, spams, gastroparesis, gas and other associated symptoms. Example 1-5

[0138] Liquid fill for encapsulation comprising simethicone and loperamide hydrochloride were prepared according to composition given below. BRIEF MANUFACTURING PROCESS:

[0139] Liquid Fill Preparation

[0140] 1. Active Ingredient (loperamide hydrochloride), oil (propylene glycol monocaprylate), co-solvent (propylene glycol) and purified water were loaded into a compounding tank. Optionally, a colorant may be dissolved in purified water prior to mixing with other components.

[0141] 2. The above mixture was stirred to dissolve the solids, until a clear, solution is formed.

[0142] 3. Simethicone was added into the compounding tank

[0143] 4. The above mixture was homogenized to form an opaque emulsion.

[0144] Based on the examples above, when the vehicle used is composed of propylene glycol monocaprylate as oil, propylene glycol as co-solvent with additional purified water, the desired transient emulsion is formed from ratio internal phase to external phase of 1 :4 to 25:36. Wherein, simethicone is present in amount of 80% down to about 59% by weight based on the weight of the emulsion.

[0145] Example 6-9

[0146] Liquid fill for encapsulation comprising simethicone and hyoscine N-butyl bromide or dicyclomine hydrochloride were prepared according to composition given below. The preparation process of these examples was in line with the liquid fill preparation process of examples 1-5.

[0147] Anticholinergic / antispasmodic agents hyoscine and dicyclomine dissolve in an appropriate solvent mixture consist mainly of oil. The resulting solution was subsequently emulsified with Simethicone. In Examples 6 and 8, which used NuSil Simethicone MED- 340 simethicone, the desired transient emulsion was produced. The ratio internal phase to external phase are 1: 1 and 25:64 respectively. Wherein, simethicone is present in amount of 50% and 72% by weight respectively, based on the weight of the emulsion.

[0148] On the other hand, the desired transient oil-in-simethicone emulsion is not produced when Basildon Chemicals Co. Simethicone Antifoam C100LV was used, as shown in Examples 7 and 9.

[0149] From these examples, it can be seen that not all type of simethicone will work to produce the desired transient emulsion. There are various commercially available simethicones which contain silicon dioxides having different FTIR Absorbance of free and vicinal silanol and alkylsilyl moiety (both normalized against Si-O).

[0150] Example 10-11

[0151] Emulsion to be filled in the capsules comprising simethicone and otilonium bromide were prepared according to composition given below. The preparation process of these examples was in line with the liquid fill preparation process of examples 1-5.

[0152] Anticholinergic / antispasmodic agent otilonium dissolves in an appropriate solvent mixture consist mainly of the selected oil. The resulting solution was subsequently emulsified with simethicone. The desired transient oil-in-simethicone was produced using the DuPont Liveo™ Q7-2243 LVA simethicone as shown in Examples 10 and 11. The ratio internal phase to external phase are 4:5 and 2:3 respectively. Wherein, simethicone is present in amount of about 56% and about 60% by weight respectively, based on the weight of the emulsion. Example 12-13

[0153] Emulsion to be filled in capsules comprising simethicone and domperidone and comprising simethicone and cisapride monohydrate were prepared according to compositions given below. The preparation process of these examples was in line with the liquid fill preparation process of examples 1-5.

[0154] Prokinetic agents domperidone and cisapride dissolve in an appropriate oil solvent i.e. caprylic acid. The resulting solution was subsequently emulsified with simethicone. The desired transient oil-in-simethicone was produced using the DuPont Liveo™ Q7-2243 LVA simethicone as shown in Examples 12 and 13. The ratio internal phase to external phase for both is 1 :2. Wherein, simethicone is present in amount of about 67% by weight based on the weight of the emulsion.

[0155] Example 14-15 Emulsion to be filled in capsules comprising simethicone and pinaverium bromide were prepared according to composition given below. The preparation process of these examples was in line with the liquid fill preparation process of examples 1-5.

