Delayed release sodium bicarbonate tablet composition

Abstract

The present invention relates to develop a long term stable enteric coated tablet formulation comprising sodium bicarbonate having one or more film-forming polymers and one or more enteric components for retention of the release in the stomach, wherein the said tablet coated with 12.5%-25% enteric coating and a process for the production of said enteric coated tablets providing storage stability under high temperature and moisture absorption.

Description

[0001] DELAYED RELEASE SODIUM BICARBONATE TABLET COMPOSITION

[0002] Technical field:

[0003] The present invention relates to a stable enteric coated tablet dosage form of sodium bicarbonate formulation and a process for the manufacture of said formulation with long-term storage stable properties.

[0004] Prior Art:

[0005] Sodium bicarbonate, also called sodium hydrogen carbonate, is used as a pH regulatory agent in oral drug formulations for mild metabolic acidosis and for supportive therapy in chronic kidney diseases. Infusions containing sodium bicarbonate are indicated in life-threatening conditions such as acute renal failure and acute asthma.

[0006] Sodium bicarbonate, commonly known as baking soda or bicarbonate of soda, is a chemical compound with the formula of NaHCO3It is a salt composed of a sodium cation (Na+) and a bicarbonate anion (HCO3"). Sodium bicarbonate is a white solid that is crystalline, but often appears as a fine powder. It has a slightly salty, alkaline taste resembling that of washing soda (sodium carbonate).

[0007] Knowing the effect of sodium bicarbonate on the intestinal system and the difference between sodium bicarbonate on the gastric system is essential for treatment. Orally ingested gastric soluble sodium bicarbonate is hydrolyzed by gastric hydrochloric acid. Sodium bicarbonate decomposes into sodium chloride and carbon dioxide at the end of the reaction. This pharmaceutical form has been used in the treatment of gastric hyperacidity.

[0008] NaHCCh HCI - ► aC1 CO2-i-HiO

[0009] However, the method in which gastric soluble sodium bicarbonate is used is a method that requires the use of excessive amounts of hydrogen carbonate, which cannot be used in practice. In addition, sodium chloride formed at the end of the reaction with the use of gastric soluble sodium bicarbonate increases the sodium load of the organism, while the excess carbon dioxide that will occur in the stomach causes excessive bloating and discomfort. Therefore, oral treatment of metabolic acidosis should be with enteric-coated, intestinal soluble sodium bicarbonate. Acidosis is understood to be a state of hyperacidity of the human or animal body. If the blood pH is below 7.36, it is called acidosis. The normal pH of the blood is in the range of 7.36 to 7.44. At higher pHs, alkalosis is present.

[0010] Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys to excrete excess acids which is occurred in the body due to kidney disease or kidney failure. When the buffer capacity of the blood buffer is depleted from the acids, the pH drops. This leads to a sudden sharp drop in pH and acute acidity. These can often be acute life-threatening conditions.

[0011] The most common causes of metabolic acidosis are renal insufficiency or an isolated renal tubular H+secretion defect, diabetic metabolic degeneration, uremia or intoxication with acidic substances such as acetylsalicylic acid. A patient with metabolic acidosis stands out above all for his intensified, deep and accelerated breathing. In diabetic ketoacidosis, a characteristic acetone odor is noticeable on the breath. It is a blood gas analysis that easily includes the pH and CO2partial pressure and the extent of metabolic acidosis and the extent of the body's respiratory compensation, which must be done to detect and quantify metabolic acidosis.

[0012] Sodium bicarbonate is a basic agent that is unstable in an acidic environment. If it comes into contact with protons, carbonic acid is formed that separates into carbon dioxide and water. As carbon dioxide evaporates the reaction usually develops rapidly and completely. The development of oral dosage forms with sodium bicarbonate as a therapeutic agent is a special challenge for pharmaceutical technology. Due to its chemical and physicochemical properties, sodium bicarbonate must be prevented, as much as possible, from coming into contact with protons and water molecules of the gastric juice by enteric coating. If the protection is incomplete, carbon dioxide will develop due to drug degradation and will additionally stress the coating. Furthermore, dissolving sodium bicarbonate in water can diminish the protective efficiency of the acidic coatings due to the basic character of the salt. In the development of sodium bicarbonate containing pellet formulations the interactions became quite obvious, indicated by the failure of aqueous dispersions or organic solutions of the Eudragit L product line to form an intact enteric coating around the extrusion pellets. Additionally, enteric coated pellets were coated with extraordinary thick polymer layers obtained from up to 60% weight gain using polyvinyl alcohol as a subcoat and Eudragit L 30 D- 55 Oas the enteric layer. This creates a disadvantage for the enteric coated pellet product. Also, the unwanted drug release from the pellets was still higher than from the marketed soft capsule products.

