IMPROVED MANUFACTURING METHOD FOR FORMULATIONS CONTAINING AMORPHOUS TOLVAPTAN

Abstract

The present invention relates to an immediate-release stable pharmaceutical composition, produced using a direct printing method, containing tolvaptan or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

Description

FOR FORMULATIONS CONTAINING AMORPHOUS TOLVAPTAN IMPROVED PRODUCTION METHOD Field of Invention The present invention relates to the production of tolvaptan or other materials using a direct printing method. a pharmaceutically acceptable salt and a pharmaceutically acceptable maximum It relates to immediate-release, stable pharmaceutical compositions containing a small amount of excipient. State of the Art Arginine vasopressin (AVP) is a compound synthesized in the brain by the hypothalamus. It is a neuropeptide hormone. It is involved in the excretion of water and dissolved substances from the kidneys. in the regulation, control of blood pressure and congestive heart failure (CHF), liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH), for example It plays an active role in related disorders. Traditional methods for treating patients suffering from elevated AVP levels. Treatment often promotes water loss along with electrolytes, leading to hyponatremia and It exacerbates other electrolyte imbalances. To minimize the effects of increased AVP levels and maintain electrolyte balance. A selective vasopressin V2 receptor to reduce water retention without disrupting it. The antagonist can be used. Tolvaptan (OPC-41061) targets V2 receptors located in the renal collecting ducts. By blocking it, it selectively inhibits water reabsorption induced by AVP. It is a selective vasopressin V2-receptor antagonist that increases water excretion. This occurs without any change in electrolyte excretion. The chemical name of tolvaptan is (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1- It is benzoazepine-1-yl]carbonyl]-o-tolu-m-toluide. Its molecular formula is C26H25ClN2O3. and the molecular weight of the compound is 448.94 g / mol. 1 The structural formula of tolvaptan is shown in Formula I. Tolvaptan appears as a white crystalline powder, is not hygroscopic, and It is soluble in benzyl alcohol and methanol, but not in hexane and over a wide pH range. It is virtually insoluble in water (0.00005% w / v at 25°C). Hypertension, edema, ascites, heart failure, kidney dysfunction, vasopressin parasecretion syndrome (SIADH), hepatocirrhosis, hyponatremia, Tolvaptan is used for the treatment of hypokalemia, diabetes, and circulatory disorders. The pharmaceutically acceptable salts of this were first developed by Otsuka Pharmaceutical. This is described in patent document number EP1028111 by Co. Tolvaptan has an asymmetric center and exists as two enantiomers. It can be found. However, the active substance is racemic with R and S enantiomers. It was developed as a mixture. Since the drug is a racemic mixture, optical rotation It does not show. Tolvaptan was first commercially released by the U.S. Food and Drug Administration in August 2009. ® It has been approved as a medicinal product in immediate-release tablet dosage form by SAMSCA. It is marketed under the name [name of the drug] in 15 mg and 30 mg doses. Heart failure, Patients with cirrhosis and syndrome of inappropriate antidiuretic hormone (SIADH) also have clinical conditions. significant (serum sodium less than 125 mEq / L or symptomatic and (less pronounced hyponatremia that is resistant to correction with fluid restriction) It is indicated for treatment. Then, in 2013, Otsuka Pharmaceutical Co. developed autosomal dominant polycystic Decrease in kidney function in patients with renal disease (ADPKD) They recommended a higher dosage regimen to slow its progression. The proposed new indication for tolvaptan is in film-coated tablet dosage form. Available under the names JINARQUE® and JINARC® in doses of 15 mg, 30 mg, 45 mg, and 60 mg. It has been launched on the market in 15 mg and 30 mg doses, containing the active ingredient and 2 The dosage is proportional to the excipients. The 45 mg and 90 mg tablet dosages are 60 mg each. It is designed to be quantitatively proportional to the mg tablets. There are numerous patents / patent applications in the known state of the art, This is summarized below. EP2167046, tolvaptan or its pharmaceutically acceptable salt, 50% by weight. or hydroxypropylcellulose containing a higher or greater amount of hydroxypropyl groups; and carmellose, sodium carboxymethyl starch, crospovidon, and average particle. low particle diameters of 30 to 70 µm and 90% cumulative particle diameters of 100 to 200 µm at least one component selected from the group formed by substituted hydroxypropylcellulose It is a solid pharmaceutical composition containing wet granulation method. It is produced using [methods]. EP2961383 contains amorphous tolvaptan, hydroxypropyl methylcellulose (HPMC), and water. This relates to a suspension intended for oral pharmaceutical composition. JPH1121241 is dissolved in an organic solvent with hydroxypropyl cellulose. and by spraying it onto the mixture to obtain a powder and