Description:FIELD OF THE INVENTION
[0001] The present disclosure pertains to a co-processed excipient composition and to a method of producing the same. In particular, the present disclosure provides a particulate co-processed excipient composition for oral solid dosage forms comprising a co-processed mixture of a filler, a glidant, and a binder having superior flowability, compressibility and satisfactory tableting profile; and methods for producing the same.

BACKGROUND OF THE INVENTION
[0002] The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the present invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Tablet is easiest way to administered Pharmaceutical active and requires binder to bind the active ingredient, glidant to increase flow of the blend, disintegrant to break down tablet into pieces after administered and enhance dissolution rate of the tablet, lubricant is used to increase flow and reduced die frication during tableting, and some time used taste masking agent to mask taste when API having bitter taste. Microcrystalline cellulose (MCC), Mannitol and colloidal silicon dioxide (CSD) are individually used in pharmaceutical industries to be manufacturing tablets formulation. MCC generally knows as dry binder, it provides sufficient flow with superior binding properties. Whereas Mannitol used sweetening agent, or as binder, filler but it helps to tablet disintegrant fast. Colloidal silicon dioxide used as a glidant or flow enhancer in formulation industries.
[0004] Various filler, binders which are applied for the formulation of solid oral dosage forms are assessed for their benefits and drawbacks, including lactose, sorbitol, mannitol, starch, and calcium hydrogen phosphate dihydrate. it was observed that this excipient is gaining more and more attention in pharmaceutical formulation development and production. While one of the main advantages of conventional fillers, binders such as lactose, starch, and calcium hydrogen phosphate dihydrate is their low-price level, mannitol excels regarding its physicochemical characteristics such as a low hygroscopicity, a strong inertness towards both the API and the patient's body, its good compatibility, and the ability to produce extremely robust tablets. Additionally, the suitability of mannitol for the emerging formulation technology of orally disintegrating tablets is pointed out. It is emphasized that the selection of the filler/binder is highly individual, depending, for example, on the preferred characteristics of the final solid dosage form, the applied API.
[0005] Glidants are incorporated into solid dosage forms to improve the flow properties of powders or granulates. These are excipients adsorbing during mixing (preparation of tableting mixture) on the surface of the powders – particles of other excipients or active pharmaceutical substances. In the phase of pouring the tableting mixture from the hopper into the tableting press die glidants reduce friction between particles and between particles and the wall of the hopper. The consequence of friction reduction (i.e., improving of the mixture flowability) is the uniform die filling with the powder mixture, ensuring of required weight and content uniformity of produced tablets. Glidants also prevent sticking of pressed powders on compression thorns and tablets capping, addition of glidants ensures a high accuracy of metering and a uniform distribution of active ingredients. There is some controversy over the exact mechanism, but two theories exist. The first is that fine glidant powders coat the relatively larger host powders, increasing interparticle distance and decreasing interparticle forces. The second one is that the glidant powders act in a manner analogous to ball-bearings, decreasing friction of rough surfaces. Finely divided amorphous silica, silicon dioxide and magnesium stearate are commonly used glidants. The above listed were therefore used in this study. This work compares accessible and simple flowability methods for glidants which can be used and show a new patented method of angle of repose determination to classify powders into flowability modes.
[0006] Microcrystalline cellulose is native from plants, it is manufactured by hydrolysis reaction. High polymer is converted into low polymer in presence of water, mineral acid, Heat, and pressure. Microcrystalline cellulose is white, odorless, tasteless, relatively free flowing, crystalline powder. It is insoluble in water and mostly all organic solvent. It is free from all inorganic and organic contaminations. It is a highly crystalline particulate cellulose consisting primarily of crystalline accumulates which are obtain by removing amorphous regions of cellulosic material. Microcrystalline cellulose is used in a variety of applications including food, pharma, Nutra, chemical and cosmetics.
[0007] Microcrystalline cellulose (MCC) is highly consumable ingredient in formulation industry, it is used as binder in tablet preparation, as diluent in hard capsule filling. It is known as ideal binder for direct compression oral solid dosages forms as tablet. It provides excellent flow to the final blend and improves compressibility of API and delivered good tablet profile to the final product.
[0008] Co-processing is based on the novel concept of two or more excipients interacting at the sub particle level, the objective of which is to provide a synergy of functionality improvements as well as masking the undesirable properties of individual excipients. The availability of a large number of the excipients for coprocessing ensures numerous possibilities to produce tailor‐made “designer excipients” to address specific functionality requirements. Co-processed excipients are prepared by incorporating one excipient into the particle structure of another excipient using processes such as co‐drying. Thus, they are simple physical mixtures of two or more existing excipients mixed at the particle level. Development of co-processed excipients starts with the selection of the excipients to be combined, their targeted proportion, selection of preparation method to get optimized product with desired physio-chemical parameters and it ends with minimizing avoidance with batch-to-batch variations. An excipient of reasonable price must be combined with the optimal amount of a functional material in order to obtain integrated product, with superior functionality than the simple mixture of components. Co-processing is interesting because the products are physically modified in a special way without altering the chemical structure. A fixed and homogenous distribution for the components is achieved by embedding them into mini granules.
[0009] Thus, there is a need for developing a co-processed excipient composition comprising a mixture of filler, glidant, and binder having superior flowability, compressibility and satisfactory tableting profile that are useful for the formulation of a wide variety of drugs.