[0013] Comparing the tablet and the pellet formations, the tablet has the advantage that the specific surface is much lower than for the pellets. Fewer polymer masses are therefore required to ensure gastric juice resistance and this could be of importance as huge doses of 3-4.5 g of sodium bicarbonate are required per day.

[0014] EP1970066 patent and especially the studies by Breitkreutz et al., “Enteric-coated solid dosage forms containing sodium bicarbonate as a drug substance: an exception from the rule?”, JPP 2007, 59: 59-65 (2007), describe a medicament, Nephrotrans, in the form of soft capsules comprising sodium bicarbonate at a unit dose of 500 mg per capsule, prescribed for the treatment of metabolic hyperacidity of the blood (metabolic acidosis) and for maintenance treatment for preventing recurrence of excessive metabolic acidosis in chronic renal failure.

[0015] Also, Antiasidoz® 500 mg Soft Capsule (ASSOS Pharmaceuticals) is a known reference product, available on the market. It has an enteric-coated, intestinal soluble form. These capsules are enteric-coated and dissolve only in the small intestine. This leads to an increase in the plasma bicarbonate level and to remedy a hydrocarbonate deficites for buffering a high hydrogen ion concentration and to increase the blood pH in metabolic acidosis. In the present study, Antiasidoz® was selected as a reference product to compare the test products.

[0016] Pharmaceutical compositions in dosage unit form encapsulated in soft gelatin capsules are well known and basically consist of a "fill", comprising one or more pharmaceutically active materials dissolved or dispersed in an appropriate liquid vehicle, encapsulated in a soft gelatin shell, generally comprising gelatin together with a plasticizer therefor such as glycerin.

[0017] Soft gelatin capsule that is resistant to gastric juice has a soft capsule shell made of enteric coated gelatin with a hypromellose phthalate film coating.

[0018] According to literature, all coating processes have inherent problems including possible uneven distribution of the coating ingredients, which can occur under multivariate coating processes. These problems are common to all enteric dosage forms. However, due to the delicate and heat sensitive nature of the soft elastic capsule, the problems encountered during the coating of the capsules are even more critical. Both hard and soft capsules are easily subject to agglomeration and deterioration due to their heat sensitive composition. As a result of deterioration, active substance release can be seen in gastric acid from capsules. Another disadvantage of enteric coating for soft capsules is the loss of the normally shiny and clear appearance of capsules during shelf life. As can be understood from the disadvantages mentioned above, the enteric soft capsule has serious stability problems besides its high production cost. Moreover, enteric soft capsule manufacturing processes are time consuming and laborious, involve many steps in the manufacture of the composition, and consequently increase the cost of the final composition considerably.

[0019] The most important stability problems of the enteric soft capsule is the degradation of the enteric coating, visual disturbance and drug release disruption, e.g. release in the stomach. For the treatment of metabolic acidosis, the release of sodium bicarbonate in the stomach must be avoided at all costs, since hydrogencarbonate is converted to sodium chloride and carbon dioxide gas by the HCI contained in the gastric acid and is therefore no longer available for any therapeutic use for raising the blood pH.

[0020] Due to the fact that the commercially available reference product (Andiasidoz®) is a soft capsule, it has the propension of deformations and deteriorations on the outer surface during the storage in the presence of heat and moisture. This may create problematic situations during the storage as the degradation of the enteric coating both deteriorates the appearance of the tablet and fails to achieve the expected release profiles in in vitro dissolution tests.

[0021] In addition to being an important problem for patient compliance, this situation will also impair the curativeness of the drug, as it will increase the possibility of deterioration of the enteric coating. This problem could not be demonstrated because there is no prior art references dealing with stability studies of products containing sodium bicarbonate. The oral formulations disclosed in the prior art demand further improvements in light of the heat and moisture sensitive nature of tablets.