[0156] Anticholinergic or antispasmodic agent pinaverium dissolves in an appropriate solvent mixture consist mainly of oil. The resulting solution was subsequently emulsified with simethicone. The desired transient oil-in-simethicone was produced using the combination of RioCare FILIX-110 500-700 cSt + NuSil Simethicone MED-340 in 1 :1 ratio. The ratio internal phase to external phase for both is 1 :2. Wherein, simethicone is present in amount of about 67% by weight based on the weight of the emulsion. Example 16-20

[0157] Liquid fill for encapsulation comprising simethicone and loperamide hydrochloride were prepared according to composition given below. The preparation process of these examples was in line with the liquid fill preparation process of examples 1-5.

[0158] In Example 16, when simethicone used is Basildon Chem. Antifoam C100EP, the desired transient emulsion was not produced. However, the desired transient oil-in- simethicone is produced in Example 17 using the same simethicone in Example 16 but with addition of 0.25% Evonik Aerosil 200 (ratio of commercially available simethicone to additional silicon dioxide is 400:1) to increase the FTIR Absorbance of free and vicinal silanol normalized against Si-0 to 1.2. The desired transient emulsion is also produced in Example 18 using a combination of two commercially available simethicones DuPont Liveo™ Q7-2243 and Basildon Chem. Antifoam Cl 00EP in the ratio 1 :3, Example 19 using a simethicone produced from combining polydimethylsiloxane DuPont Liveo™ Q7-9120 Silicone Fluid 350 cSt with silicon dioxide Wacker Chemie HDK H20 in the ratio of 19: 1, and Example 20 using a simethicone produced from combining polydimethylsiloxane DuPont Liveo™ Q7-9120 Silicone Fluid 350 cSt with silicon dioxide Evonik Aerosil R8200 in the ratio of 19: 1

[0159] From examples 6-20 it was surprisingly observed that only simethicones having certain range of a. FTIR Absorbance of free and vicinal silanol normalized against Si- O, and b. FTIR Absorbance of alkylsilyl normalized against Si-0 were particularly useful for the preparation of transient emulsion. It is preferred that silicon dioxide present in simethicone has FTIR Absorbance of total free and vicinal silanol normalized against Si-0 greater than or equal to 1.1, preferably 1.1 to 4.1 and FTIR Absorbance of alkylsilyl normalized against Si-0 greater than or equal to 1.3, preferably 3.6 to 24.9. The weight percentage of simethicone in the emulsion fill composition ranges from about 50% w / w to about 80% w / w, in particular about 60% w / w to about 70% w / w of the emulsion.

[0160] Example 21-25

[0161] Capsules comprising simethicone and loperamide hydrochloride were prepared according to composition given below.

[0162] BRIEF MANUFACTURING PROCESS:

[0163] Liquid Fill Preparation The preparation process of these examples was in line with the liquid fill preparation process of examples 1-5.

[0164] Capsule Shell Preparation

[0165] Prepared using conventional equipment and methods known in the art. Materials include gelatin, sorbitol sorbitan solution, and water. Encapsulation and Drying

[0166] Prepared using conventional equipment, for example, rotary die encapsulation machine and methods known in the art. The capsules were dried until desired hardness is achieved.

[0167] Example 21 was prepared using glycerol ester glyceryl monocaprylate as the vehicle in the internal phase to contain the active ingredient. The active ingredient (i.e. loperamide hydrochloride) is almost completely dissolved. When the transient emulsion referred to in this invention is formed, there are no problems seen in the dissolution test.

[0168] As seen in examples 22, 23, and 24, the choice of vehicle for the active ingredient (i.e. loperamide hydrochloride) affects the release of the active ingredient as seen in the dissolution results. It is notable that when surfactants with polyethylene glycol (PEG) moieties (i.e. Polysorbate 80, Polyethylene Glycol 400 Caprylate / Caprate Glycerides, and Polyoxyl 35 Castor Oil) are used as the vehicle in the internal phase to contain the active ingredient, low % dissolutions of the active ingredient are obtained.