OBJECTS OF THE INVENTION
[00010] An object of the present invention is to provide a co-processed excipient composition for oral solid dosage forms.
[00011] Another object of the present invention is to provide a method for producing a co-processed excipient composition comprising MCC, Mannitol and Colloidal silicon dioxide for oral solid dosage forms.
[00012] An object of the present invention is to provide a co-processed excipient composition that enhances final product tablet quality.
[00013] Another object of the present invention is to provide a co-processed excipient composition comprising MCC, Mannitol and Colloidal silicon dioxide, which helps to protect pharmaceutical active ingredient form moisture.
[00014] Another object of the present invention is to provide a co-processed excipient composition comprising MCC, Mannitol and Colloidal silicon dioxide, which helps to increase flowability and tablet hardness.
[00015] Yet another object of the present invention is to provide a tablet formulation comprising a therapeutically active ingredient, co-processed excipient composition, and pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION
[00016] The present disclosure pertains to a co-processed excipient composition and to a method of producing the same. In particular, the present disclosure provides a particulate co-processed excipient composition for oral solid dosage forms comprising a co-processed mixture of a filler, a glidant, and a binder having superior flowability, compressibility and satisfactory tablet profile; and methods for producing the same.
[00017] In some aspects, the present invention provides a co-processed excipient composition comprising a filler, a glidant, and a binder.
[00018] In some aspects, the present invention provides a method for the preparation of co-processed excipient composition comprising a filler, a glidant, and a binder.
[00019] In an aspect, the present invention provides a particulate co-processed excipient composition for oral solid dosage forms comprising co-processed mixture of a filler, a glidant, and a binder; wherein said co-processed excipient composition comprises based on total weight of the composition:
filler in an amount ranging between 6% w/w and 90% w/w;
binder in an amount ranging between 6% w/w and 93% w/w; and
glidant in an amount ranging between 1% w/w and 4% w/w.
[00020] In a preferred aspect, the present invention provides a particulate co-processed excipient composition for oral solid dosage forms comprising co-processed mixture of a filler, a glidant, and a binder; wherein said co-processed excipient composition comprises based on total weight of the composition:
mannitol in an amount ranging between 6% w/w and 90% w/w;
microcrystalline cellulose (MCC) in an amount ranging between 6% w/w and 93% w/w; and
colloidal silicon dioxide in an amount ranging between 1% w/w and 4% w/w.
[00021] In another aspect, the present invention provides a method for the preparation of co-processed excipient composition comprising the steps of:
forming a homogeneous slurry of filler using demineralized water;
forming a homogeneous slurry of binder using demineralized water;
forming a homogeneous slurry of glidant using demineralized water;
mixing the individual homogenous slurry of filler, binder, and glidant by stirring to obtain a homogenous mixed slurry; and
spray drying the homogeneous mixed slurry to form powder.
[00022] In a preferred aspect, the present invention provides a method for the preparation of co-processed excipient composition comprising the steps of:
forming a homogeneous slurry of mannitol using demineralized water;
forming a homogeneous slurry of MCC using demineralized water;
forming a homogeneous mixed slurry of colloidal silicon dioxide using demineralized water; and
spray drying the homogeneous mixed slurry to form powder.
[00023] In a preferred embodiment, the present invention provides a tablet formulation comprising:
the co-processed excipient composition in an amount ranging between 30% w/w and 98% w/w;
a therapeutically active ingredient in an amount ranging between 1% w/w and 60% w/w; and
pharmaceutically acceptable excipient in an amount ranging between 1% w/w and 10% w/w.
[00024] In yet another aspect, the present invention provides a co-processed excipient composition that enhances final product tablet quality.
[00025] In yet another aspect, the present invention provides a co-processed excipient composition comprising MCC, Mannitol and Colloidal silicon dioxide, which helps to protect pharmaceutical active ingredient form moisture.
[00026] In yet another aspect, the present invention provides a co-processed excipient composition comprising MCC, Mannitol and Colloidal silicon dioxide, which helps to increase flowability and tablet hardness.
[00027] In yet another aspect, the present invention provides a tablet formulation comprising a therapeutically active ingredient, co-processed excipient composition, and pharmaceutically acceptable excipients.
[00028] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

BRIEF DESCRIPTION OF DRAWINGS
[00029] Characteristics and advantages of the subject matter as disclosed in the present disclosure will become clearer from the detailed description of an embodiment thereof, with reference to the attached drawing, given purely by way of an example, in which:
[00030] FIG. 1A relates to the flow diagram of a method for preparing co-processed excipient composition comprising Mannitol, MCC and SiO2.
[00031] FIG. 1B relates to the flow diagram of another method for preparing co-processed excipient composition comprising Mannitol, MCC and SiO2.
[00032] FIG. 2A and 2B relates to the scanning electron microscopic image co-processed excipient composition comprising Mannitol, MCC and SiO2.
[00033] FIG. 3A & 3B shows the tablet hardness comparison of co-processed excipient composition of present invention and physical blend at different compression force.
[00034] FIG. 3C shows the tablet hardness and angle of repose comparison at different percentage of colloidal silicon dioxide where Mannitol and MCC quantity is constant.