[0022] Thus, there is still a need for physically and chemically stable composition comprising sodium bicarbonate that can be used to treat metabolic acidosis or hyperacidity of the blood throughout the shelf life without release in the stomach and therefore provide excellent storage stability. The present invention addresses this problem and provides a solution thereto. It is thus an object of the present invention to provide a dosage form for oral administration which provides physical and chemical stability for controlled delivery of sodium bicarbonate in the small intestine and thus can be used to adjust blood pH properly.

[0023] Description of the Invention:

[0024] The present invention provides a stable sodium bicarbonate enteric coated tablet and a preparation method thereof.

[0025] The present invention relates to a modified release system in the form of a stable enteric coated tablet comprising sodium bicarbonate, wherein the coating comprises one or more film-forming polymers and one or more enteric components for retention of the release in the stomach.

[0026] The present invention provides a stable sodium bicarbonate enteric coated pharmaceutical tablet composition comprising one or more film-forming polymers and one or more enteric components for retention of the release in the stomach, wherein the said tablet coated with 12.5% - 25.0% enteric coating, preferably coated with 15.0%

[0027] - 25.0% enteric coating.

[0028] The present invention provides a stable sodium bicarbonate enteric coated pharmaceutical tablet composition, wherein the said formulation comprises at least one diluent, at least one binder, at least one glidant and at least one lubricant.

[0029] The present invention provides a stable sodium bicarbonate enteric coated pharmaceutical tablet composition, wherein the diluent is microcrystalline cellulose; the binder is a combination of copovidone and hydroxypropyl cellulose; glidant is silicon dioxide; the lubricant is magnesium stearate.

[0030] The present invention provides a stable sodium bicarbonate enteric coated pharmaceutical tablet composition comprising 60%-80% (w / w) sodium bicarbonate, 15%-25% (w / w) microcrystalline cellulose, 2%-10% (w / w) hydroxypropyl cellulose, 1%- 5% (w / w) copovidone, 0.1%-2% (w / w) silicon dioxide and 0.1%-2% (w / w) magnesium stearate by weight of the tablet composition; wherein the said tablet coated with 12.5%

[0031] - 25.0% (w / w) enteric coating, preferably coated with 15.0% - 25.0% (w / w) enteric coating. The present invention provides a stable sodium bicarbonate enteric coated pharmaceutical tablet composition comprising 60%-80% (w / w) sodium bicarbonate, 15%-25% (w / w) microcrystalline cellulose, 2%-10% (w / w) hydroxypropyl cellulose, 1%- 5% (w / w) copovidone, 0.1%-3% (w / w) silicon dioxide and 0.1%-2% (w / w) magnesium stearate by weight of the tablet composition; wherein the said tablet prepared by direct compression process and coated with 12.5% - 25.0% (w / w) enteric coating, preferably coated with 15.0% - 25.0% (w / w) enteric coating

[0032] According to another objective of the invention there is provided a pharmaceutical composition of sodium bicarbonate enteric coated tablet, a stable sodium bicarbonate enteric coated tablet formulation has been developed to ensure proper in-vitro release initially and during storage conditions when the prepared tablet product is stored at high temperature or at normal temperature for long period.

[0033] According to another embodiment of the invention, the enteric tablet releases less than 10% of the labeled amount of sodium bicarbonate after 2 hours acid stage when measured using USP dissolution apparatus II (paddle method), 100 rpm, 1000 mL of 0.1 N hydrochloric acid medium and pH 4.5 buffer medium after the production and throughout the shelf life.

[0034] It is thus the most important object of the present invention to provide sodium bicarbonate enteric coated tablet composition for oral administration which provides physical and chemical stability during shelf life.

[0035] Enteric-coated dosage forms are typically produced by a film coating process, where a film layer of an acid-insoluble (enteric) polymer is applied to the surface of a premanufactured dosage form, such as a tablet.

[0036] By preparing the sodium bicarbonate into the enteric tablet, the release of the sodium bicarbonate in the intestinal tract can be controlled, so that the sodium bicarbonate is more suitable for treating metabolic acidosis due to various causes, especially in chronic renal failure. Thereby, by regulating the acid-base balance of body fluid, it reduces the adverse effects caused by the sodium bicarbonate in the stomach, and reduces the administration dosage of the sodium bicarbonate.

