Calcium carbonate formulations and method of treatment of gastroesophageal reflux disease (GERD)

Abstract

The subject matter disclosed generally relates to antacid solid dose tablets with an improved formulation containing granulated calcium carbonate of different sizes, between 30 and 200 pm, and sodium-free excipients. Said formulation is useful in the treatment of gastroesophageal reflux disease (GERD).

Description

CALCIUM CARBONATE FORMULATIONS AND METHOD OF TREATMENT OF GASTROESOPHAGEAL REFLUX DISEASE (GERD)BACKGROUND(a) Field

[0001] The subject matter disclosed generally relates to antacid solid dose tablets with an improved formulation containing calcium carbonate and sodium- free excipients.(b) Related Prior Art

[0002] Heartburn is an unpleasant, burning sensation in the upper part of the abdomen that sometimes spreads to the throat, specifically related to the reflux of gastric acid through the lower esophageal sphincter, which is a typical symptom of gastroesophageal reflux disease (GERD). Although there are several treatment options available, antacids remain the mainstream treatment for gastroesophageal reflux-related symptoms based on their efficacy, safety, and over-the-counter availability. In the formulation of antacid tablets besides active pharmaceutical ingredients (API), excipients are added which are inert substances used as diluents or vehicles. Commonly used excipients in tablets are binders or adhesives, disintegrants, lubricants, glidants, flavors, colors, and sweeteners and these excipients must be physiologically inert, acceptable to regulatory agencies, physiologically and chemically stable, free from bacteria, should not interfere with the bioavailability of the drug, commercially available to pharmaceutical standards and inexpensive (Varma K. Excipients used in the Formulation of Tablets. Res Rev J Chem. 2016;5(2): 143-154). Antacids are mostly carbonates and hydroxides of calcium, magnesium, and aluminum (Garg V, Narang P, Taneja R. Antacids revisited: review on contemporary facts and relevance for self-management. J Int Med Res. 2022;50(3). doi: 10.1177 / 03000605221086457).

[0003] There are several antacid brands based on CaCOs available in the market like TUMS™, ROLAIDS™ and EQUATE™ among them TUMS™ is a popular brand in CANADA that has been in the market for over 90 years. In ourinvestigation, we have considered TLIMS as a benchmark product. The active pharmaceutical ingredient (API) in TLIMS™ is CaCOs and the excipients in TLIMS™ are adipic acids, com starch FD&C blue #1 lake, FD&C yellow #5 (tartrazine) lake, FD&C yellow # 6 lake, flavors, mineral oil, sodium polyphosphate, sucrose, and talc.

[0004] From the excipients list it can be observed that there are many excipients in the formulation of TLIMS™. Among these excipients, talc has been identified as a harmful constituent to human health (Govt, of Canada. Talc - information sheet. CAS Registry Number 14807-96-6. Published 2021. https: / / www.canada.ca / en / health-canada / services / chemical-substances / fact- sheets / chemicals-glance / talc.html).

[0005] Adipic acid is commonly added to antacids to provide a tart taste and controlled release of the drug, but in one study it was found to have low acute toxicity in rats with LD50 > 5000 mg / kg (Gerald L. Kennedy Jr. TOXICITY OF ADIPIC ACID. Drug Chmical Toxicol. 2002;25(2)). Therefore, in the pharmaceutical formulation, it is better to avoid adipic acid.

[0006] Mineral oils are usually used for lubrication and anti-corrosion agents during tableting and sodium polyphosphates are used for solid dispersion or anticaking agents, also these two ingredients can be avoided for simplicity and also to avoid unnecessary sodium ingestion in the body.

[0007] Further, the use of starch and sucrose can also be avoided as it adds extra calories to the body while taking an antacid tablet, which is not recommended for a diabetic patient.

[0008] In addition, wet granulation is used in the production process of API, which requires the use of organic solvents and the subsequent drying of the solvent to obtain the granulated API.

[0009] Therefore, it is obvious that by adding many excipients to a drug and also due to the wet granulation process of the API, the entire manufacturing process becomes complex and requires many production steps, which affects the time and cost of production.

[0010] Therefore, from the above discussion, it is obvious that there is a gap in the knowledge of the exact excipients required for the formulation of calcium carbonate (CaCOs) antacid. In addition, there has been little research in the literature on the exact physical form of the CaCOs API that is suitable for compression with compatible excipients.

