PHARMACEUTICAL COMPOSITION OF BCS CLASS II DRUG WITH HAVING ENHANCED BIOPHARMACEUTICAL PROPERTIES AND THEREOF

Abstract

The current invention discloses a pharmaceutical composition comprising a solid dispersion system encapsulated formulation aimed at enhancing the biopharmaceutical properties of BCS Class II drug candidates. This formulation utilizes rock sugar and monosodium glutamate (MSG) as carrier systems to improve solubility and bioavailability. Additionally, the invention details the formulation of the capsule dosage form incorporating the developed solid dispersion system along with pharmaceutically acceptable excipients, while evaluating key properties such as flow characteristics and compressibility index. In vitro release studies of capsules filled with the solid dispersion system of albendazole are also presented, demonstrating the efficacy of the formulation. This invention specifically addresses the need for improved biopharmaceutical properties in BCS Class II drug candidates and outlines the preparation methods for the solid powder composition, which is filled in capsules using approved ingredients. Ultimately, the invention emphasizes the potential of using sugar as a carrier in the solid dispersion composition to enhance therapeutic outcomes.

Specification

Description:Technical field:
[0001] The present invention relates to pharmaceutical composition specifically for BCS Class II drug candidates for improved biopharmaceutical properties and its preparation methods. More specifically the invention relates to solid powder composition filled in capsule using pharmaceutically accepted ingredients to have the capsule dosage form. Further the invention relates to the solid dispersion composition using sugar as carrier for developing the same.