[0037] The term “therapeutically effective amount” refers to an amount, which achieves a desired effect, when administered to a living subject. The term "enteric coating" refers to a coating comprising one or more layers generally resistant to disintegration in human gastric fluids, but which will disintegrate in human intestinal fluids. Enteric coatings consist of pH sensitive polymers, which mean the coating remains intact in the acidic environment of the stomach and then solubilizes in the more alkaline environment of the small intestine. Enteric protection for solid oral dosage forms is required to prevent gastric mucosal irritation, to protect a drug which is unstable in gastric fluids or to delay release for local release in the intestine.

[0038] In this invention, weight percentages (w / w) refer to the weight of the component relative to weight of the tablet composition.

[0039] The term "active ingredient" or "active pharmaceutical ingredient" means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. In the present invention, the active ingredient is sodium bicarbonate. The enteric tablet composition is provided in a unit dose formulation comprising 500 mg sodium bicarbonate.

[0040] The term 'stable' as used herein means the enteric tablet release the therapeutically effective amounts of active ingredient sodium bicarbonate into specific delivery region after production (To, initially) and during the storage conditons throughout the shelf life. The proposed USP tests for enteric tablets requires that the product withstand agitation (paddle at 100 rpm) in the artificial gastric fluid (0.1 N hydrochloric acid) at 37°C ± 0.5°C, releasing less than 10% sodium bicarbonate for 2 hours, while not less than 85% sodium bicarbonate at the end of 4 hours at 37°C ± 0.5°C with a buffer of pH 6.8. This is also considered as dissolution stability as well. The stability of the products can be determined by in-vitro dissolution studies of real time studies or during storage conditions.

[0041] In addition to the therapeutically active agent sodium bicarbonate the compositions of this invention also generally comprise pharmaceutically acceptable excipients. As used herein, "excipient" means one or more compatible solid or liquid diluents, binders, glidants, lubricants which are suitable for administration to a subject. Excipients may act to facilitate incorporation of the therapeutically active agent into the dosage form, modify the release of the therapeutically active agent from the dosage form, stabilize the therapeutically active agent, or enhance absorption of the therapeutically active agent. The term 'diluent' are herein used for fill out the size of a composition, making it practical to produce and convenient for the consumer to use. Examples of suitable filler / diluent include but are not limited to lactose, microcrystalline cellulose, mannitol, ethyl cellulose, sorbitol, starch, sucrose, calcium phosphate, powdered cellulose, silicified microcrystalline cellulose, isomalt, and mixtures thereof. In the present invention, microcrystalline cellulose was used.

[0042] Examples of suitable ‘binders’ include, but are not limited to one or more of povidone, copovidone, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), ethyl cellulose, sodium carboxymethyl cellulosexylitol, starch, and the like. In this present invention, a combination of copovidone and hydroxypropyl cellulose was used as a binder.

[0043] Examples of suitable lubricants include, but are not limited to one or more of magnesium stearate and stearic acid. In the present invention, the pharmaceutical composition comprises magnesium stearate as a lubricant. Magnesium stearate is primarily used as a lubricant in capsule and tablet manufacture at concentrations between 0.25% and 5.0% w / w.

[0044] The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.

[0045] Example 1. Production Methods:

[0046] In the formulation, the reference product produced by Assos Pharmaceuticals under the trademark Antiasidoz® was referenced. The formulation development studies started with the investigation of the physical properties, chemical properties, solubility and pharmacokinetic properties of the active ingredients, and enteric coating was applied to formulate delayed release sodium bicarbonate tablet composition.

[0047] The sodium bicarbonate enteric tablet is prepared by the following steps of: preparing a tablet core from sodium bicarbonate, a filling agent, a lubricating agent and a flow aid; preparing an isolation coating and an enteric coating from an isolation material, an enteric material, a plasticizing agent, an anti-sticking agent and a dispersing medium; preparing a sodium bicarbonate tablet core by direct compression; and then, wrapping the isolation coating and enteric film coating to obtain the sodium bicarbonate enteric tablet. The tablet core of sodium bicarbonate enteric coated pharmaceutical tablet composition comprises 60%-80% sodium bicarbonate, 15%-25% microcrystalline cellulose, 2%-10% hydroxypropyl cellulose, 1%-5% copovidone, 0.1%-2% silicon dioxide and 0.1%-2% magnesium stearate.

