Compositions for solid self-emulsifying drug delivery system and methods for preparing the same

Abstract

The present disclosure provides a solid oral composition containing self-emulsifying drug delivery system (SEDDS) loaded with a biologically active agent and a method for preparing the same, wherein the oral composition contains a polymer having a Tg higher than 100 °C, the method uses a continuous melting granulation process.

Description

COMPOSITIONS FOR SOLID SELF-EMULSIFYING DRUG DELIVERY SYSTEM AND METHODS FOR PREPARING THE SAMECROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 612,932 filed on December 20, 2023, the contents of which is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure relates to compositions of solid self-emulsifying drug delivery system (SEDDS) and methods for preparing thereof.BACKGROUND

[0003] Poorly soluble drugs are one of the major challenges pharmaceutical manufacturers are facing. More and more drugs in development exhibit low water solubility which can affect bioavailability or therapeutic index of the drugs. There are various efforts to improve the solubility of the poorly soluble drugs for therapeutic usage.

[0004] One of the efforts provided self-emulsifying drug delivery systems (SEDDS) that are mixtures of oils, surfactants, solvents, and drug substance that rapidly and spontaneously form oil-in-water emulsions or microemulsions when introduced into aqueous phases under gentle agitation. Upon emulsification, the lipophilic components disperse to form small lipid cores surrounding by surfactant in an aqueous continuous phase. Depending on the exact characteristics of the drug, it may be incorporated into the core, surfactant layer, or a combination of the two. From the perspective of oral formulations, these mixtures are typically loaded into softgel capsules. Upon ingestion and digestion, the formulation readily disperses in the stomach and forms a stable emulsion or microemulsion with the drug evenly dispersed throughout via the small lipid cores. These, in turn, can get readily absorbed either through the gastric or hepatic pathways.

[0005] Marketed lipid formulation of self-emulsifying drug delivery system (SEDDS) are available as liquid in softgel pills, which requires complex and special manufacturing processes and poses costly and time-consuming technical requirements. Additionally, the products show the physiochemical stability issue and requited special storage issue due to the compromise oxygen and moisture barrier properties of gelatin shell of the softgel capsule. It is proposed invarious literature to adsorb the liquid SEDDS on the absorptive materials, e.g. silicon dioxide. Generally, these materials have high surface to volume ratio but demonstrated issues such as change in solubilization capabilities after redispersion, poor compression and compaction properties of the material, or requires others functional excipients such as binders, disintegrants, and lubricants to prepare solid oral dosage form leading to poor drug loading of drug in the dosage form.SUMMARY

[0006] One embodiment of the present disclosure provides a solid oral composition comprising: a polymer; a pharmaceutically active agent; and a self-emulsifying drug delivering system (SEDDS), wherein, the polymer has glass transition temperature (Tg) higher than 100 °C; and the pharmaceutically active agent is contained within the SEDDS, the pharmaceutically active agent is a small molecule drug, a peptide, a nucleotide, polynucleotide or polypeptide.

[0007] Another embodiment of the present disclosure provides a method for preparing the solid oral composition comprising: mixing a SEDDS with a pharmaceutically active agent to obtain a mixture of Drug- SEDDS to obtain Drug- SEDDS; and feeding the Drug-SEDDS and a polymer separately through melting granulation processor continuously at 30-150 °C to produce a solid oral composition.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 presents a conventional SEDDS in liquid form.

[0009] FIG. 2 presents tablets prepared from Syloid 3150 / SEDDS F2 with various amount of Kollidon VA 64®.

[0010] FIG. 3 presents results of Solid-SEDDS (Kollidon® VA 64 + SEDDS F2) prepared with 40 or 50% wt / wt of SEDDS loadings.

[0011] FIG. 4 presents results of Solid SEDDS: SEDDS + Kollidon® VA 64 matrix under different processing temperature in MGP.

[0012] FIG. 5 presents results of Solid SEDDS prepared with various % loading of SEDDS in VA 64 matrix at low temperature in MGP.

[0013] FIG. 6 presents results of Danazol release from Solid SEDDS, where Danazol was released more than 85% in about 20 minutes, which is almost an instant release.