Background and Prior art:
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or
relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] The term solid dispersion refers to a group of solid products consisting of at least two components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles or in crystalline particles.
[0004] Oral availability of drug depends on its solubility and/or dissolution rate, therefore major problems associated with these drugs were its very solubility in biological fluids, which results into poor bioavailability after oral administration. Many methods are available to improve dissolution rate, solubility characteristics, including salt formation, marinization and addition of solvent or surface-active agents. The term solid dispersion refers to a group of solid products consisting of at least two components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles or in crystalline particles.
[0005] Solid dispersion is one of these methods, which were most widely and successfully applied to improve the solubility, dissolution rates and consequently the bioavailability of poorly soluble drugs. The concept of solid dispersions (SDS) were introduced in 1961 by Sekiguchi and Obi, in which the drug is dispersed in inert water-soluble carrier at solid state. Several water-soluble carriers such as hydroxyl propyl methyl cellulose, ethyl cellulose, beta cyclodextrin, urea, lactose, citric acid, poly vinyl pyrrolidone (PVP) and poly ethylene glycols such as carriers for Solid dispersion
[0006] Albendazole is used to treat neurocysticercosis (infection caused by the pork tapeworm in the muscles, brain, and eyes that may cause seizures, brain swelling, and vision problems). Albendazole is also sometimes used to treat infections caused by roundworms, hookworms, threadworm, whipworm, pinworm, flukes, and other parasites (a plant or animal that lives within another living organism to receive some benefit).
[0007] Albendazole, an anti-parasitic drug with poor water solubility, presents challenges in achieving optimal bioavailability. Several strategies can be employed to enhance its solubility and absorption. The use of solubilizers, such as non-ionic surfactants (e.g., Tween 80) and cyclodextrins, can improve solubility by forming micelles or inclusion complexes. Particle size reduction techniques, like micronization and nanosuspension formulations, increase surface area, thereby enhancing the dissolution rate. Solid dispersions in hydrophilic polymers (e.g., PVP, PEG) can maintain albendazole in an amorphous form, improving solubility. Lipid-based formulations, such as self-emulsifying drug delivery systems (SEDDS) and liposomes, enhance drug solubility and absorption by forming fine emulsions or encapsulating the drug. pH modification with acidifying agents can further improve solubility in acidic environments. Additionally, co-crystallization with appropriate co-formers and exploring salt formation with excipients can modify the physicochemical properties of albendazole to enhance dissolution. Each of these approaches offers potential pathways to overcome albendazole's solubility limitations and optimize its therapeutic efficacy.
[0008] Rock sugar, also known as crystal sugar or rock candy, is a type of large-crystal sugar widely used in various cultures for both culinary and medicinal purposes. It is made by dissolving sugar in water and allowing the solution to slowly evaporate, forming large crystals over time. In Asian cuisines, particularly Chinese, rock sugar is used to sweeten teas, soups, and sauces, offering a subtler sweetness than granulated sugar. In India, rock sugar, called mishri, is often paired with fennel seeds as a digestive aid. It is also used in Traditional Chinese Medicine and Ayurveda for soothing sore throats, coughs, and indigestion, believed to have cooling properties. Available in white or brown varieties, it can add a caramelized flavor to dishes and is sometimes used decoratively in Western desserts and beverages. Rock sugar holds cultural significance, symbolizing good luck and prosperity in certain traditions, and is often used in festivals and rituals. [0009] Rock sugar, due to its crystalline and inert nature, presents potential as a carrier in solid dispersions to enhance the solubility and bioavailability of poorly soluble drugs. Its stable composition helps maintain drug stability, and its fast dissolution in water can accelerate drug release in the gastrointestinal tract. Sucrose, the main component of rock sugar, is biocompatible and safe for oral use, making it an attractive, cost-effective carrier option. However, challenges like hygroscopicity and temperature sensitivity must be considered, particularly in ensuring proper storage and selecting suitable formulation methods, such as solvent evaporation. Rock sugar could be particularly useful in developing fast-dissolving tablets or powders, where rapid drug release is essential for improving therapeutic outcomes.
[0010] Albendazole solid dispersions using rock sugar as a carrier offer a promising approach to enhance the drug's poor solubility and bioavailability. Rock sugar's crystalline structure and rapid dissolution can accelerate albendazole's release and absorption. By stabilizing albendazole in its amorphous form within the sugar matrix, the drug's solubility is improved. These dispersions can be prepared via solvent evaporation or by gently heating rock sugar to create a molten mixture with albendazole. Rock sugar's fast solubility makes it suitable for developing fast-dissolving tablets, ensuring quicker drug release in the gastrointestinal tract. Additionally, rock sugar's biocompatibility and safety make it an ideal carrier, though attention must be given to moisture sensitivity and optimizing the drug load. Overall, this formulation strategy could significantly enhance albendazole's therapeutic efficacy and patient compliance.
[0011] US 11485901B2 provides polymeric systems useful for maintaining particle dispersions for extended periods of time. Polymeric systems are also useful for maintaining particle dispersions for extended periods of time at elevated temperatures and/or in high brine conditions. Also provided are dry polymeric systems that are able to undergo fast hydration.
[0012] JP6619386B2 relates to a method for improving the dissolution profile of biologically active substances using a dry milling method. The invention also provides a particulate biologically active substance produced by the method, a composition comprising such a substance, the biologically active substance in particulate form and / or the biologically active substance in the composition and a method of treating animals, including humans, with a therapeutically effective amount of the biologically active substance administered via the medicament.
[0013] CN101208094B relates to inhibitors of ROCKl and R0CK2 and methods of modulating the pharmacokinetic and/or pharmacodynamic properties of such compounds. Also provided are methods of inhibiting ROCKl and or R0CK2 that are useful for the treatment of disease.
[0014] IN 202411059158 invention addresses the challenges of poor solubility and low bioavailability of Xanthohumol (XH) in treating Parkinson's disease (PD). XH's pharmacological efficacy is limited by its low solubility and poor intestinal absorption, leading to reduced therapeutic effectiveness. This invention formulates a solid dispersion (SD) of XH to enhance its solubility, dissolution rate, and bioavailability. The SD method disperses XH in a carrier matrix, such as polymers or surfactants, creating a homogenous solid mixture that improves drug delivery and effectiveness. The formulated XH SD increases drug concentration at the target site, enhances therapeutic efficacy, and enables crossing the blood-brain barrier (BBB). The SD method involves dissolving XH and a carrier in ethanol, evaporating the solvent, and obtaining a powdered material that can be reconstituted for oral administration. Pharmacokinetic studies revealed that the XH-SD formulation significantly improved absorption, while in vitro drug release studies showed enhanced drug release. Pharmacodynamic evaluations confirmed the improved antiparkinsonian effect of XH-SD. This innovative approach offers a promising therapeutic option for PD and other neurodegenerative diseases, providing enhanced bioavailability, brain permeability, and antioxidant and anti-inflammatory properties.
[0015] IN 1104/CAL/1998 discloses solid dispersions of poorly soluble drugs are disclosed which are prepared using a solvent or fusion process. Such dispersions are manufactured with the free base of the drug, specifically paroxetine free base, an oil, allowing for a low temperature for the fusion process, decreased organic solvent volumes for the solvent process and the formation of a paroxetine salt during the solid dispersion manufacture process.
[0016] Hence, there is a need to develop solid dispersion compositions using naturally available carriers like rock sugar, which offer enhanced biopharmaceutical properties, including improved in vitro and in vivo dissolution of poorly water-soluble drugs like the BCS Class II candidate albendazole. These compositions are expected to be more effective compared to existing formulations, while also providing additional advantages.
OBJECTIVE OF THE INVENTION:
[0017] Primary objective of present invention is to provide Solid dispersion composition for BCS Class II drug candidate by using rock sugar as carrier along with pharmaceutically acceptable ingredients using advanced formulation technique.
[0018] Another objective of this invention is to provide a development of suitable solid dosage formulation and process for capsule dosage form of disclosed solid dispersion composition of albendazole with its optimization process according to need of the composition.
[0019] Still another objective is to optimizing the solid dispersion process for albendazole and BCS class II drug candidate using suitable mixture or ratio using rock sugar and pharmaceutically acceptable excipients.
[0020] Another object of the invention is to provide evaluation studies for developed solid dispersion formulation filled into capsule dosage form using suitable analytical techniques.