[0048] Since the most important criterion in tablets containing enteric coating is the percentage of enteric coating used, different coating percentages of enteric coating were applied to the prepared tablet cores.

[0049] Table 1. Comparison of formulations containing different amounts of enteric coating with USP Performance Test

[0050] Film coating %

[0051] Enteric Coating %

[0052] (HPMC based film coating*)

[0053] Formulation-1 2% 10%

[0054] Formulation-2 2% 15%

[0055] Formulation-3 2% 20%

[0056] Formulation-4 2% 25%

[0057] * Hydroxypropylmethylcellulose Based Film Coating

[0058] Example 2. In-Vitro Dissolution Studies:

[0059] Comparative dissolution tests were conducted based on the general dissolution test method. According to literature, the drug release profiles were determined using the paddle setup for tablets and capsules. For the acid stage, the dissolution medium was 1000 mL of 0.1 M hydrochloric acid (HCI) having the paddle rotated at 100 rpm and the temperature of the dissolution media was continuously kept at 37°C±0.5°C. After the test the releasing should be less than 10% sodium bicarbonate for 2 hours.

[0060] For the buffer stage, the dissolution medium was 1000 mL of pH 6.8 phosphate buffer having the paddle rotated at 100 rpm and the temperature of the dissolution media was continuously kept at 37°C±0.5°C. After the test the releasing should be less than 70% sodium bicarbonate at the end of 1 hour (in-house specification) and not less than 85% sodium bicarbonate at the end of 4 hours at 37°C ± 0.5°C with a buffer of pH 6.8.

[0061] The in-vitro release was analysed with Atomic absorption spectroscopy (AAS). The measurements were performed at 330.3 nm and operated at a slit width of 0.2 nm. The carrier gases used were synthetic air and acetylene. Comparative dissolution tests were conducted with Test products (Formulation-1 , Formulation-2, Formulation-3 and Formulation-4) and reference product of Antiasidoz® 500 mg Soft Capsule. The conditional release profiles of the test products and reference product were plotted as the cumulative percent of drug dissolved vs. time. According to the studies conducted above, in in-vitro dissolution studies with tablets obtained as a result of different enteric coatings Formulation-1 , Formulation-2, Formulation-3 and Formulation-4 containing 10%, 15%, 20% and 25%, respectively; no sodium bicarbonate was released in acidic medium (0.1 M HCI), but products Formulation-1 containing 10% enteric coating showed faster release in pH 6.8 compared to the reference product and also the similarity factor (f2) value with comparing Antiasidoz® Soft Capsule is below 50.

[0062] According to the information available in the literature, rapid release in a pH 6.8 medium increases the adverse drug effects in patients. For this reason, formulation developed in the present invention, since it is aimed to increase patient compliance by obtaining slow release in a pH 6.8 medium, a rapid release formulation (Formulation-1) was not found appropriate.

[0063] On the other hand, the finished products of Formulation-2, Formulation-3 and Formulation-4 containing 15%, 20% and 25% enteric coating performed slow release compatible with the reference product in pH 6.8 environment. The dissolution profiles were compared; the dissolution profiles obtained were evaluated by similarity factor (f2) which is higher than 50 (Helmy & Bedaiwy, 2013). An f2value between 50 and 100 suggests that the two dissolution profiles are similar (EMEA Guideline on the Investigation of Bioequivalence, 2010).