[0169] In example 25, another surfactant, sugar-alcohol ester sorbitan monolaurate was used as the vehicle in the internal phase to contain the active ingredient. The % dissolution was again diminished. This trend is due to stabilization of the emulsion of the drugcontaining internal phase with external phase simethicone in the presence of PEG or sugar alcohol moieties.

[0170] Examples 21 -25 reinforces the advantage of preparing a transient oil-in-simethicone emulsion over stable emulsion. Stable emulsions tend to diminish the extent to which the active pharmaceutical ingredient is released in the dissolution medium. Better dissolution results are obtained when a transient oil-in-simethicone emulsion is prepared.

[0171] Example 26

[0172] BRIEF MANUFACTURING PROCESS:

[0173] Liquid Fill Preparation

[0174] 1. Loperamide hydrochloride, propylene glycol monocaprylate, propylene glycol and purified water with predissolved colorant FD&C Red No. 40 were loaded into a compounding tank.

[0175] 2. The above mixture was stirred to dissolve the solids, until a clear, red solution is formed.

[0176] 3. Simethicone was loaded into the compounding tank

[0177] 4. The above mixture was homogenized to form an opaque, pink emulsion.

[0178] The emulsion had a ratio of internal phase (loperamide layer) to external phase (simethicone layer) of 1 :2. The droplet size of the emulsion was measured and found to be 5-30 pm by microscopy.

[0179] FTIR Absorbance of free and vicinal silanol normalized against Si-O: 2.1

[0180] FTIR Absorbance of alkylsilyl normalized against Si-O: 11.6

[0181] Capsule Shell Preparation

[0182] Prepared using conventional equipment and methods known in the art. Materials include gelatin, sorbitol sorbitan solution, methylparaben, propylparaben, FD&C Red No. 40 and water.

[0183] Encapsulation and Drying

[0184] Prepared using conventional equipment, for example, rotary die encapsulation machine and methods known in the art. The capsules were dried until desired hardness is achieved.

[0185] MULTIMEDIA DISSOLUTION

[0186] Multimedia Dissolution of the composition of Example 26: Dissolution characterization was performed in three dissolution media 0.1 HC1, pH 4.5 acetate buffer and pH 6.8 phosphate buffer accordance with USP monograph (250 mL, Reciprocating cylinder, 25 dpm). The temperature of the dissolution media was maintained at 37 ± 0.5°C and the released drug concentration was determined using HPLC. Multimedia dissolution profiles for loperamide and simethicone capsule vis-a-vis reference product Imodium® Liqui-Gel Capsules are shown in Table 1 and Figure 1. Multimedia dissolution profiles for loperamide and simethicone capsule vis-a-vis Imodium® Multi-symptom Relief Tablet Table 2 and Figure 2.

[0187] Table 1: Multimedia Dissolution Data for loperamide and simethicone capsule vis- a-vis reference product Imodium® Liqui-Gel Capsules

[0188] Conclusion: the composition of Example 26 exhibited rapid dissolution with more than 80% drug release within 30 minutes in all three studied media. The test and reference products were found to be similar in all three dissolution media.

[0189] Table 2: Multimedia Dissolution Data for loperamide and simethicone capsule vis- a-vis reference product Imodium® Multi-symptom Relief Tablet

[0190] For acetate buffer - n = 4, F2 = 27.28; For phosphate buffer - n = 4, F2 = 19.67

[0191] Specification: Similarity Factor (F2) should not be less than 50.00

[0192] Conclusion: The dissolution performance of the reference and test product is similar at 0.1N HC1 but is not similar in pH 4.5 acetate buffer and pH 6.8 phosphate buffer dissolution media. Even though the capsule dosage form of present invention does not show comparable dissolution profile to Imodium® Multi-Symptom Relief tablet in 2 out of 3 dissolution media tested above, the capsule dosage form of present invention was surprisingly found to be bioequivalent to Imodium® Multi-Symptom Relief Tablet (as given below in the bioavailability study).