drying it. This relates to a pharmaceutical composition containing amorphous tolvaptan that has been prepared. WO2014068586, tolvaptan or a pharmaceutically acceptable salt of it, povidone, polyethylene glycol, polyvinylcaprolactam and polyvinyl acetate grafts a solid containing a polymer selected from copolymers and combinations thereof It relates to pharmaceutical composition and fluidized bed top spray granulation. It is produced using this method. EP2586464 is a solid containing amorphous tolvaptan and cross-linked polyvinylpyrrolidone. This relates to the pharmaceutical composition; where the active ingredient tolvaptan is cross-linked. The ratio of polyvinylpyrrolidone by weight is 1:0.1-10. Production of the composition. The process begins with the dissolution of tolvaptan in an organic solvent. WO2020122670, tolvaptan or a pharmaceutically acceptable salt of it, added to water. polyvinylpyrrolidone and tolvaptan as penetration enhancers methylene chloride and ethanol are used as organic solvents to dissolve it. It relates to pharmaceutical composition that includes at least one of the groups. 3 CN109646391 is a sustained-release medication containing tolvaptan, hypromellose, and at least one excipient. It relates to a pharmaceutical composition; here, the amount of hypromellose, viscosity the total amount of preparation varying between 50 mPas and 10,000 mPas It is between 30% and 45%. The active ingredient tolvaptan is sparingly soluble in water, and its solubility is across the entire pH range. It is weak. Therefore, due to its low solubility, it has low absorption. It is expected. However, in healthy volunteers, following single doses of 30 to 480 mg, The median duration of peak plasma concentration is approximately 2 hours, and it subsides rapidly. It is absorbed. The absolute bioavailability is approximately 56%, varying between different doses. There is a close relative bioavailability. The average elimination half-life is 7.8 hours. Taking it with food does not significantly affect plasma concentrations. It has no clinical effect. In plasma, it mainly reduces serum albumin and α1-acids. The glycoprotein binds highly to plasma proteins. Based on the known documentation of the technique given above, tolvaptan's effect on the stomach... overcoming low solubility and poor absorption in the intestinal tract for this, by treating with a solvent or before subsequent production steps one or more times. Multiple formulation strategies are achieved by pretreating with more than one excipient. It has been accomplished. However, the inventors of the current invention developed it without any surfactants. tolvaptan, or a pharmaceutically acceptable alternative, offers stability and resolution. direct imprint containing salt and at least one pharmaceutically acceptable excipient a pharmaceutical in immediate-release dosage form produced using this method He has managed to improve his composition skills. Brief Description of the Invention The aim of this invention is to develop a therapeutic selective vasopressin V2 receptor antagonist. as an effective amount of tolvaptan or a pharmaceutically acceptable salt of it The goal is to develop a fast-release, stable pharmaceutical composition containing these ingredients. Another objective of the present invention is to produce immediate-release tolvaptan in amorphous form. The goal is to develop stable pharmaceutical compositions. 4 According to the current state of the art, the active ingredient tolvaptan is very, very weak. It is known to be fluid and only slightly soluble in physiological pH ranges. Therefore, the aim of the present invention is to produce amorphous tolvaptan exhibiting suitable fluidity. The aim is to provide a pharmaceutical composition containing [specific ingredients]. Thus, processability, It can be improved in parallel with the improvement of the dissolution profile. Another objective of the present invention is to include the most unstable natural form, amorphous tolvaptane. The immediate release aims to obtain a stable pharmaceutical composition. Another objective of the present invention is to provide the active substance according to its intended form of application. a pharmaceutical containing filler, binder, dispersant and lubricant It relates to the composition. The formulation does not contain any surfactants. Another objective of the present invention is to use amorphous tolvaptan and the direct printing method. Immediate-release stable pharmaceutical containing suitable excipients selected for use. The goal is to create a composition. Detailed Description of the Invention The present invention aims to develop a stable product with an improved dissolution profile. tolvaptan or a pharmaceutically acceptable salt thereof and pharmaceutically using a suitable manufacturing method, containing at least one acceptable excipient. The goal is to produce and deliver an immediate-release pharmaceutical composition. Tolvaptan promotes the reabsorption of free water from the glomerular filtrate in the kidneys. to block renal collecting ductal arginine-vasopressin (AVP) V2 receptors It is a selective