DETAILED DESCRIPTION OF THE INVENTION
[00035] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[00036] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[00037] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[00038] In some embodiments, numbers have been used for quantifying weight percentages, angles, and so forth, to describe and claim certain embodiments of the invention and are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[00039] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[00040] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[00041] Unless the context requires otherwise, throughout the specification which follows, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[00042] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[00043] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[00044] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified.
[00045] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[00046] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[00047] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[00048] Various terms are used herein. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[00049] While a particular form of the invention has been illustrated and described, it will be apparent that various modifications can be made without departing from the spirit and scope of the invention.
[00050] The present disclosure pertains to a co-processed excipient composition and to a method of producing the same. In particular, the present disclosure provides a particulate co-processed excipient composition for oral solid dosage forms comprising a co-processed mixture of a filler, a glidant, and a binder having superior flowability, compressibility and satisfactory tableting profile; and methods for producing the same.
[00051] The term “co-processed excipient composition” as used herein, refers to a mixture of two or more components, i.e., a filler, a binder, a glidant and optionally lubricant and disintegrant, that have been co-processed using various means but not limited to co-milling, mechanical milling, spray drying, freeze-drying, and the like.
[00052] In some embodiments, the filler include, but are not limited to carbohydrates including sugars such as sorbitol, mannitol, xylitol, erythritol, maltitol, lactitol, isomalt, lactose, fructose, dextrose, sucrose, maltose, and mixtures thereof. Most preferably mannitol.
[00053] In some embodiments, the co-processed excipient composition includes about 6 wt % to about 90 wt% of filler; In some embodiments, about 6.5 wt % ; about 7 wt % ; about 7.5 wt % ; about 8 wt % ; about 8.5 wt % ; about 9 wt % ; about 10 wt % ; about 11 wt % ; about 12 wt % ; about 13 wt % ; about 14 wt % ; about 15 wt % ; about 16 wt % ; about 17 wt % ; about 19 wt % ; about 20 wt % ; about 21 wt %; about 22 wt %; about 23 wt %; about 24 wt %; about 25 wt %; about 26 wt %; about 27 wt %; about 28 wt %; about 29 wt %; about 30 wt %; about 35 wt %; about 40 wt %; about 45 wt %; about 50 wt %; about 55 wt %; about 60 wt %; about 65 wt %; about 70 wt %; about 70 wt % ; about 70.5 wt %; about 71 wt %; about 71.5 wt %; about 72 wt %; about 72.5 wt %; about 73 wt %; about 73.5 wt %; about 74 wt %; about 74.5 wt %; about 75 wt %; about 75.5 wt %; about 76 wt %; about 76.5 wt %; about 77 wt %; about 77.5 wt %; about 78 wt %; about 78.5 wt %; about 79 wt %; about 79.5 wt %; about 80 wt % ; about 80.5 wt % ; about 81 wt % ; about 81.5 wt % ; about 82 wt % ; about 82.5 wt % ; about 83 wt % ; about 83.5 wt % ; about 84 wt % ; about 84.5 wt % ; about 85 wt % ; about 85.5 wt % ; about 86 wt % ; about 86.5 wt % ; about 87 wt % ; about 87.5 wt % ; about 88 wt % ; about 88.5 wt % ; about 89 wt % ; about 89.5 wt % ; or about 90 wt % .
[00054] In some embodiments, the co-processed excipient composition includes about 6 wt % to about 90 wt% mannitol; In some embodiments, about 6.5 wt % ; about 7 wt % ; about 7.5 wt % ; about 8 wt % ; about 8.5 wt % ; about 9 wt % ; about 10 wt % ; about 11 wt % ; about 12 wt % ; about 13 wt % ; about 14 wt % ; about 15 wt % ; about 16 wt % ; about 17 wt % ; about 19 wt % ; about 20 wt % ; about 21 wt %; about 22 wt %; about 23 wt %; about 24 wt %; about 25 wt %; about 26 wt %; about 27 wt %; about 28 wt %; about 29 wt %; about 30 wt %; about 35 wt %; about 40 wt %; about 45 wt %; about 50 wt %; about 55 wt %; about 60 wt %; about 65 wt %; about 70 wt %; about 70 wt % ; about 70.5 wt %; about 71 wt %; about 71.5 wt %; about 72 wt %; about 72.5 wt %; about 73 wt %; about 73.5 wt %; about 74 wt %; about 74.5 wt %; about 75 wt %; about 75.5 wt %; about 76 wt %; about 76.5 wt %; about 77 wt %; about 77.5 wt %; about 78 wt %; about 78.5 wt %; about 79 wt %; about 79.5 wt %; about 80 wt % ; about 80.5 wt % ; about 81 wt % ; about 81.5 wt % ; about 82 wt % ; about 82.5 wt % ; about 83 wt % ; about 83.5 wt % ; about 84 wt % ; about 84.5 wt % ; about 85 wt % ; about 85.5 wt % ; about 86 wt % ; about 86.5 wt % ; about 87 wt % ; about 87.5 wt % ; about 88 wt % ; about 88.5 wt % ; about 89 wt % ; about 89.5 wt % ; or about 90 wt % .
[00055] In some embodiments, the co-processed excipient composition includes about 6 wt % to about 95 wt% binder; In some embodiments, about 6.5 wt % ; about 7 wt % ; about 7.5 wt % ; about 8 wt % ; about 8.5 wt % ; about 9 wt % ; about 10 wt % ; about 11 wt % ; about 12 wt % ; about 13 wt % ; about 14 wt % ; about 15 wt % ; about 16 wt % ; about 17 wt % ; about 19 wt % ; about 20 wt % ; about 21 wt %; about 22 wt %; about 23 wt %; about 24 wt %; about 25 wt %; about 26 wt %; about 27 wt %; about 28 wt %; about 29 wt %; about 30 wt %; about 35 wt %; about 40 wt %; about 45 wt %; about 50 wt %; about 55 wt %; about 60 wt %; about 65 wt %; about 70 wt %; about 70 wt % ; about 70.5 wt %; about 71 wt %; about 71.5 wt %; about 72 wt %; about 72.5 wt %; about 73 wt %; about 73.5 wt %; about 74 wt %; about 74.5 wt %; about 75 wt %; about 75.5 wt %; about 76 wt %; about 76.5 wt %; about 77 wt %; about 77.5 wt %; about 78 wt %; about 78.5 wt %; about 79 wt %; about 79.5 wt %; about 80 wt % ; about 80.5 wt % ; about 81 wt % ; about 81.5 wt % ; about 82 wt % ; about 82.5 wt % ; about 83 wt % ; about 83.5 wt % ; about 84 wt % ; about 84.5 wt % ; about 85 wt % ; about 85.5 wt % ; about 86 wt % ; about 86.5 wt % ; about 87 wt % ; about 87.5 wt % ; about 88 wt % ; about 88.5 wt % ; about 89 wt % ; about 89.5 wt % ; about 90 wt %; about 91 wt %; about 92 wt %; about 93 wt %; about 94 wt %; or about 95 wt %.