[0014] FIG. 7 presents results of Solid SEDDS prepared using Kollidon®VA64, SEDDS F2 and Kollidon®CL in various ratios. The results provide that it is possible to control the release profile of formulation containing Kollidon® VA 64 matrix by adding Kollidon® CL or other similar matrix polymers.

[0015] FIG. 8 presents results of comparative example containing Syloid 3150 / SEDDS F2 by Danazol dissolution testing at 37 °C, 75 rpm USP II apparatus. Drug was released more than 90% within 2 minutes but the drug concentration decreased due to crystallization of the drug.DETAILED DESCRIPTION

[0016] The present disclosure provides a composition of SEDDS-polymer wherein the liquid SEDDS is trapped within the matrix of polymer to provide a solid SEDDS. The solid SEDDS provides enhanced stability and convenience for storage over the typical SEDDS which is in liquid form.

[0017] One embodiment of the present disclosure provides a solid oral composition comprising: a polymer; a pharmaceutically active agent; and a self-emulsifying drug delivering system (SEDDS), wherein, the polymer has Tg higher than 100 °C; and the pharmaceutically active agent is contained within the SEDDS.

[0018] In one specific embodiment, the pharmaceutically active agent is a small molecule drug, a peptide, a nucleotide, polynucleotide or polypeptide.

[0019] In another embodiment, the polymer forms a matrix structure and absorbs SEDDS.

[0020] In yet another embodiment, the polymer is a vinylpyrrolidone-vinyl acetate copolymers, copovidone, copolyvidone, glycerol monostearate, and hydrogenated castor oil, cetyl alcohol, cetostearyl alcohol, myristyl alcohol, stearyl alcohol, stearic acid, or a mixture thereof, preferably, the polymer is co-povidone or povidone polymers.

[0021] In an embodiment, the weight% of SEDDS is 20-60%, 30-60%, or 35-55%; by weight of the total solid SEDDS; or the weight% of the pharmaceutically active agent is 0.5- 60%, 1-50%, 1-40%, or 1-30%.

[0022] The solid SEDDS composition of the present disclosure provides 40% SEDDS loading, which is significantly higher than the published value (typical value <30%). Hence, reducing pill frequency or size that are a burden on the patient and improve the patience compliance to improve the therapeutic result.

[0023] The polymers in the present disclosure have Tg higher than 100 °C and lower than 300 °C in a certain embodiment.

[0024] The polymer forms a matrix structure and absorbs SEDDS. Examples of the polymers are Kollidon® grades, methacrylic polymers / copolymers or Polyvinyl acetate / povidone.

[0025] In one embodiment, weight ratio of 10-40% of SEDDS compared to polymer based on a polymer having a Tg value of 100-110 °C. However, it is not necessary to have less SEDDS than polymer to be employed. If the Tg of the matrix polymer is high enough such as higher than 200 °C, higher than 40% weight of SEDDS can be loaded to provide more drug loading.

[0026] The pharmaceutically active agent is selected from among small molecule drugs, peptide, or biologies, but not limited to these only. The loading of the pharmaceutically active agent can be adjusted by using polymer with various Tg, different amount of SEDDS, or processing method.

[0027] The amount of the SEDDS containing pharmaceutically active agent loaded in the present disclosure can be 0.1-40%, 0.1-30%, 0.5-20%, or 1-10%.

[0028] The stability and the storage issue of liquid SEDDS is overcome by converting the liquid to solid using melt granulation technique and a high Tg polymer (>100°C), such as copovidone (Kollidon® VA 64), or povidone material (Kollidon® grades). After processing, the liquid SEDDS trapped in the matrix of polymer is more stable at room temperature, easy to handle and soluble in biological fluids. This SEDDS-polymer mixture, i.e. solid SEDDS, provides the same release profile as the liquid SEDDS and thus, the solid matrix does not affect the release profile of the drug.

[0029] The solid SEDDS with a matrix containing lower Tg / melting temperatures forms softer or semi-solid material at room temperature and highly depends on the compositions of SEDDS formulation.