[0193] COMPARATIVE BIOAVAILABILITY STUDY

[0194] The bioavailability of loperamide and simethicone composition of Example 26 was assessed and compared to the bioavailability of the reference 1, Imodium® Liqui-Gel Capsules (Loperamide HC1 2mg, manufactured by McNeil-PPC Inc) and reference 2, Imodium® Multi-symptom Relief Tablet (Loperamide HC1 2mg and Simethicone 125 mg manufactured by McNeil-PPC Inc) on eighteen healthy volunteers in a randomized, balanced, 3-period, 6-sequence, 3-treatment, single dose cross-over pharmacokinetic study. Each volunteer was administered two unit dosage forms of either test product or the reference product. The plasma concentration of loperamide was quantified using a fully validated LC / MS / MS method. The following in Table 3 and 4 provides the value of the main pharmacokinetics parameters obtained for test as well as reference products.

[0195] Table 3: Bioequivalence results summary: Test (Example 26) vs. Reference 1 (Imodium® Liqui-Gel Capsules)

[0196] Table 4: Bioequivalence results summary: Test (Example 26) vs. Reference 2 (Imodium® Multi-symptom Relief Tablet)

[0197] Conclusion: the composition of Example 26 was found to be bioequivalent to both the reference products Imodium® Liqui-Gel Capsules and Imodium® Multi-symptom Relief Tablet.

[0198] STABILITY

[0199] The formulation of example 26 was tested for physical and chemical stability after being subjected for stability conditions of 30°C and 75%RH for a period of two years. The samples were analyzed at regular time intervals such as initial, 3, 6, 12 and 24 months, and all the samples were found to meet all the specification desired for the capsules.

[0200] Table 5: Stability study for composition of example 26 stored at 30°C ± 2°C / 75%

[0201] RH ± 5% RH Table 5 shows that the capsules produced using the liquid fill described in the invention passed the USP test for Uniformity of Dosage Units for both loperamide hydrochloride and simethicone. Moreover, the capsules are physically and chemically stable up to 24 months at 30°C ± 2°C / 75% RH ± 5% RH in terms of the parameters (1) appearance of capsule (2) disintegration time (3) assay of loperamide hydrochloride (4) assay of simethicone (5) dissolution of loperamide hydrochloride and (6) related substances

[0202] (loperamide N-oxides)

Claims

CLAIMS1. A transient oil-in-simethicone emulsion for oral administration wherein simethicone is present from 50% to 80% by weight of the emulsion.

2. The transient oil-in-simethicone emulsion according to claim 1 wherein the emulsion is filled into a capsule.

3. The transient oil-in-simethicone emulsion according to claim 2 wherein the capsule is selected from the group consisting of hard capsule and soft capsule.

4. The transient oil-in-simethicone emulsion according to claim 3 wherein the capsule is a soft capsule.

5. The transient oil-in-simethicone emulsion according to claim 3 wherein the capsule size is from 3 mm to 20 mm.

6. The transient oil-in-simethicone emulsion according to claim 1 wherein the emulsion contains less than two surfactants.

7. The transient oil-in-simethicone emulsion according to claim 1 wherein the emulsion further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of oil, antioxidants, cosolvents, colorant, and opacifier.

8. The transient oil-in-simethicone emulsion according to claim 7 wherein the oil is selected from the group consisting of free fatty acid; propylene glycol mono- and diesters; glycerol mono- and di-esters and mixtures thereof.

9. The transient oil-in-simethicone emulsion according to claim 8 wherein the oil is present in an amount of 5% to 50% by weight based on the weight of the emulsion.

10. The transient oil-in-simethicone emulsion according to claim 1 wherein the emulsion has a droplet size of less than 70 pm when measured by microscopy.

11. The transient oil-in-simethicone emulsion according to claim 1 wherein the simethicone has a silicon dioxide present which has FTIR Absorbance of free and vicinal silanol normalized against Si-0 greater than or equal to 1.1, and FTIR Absorbance of alkylsilyl normalized against Si-0 greater than or equal to 1.3.