[00056] In some embodiments, the co-processed excipient composition includes about 6 wt % to about 95 wt% microcrystalline cellulose (MCC); In some embodiments, about 6.5 wt % ; about 7 wt % ; about 7.5 wt % ; about 8 wt % ; about 8.5 wt % ; about 9 wt % ; about 10 wt % ; about 11 wt % ; about 12 wt % ; about 13 wt % ; about 14 wt % ; about 15 wt % ; about 16 wt % ; about 17 wt % ; about 19 wt % ; about 20 wt % ; about 21 wt %; about 22 wt %; about 23 wt %; about 24 wt %; about 25 wt %; about 26 wt %; about 27 wt %; about 28 wt %; about 29 wt %; about 30 wt %; about 35 wt %; about 40 wt %; about 45 wt %; about 50 wt %; about 55 wt %; about 60 wt %; about 65 wt %; about 70 wt %; about 70 wt % ; about 70.5 wt %; about 71 wt %; about 71.5 wt %; about 72 wt %; about 72.5 wt %; about 73 wt %; about 73.5 wt %; about 74 wt %; about 74.5 wt %; about 75 wt %; about 75.5 wt %; about 76 wt %; about 76.5 wt %; about 77 wt %; about 77.5 wt %; about 78 wt %; about 78.5 wt %; about 79 wt %; about 79.5 wt %; about 80 wt % ; about 80.5 wt % ; about 81 wt % ; about 81.5 wt % ; about 82 wt % ; about 82.5 wt % ; about 83 wt % ; about 83.5 wt % ; about 84 wt % ; about 84.5 wt % ; about 85 wt % ; about 85.5 wt % ; about 86 wt % ; about 86.5 wt % ; about 87 wt % ; about 87.5 wt % ; about 88 wt % ; about 88.5 wt % ; about 89 wt % ; about 89.5 wt % ; about 90 wt %; about 91 wt %; about 92 wt %; about 93 wt %; about 94 wt %; or about 95 wt %.
[00057] In some embodiments, the co-processed excipient composition includes about 1 wt % to about 5 wt% glidant; In some embodiments about 1 wt % ; about 1.5 wt % ; about 2 wt % ; about 2.5 wt % ; about 3 wt % ; about 3.5 wt % ; about 4 wt % ; about 4.5 wt % ; or about 5 wt %.
[00058] In some embodiments, the co-processed excipient composition includes about 1 wt % to about 5 wt% colloidal silicon dioxide; In some embodiments about 1 wt % ; about 1.5 wt % ; about 2 wt % ; about 2.5 wt % ; about 3 wt % ; about 3.5 wt % ; about 4 wt % ; about 4.5 wt % ; or about 5 wt %.
[00059] In some embodiments, the co-processed excipient composition includes, when present, about 0.1 wt % to about 6 wt% lubricant; In some embodiments about 0.1 wt % ; about 0.25 wt % ; about 0.5 wt % ; about 0.75 wt % ; about 1 wt %; about 1.1 wt % ; about 1.25 wt % ; about 1.5 wt % ; about 1.75 wt % ; about 2 wt %; about 2.5 wt % ; about 3 wt % ; about 3.5 wt % ; about 4 wt %; about 4.5 wt % ; about 5 wt %%; about 5.5 wt % ; about 6 wt %.
[00060] In some embodiments, the co-processed excipient composition includes, when present, about 0.1 wt % to about 6 wt% disintegrant. In some embodiments about 0.1 wt % ; about 0.25 wt % ; about 0.5 wt % ; about 0.75 wt % ; about 1 wt %; about 1.1 wt % ; about 1.25 wt % ; about 1.5 wt % ; about 1.75 wt % ; about 2 wt %; about 2.5 wt % ; about 3 wt % ; about 3.5 wt % ; about 4 wt %; about 4.5 wt % ; about 5 wt %%; about 5.5 wt % ; about 6 wt %. More preferably 4.5 wt% disintegrant.
[00061] In an embodiment of the present invention, the lubricant is selected from but not limited to magnesium stearate or sodium stearyl fumarate.
[00062] In an embodiment of the present invention, the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crosspovidone or calcium carboxyl methyl cellulose.
[00063] In an embodiment, the present invention provides a particulate co-processed excipient composition for oral solid dosage forms comprising co-processed mixture of a filler, a glidant, and a binder; wherein said co-processed excipient composition comprises based on total weight of the composition:
filler in an amount ranging between 6% w/w and 90% w/w;
binder in an amount ranging between 6% w/w and 93% w/w; and
glidant in an amount ranging between 1% w/w and 4% w/w.
[00064] In an embodiment, the present invention provides a particulate co-processed excipient composition for tablet formulation comprising a filler, a glidant, and a binder; wherein the weight ratio of filler:Binder:glidant ranging between 6:93:1 and 90:6:4.
[00065] In an embodiment, the present invention provides a particulate co-processed excipient composition for oral solid dosage forms comprising co-processed mixture of a filler, a glidant, and a binder; wherein said co-processed excipient composition comprises based on total weight of the composition:
mannitol in an amount ranging between 6% w/w and 90% w/w;
microcrystalline cellulose (MCC) in an amount ranging between 6% w/w and 93% w/w; and
colloidal silicon dioxide in an amount ranging between 1% w/w and 4% w/w.
[00066] In an embodiment, the present invention provides a particulate co-processed excipient composition for tablet formulation comprising mannitol, Microcrystalline cellulose, and colloidal silicon dioxide; wherein the weight ratio of mannitol:Microcrystalline cellulose:colloidal silicon dioxide ranging between 6:93:1 and 90:6:4.
[00067] In an embodiment of the present invention, the pH of the co-processed excipient composition ranges between 5.0 and 7.5.
[00068] In an embodiment of the present invention, the bulk density of the particulates of the co-processed excipient composition ranges between ranges between 0.20 g/ml to 0.60 g/ml.