[0030] An embodiment of the present disclosure provides a solid formulation comprising a solid self-emulsifying drug delivery system (Solid SEDDS), or a solid composition comprising a liquid SEDDS entrapped within a polymer matrix, wherein SEDDS is selected from, but not limited to, Fl, F2, F3, F4, F5, F6, F7, F8, F9 or F10 as provided in BASF SEDDS Formulary or other available SEDDS. (world wide web at pharma.basf.com / learning- center / protected-download / 69588)

[0031] A summary of representative SEDDS -Formulary by BASF PHARMA is provided below Table 1.Table 1. BASF Pharma SEDDS Formulary

[0032] Another embodiment of the present disclosure provides a method for preparing the solid oral composition comprising: mixing a SEDDS with a pharmaceutically active agent to obtain a mixture of Drug- SEDDS (e.g., in a water bath with stirring); and feeding the Drug-SEDDS and a polymer separately through melting granulation processor continuously at 30-150 °C to produce a solid oral composition.

[0033] In an embodiment, the SEDDS and the pharmaceutically active agent are mixed at 40-60°C; the melting granulation processor was operated at 50-100°C, 60-100 °C, 60-90 °C, or 75-95 °C.

[0034] Optionally, one or more plasticizers can be added to the mixture of polymer and SEDDS.

[0035] The plasticizer is selected from glycerin, polyethylene glycols, polyethylene glycol monomethyl ether, propylene glycol, sorbitol sorbitan solution, acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, triacetin, tributyl citrate, triethyl citrate, or mixtures thereof.

[0036] In the process of the present disclosure the granulation is operated at the processing temperature below <100 °C to prevent or reduce the impurity formation during the manufacturing process.

[0037] In the event the Tg of the polymer is 200 °C or higher, additional plasticizer or increased amount of liquid SEDDS may be used to provide the solid SEDDS at a lower process temperature.

[0038] In one aspect, this disclosure provides a method for preparing the solid SEDDS composition using a continuous solidification of liquid self-emulsifying drug delivery system (SEDDS) via melt granulation procedure using a polymer such as co-povidone (Kollidon® VA 64).

[0039] The solid SEDDS formulation is formed by a various combination of polymers with different melting temperatures, heating temperature, mixing temperature, mixing pressure, or ratios of different polymer mixtures to provides a suitable matrix for solid SEDDS depending on the drug loaded.

[0040] For example, Kollidon® VA 64 or other povidone grades polymers such as Kollidon® 30, or 90F can be used alone or as a mixture to provide solid SEDDS composition of the present disclosure.

[0041] Polymers with higher melting temperature tend to provide harder solid, but it may change by the weight ratio of the mixed polymers.

[0042] The present disclosure provides a process for preparing the solid SEDDS of the present disclosure by using melt granulation technique and a high Tg polymer (>100°C), such as, but not limited to, co-povidone (Kollidon VA 64®), povidone material (Kollidon® grades). After processing, the liquid SEDDS trapped in the matrix of polymer were found to be stable at room temperature, easy to handle and soluble in biological fluids. This SEDDS-polymer mixtures (has the same release profile as the liquid SEDDS meaning matrix is not negatively affecting the release profile of drug. We have also tested the polymers with lower Tg / melting temperatures. However, the mixture with SEDDS and low melting temperature polymer formed soft or semi-solid material at room temperature suggesting stability and handling issues.

[0043] The present disclosure utilized optimized SEDDS formulations that can be selected from SEDDS that have been tested for stability, robustness and ability to solubilize poorly water-soluble drugs. These formulations are simple to create, and highly effective in vitro, in vivo and in commercial pharmaceutical formulations.