vasopressin V2 receptor antagonist that blocks the receptor. The inventors improved the dissolution rate and absorption from the gastrointestinal tract, and Therefore, bioavailability is increased, amorphous tolvaptan or pharmaceutically accepted amorphous tolvaptan for obtaining a pharmaceutical composition containing a usable salt He conducted a characterization study on it. Amorphous dosage forms are used for drugs that are poorly soluble in water and have low oral bioavailability. One of the promising strategies for overcoming this is higher freedom. Due to its higher energy content, tolvaptan's dissolution compared to similar crystals... It can increase speed and apparent resolution. However, it also has thermodynamic implications. This also leads to the production of unstable forms. According to the state of the art, the Biopharmaceutical Classification System (BCS) According to this, tolvaptan is a compound with low solubility and low permeability, BCS It is classified as Class IV. Table 1: Solubility results of the amorphous tolvaptan active ingredient. Resolution, 25ºC Ambient pH (a / h %) 2.0 0.00004 4.0 0.00004 7.0 0.00004 10.0 0.00004 12.0 0.00003 The given solubility results indicate that tolvaptan is not water-soluble and This shows that its solubility is independent of pH. In addition, oxidation and degradation were used to assess the degree of degradation of amorphous tolvaptan. A study of degradation was conducted under stressful conditions induced by sunlight. The study involved inoculating a 30.0 mg sample of amorphous tolvaptan with 30% solution at 80°C (±2°C) for 4 days. This occurred in a hydrogen peroxide solution. Additionally, under daylight stress conditions, 3 A separate study lasting 5 days was also conducted. Afterwards, the samples were subjected to HPLC analysis. It has been subjected to this. Table 2: Compelled degradation study conducted on amorphous tolvaptan. results Maximum Impurity, % 30% hydrogen under daylight Beginning 4 days in peroxide, 3-5 days Oxidative decomposition 0.12 0.32 0.12 According to the stressed degradation study, amorphous tolvaptan undergoes oxidation stress. It degrades under sunlight and remains unchanged under daylight stress conditions. 6 In addition, the fluidity properties of amorphous tolvaptan have been investigated. The fluidity of amorphous tolvaptan is shown in USP. <1174> by applying the appropriate analytical method determined; here, the compressibility index and Hausner ratio of compressed and This corresponds to the bulk density ratio. The study found the compressibility index and Hausner ratio to be 44.00 and 1.738, respectively. It has been presented; here, bulk density is 0.019 g / ml and compressed density is 0.34 It is in g / ml. Fluidity scale results were obtained taking into account international guidelines. Upon evaluation, the fluidity was classified as "very, very poor". In the known state of the art, tolvaptan has a low physiological pH range. To overcome the tendency of solubility and crystallization over time, tolvaptan at least one that is pharmaceutically acceptable in crystalline or amorphous form an amorphous composite containing an excipient, tolvaptan and at least one polymer in a solvent It is produced in many ways, such as by dissolving in a solvent mixture. Information on the solubility, fluidity, and degradation of amorphous tolvaptan and Development work is based on information in known documentation of the technique. can be produced by wet granulation method using organic solvents It started with the proposal of formulation design. First, amorphous tolvaptan, or a pharmaceutically acceptable salt of it, and a pharmaceutical containing at least one pharmaceutically acceptable excipient The composition is based on known documentation of the technique, using the wet granulation method. It was produced using Wet granulation method is a unit operation in the production of pharmaceutical dosage forms. It is one of the types, and the desired properties are obtained for subsequent processes. This refers to the process of granulating the powder with a granulation solution for the purpose of; where Granulation solution alone or containing a binder or granulation agent. It could be a solvent. In the preferred application of the present invention, tolvaptan or pharmaceutically wet granulation of a pharmaceutical composition containing acceptable salt 7 This is achieved using the method; the aim here is to provide the best possible application form. The active ingredient, filler, and binder are selected to be suitable. tablets containing dispersing agent, surfactant, lubricant and granulation solvent production is provided. In the preferred application of the present invention, the filler material shall be limited to the following: including but not limited to, dibasic calcium phosphate dihydrate, polysaccharides, mainly microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic Salts may include, but are not limited to, mainly calcium salts and their mixtures. Preferably, the fillers are lactose and microcrystalline cellulose. In the preferred application of the present invention, the