[00069] In an embodiment of the present invention, the particulate co-processed excipient composition have mean particle size distribution of the composition ranging in the micometer scale. However, many microparticles have wider ranges of sizes. In some embodiments, the microparticles may have a diameter of at least about 1 micron, 10 micron, 50 micron, 100 micron, 200 micron, 300 micron, 400 micron, 500 micron, 600 micron, 700 micron, 800 micron, 900 micron, or 1000 micron. In some embodiments, the microparticles may have a diameter of less than 1000 micron, 900 micron, 800 micron, 700 micron, 600 micron, 500 micron, 250 micron, or less than 100 micron. The diameter of microparticles can range from any of the minimum values described above to any of the maximum values described above, for example from 1 micron to 1000 micron, 50 micron to 500 micron, 10 micron to 250 micron, 20 micron to 200 micron, or 50 micron to 100 micron. Preferably, the size of the microparticles ranges from about 100 micron to about 150 micron. Most preferably, the size of the microparticles ranges from about 110 micron to about 130 micron.
[00070] In an embodiment, the present invention provides a method for the preparation of co-processed excipient composition comprising the steps of:
forming a homogeneous slurry of filler using demineralized water;
forming a homogeneous slurry of binder using demineralized water;
forming a homogeneous slurry of glidant using demineralized water;
mixing the individual homogenous mixed slurry of filler, binder, and glidant by stirring to obtain a homogenous mixture slurry; and
spray drying the homogeneous mixed slurry to form powder.
[00071] In an embodiment, the present invention provides a method for the preparation of co-processed excipient composition comprising the steps of:
forming a homogeneous slurry of mannitol using demineralized water;
forming a homogeneous slurry of MCC using demineralized water;
forming a homogeneous mixed slurry of colloidal silicon dioxide using demineralized water; and
spray drying the homogeneous mixed slurry to form powder.
[00072] In another embodiment of the present invention, the method of preparing a co-processed excipient composition comprises the step of disintegrant the homogenous mixture slurry.
[00073] In another embodiment of the present invention, the method comprises the step of lubricant the homogenous mixture slurry.
[00074] In another embodiment of the present invention, the homogenous slurry can be obtained by adding the slurry filler, binder with water and powder glidant to water under stirring.
[00075] In another embodiment of the present invention, the homogenous slurry can be obtained by adding powder filler, glidant and powder binder to water under stirring.
[00076] In another embodiment of the present invention, solid content of the homogenous slurry is less than 50%. In preferred embodiment, the solid content of homogeneous slurry is 15%-50%.
[00077] In an embodiment of the present invention, the temperature of homogeneous slurry maintained at 30 °C to 150 °C.
[00078] In an embodiment of the present invention, the pH of homogeneous slurry maintained at 6 to 9.
[00079] In a preferred embodiment of the present invention, the moisture of homogeneous slurry is less than 5%.
[00080] In an embodiment, the co-processed excipient composition of the present invention ranges from about 0.25 to 5 wt % of the total oral solid dosage formulation. In a preferred embodiment, the amount ranges from about 3% to about 5 wt %.
[00081] In an embodiment of the present invention, the co-processed excipient composition may further comprise pharmaceutically acceptable excipients selected from the group consisting of diluents, disintegrants, fillers, bulking agents, vehicles, pH adjusting agents, stabilizers, anti-oxidants, binders, buffers, lubricants, antiadherants, coating agents, preservatives, emulsifiers, suspending agents, release controlling agents, polymers, colorants, flavoring agents, plasticizers, solvents, preservatives, glidants, and chelating agents; used either alone or in combination.
[00082] In an embodiment of the present invention, the term “oral solid dosage formulation” shall be construed to include a co-processed excipient composition plus a therapeutically active ingredient, lubricant, optionally a disintegrant, optionally a glidant, optionally a sweetener, optionally a flavor, optionally a color, and optionally other excipients.
[00083] In another embodiment of the present invention, the therapeutically active ingredient includes but not limited to an active pharmaceutical ingredient (For example, but not limited to Diclofenac sodium, Cetirizine Hydrochloride, Metformin Hydrochloride, Aceclofenac), a biosomilar, a biological, a nutraceutical, Vitamins (For example, but not limited to Ascorbic acid, Pyridoxine, Thiamine, Folic acid), Minerals (For example, but not limited to Iron, Calcium, Zinc, Magnesium, and the like) , an herbal active, (For example, but not limited to Ginseng, Curcumin , Garlic, Ginger, milk Thistel, and the like), and the like.
[00084] In an embodiment of the present invention, the oral solid dosage formulations are generally administered orally to patients, which include, but are not limited to, mammals, for example, humans, in the form of, for example, a tablet, a caplet, pills, capsules, granules or a suspension.
[00085] In a preferred embodiment, the present invention provides a tablet formulation comprising:
the co-processed excipient composition in an amount ranging between 30% w/w and 98% w/w;
a therapeutically active ingredient in an amount ranging between 1% w/w and 60% w/w; and
pharmaceutically acceptable excipient in an amount ranging between 1% w/w and 10% w/w.
[00086] While the foregoing description discloses various embodiments of the disclosure, other and further embodiments of the invention may be devised without departing from the basic scope of the disclosure. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
EXAMPLES
[00087] The present disclosure is further explained in the form of following examples. However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.
Example:1 Co-processed excipient composition 1
Table 1: Co-processed excipient composition 1
Mannitol (6%) Microcrystalline cellulose (92%) Colloidal silicon dioxide (2%)
pH 5.81
Loss on drying (%) 3.0
Bulk density (g/CC) 0.25
Mean Particle Size (µm) 102
Angle of Repose (°) 32
Hardness (N) 180
Disintegration Time (Secs) 120