[0011] There is a need for antacid solid dose tablets with an improved formulation containing calcium carbonate and sodium-free excipients.SUMMARY

[0012] According to an embodiment, there is provided antacid solid dose tablets with an improved formulation containing calcium carbonate and sodium- free excipients.

[0013] In this context, a systematic investigation was conducted to alter the physical form of the API from the conventional form and also to reduce the number of excipients by adding FDA-approved excipients while maintaining the efficacy of the drug.

[0014] According to another embodiment, there is provided a formulation for the preparation of antacid solid dose tablets, which comprises:

[0015] an active pharmaceutical ingredient consisting of calcium carbonate powder chosen from

[0016] - granulated calcium carbonate of different sizes;

[0017] - calcium carbonate with different morphology; and

[0018] - functionalized calcium carbonate; and

[0019] excipient chosen from Silicon Dioxide, HPMC, Xanthum Gum and Magnesium stearate, flavors, sweetener, and combination thereof.

[0020] The following terms are defined below.

[0021] The term "API" is intended to mean active pharmaceutical ingredient.

[0022] Features and advantages of the subject matter hereof will become more apparent in light of the following detailed description of selected embodiments, as illustrated in the accompanying figures. As will be realized, the subject matter disclosed and claimed is capable of modifications in various respects, all without departing from the scope of the claims. Accordingly, the drawings and the description are to be regarded as illustrative in nature, and not as restrictive and the full scope of the subject matter is set forth in the claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Further features and advantages of the present disclosure will become apparent from the following detailed description, taken in combination with the appended drawings, in which:

[0024] Fig. 1 illustrates a manufacturing process flow chart;

[0025] Fig. 2 illustrates friability and hardness observation for all the formulation based on particle size of calcium carbonate.DETAILED DESCRIPTION

[0026] In the present improved antacid formulation, the number of excipients is reduced, and the weight of the tablet is low, a 34% weight reduction for the 750 mg strength tablet compared to Turns.

[0027] Excipients such as adipic acid, sugar, mineral oil, sodium hexametaphosphate and talc are eliminated, making it sodium (Na+) free in addition to other excipients.

[0028] Dry granulation is used therefore organic solvent is not required.

[0029] To investigate our hypothesis, the following steps were followed systematically.1. Formulation requirement

[0030] The formulation requirement was outlined clearly according to the desired characteristics of the antacid tablet, including dosage strength, tablet size, disintegration time, shelf-life stability, and patient preferences (such as taste and ease of swallowing).2. Review pharmacopeia! standards

[0031] Relevant pharmacopeias were reviewed for monographs on antacids and related excipients. These standards provided guidance on acceptable excipients, their specifications, and testing methods.3. Identifying active ingredients and physical form

[0032] The active ingredient was identified among all the antacids e.g. aluminum hydroxide, magnesium hydroxide, calcium carbonate, and sodium bicarbonate, and solubility, reactivity, and compatibility with other excipients were considered. In this case, granular calcium carbonate was considered.4. Research on excipientsBinders, disintegrants, and stabilizers

[0033] Proper tablet cohesion was considered for finding binders and in the case of disintegrants shorter disintegration time was considered since the formulation is an orally disintegrated tablet (ODT). As binders besides starch, the other options were considered as Xanthum gum Xanthan gum can act as a binder, helping to bind the powder particles together and maintain the integrity of the tablet also it aids in suspending the active ingredients evenly throughout the tablet matrix, ensuring uniform distribution and consistent dosing. Xanthum gum also acts as a disintegrant as well. Another secondary binder and disintegrant was consideredfrom cellulose derivatives as it has a shorter disintegration time compared to non- cellulose-based derivatives6.Fillers / diluents

[0034] These ingredients act as diluents to aid in uniform tablet compression. The available options include dextrose, lactose, mannitol, sorbitol, and dicalcium phosphate. Dextrose was considered in this case.Anticaking agents

[0035] These agents prevent the clumping of powders. Silica and magnesium stearate are commonly used, in this case, both agents were considered.Lubricants

[0036] Lubricants Prevent tablets from sticking during manufacturing and also prevent corrosion on the machine, examples include magnesium stearate, stearic acid, etc. Magnesium stearate was considered in this case as it also acts as an anticaking agent.Flavoring agents

[0037] They mask the unpleasant taste of active ingredients, common flavoring agents include mint, fruit flavors, and sweeteners. This will be selected according to the demand in the market.Colorants