[0044] Poorly soluble drugs are one of the major challenges pharmaceutical manufacturers are facing. More and more drugs in development exhibit low solubility. For example, BASF Guidance of SEDDS Formulary (https: / / pharma.basf.com / learning-center / protected- download / 69588) offers a variety of formulation with different HLB value by combining various solubilizers, namely Fl - F10, and one or more of those can be combined and included in the solid SEDDS of the present disclosure. Utilizing different SEDDS can increase the possibility to achieve effective solubilization across a range of dosage forms. Often, techniques such as high throughput robotic techniques to identify true microemulsions of the target drug to solubilize can be used to determine the optimum selection of SEDDS for a drug.Self-emulsifying Drug Delivery System (SEDDS)

[0045] Formulators face API solubility and bioavailability challenges; lipid-based drug delivery systems (LBDDS), utilize the body’s natural digestive system to effectively deliver poorly water-soluble drugs to the body. To maximize drug solubility and absorption, the LBDDS are formulated into what is frequently called a Self-emulsifying Drug Delivery System (SEDDS), where the contents of the liquid filled capsule spontaneously emulsify to micro- and nano-scale droplets upon release in the aqueous Gl-tract. These microemulsions are clear, low- viscosity or have low viscosity and thermodynamically stable - all advantages to formulatinga pharmaceutical formulation. Upon contact with the Gl-tract, these microemulsions shift to a fine-, micro- or nano-scale emulsion where it is subsequently digested, and the drug is absorbed. Commercially available SEDDS includes, F1-F10 SEDDS Formulary from BASF, that can be utilized by formulators to evaluate their capability to solubilize and make bioavailable lead compounds at various drug product development stages.

[0046] Conventional SEDDS are provided in a liquid form and the present disclosure provides a solid SEDDS to provide advantage of the solid form. See FIG. 1.Process for preparing Solid SEDDS

[0047] The present disclosure provides a continuous solidification of liquid selfemulsifying drug delivery system (SEDDS) via melt granulation procedure using co-povidone (Kollidon® VA 64). To solidify the liquid SEDDS formulation, different polymers with different melting temperatures can be used. For example, a commercially available copovidone polymer, Kollidon® VA 64, was used for further testing because of its highest melting temperature. Other povidone grades (Kollidon® 30, 90F) can also be used for the solidification of liquid SEDDS because of their high melting point. Polymer excipient with high Tg is preferred for melting granulation process.

[0048] Conventional processing of polymer containing solid composition includes simple mixing and heating (60-140 °C), mixing on a hot plate, or heating (60-140 °C) and mixing using rota-vapor, etc. However, it was reported (Pharmaceutics 2022, 1 , 2717) that the use of a hot extrusion process to create solid SEDDS is not ideal for preparing solid SEDDS of the present disclosure, as it results in low SEDDS loading (<30%).

[0049] Also, in a comparative experimental, it was found that in the hot melt extrusion (HME) with SEDDS and Kollidon® VA64 at 30% (or more), SEDDS loading was difficult to handle due to the sticky nature of the hot molten brownish extrude.

[0050] On the other hand, the present disclosure provides a process for preparing the solid SEDDS of the present disclosure by using a melt granulation process at either low temperature, such as 30-100 °C or high temperature >100 °C and but <200 °C.Melt granulation process

[0051] The process of the present disclosure provides uniform mixing of SEDDS and matrix polymers such as Kollidon® VA 64. Melt granulation process is a continuousmanufacturing process and easy to adopt at commercial scale level to provide advantage of easy scale-up.

[0052] Use of syringe pump for the liquid SEDDS injection would also provide better mixing than a peristaltic pump.

[0053] An example of parameters for Melt granulation protocol are provided below Table 2, for standard screw setup with an extra mixing screw configuration.Table 2. Parameters for Melt Granulation Protocol

[0054] Excipient Material for melt granulation process includes, but not limited to, crystallization inhibitors, solubilizers, and solvents. Kollidon® VA 64, Kollisolv® MCT 70, Glyceryl monooleate and Kolliphor® RH 40, etc. Liquid SEDDS containing a drug can be prepared using a method known in the art or provided with the SEDDS material.

[0055] An example of procedure for preparing the composition of SEDDS is as following:

[0056] Oil phase: Prepare oil phase by adding each of hydrophobic ingredients (Oil phase) into an appropriately sized container. Heat the mixture to 50°C.

[0057] Water phase: Prepare water phase by adding each of hydrophilic ingredients (Water phase). Heat the mixture to 50°C.

[0058] Mix the oil phase and water phase together at 50°C under the overhead mixer and set to 200-300 rpm.