Example:2 Co-processed excipient composition 2
Table 2: Co-processed excipient composition 2
Mannitol (10%) Microcrystalline cellulose (88%) Colloidal silicon dioxide (2%)
pH 6.10
Loss on drying (%) 3.0
Bulk density (g/CC) 0.30
Mean Particle Size (µm) 100
Angle of Repose (°) 33
Hardness (N) 160
Disintegration Time (Secs) 100

Example:3 Co-processed excipient composition 3
Table 3: Co-processed excipient composition 3
Mannitol (20%) Microcrystalline cellulose (78%) Colloidal silicon dioxide (2%)
pH 6.23
Loss on drying (%) 2.80
Bulk density (g/CC) 0.33
Mean Particle Size (µm) 110
Angle of Repose (°) 30
Hardness (N) 150
Disintegration Time (Secs) 90

Example :4 Co-processed excipient composition 4
Table 4: Co-processed excipient composition 4
Mannitol (35%) Microcrystalline cellulose (63%) Colloidal silicon dioxide (2%)
pH 6.32
Loss on drying (%) 2.5
Bulk density (g/CC) 0.35
Mean Particle Size (µm) 120
Angle of Repose (°) 28
Hardness (N) 120
Disintegration Time (Secs) 30

Example: 5 Co-processed excipient composition 5

Table 5: Co-processed excipient composition 5
Mannitol (50%) Microcrystalline cellulose (48%) Colloidal silicon dioxide (2%)
pH 6.15
Loss on drying (%) 2.4
Bulk density (g/CC) 0.38
Mean Particle Size (µm) 115
Angle of Repose (°) 31
Hardness (N) 110
Disintegration Time (Secs) 30

Example: 6 Co-processed excipient composition 6
Table 6: Co-processed excipient composition 6
Mannitol (65%) Microcrystalline cellulose (33%) Colloidal silicon dioxide (2%)
pH 6.25
Loss on drying (%) 2.8
Bulk density (g/CC) 0.45
Mean Particle Size (µm) 105
Angle of Repose (°) 30
Hardness (N) 98
Disintegration Time (Secs) 28

Example: 7 Co-processed excipient composition 7
Table 7: Co-processed excipient composition 7
Mannitol (75%) Microcrystalline cellulose (23%) Colloidal silicon dioxide (2%)
pH 6.32
Loss on drying (%) 2.4
Bulk density (g/CC) 0.48
Mean Particle Size (µm) 100
Angle of Repose (°) 31
Hardness (N) 90
Disintegration Time (Secs) 20

Example: 8 Co-processed excipient composition 8
Table 8: Co-processed excipient composition 8
Mannitol (80%) Microcrystalline cellulose (18%) Colloidal silicon dioxide (2%)
pH 6.15
Loss on drying (%) 2.2
Bulk density (g/CC) 0.55
Mean Particle Size (µm) 99
Angle of Repose (°) 30
Hardness (N) 88
Disintegration Time (Secs) 19

Example: 9 Co-processed excipient composition 9
Table 9: Co-processed excipient composition 9
Mannitol (90%) Microcrystalline cellulose (8%) Colloidal silicon dioxide (2%)
pH 6.02
Loss on drying (%) 1.50
Bulk density (g/CC) 0.60
Mean Particle Size (µm) 65
Angle of Repose (°) 25
Hardness (N) 50
Disintegration Time (Secs) 15

Example: 10 Co-processed excipient composition 10
Table 10: Co-processed excipient composition 10
Mannitol (20%) Microcrystalline cellulose (79%) Colloidal silicon dioxide (1%)
pH 5.98
Loss on drying (%) 3.2
Bulk density (g/CC) 0.26
Mean Particle Size (µm) 103
Angle of Repose (°) 35
Hardness (N) 170
Disintegration Time (Secs) 110