[0038] Enhance product appearance and aid in identification. Use FD&C dyes were selected in this case.Sweetener

[0039] Enhance palatability. Options include sucrose, fructose, and artificial sweeteners like aspartame. Sucralose was selected as a sweetener also dextrose is acting as a sweetener.List of Ingredients

[0040] According to one embodiment of the present invention, the proposed physical form of the calcium carbonate powder and excipients are listed in Table 1.Table 15. Evaluate Excipient Compatibility

[0041] Conduct compatibility studies to ensure the selected excipients are compatible with the active ingredients and each other. Techniques such as differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and stability studies can be employed.6. Manufacturing process flow chart

[0042] The manufacturing process flow chart of the proposed tablet compression is illustrated in Fig. 1.7. Regulatory requirements consideration

[0043] Regulatory requirements were checked to ensure that the selected excipients comply with the regulatory requirements of relevant authorities (e.g., FDA, EMA).8. Document and Validate

[0044] Documentation was performed for all formulation development activities, including the rationale for excipient selection, experimental data, andmanufacturing procedures. Validation was done for the final formulation through robust testing to ensure consistency and reproducibility.9. Quality Control and Assurance

[0045] Quality control procedures were followed for in-house established procedures to monitor excipient quality and ensure compliance with specifications. Quality assurance measures were taken to maintain product integrity throughout manufacturing.Advancement in scientific knowledge

[0046] There have been several scientific advances that have influenced the selection of granulated and modified engineered calcium carbonate as API and key excipients, such as the use of silica, HPMC (hydroxypropyl methylcellulose), xanthan gum, and magnesium stearate, which have not only contributed to the multiple functions at once but also minimized the number of excipients. Below is an overview of how changing the physical form of the active ingredient and these key excipients have contributed to an advancement in scientific knowledge for antacid tablet formulations.Calcium carbonate

[0047] Particle engineering: Recent literature and our investigations have shown that by manipulating particle size, shape, surface area, and porosity, the dissolution kinetics and bioavailability of calcium carbonate in antacid formulations can be improved, potentially enhancing their efficacy.

[0048] Surface Modification: Also, other studies showed that surface modification methods, such as coating or functionalization, can modify the surface characteristics of calcium carbonate particles to enhance their acid-neutralizing capacity, stability, or compatibility with other excipients in antacid formulations.Silica

[0049] Improved flow Characteristics: Scientific advances in surface modification techniques enhanced the flow properties of silica which ensures betterpowder flow during manufacturing processes such as blending and tablet compression, resulting in improved tablet uniformity and content consistency.

[0050] Enhanced Disintegration and Dissolution: Advanced forms of silica can have enhanced disintegration and dissolution properties, contributing to faster onset of action and improved efficacy of antacid tablets.

[0051] Moisture Control: Innovations in silica technology have led to the development of moisture-resistant forms, which can improve the stability and shelflife of antacid tablets, particularly in humid environments.HPMC

[0052] Tailored Release Profiles: Advances in polymer chemistry and processing techniques have made it possible to customize HPMC-based matrices for controlled release of active ingredients in antacid tablets, allowing for extended drug release, maintenance of therapeutic levels over time, and potentially reduced dosing frequency.

[0053] Improved Film Coating: Innovations in film coating technology have optimized the performance of HPMC-based coatings to improve the swallowability and visual appeal of antacid tablets.

[0054] Compatibility with Active Ingredients: Scientific research has elucidated the interaction between HPMC and the active ingredient in antacids, resulting in improved compatibility and stability under various storage conditions.Xanthan Gum

[0055] Enhanced Gel Formation Advancements in xanthan gum production and processing have resulted in improved gel formation properties, which can contribute to better suspension of active ingredients in antacid formulations. This ensures uniform distribution of the drug within the tablet matrix, leading to consistent dosing.

[0056] Improved Rheological Properties -Scientific studies have explored the rheological behavior of xanthan gum dispersions, leading to a better understanding of its thickening and stabilizing effects.

[0057] Compatibility with Other Excipients- Research has investigated the compatibility of xanthan gum with other excipients commonly used in antacid formulations, ensuring synergistic interactions and avoiding potential formulation challenges such as phase separation or reduced drug bioavailability.Magnesium Stearate

[0058] Particle Engineering: Advances in particle size control and surface treatment techniques have optimized the flow and lubricating properties of magnesium stearate, facilitating uniform distribution in antacid tablets, and preventing tablet sticking or picking during manufacturing.