[0059] An example of solidification of liquid SEDDS process of the present disclosure is as following and was carried out on ThermoFisher® Process 11 Parallel Twin Screw Extruder system. The feeding of polymers and liquid SEDDS was performed separately with a feeding rate < 0.12 kg / h and < 0.08 kg / h, respectively. Polymer powder was continuously fed in the first extruder segment. Liquid SEDDS was fed in the third extruder segment through a 50 mL syringe by syringe pump. The screw has a standard melt granulation configuration setup with an extra mixing zone right after the liquid SEDDS injection port. The screw speed changed from 60 rpm to 100 rpm to control the solid SEDDS particle size. An example of processing temperatures is shown in Table 3.Table 3. Example of Processing Temperature for Melt Granulation

[0060] An example of the polymers used to entrap SEDDS formulation and to enhance the solidification of SEDDS can be selected based on the following properties relevant to the solid SEDDS composition of the present disclosure. See Table 4.Table 4. Example Polymers to Entrap SEDDS Formulation and Their Properties

[0061] The solid SEDDS compositions and the process for preparing the same as provided by the present disclosure provides advantages such as: (1) while stability and handling of SEDDS is improved, the drug release profile of the solid SEDDS is the same as liquid SEDDS; (2) processing temperature is much lower (e.g. less than 100 °C) than conventional meltextrusion process that is typically 140 °C or higher, to reduce and minimize any degradation of ingredients; and (3) loading and retention of SEDDS-drug is higher (about 40 % or higher) than Liquid SEDDS (published data < 30%).

[0062] Lastly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present disclosure, which is defined solely by the claims. Accordingly, the present disclosure is not limited to that precisely as shown and described.EXAMPLES

[0063] The following non-limiting examples illustrate the content and technical solutions of the disclosure, but do not limit the scope of the invention.

[0064] Example 1. Preparation of Solid SEDDS Formulation with different matrix excipient with different ratio (w / w)

[0065] Kollidon® VA64: SEDDS F5 = 1:1. 2.0035 g of Kollidon® VA64 was mixed with2.0052 g of F5 SEDDS in a 20 mL glass vial. The vial was heated at 120 °C for 10 minutes.

[0066] Kollidon® VA64: SEDDS F5 = 3:2. 2.3953 g of Kollidon® VA64 was mixed with 1.6063 g of F5 SEDDS in a 20 mL glass vial. The vial was heated to 120 °C for 10 minutes.

[0067] GELUCIRE® 48 / 16 : SEDDS F5 = 1:1. 2.0098 g of GELUCIRE48 / 16 was mixed with 2.0232 g of F5 SEDDS in a 20 mL glass vial. The vial was stored at 40 °C for 48 hours.

[0068] GELUCIRE® 48 / 16 : SEDDS F5 = 3:2. 2.4003 g of GELUCIRE48 / 16 was mixed with 1.6160 g of F5 SEDDS in a 20 mL glass vial. The vial was stored at 40 °C for 48 hours.

[0069] GELUCIRE® 44 / 14 : SEDDS F5 = 1:1. 1.9950 g of GELUCIRE44 / 14 was mixed with 1.9998 g of F5 SEDDS in a 20 mL glass vial. The vial was stored at 40 °C for 48 hours.

[0070] GELUCIRE® 44 / 14 : SEDDS F5 = 3:2. 2.4151 g of GELUCIRE48 / 16 was mixed with 1.6646 g of F5 SEDDS in a 20 mL glass vial. The vial was stored at 40 °C for 48 hours.

[0071] Kolliwax® GMS II : SEDDS F5 = 1:1. 2.0078 g of Kolliwax GMS II was mixed with 2.0082 g of F5 SEDDS in a 20 mL glass vial. The vial was stored at 40 °C for 48 hours.

[0072] Kolliwax® GMS II : SEDDS F5 = 3:2. 2.4019 g of GELUCIRE48 / 16 was mixed with 1.6099 g of F5 SEDDS in a 20 mL glass vial. The vial was stored at 40 °C for 48 hours.