Example: 11 Co-processed excipient composition 11
Table 11: Co-processed excipient composition 11
Mannitol (20%) Microcrystalline cellulose (77%) Colloidal silicon dioxide (3%)
pH 5.99
Loss on drying (%) 3.4
Bulk density (g/CC) 0.28
Mean Particle Size (µm) 102
Angle of Repose (°) 28
Hardness (N) 183
Disintegration Time (Secs) 122

Example: 12 Co-processed excipient composition 13
Table 12: Co-processed excipient composition 13
Mannitol (20%) Microcrystalline cellulose (76%) Colloidal silicon dioxide (4%)
pH 6.12
Loss on drying (%) 3.0
Bulk density (g/CC) 0.44
Mean Particle Size (µm) 102
Angle of Repose (°) 25
Hardness (N) 187
Disintegration Time (Secs) 129

Example 13: Method of producing co-processed excipient composition using steps of FIG. 1A
MCC wet cake 88.5% w/w (on dried basis), Mannitol powder 10%w/w and CSD 1.5% w/w were used to make the co-processed excipient composition using the method defined in FIG. 1A. Individual slurries were made and added together to make homogeneous slurry. The slurry was heated and maintained at temperature between 80 -150 °C(100°). Slurry parameters were maintained at pH: 6.0, Solid content: 22%. The slurry was then spray dried and tested. The test showed that the dried slurry had pH: 6.02, and Loss on drying : 1.2% with average PSD 83 µm.
Example 14: Method of producing co-processed excipient composition using steps of FIG. 1B
a. MCC wet cake of 88.5% w/w (on dried basis) mixed with sufficient quantity of demineralised water and stirred till it formed a homogeneous mixer.
b. 10% Mannitol, and 1.5% CSD were blended in a powder blender at 25 RPM for 5 minutes. The slurry was then transferred to a slurry preparation tank and sufficient quantity of water was added and stirred continuously to make lumps free slurry.
c. Slurries from both a) and b) were mixed together to make homogenous slurry under maintenance temperature of the slurry between 80 to 150 °C (145°C) and pH of 6.8. and a solid content of 30%. The slurry was spray dried and tested, which showed that the spray dried powder had a pH of 6.42, Loss on drying : 3.2%, and an average PSD 200 µm.
Example 15: Scanning electron microscopy (SEM) of co-processed excipient composition
The co-processed excipient composition was analyzed by SEM, which clearly shows that the mannitol and colloidal silicon di oxide were coated on MCC particles, and formed more or less spherical particles, whereas MCC particles are rod shaped but all particles were spherical with rough surface (FIG. 2A and 2B).
Example 16: Tablet hardness of co-processed excipient composition
The co-processed excipient composition was analyzed for tablet hardness, with and without lubrication and compared with physical blend. Further, angle of repose was measured for different percentages of colloidal silicon dioxide where Mannitol and MCC quantity were constant.

FIG. 3A showed that the co-processed excipient composition gave more tablet hardness with lubrication and without lubrication, and also the tablet hardness was increasing with compression force.
Table 13: Tablet hardness of the co-processed excipient composition:
S. No.: Compression Force (KN) Mannitol 35%/MCC 63.5%/SiO2 1.5% Co-processed Unlubricated Mannitol 35%/MCC 63.5%/SiO2 1.5% blend Unlubricated Mannitol 35%/MCC 63.5%/SiO2 1.5%
Co-processed lubricated Mannitol 35%/MCC 63.5%/SiO2 1.5% blend lubricated
1 0 0 0 0 0
2 2 50 30 45 25
3 4 80 60 70 55
4 6 120 100 110 95
5 8 180 120 175 110
6 10 210 150 205 130
7 12 250 180 235 150
8 14 280 190 275 189

FIG. 3B showed that the tablet hardness increased with compression force but co-processed excipient composition gave more tablet hardness than simple physical blend.

 
Table 14: Tablet hardness of the co-processed excipient composition compared with physical blend:
S. No.: Compression Force
(KN) Mannitol 49%/MCC 49%/SiO2 2% Co-processed Mannitol 49%/MCC 49%/SiO2 2% blend
1 0 0 0
2 2 65 35
3 4 85 55
4 6 100 75
5 8 150 98
6 10 180 110
7 12 200 155
8 14 250 185

FIG. 3C showed that when colloidal silicon dioxide quantity was increased, the angle of repose decreased, while tablet hardness increased.

Table 15: Tablet hardness of the co-processed excipient composition compared with angle of repose:
S. No.: Composition (%) Angle of Repose (°) Hardness (N)
1 Mannitol 20%/MCC 79%/SiO2 1% 35 170
2 Mannitol 20%/MCC 78.5%/SiO2 1.5% 33 175
3 Mannitol 20%/MCC 78%/SiO2 2% 30 180
4 Mannitol 20%/MCC 77.5%/SiO2 2.5% 29 182
5 Mannitol 20%/MCC 77%/SiO2 3% 28 183
6 Mannitol 20%/MCC 76.5%/SiO2 3.5% 26 185
7 Mannitol 20%/MCC 76%/SiO2 4% 25 187

Example 17: Multivitamin and mineral tablet with co-processed excipient composition
Table 16: Multivitamin and mineral tablet with co-processed excipient composition:
Tablet Ingredient Composition per Tablet
Vitamin C 120 mg
Vitamin B1 50 mg
Vitamin B6 3.0 mg
Vitamin B9 1.0 mg
Vitamin B12 8.0 mcg
Biotin 30.0 mcg
Calcium Carbonate 200 mg
Potassium Iodide 150.0 mcg
Magnesium Oxide 100.0 mg
MagLub® Magnesium Stearate 3.75 mg
Co-processed Mannitol+MCC+CSD 320.25 mg
Total tablet weight 750 mg