[0059] Reduced Sensitivity to Manufacturing: Scientific studies have identified factors that affect the lubricity of magnesium stearate, allowing formulation scientists to address potential variations in tablet hardness, disintegration or dissolution associated with manufacturing process parameters.

[0060] Compatibility with Tablet Coating: Innovations in magnesium stearate tablet coating technology have addressed coating adhesion and integrity. This ensures a uniform and durable coating on antacid tablets, protecting them from moisture and mechanical damage.

[0061] Overall, these scientific advancements have contributed to the development of more effective, stable, and patient-friendly antacid tablet formulations by optimizing the selection and utilization of silica, HPMC, adipic acid, xanthan gum, and magnesium stearate as key excipients.Scientific / Technological uncertainty

[0062] The uncertainties encompass the influence of the granulated, engineered, or surface-modified active pharmaceutical ingredient (API) and the compression process, as well as the effects of process scaling on tablet properties,such as hardness, friability, and disintegration. These uncertainties arise due to the complexity of interactions between ingredients and raw materials during the formation of dry granulated / engineered / surface-modified API, as well as the potential variations in tablet properties when scaling up the manufacturing process. Moreover, ensuring uniform blending of dry granulated / engineered / surface modified API with the excipients is crucial for maintaining dose uniformity, achieving consistent blend uniformity, especially with a reduced number of excipients poses challenges and uncertainties. Dry granules may exhibit different compression properties compared to wet granules.

[0063] In addition, different forms of, API may exhibit different compression properties. Achieving the desired tablet hardness and disintegration profile while reducing tablet weight significantly requires an understanding of compression force and dwell time. Finally, changes in formulation and manufacturing process can affect the stability and shelf-life of the tablets. Without experiments, it’s not possible to determine the impact of reduced excipients and tablet weight on stability such as degradation kinetics, moisture content, and physical integrity. Addressing these uncertainties requires a comprehensive approach and a systematic investigation.Conclusion

[0064] The results obtained in this study showed that by changing the physical form of the API and with the selected excipients effective low-cost antacid tablets can be manufactured according to the patient and market requirements.

[0065] The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its scope.EXAMPLE 1

[0066] The influence of granular CaCOs API of different sizes on the mixing process and the final tablet properties after mixing with different excipients was evaluated.Independent variables:

[0067] Particle size of CaCOs API (e.g., coarse, medium, fine).

[0068] Types and concentrations of excipients (e.g., binders, lubricants etc.).Dependent variables:

[0069] Mixing sequence of the excipients with the API, blending time and homogeneity of blend, Flow properties of blend, Tablet properties (e.g., hardness, friability, and disintegration time).Materials and Equipment:

[0070] Materials: CaCOs API of different particle morphologies, excipients (Silicon Dioxide, HPMC, Xanthum Gum, Dextrose, Sucralose, Flavors, Magnesium stearate FD&C Yellow#6 Alu lake.

[0071] Equipment: Blender (e.g., V-blender, ribbon blender), Tablet press (Single punch machine, Hardness tester (Sourced from Key international), Disintegration tester (Sourced from Boekel Scientific Inc. ). Shelf life study chamber (Sourced from Lunaire) and Other necessary laboratory equipment.

[0072] Below are 4 different recipes with different calcium carbonate particle sizes.Table 2 : Recipe 1Evaluation test of tablet (1000 mg) for recipe 1Table 3 : Recipe 2Evaluation test of tablet (1000 mg) for recipe 2Table 4 : Recipe 3Evaluation test of tablet (1000 mg) for recipe 3Table 5 : Recipe 4Evaluation test of tablet (1000 mg) for recipe 4RESULTS:

[0073] Satisfactory results were observed for the tablet obtained from all the recipes above as shown in Fig. 2.

[0074] While preferred embodiments have been described above and illustrated in the accompanying drawings, it will be evident to those skilled in the art that modifications may be made without departing from this disclosure. Such modifications are considered as possible variants comprised in the scope of the disclosure.

Claims

CLAIMS:

1. A formulation for the preparation of antacid solid dose tablets, which comprises:• an active pharmaceutical ingredient consisting of granulated calcium carbonate of different sizes between 30 to 200 pm;• an excipient chosen from Silicon Dioxide, HPMC, Xanthum Gum and Magnesium stearate, flavors, sweetener, and combination thereof.

2. The formulation of claim 1 which comprises the following ingredients:

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