[0073] A summary of the composition prepared are provided in Table 5 with the result.Table 5. Composition of Example 1 and the result

[0074] Among the resulting products, the formulations containing Gelucire® showed layer separation at 40% w / w SEDDS loading. This matrix resulted, upon storage, a phase separation to form a mixture of solid SEDDS and liquid SEDDS, possibly due to overloading than the capacity of Gelucire® which has low SEDDS loading capability. On the other hand, the formulations containing Kolliwax® GMS II did not show any layer separation at 40% w / w SEDDS loading but it provided cloudy solution after dissolution.

[0075] The formulation containing Kollidon® VA64 did not show layer separation and for a clear solution.

[0076] The solid SEDDS prepared using Gelucire® (Comp#l-4) and Kolliwax® GMS II (Comp#5-6) are compared in solubility test. The result indicated Gelucire® provided complete dissolution while Kolliwax® left cloudy solution and some solids were left in water.

[0077] Example 2. Compression of the Syloid® 3150 / SEDDS F2: compression force 15kN

[0078] The effect of the matrix polymer on compressibility of the formulation into tables. Various amount of Kollidon® VA 64 was included and found only high percentage of Kollidon® VA 64 provided good property to make tablets. See FIG. 2.

[0079] Example 3. Solid SEDDS formulation development with Kollidon®VA 64 matrix (no Syloid®): Simple mixing of components at high temperature

[0080] Therefore, the effect of low temperature melt granulation was compared by preparing mixing the ingredients using hot melt method. The ingredients, Kollidon® VA 64and SEDDS, were simply mixed by heating on a hot plate at high temperature (>120 °C). A mixture of Kollidon® VA 64 and SEDDS F2 (60:40, w / w) provided no wiping liquid leaks from the solid. The prepared Solid SEDDS were dissolved in Dl-water and no biphasic or separation of oil and water phase. However, problem with the melt mixing process were, (1) Mixing of SEDDS and Kollidon®VA 64 is not uniform; (2) Operating temperature is high (>120 °C) and prolong exposure of SEDDS and Kollidon® VA 64 led to color change to brown suggesting quality issues in the formulation. See FIG. 3.

[0081] Example 4. Solid SEDDS: SEDDS + Kollidon® VA 64 matrix under different processing temperature in MGP process

[0082] The effect of temperature of the melt granulation on different ratio of matrix polymer and SEDDS were tested.

[0083] 10% Solid SEDDS. Kollidon®VA64 + SEDDS F2 at feed rate VA 64 at 120 g / hour, and SEDDS F2 at 13.3 g / hour. Temperature scheme 30 50 100 100 100 80 80, Speed 8060 rpm, Torque 0.30.6 N.m.

[0084] 20% Solid SEDDS. Kollidon®VA64 + SEDDS F2 at feed rate VA 64 at 120 g / hour, and SEDDS F2 at 30 g / hour. Temperature scheme 30 50 100 100 100 80 80, Speed 8060 rpm, Torque 0.30.6 N.m.

[0085] 30% Solid SEDDS. Kollidon®VA64 + SEDDS F2 at feed rate VA 64 at 120 g / hour, and SEDDS F2 at 51.43 g / hour. Temperature scheme 30 50 100 100 100 80 80, Speed 8060 rpm, Torque 0.30.6 N.m.

[0086] 40% Solid SEDDS. Kollidon®VA64 + SEDDS F2 at feed rate VA 64 at 120 g / hour, and SEDDS F2 at 80 g / hour. Temperature scheme 30 50 100 100 100 80 80, Speed 8060 rpm, Torque 0.3 N.M.0.6 N.m. Also lower (80°C) temperature was applied in different batch at 30 50 80 80 80 50 40 temperature scheme and was found that lower temperature process provided equal or better properties than the ones processed at 100 °C. The results proves that the current low temperature melt granulation is an excellent process for preparing the solid SEDDS. The results are provided in the following Table and provide that melt granulation process (MGP) at low temperature setting gave solid SEDDS with better handling property than high temperature setting at 40% SEDDS loading. See FIG. 4.