binding agent shall be limited to these. not including lactose monohydrate, starch, pregelatinized starch, cellulose or It may contain cellulose derivatives, povidone, sucrose, polyethylene glycol, or mixtures thereof. Ideally, the binding agent is pregelatinized starch. In the preferred application of the present invention, the dispersing agent is limited to these. not to mention, croscarmellose sodium, sodium starch glycolate, crospovidon, corn starch, pregelatinized starch, low-substitution hydroxypropyl cellulose, and It may contain microcrystalline cellulose. Preferably, the dispersing agent is croscarmellose. It is sodium. In the preferred application of the present invention, surfactants include but are not limited to these. These may include betaine, quaternary ammonium salts, polysorbates, and poloxamer. Preferably, the surfactant is poloxamer. In the preferred application of the present invention, the lubricant shall include, but not be limited to, the following: including sodium stearyl fumarate, magnesium stearate, calcium stearate, talc, stearic acid. It may contain acids and mixtures thereof. Preferably, lubricants include talc and magnesium. It is stearate. In the preferred application of the present invention, the solvent shall include, but not be limited to, these. including methanol, ethanol, isopropyl alcohol, acetone, methyl ethyl ketone, dichloromethane, dichloroethane, chloroform or carbon tetrachloride and solutions of these mixtures It may contain. Preferably, the solvents are ethanol and dichloromethane. 8 Additionally, in the preferred application, a mixture containing dichloromethane and ethanol. The solvent ratio is 4:1. The proposed approach provides an immediate-release pharmaceutical composition, where The weight amounts of the total composition are given as w / w % in Table 3 below. It is as stated: Table 3: Unit Formula for Example 1 Contents a / a, % Amorphous Tolvaptan 15.0 – 18.0 Lactose 48.0 – 50.0 Microcrystalline cellulose 10.0 – 12.0 Croscarmellose sodium 10.0 – 12.0 Pregelatinized starch 10.0 – 12.0 Poloxamer 0.0 – 1.0 Talk 0.0 – 1.0 Magnesium stearate 0.0 – 1.0 Dichloromethane: Ethanol in sufficient quantity. Core tablet 100.0 The detailed manufacturing steps for the immediate-release pharmaceutical Sample 1 are given below: i. Amorphous tolvaptan, croscarmellose sodium, microcrystalline cellulose, lactose and Pregelatinized starch was sieved through a suitable sieve and cubic It was transferred to the mixer and mixed. ii. Poloxamer in a sufficient mixture of dichloromethane and ethanol It has been dissolved. iii. The solution from Step (ii) is added to the preparation from Step (i) to obtain a high-disintegration solution. The granulation process has been carried out. The granules prepared in step (iii) are dried and passed through a suitable sieve. has been passed, v. Magnesium stearate and talc were sieved through a suitable sieve and Step by adding to the granules prepared in (iv) to obtain a homogeneous final mixture. It is mixed. After obtaining the final mixture for Sample 1, printing was accomplished with difficulty. Then, The printed tablets were subjected to in vitro dissolution studies, and the dissolution 9 conditions, gastrointestinal tract considerations of orally administered solid dosage forms determined by taking into account the following. Dissolution test, in 0.22% sodium lauryl sulfate (SLS) aqueous solution This is being carried out. Other conditions are: dissolution medium volume 900 ml, temperature. 37°C±0.5, rotation speed 50 rpm, apparatus, pallet and dissolution working time 60 minutes It has been determined as follows. The amount of active substance that dissolved over time was determined by HPLC. Table 4: Sample 1 and reference in 0.22% sodium lauryl sulfate (SLS) aqueous solution. Comparison of product dissolution profiles Results, % Duration, minutes. Reference product Example 1 62 37 79 37 88 38 94 37 45 96 39 60 97 39 According to the results given in Table 3 above, the emission pattern of Sample 1 is similar to the reference pattern. It is significantly slower than the product. The f2 similarity factor is a value used to compare two drug profiles, and if this If the value is higher than 50, the two products being compared have similar dissolution profiles. It shows. The f2 similarity factor of Sample 1 and the reference product was calculated as 17, and this The value is less than 50, and the products being compared are not similar. Surfactants increase the dissolution rate in pharmaceutical formulations by increasing hydrophilicity. or pharmaceutically accepted as being used to increase the release of the active substance It is one of the available excipients. However, in current practice, the dissolution medium and pharmaceutical composition Even if it contains surfactant, in Example 1 the rate of active substance release is not the desired therapeutic. It is not suitable for effective resolution. Therefore, it is necessary to overcome the low dissolution profile and be stable against oxidation. Another example has been suggested. Therefore, the solvent in the production process. It is not