[0064] Another issue is that when the in-vitro versus in-vivo variability is considered, it is not sufficient to monitor the in-vitro release of the developed drug in an acidic environment of pH 1.2 only to control the release in the gastric fluid. An explanation for the observed differences in-vitro and in-vivo may be the varying pH values in-vivo caused by gastric and intestinal motility as well as the intake of food. The gastric pH value in the fasted state has been determined to be 1-2 using a telematical pH sensor (Heidelberger Kapsel) attached to a magnet that can be maintained in the stomach for hours by a strong external magnet (Berntgen 1997). In this experimental setup, transitory peaks up to pH 4 were measured in-vivo, which were attributed to the reflux of intestinal fluid during the rhythmical reoccurring housekeeper waves. Using a permanent nasal gastric tube with a permanent gastric pH sensor (Meditronic), pH profiles can be obtained under more realistic conditions, including food uptake and movements. In a recent study on proton pump inhibitors, the baseline pH profiles before the medication exhibited pH peaks of 4.5 and troughs of pH 1.4 (Thyroff-Friesinger 2002). The peaks could be clearly attributed to the food ingestion during the day. After lunch, the averaged gastric pH value of 21 healthy male subjects increased to 4.4, and descended within 3 h back to the fasted conditions.

[0065] In the tests carried out in the literature studies, it was concluded the drug release was preserved in the pH 4.5 medium (maximum 10% after 2 hours) was only in Nephrotrans enteric-coated soft gelatine capsule (equivalent to Antiasidoz® 500 mg Soft Capsule). In bicaNorm enteric-coated tablets sold in the market, the sodium bicarbonate active substance is almost completely released in the pH 4.5 medium.

[0066] As a result of the above study, it was determined that additional dissolution studies on sodium bicarbonate dosage forms using a pH 4.5 buffer to simulate more realistic conditions are important for the therapeutics of the developed product.

[0067] In this direction, sodium bicarbonate release was tested by in-vitro dissolution study with Formulation 2, Formulation 3 and Formulation-4 with comparing the reference product (Antiasidoz®) in pH 4.5 medium. In the study, it was determined that the formulation developed in the present invention did not release the active substance in the pH 4.5 medium. According to the results, the release was found to be maximum 10% after 2 hours at pH 4.5 buffer.

[0068] The products developed in the present invention exhibit similar pH 1.2, pH 4.5 and pH 6.8 profiles with Antiasidoz® 500 mg Soft Capsule. It has been shown in the literature that Nephrotrans enteric-coated soft gelatine capsule (equivalent to Antiasidoz® 500 mg Soft Capsule) has different in-vitro and in-vivo profiles than other enteric-coated tablets on the market, and the present studies have also shown that the product developed in the present invention is different from the enteric tablets on the market.

[0069] Example 3. Stability Studies

[0070] It is known that the successful treatment of the acute episode acidosis due to various causes as well as the prevention of recurrency with enteric coated tablets comprising sodium bicarbonate require a defined release profile of sodium bicarbonate from the dosage form. Since the criterion for stability of an enteric coated dosage form is that it should not release a significant amount of the active ingredient in the stomach, but should dissolve slowly in the higher pH environment of the intestine, in vitro dissolution stability is monitored in 0.1 N hydrochloric acid, pH 4.5 buffer (additional) and pH 6.8 phosphate buffer. The USP standards for enteric coated tablets entails stability testing of the products at elevated temperatures for extended periods of time. The enteric tablets coated with enteric coating polymers prepared as per the Formulation-2, Formulation-3 and Formulation-4 were packed in PVC / PVDC-ALU blisters and kept for stability testing together with reference products Antiasidoz® 500 mg Soft Capsule (ASSOS Pharmaceuticals) under conditions given as 40°C / 75% relative humidity for 6 months and 25°C / 60% relative humidity for 12 months duration.

[0071] The stability of a drug substance is an important factor in the manufacture of safe and effective pharmaceutical products. Stability studies are required to be submitted by any applicant seeking approval for a new pharmaceutical product. The rules in force (e.g. "Note for Guidance on Impurities in New Drug Products" CPMP / ICH / 2738 / 99, issued by EMEA, European Medicines Agency) provide strict limitations for impurities, nevertheless it is better to prevent or reduce as possible the degradation to avoid the exposure of patients to substances.

[0072] The stability of a pharmaceutical dosage form is related to maintaining its appearance, physical, chemical, microbiological, therapeutic, and toxicological properties when stored, i.e. , in a particular container and environment.

[0073] The products were tested for appearance, content and in-vitro dissolution of sodium bicarbonate from enteric-coated tablets at acid and buffer medium conditions in regular intervals. Changes in appearance was determined with visually. Determination of content and dissolution tests were performed with a validated Atomic absorption spectroscopy (AAS) method. The measurements were performed at 330.3 nm and operated at a slit width of 0.2 nm. The carrier gases used were synthetic air and acetylene.