Table 17: Tablet Pre compression Parameters
Parameters Results
Bulk density 0.69 g/ml
Compressibility Index 24.20 %
H.Ratio 1.32
Angle of Repose 35°

Table 18: Tablet Pre Evaluation Parameters
Parameters Result
Tablet weight 750 mg
Weight uniformity, RSD% 0.293 %
Average Hardness 118.59 N
Friability 00%
Disintegration Time 18.67 Sec

Example 18: Herbal extract Direct compressible tablet with co-processed excipient composition
Table 19: Alo-vera Direct Compressible tablet with co-processed excipient composition:
Ingredient Composition per Tablet (mg)
Aloe Vera 500.0
Co-processed Mannitol+ MCC+CSD 314.3
HiLose CCS 29.75
MagLub Magnesium stearate 5.95

Table 20: Tablet Pre compression Parameters
Parameters Results
Bulk density 0.42 g/ml
Compressibility Index 25 %
H.Ratio 1.35
Angle of Repose 36°

Table 21: Tablet Pre Evaluation Parameters
Parameters Result
Tablet weight 850.0 mg
Weight Uniformity, RSD% 0.390%
Thickness 6.3mm
Hardness 77.4 N
Friability 00%
Disintegration Time 2 min

Example 19: Cetirizine Hydrochloride 10 mg tablet with co-processed excipient composition
Table 22: Cetirizine Hydrochloride 10 mg tablet with co-processed excipient composition:
Ingredient Composition per Tablet (mg)
Cetirizine Hydrochloride 10
Co-processed Mannitol+ MCC+CSD 104
HiLose CCS 5.40
MagLub Magnesium stearate 0.60

Table 23: Tablet Pre compression Parameters
Parameters Result
Bulk density 0.40 g/ml
Compressibility Index 23 %
H.Ratio 1.37
Angle of Repose 38°

Table 24: Tablet Pre Evaluation Parameters
Parameters Result
Tablet weight 120.0 mg
Weight Uniformity, RSD% 0.890%
Thickness 5.5 mm
Hardness 89.4 N
Friability 00%
Disintegration Time 1 min

[00088] Various modification and variation of the described assays, techniques and various means disclosed herein to implement the assays/methods in accordance with the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.
, Claims:1. A particulate co-processed excipient composition for oral solid dosage forms comprising co-processed mixture of a filler, a glidant, and a binder; wherein said co-processed excipient composition comprises based on total weight of the composition:
filler – mannitol in an amount ranging between 6% w/w and 90% w/w;
binder – microcrystalline cellulose (MCC) in an amount ranging between 6% w/w and 93% w/w; and
glidant – colloidal silicon dioxide in an amount ranging between 1% w/w and 4% w/w.

2. The co-processed excipient composition as claimed in claim 1, wherein the mean particle size of the particulates ranges between 50 microns and 300 microns.

3. The co-processed excipient composition as claimed in claim 1, wherein the pH of the composition is 5.0 to 7.5.

4. The co-processed excipient composition as claimed in claim 1, wherein the bulk density of the particulates ranges between 0.20 g/ml to 0.60 g/ml.

5. The co-processed excipient composition as claimed in claim 1, further comprises a lubricant and/or a disintegrant.

6. The co-processed excipient composition as claimed in claim 1, wherein the oral solid dosage formulation is a tablet, a pill, or a capsule.

7. A method for the preparation of said co-processed excipient composition as claimed in claim 1, the method comprising the steps of:
forming a homogeneous slurry of mannitol using demineralized water;
forming a homogeneous slurry of MCC using demineralized water;
forming a homogeneous mixed slurry of colloidal silicon dioxide using demineralized water; and
spray drying the homogeneous mixed slurry to form powder,
wherein, solid content of homogeneous slurry is 15%-50%;
wherein, temperature of homogeneous slurry maintained at 30 °C to 150 °C;
wherein, pH of homogeneous slurry maintained at 6 to 9; and

8. The method as claimed in claim 7, said method further comprises the step of adding disintegrant to the homogeneous slurry.

9. The method as claimed in claim 7, said method further comprises the step of adding lubricant to the homogeneous slurry in an amount ranging between 0.25% w/w and 6% w/w.

10. The method as claimed in claim 8, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crosspovidone or calcium carboxyl methyl cellulose.

11. The method as claimed in claim 9, wherein the lubricant is selected from magnesium stearate or sodium stearyl fumarate

12. A tablet formulation comprising:
the co-processed excipient composition as claimed in claim 1 in an amount ranging between 30% w/w and 98% w/w;
a therapeutically active ingredient in an amount ranging between 1% w/w and 60% w/w; and
pharmaceutically acceptable excipient in an amount ranging between 1% w/w and 10% w/w.
13. The tablet formulation as claimed in claim 12, wherein the therapeutically active ingredient is selected from active pharmaceutical ingredient, a biosomilar, a biological, a nutraceutical, Vitamins, Minerals, an herbal active, and the like.

14. The tablet formulation as claimed in claim 12, wherein the pharmaceutically acceptable excipient is selected from the group consisting of diluents, disintegrants, fillers, bulking agents, vehicles, pH adjusting agents, stabilizers, anti-oxidants, binders, buffers, lubricants, antiadherants, coating agents, preservatives, emulsifiers, suspending agents, release controlling agents, polymers, colorants, flavoring agents, plasticizers, solvents, preservatives, glidants, and chelating agents; used either alone or in combination.