SUMMARY OF THE INVENTION:
[0021] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in Detailed Description section. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
[0022] The primary objective of the present invention is to provide a solid dispersion composition for a BCS Class II drug candidate by utilizing rock sugar as a carrier in combination with pharmaceutically acceptable ingredients, prepared through advanced formulation techniques. Additionally, the invention aims to develop a suitable solid dosage formulation and process for a capsule dosage form of the disclosed solid dispersion composition of albendazole, including an optimization process tailored to meet the specific requirements of the composition.
[0023] Another goal is to optimize the solid dispersion process for albendazole and other BCS Class II drug candidates by determining the appropriate mixture or ratio of rock sugar and pharmaceutically acceptable excipients. Furthermore, the invention includes conducting evaluation studies on the developed solid dispersion formulation, particularly when filled into capsule dosage forms, utilizing appropriate analytical techniques for assessment.
DETAILED DESCRIPTION OF DRAWINGS OF THE INVENTION:
[0024] The following drawings form part of the present specification and are included to further illustrate aspects of the present disclosure. The disclosure may be better understood by reference to the drawings in combination with the detailed description of the specific embodiments presented herein.
[0025] Figure 1 depicts FTIR Spectrum of Albendazole+ Rock sugar + MSG
[0026] Figure 2 depicts In vitro drug release study of solid dispersion containing Drug and carriers for various formulations
[0027] Figure 3 depicts Differential Scanning Calorimetry of Albendazole and MSG
[0028] Figure 4 shows Differential Scanning Calorimetry of Albendazole and rock sugar
[0029] Figure 5 shows Differential Scanning Calorimetry of Albendazole, MSG and rock sugar
[0030] Figure 6 shows XRD Of Albendazole and MSG
[0031] Figure 7 highlights XRD Of Albendazole and Rock sugar
[0032] Figure 8 shows XRD of Albendazole + MSG + Rock sugar
[0033] Figure 9 represents SEM of Albendazole + MSG + Rock sugar
[0034] Figure 10 represents SEM Albendazole and MSG
[0035] Figure 11 represents SEM of Albendazole and rock sugar
[0036] Figure 12 highlights XRD of Albendazole + MSG+ ROCK SUGAR (Optimized batch)
[0036] Figure 13 shows Differential Scanning Calorimetry of Albendazole, MSG and rock sugar (Optimized batch)
[0037] Figure 14 shows FTIR Spectrum of Albendazole+ Rock sugar + MSG (Optimized batch)
[0038] Figure 15 shows SEM of Albendazole +Rock sugar + MSG (Optimized batch)
[0039] Table 1 enlists Saturation Solubility of Different samples
[0040] Table 2 highlights values for Angle of Repose, Loose Bulk Density, Tapped Bulk Density and Carr's Compressibility Index, Hausner's ratio
[0041] Table 3 summarizes % Practical Yield and Drug Content Uniformity (F1 to F7)
[0042] Table 4 shows In vitro drug release study of solid dispersion containing Drug and carriers for various formulations