12. The transient oil-in-simethicone emulsion according to claim 11 wherein the simethicone has a silicon dioxide present which has FTIR Absorbance of free and vicinal silanol normalized against Si-0 of 1.1 to 4.1 and FTIR Absorbance of alkylsilyl normalized against Si-0 of 3.6 to 24.9.

13. A transient oil-in-simethicone emulsion for oral administration comprising an external phase and an internal phase, and wherein the external phase comprises an active ingredient, and the internal phase comprises one or more additional active ingredients.

14. A transient oil-in-simethicone emulsion according to claim 13, wherein the active ingredient in external phase is simethicone that is present from 50% to 80% by weight of the emulsion.

15. The transient oil-in-simethicone emulsion according to claim 13 wherein the ratio of the internal phase to external phase is 1 :2.

16. The transient oil-in-simethicone emulsion according to claim 13 wherein the ratio of the internal phase to external phase is 2:3.

17. The transient oil-in-simethicone emulsion according to claim 13 wherein the ratio of the internal phase to external phase is 4:5.

18. The transient oil-in-simethicone emulsion according to claim 13 wherein the active ingredients in the emulsion are effective for the treatment of gastrointestinal disorders.

19. The transient oil-in-simethicone emulsion according to claim 18 wherein the active ingredients in the internal phase of the emulsion are selected from the group consisting of antidiarrheal agent, anticholinergic or antispasmodic agent, prokinetic agent, proton pump inhibitor, histamine h2 blockers, antacid, dopamine antagonist and combination thereof.

20. The transient oil-in-simethicone emulsion according to claim 19 wherein the active ingredients in the internal phase are selected from the group consisting of loperamide, domperidone, otilonium, hyoscine, dicyclomine, pinaverium, cisapride, pharmaceutically acceptable salts thereof and combination thereof.

21. The transient oil-in-simethicone emulsion according to claim 14 wherein the emulsion is filled into a capsule.

22. The transient oil-in-simethicone emulsion according to claim 21 wherein the capsule is either hard capsule or soft capsule.

23. The transient oil-in-simethicone emulsion according to claim 20 wherein the capsule is either gelatin or non-gelatin.

24. The transient oil-in-simethicone emulsion according to claim 14 wherein the emulsion further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of oil, antioxidants, cosolvents, colorant and opacifier.

25. The transient oil-in-simethicone emulsion according to claim 14 wherein the emulsion has a droplet size of less than 70 pm when measured by microscopy.

26. The transient emulsion according to claim 14 wherein the emulsion contains less than two surfactants.

27. A capsule dosage form comprising a transient oil-in-simethicone emulsion for oral administration, the capsule comprises: a. A capsule shell, and b. An emulsion fill composition comprising simethicone and one or more additional active ingredient, wherein simethicone is present in amount of 50% to 80% by weight based on the weight of the emulsion.

28. The capsule dosage form according to claim 27, wherein the capsule is a soft capsule.

29. The capsule dosage form according to claim 28, wherein the active ingredients are selected from the group consisting of antidiarrheal agent, anticholinergic or antispasmodic agent, prokinetic agent, proton pump inhibitor, histamine h2 blockers, antacid, dopamine antagonist and combination thereof.

30. The capsule dosage form according to claim 29, wherein the active ingredient is selected from the group consisting of loperamide, domperidone, otilonium, hyoscine, dicyclomine, pinaverium, cisapride, pharmaceutically acceptable salts thereof and combination thereof.

31. A capsule comprising transient oil- in-simethicone emulsion, wherein the emulsion comprises simethicone and loperamide dissolved in oil, which when administered to a fasting human at a dose of 2 X 2 mg of loperamide exhibits: a. a Cmax of 1.000 to 1.720 ng / mL; and b. a AUC of 17.000 to 27.000 h.ng / mL.

32. The capsule according to claim 31 wherein the transient oil-in-simethicone emulsion has a droplet size of less than 70 pm when measured by microscopy.

33. The capsule according to claim 31 wherein the transient oil-in-simethicone emulsion contains less than two surfactants.

34. The capsule according to claim 31 wherein the size of the capsule is 6 mm to 15 mm.

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