[0087] Example 5. Solid SEDDS manufacturing (various % loading in VA 64 matrix) at low temperature in MGP

[0088] Solid SEDDS were prepared using Kollidon®VA64 with SEDDS F2 in different ratio using the low temperature melt granulation process of the present disclosure to compare the properties of the resulting solids. Different SEDDS other than SEDDS F5 also provided a satisfactory solid profile sufficient to be pressed into oral dosage formulations such as tablet. See FIG. 5.

[0089] Example 6. Preparation and Dissolution of solid SEDDS (SEDDS F2) containing danazol, 37 °C, 75 rpm USP II apparatus

[0090] 568 mg of Danazol was dissolved in 50 g of SEDDS F2 without a solvent, and the mixture was heated at 50 °C in a water bath with magnetic stirrer. The mixture of Danazol in SEDDS F2 was processed through Melt granulation to mix with Kollidon®VA64 using Kollidon®VA64 feeding rate at 2 g / minute and SEDDS F2+Danazol at 1.33 g / minute. The temperature scheme was less than 100 °C and the speed of feeding was 80 rpm, at torque 0.7 N.m.

[0091] The resulting solid SEDDS containing Kollidon® VA64 (60%) + 40% SEDDS F2 containing danazol was subjected to dissolution test in a dissolution media: FASSIF V2, at pH 6.8, and stirring speed: 50 rpm.

[0092] Danazol was released more than 85% in about 20 minutes, which is almost an instant release. See FIG. 6. This release profile is similar to liquid SEDDS formulation (published data) suggesting Kollidon® VA 64 or the solid SEDDS of the present disclosure does not affect release profile of drug. No drug precipitation was found after complete release in contrast of Syloid® based solid SEDDS.

[0093] Example 7. Properties of different solid SEDDS formulations

[0094] VA64: PEG1450 = 90:10, w / w: 2.1599 g of VA64 was mixed with 0.2393 g ofPEG 1450 and the mixture was stored at 80°C for 24 hours, followed by adding 1.6085 g of SEDDS F5 to the mixture. The final mixture was stored at 80 °C for 48 hours.

[0095] VA64: PEG1450 = 80:20, w / w: 1.9127 g of VA64 was mixed with 0.4894 g ofPEG 1450 and the mixture was stored at 80°C for 24 hours, followed by adding 1.6023 g of SEDDS F2 to the mixture. The final mixture was stored at 80 °C for 48 hours.

[0096] VA64: PEG1450 = 70:30, w / w: 1.6757 g of VA64 was mixed with 0.7231 g ofPEG 1450 and the mixture was stored at 80°C for 24 hours, followed by adding 1.6428 g of SEDDS F2 to the mixture. The final mixture was stored at 80 °C for 48 hours.

[0097] Other compositions in the following Table 6 were prepared in a similar procedure using the corresponding matrix polymer and SEDDS. The properties of each composition are provided below. The results indicated that Syloid® could not provide a proper solid SEDDS while addition of polyethylene glygol (PEG) did not change the property of the solid SEDDS. Plasticizers like PEG can reduce Tg of the mixed polymer and thus, it would be useful in the event if the Tg of the polymer needs to be adjusted to be used as the matrix.Table 6.

[0098] Example 8. Stability testing

[0099] Visual observation of samples stored at 40 °C, about 50% room humidity for one month provided the following results in Table 7.Table 7.

[0100] The results provide that the solid SEDDS from the present disclosure provides a quite stable composition at room temperature for 6 months.

[0101] Example 9. Solid SEDDS: SEDDS + Kollidon® VA 64 + Kollidon® CL manufacturing at low processing temperature in MGP process

[0102] The corresponding formulations were prepared using Kollidon®VA64, SEDDS F2, and Kollidon® CL, in the ratio specified using the process of the present disclosure, low temperature melt granulation process, that is providing in the above examples. This example employed Kollidon® CL to add functionality. Formulation with Kollidon® CL disintegrated faster than the formulation without Kollidon® CL. The results provides that it is possible to control the release profile of formulation containing Kollidon VA 64 matrix by adding Kollidon® CL or other similar matrix polymer. See FIG. 7.