DETAILED DESCRIPTION OF THE INVENTION:
[0043] 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.
[0044] 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.
[0045] 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.
[0046] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention 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.
[0047] 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.
[0048] Unless the context requires otherwise, throughout the specification which follow, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense that is as "including, but not limited to."
[0049] 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. 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 unclaimed element essential to the practice of the invention.
[0050] 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.
[0051] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0052] 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.
[0053] The term "solid dispersion" refers to pharmaceutical technique used to enhance the solubility and bioavailability of poorly water-soluble drugs. In this approach, the drug is dispersed in a solid matrix, typically comprising one or more hydrophilic carriers, which can significantly improve the drug's dissolution rate and absorption in the gastrointestinal tract.
[0054] The term "BCS Class II" refers BCS Class II refers to a classification of drugs based on their solubility and permeability as defined by the Biopharmaceutics Classification System (BCS). This system categorizes drugs into four classes to predict their absorption characteristics and guide formulation development.
[0055] The term "albendazole" refers to an anti-parasitic drug, is known to have poor water solubility, which can limit its bioavailability and effectiveness. Addressing solubility issues with albendazole can improve its absorption and therapeutic potential.
[0056] The term "pharmaceutically acceptable carrier" refers to a substance or material that is safe, non-toxic, and compatible with the active pharmaceutical ingredient (API) in a pharmaceutical formulation. It serves as a vehicle or medium to facilitate the preparation, administration, and effectiveness of the pharmaceutical product while ensuring patient safety. Representative examples of pharmaceutically acceptable carrier include but are not limited to diluent, binder, disintegrant, lubricant, coating agent, release modifier, stabilizer, preservative, colorant, flavor, buffer, solublizer and surfactant, cross linking agents, encapsulating agents etc.
[0057] The current invention provides a pharmaceutical composition containing a solid dispersion system capsule formulation for improved biopharmaceutical properties of BCS class II drug candidate by using rock sugar and monosodium glutamate (MSG) as carrier systems.
[0058] One of the embodiments of present invention relate to solid dispersion system using carriers which shortly described over here as, Preparation of Solid Dispersion of Albendazole
[0059] The preparation of solid dispersions of albendazole aims to enhance the drug's solubility and dissolution rate. The solid dispersions were prepared using the kneading method, which involves several key steps. First, the required amounts of albendazole and the polymer are weighed. The polymer is then dissolved in a suitable solvent to form a solution, with the choice of solvent based on the solubility of both the polymer and the drug. Next, albendazole is added to the polymer solution, and the mixture is thoroughly kneaded using a mortar and pestle to achieve a paste-like consistency. This kneading process ensures uniform dispersion of the drug within the polymer matrix. Following the kneading, the mixture is spread onto a tray and dried using methods such as air drying, oven drying, or lyophilization, depending on the components and desired end product, ensuring complete drying to obtain a solid mass. Once dried, the solid dispersion may be ground into a fine powder using an appropriate milling technique to enhance dispersion and homogeneity. If necessary, the powdered dispersion is sieved to achieve a uniform particle size for the intended application. Finally, the solid dispersion is characterized for various parameters, including drug content, dissolution rate, and physical stability, utilizing techniques such as Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD), or Scanning Electron Microscopy (SEM) for comprehensive analysis.
[0060] Another embodiment of invention relates to formulation capsule dosage form of developed solid dispersion system using pharmaceutically acceptable excipients and evaluating its properties such as flow properties and compressibility index.
[0061] In Another embodiment of the present invention is the In-Vitro release evaluation studies for capsule filled with solid dispersion system of albendazole which briefly described In-vitro dissolution study was performed by using dissolution test apparatus (electro lab) at 50 rpm. Phosphate buffer pH 6.8, 500 ml was used as dissolution medium which time interval (2 min) and was filtered. The amount of drug dissolved was determined by UV spectrophotometer (Shimadzu 1800, Japan) by measuring the absorbance of the sample at 291 nm and Cumulative percentage drug releases are determined. maintained at 37±0.50C. Aliquot of dissolution medium (5 ml) was withdrawn at specific. The following procedure was employed throughout the study to determine the in vitro dissolution rate for all the formulations.
EXAMPLES:
[0062] The disclosure is further illustrated by the following examples which in no way should be construed as being further limiting. One skilled in the art will readily appreciate that the specific methods and results described are merely illustrative.

[0051] Example 1: Development of Solid dispersion system for Albendazole

Batch Code Composition Ratio
S.D 1 Albendazole :Rock Sugar 1:1
S.D 2 Albendazole: Rock Sugar 1:2
S.D 3 Albendazole: Rock Sugar 1:3
S.D 4 Albendazole :MSG 1:1
S.D 5 Albendazole :MSG 1:2
S.D 6 Albendazole :MSG 1:3
S.D 7 Albendazole; Rock:Sugar::MSG 1:1:1 , C , Claims:1. Pharmaceutical composition in solid dispersion form for BCS Class II drug candidate albendazole for improved biopharmaceutical properties and its preparation method.
2. Pharmaceutical composition as disclosed in claim 1 in acceptable dosage form selected from tablets capsule or granules.
3. Pharmaceutical composition as disclosed in claim 1 wherein the solid dispersion carriers selected from PEG, Cyclodextrin molecules, sugar, monosodium glutamate or combination of them.
4. Pharmaceutical Composition as claimed in claim 1 solid dispersion carrier more preferably selected from rock sugar and monosodium glutamate in the ratio of 1 part of albendazole to 3 parts of carriers.
5. Pharmaceutical Composition as claimed in claim 1 solid dispersion carrier is a mixture of rock sugar and monosodium glutamate in the ratio of 1 part of albendazole to 3 parts of carriers.
6. Pharmaceutical Composition as claimed in claim 1 solid dispersion carrier filled in capsule has in-vitro release more than 90% in Phosphate buffer pH 6.8.
7. Pharmaceutical composition as claimed in claim 1 wherein the albendazole drug is in amorphous form confirmed with X-Ray Diffraction and DSC studies.

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