[0074] In order to examine the physical and chemical stability of the products, stability test was assessed under accelerated condition (40°C±2°C, 75% Relative humidity, RH±5%) and ambient temperature condition (25°C±2°C / 60±5% Relative Humidity, RH±5%) for Test products (Formulation-2, Formulation-3 and Formulation-4) and Reference Products (Antiasidoz® 500 mg Soft Capsule) according to ICH Stability Testing Of New Drug Substances And Products Q1A(R2) Guidelines. According to literature, it is known that soft capsules lose their shell elasticity and thus their resistance to mechanical shocks encountered during transportation and handling of capsules over a period of time. Accordingly, in the stability test results, it was observed that the samples kept in 40°C±2°C, 75% RH conditions had visual defects. When the products kept at 40°C±2°C, 75% RH and the capsules in the initial condition were compared in appearance, it was determined that the integrity of the capsule was broken, some capsules melted, and as a result, the contents of the capsules could not be protected by the shells in some capsules.

[0075] On the other hand, no appearance defect was observed in the enteric coated tablets developed in the present invention (Formulation-2, Formulation-3 and Formulation-4), the amount of contents were found to be appropriate and also in vitro release tests were reported as appropriate with the samples obtained after 6 months at 40°C±2°C, 75% RH condition and 12 months at 25°C±2°C, 60% RH condition.

[0076] FIGURES

[0077] Figure 1 : Dissolution of sodium bicarbonate from commercial enteric-coated products in potassium phosphate buffer pH 4.5 (paddle apparatus Ph. Eur., 37±0.5°C, 100 rpm, n=6) (*This figure was taken from Breitkreutz J, Gan TG, Schneider B, Kalisch P. Enteric-coated solid dosage forms containing sodium bicarbonate as a drug substance: an exception from the rule? J Pharm Pharmacol. 2007 Jan;59(1):59-65. doi: 10.1211 / jpp.59.1 .0008. PMID: 17227621).

[0078] Figure 2. Capsule image of reference product Antiasidoz® initially and after 3 months 40°C±2°C, 75% RH condition

Claims

CLAIMS1. A long-term stable oral pharmaceutical sodium bicarbonate enteric coated tablet composition comprising one or more film-forming polymers and one or more enteric components for retention of the release in the stomach, wherein the said tablet coated with 12.5%-25% (w / w) enteric coating by weight of the tablet composition.

2. The pharmaceutical composition according to claim 1 , wherein the said tablet coated with 15%-20% (w / w) enteric coating by weight of the tablet composition.

3. The pharmaceutical composition according to claim 1 , wherein the said tablet comprises at least one diluent, at least one binder, at least one glidant and at least one lubricant.

4. The pharmaceutical composition according to claim 3, wherein the diluent is microcrystalline cellulose.

5. The pharmaceutical composition according to claim 4, wherein the said tablet comprises 15%-25% (w / w) microcrystalline cellulose by weight of the tablet composition.

6. The pharmaceutical composition according to claim 3, wherein the binder is a combination of copovidone and hydroxypropyl cellulose.

7. The pharmaceutical composition according to claim 6, wherein the said tablet comprises 2%-10% (w / w) hydroxypropyl cellulose by weight of the tablet composition.

8. The pharmaceutical composition according to claim 3, wherein the glidant is silicon dioxide.

9. The pharmaceutical composition according to claim 8, wherein the said tablet comprises 0.1%-2% (w / w) silicon dioxide by weight of the tablet composition.

10. The pharmaceutical composition according to claim 3, wherein the lubricant is magnesium stearate.

11. The pharmaceutical composition according to claim 1 , wherein the said tablet comprises; i. 60%-80% (w / w) sodium bicarbonate, ii. 15%-25% (w / w) microcrystalline cellulose, iii. 2%-10% (w / w) hydroxypropyl cellulose, iv. 1%-5% (w / w) copovidone, v. 0.1%-2% (w / w) silicon dioxide. vi. 0.1%-2% (w / w) magnesium stearate by weight of the tablet composition,12. The pharmaceutical composition according to any preceding claim, wherein the said tablet is prepared by direct compression process.

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