[0103] Example 10. Comparative Example - Solid SEDDS formulation development with Syloid® 3150 (its already available in market claiming excipients to make Solid SEDDS)

[0104] Two different processes were used to mix SEDDS F2 and Syloid®XDP 3150 to check the effect of mixing method on uniformity of the Solid SEDDS:(a) 4 07 g of SEDDS F2 and 5.98 g of Syloid®XDP3150 were mixed manually.(b) 16.09 g of SEDDS F2 and 23.99 g of Syloid®XDP3150 were mixed using a mechanical mixer for 15 minutes.

[0105] Both resulted in a similar product wherein SEDDS were trapped in the porous structure of Syloid®XDP3150 and was immediately released into water but leaving waterinsoluble Syloid®XDP3150 behind. This confirms that Syloid®XDP3150 or any other water insoluble polymers may not be suitable to be employed as a matrix polymer for Solid SEDDS.

[0106] Example 11. Comparative Example - Syloid® 3150 / SEDDS F2 with Danazol dissolution testing, 37 °C, 75 rpm USP II apparatus

[0107] A complete Solid SEDDS containing a drug, danazol, was prepared to measure the release of the drug. Drug was released more than 90% within 2 minutes, Drug concentration decreased after 100% release., possibly from crystallization of the drug after certain time. See FIG. 8. Thus, the drug did not stay solubilized by this formulation.

[0108] Example 12. Comparative Example - Preparation of formulation using Rotavap at high temperature

[0109] A mixture of 11.99 g of Kollidon®VA64 (50%, w / w) and 8.01 g of SEDDS F2 (40%, w / w) were used to prepare solid SEDDS formulation using Rotavap at 120 °C. No proper solid SEDDS mixture was formed even at higher temperature at 150 °C, but color started to change from white to brown with the time and increased temperature. The result confirms that the process of the present disclosure is superior and provides significant advantage to form solid SEDDS to offer efficient drug delivering oral formulation.

Claims

CLAIMSWe claim:

1. A solid oral composition comprising: a polymer; a pharmaceutically active agent; and a self-emulsifying drug delivering system (SEDDS), wherein, the polymer has Tg higher than 100 °C; and the pharmaceutically active agent is contained within the SEDDS.

2. The solid oral composition of claim 1, wherein polymer forms a matrix structure and absorbs SEDDS.

3. The solid oral composition of claim 1, wherein the polymer is a vinylpyrrolidone-vinyl acetate copolymers, copovidone, copolyvidone, glycerol monostearate, and hydrogenated castor oil, cetyl alcohol, cetostearyl alcohol, myristyl alcohol, stearyl alcohol, stearic acid, or a mixture thereof.

4. The solid oral composition of claim 1, wherein the polymer is co-povidone or povidone polymers.

5. The solid oral composition of claim 1, wherein the pharmaceutically active agent is a small molecule drug, peptide, nucleotide, polypeptide, or polynucleotide.

6. The solid oral composition of claim 1, wherein the weight% of SEDDS is 20-60%, 30- 60%, or 35-55%.

7. The solid oral composition of claim 1, wherein the weight% of SEDDS is 30-60% or 35-55%.

8. The solid oral composition of claim 1, wherein the weight% of drug is 5-60%, 5-50%, 10-60%, 10-40%, or 10-30%.

9. A method for preparing the solid oral composition of claim 1, comprising: a) mixing a SEDDS with a pharmaceutically active agent to obtain a Drug-SEDDS; and b) feeding the Drug-SEDDS and a polymer separately through melting granulation processor continuously at 30-150 °C to produce a solid oral composition.

10. The method of claim 9, wherein the temperature is 50-100°C, 60-100 °C, 60-90 °C, or 75-95 °C.

11. The method of claim 9, wherein the SEDDS and the pharmaceutically active agent are mixed at 40-60°C.

12. The method of claim 9, further comprising adding a plasticizer to step a).

13. The method of claim 12, wherein the plasticizer is selected from glycerin, polyethylene glycols, polyethylene glycol monomethyl ether, propylene glycol, sorbitol sorbitan solution, acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, triacetin, tributyl citrate, or triethyl citrate.

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