present. Furthermore, the proposed formulation does not contain surfactants. It is not available. Direct printing of the component without a pre-granulation or agglomeration process. Another production process is pressing the mixture into tablet form. Therefore, The direct printing process is where all the components are mixed together to make a tablet. Only a few are placed in the tablet press without needing to be changed. It has a process step. Therefore, it has low solubility and poor fluidity. some active ingredients present difficulties in the later stages of the direct printing method. They might encounter each other. Direct printing method of pharmaceutical compositions containing amorphous tolvaptan Producing it using this method presents many challenges due to the nature of the active ingredient. This Therefore, formulation design that can implement the direct printing method. It has been suggested. However, surprisingly, the inventors of the present invention used direct printing. It has an improved dissolution profile and stability, produced using this method. amorphous tolvaptan and containing at least one pharmaceutically acceptable excipient He succeeded in formulating a pharmaceutical composition. Therefore, Example-2, another application, will be applied to Example-1 as follows: It has been designed with modifications: - Poloxamer has been removed from the composition. - Magnesium stearate has been identified as the sole lubricant in the composition. - The amount of pregelatinized starch acts as both a binding agent and a dispersing agent. It is configured for use as such. - Microcrystalline cellulose content as a filler due to its dry binding properties. It is designed to be used as a raw material. - The amount of croscarmellose sodium used as a dispersing agent has been adjusted. 11 - Other auxiliary materials are used to ensure the final weight remains constant. It has been adjusted. The formulation for the proposed application, defined as Example 2, is shown in Table 5. It has been given. Table 5: Unit Formula for Example 2 Contents a / a, % Amorphous Tolvaptan 15.0 – 18.0 Microcrystalline cellulose 17.0 – 20.0 Lactose 48.0 – 51.0 Croscarmellose sodium 7.0 – 8.0 Pregelatinized starch 7.0 – 8.0 Magnesium stearate 0.0 – 1.0 Core tablet 100.0 Detailed manufacturing steps for immediate-release pharmaceutical compositions are listed below. is provided: i. Amorphous tolvaptan, croscarmellose sodium, microcrystalline cellulose, lactose and Pregelatinized starch was sieved through a suitable sieve and cubic It was transferred to the mixer and mixed. ii. Lactose was sieved through a suitable sieve and prepared in Step (i). added to granules, iii. Magnesium stearate was sieved through a suitable sieve and in Step (ii) by adding to the prepared granules to obtain a homogeneous final mixture. It is mixed. Tablet printing was carried out with the final mixture in step (iii). After obtaining the final mixture for Sample 1, the final mixture fluidity of Sample 2 is determined. compressed and bulk density ratio, compressibility index and Hausner ratio corresponding USP <1174> It was investigated using the appropriate analytical method. The compressibility index and Hausner ratio were 18.00 and 1.22, respectively. The calculated bulk and compressed density results were 0.89 g / ml and 1.09 g / ml, respectively. It is in g / ml. 12 Based on the fluidity scale results, the final mixture has “good” flow properties. it has flow properties resulting from the amorphous tolvaptan active ingredient. This means that the disadvantage has been improved in Example 2. Subsequently, in vitro dissolution studies were conducted under the conditions mentioned above. The printing press was used to perform this operation, and the comparative results are shown in Table 6. It has been given. Table 6: Sample 2 and reference in 0.22% sodium lauryl sulfate (SLS) aqueous solution. Comparison of product dissolution profiles Results, % Duration, minutes. Reference product Example 2 62 73 79 84 88 89 94 93 45 96 95 60 97 96 According to the results given in Table 6 above, the emission pattern of Sample 2 matches the reference pattern. The product is similar; Example 2, although it does not contain any surfactants, f 2 The similarity factor was calculated as 56. Next, we examined the degradation effects of the production process on Sample 2. To evaluate, an oxidation study was conducted as described above. It has happened. Table 7: Results of the hardened degradation study conducted in Example 2. Maximum Impurity, % 30% hydrogen peroxide Beginning 4 days Oxidative decomposition 0.12 0.12 According to the above results, amorphous materials produced using the direct printing process... Enhanced pharmaceutical composition containing tolvaptan, challenging degradation. It remains stable under stressful conditions. 13 The direct printing method is problematic due to the low solubility and poor fluidity of amorphous tolvaptan. Despite having some challenges due to its characteristics, it is the preferred choice. In its application, the improved pharmaceutical composition overcomes all challenges. It has arrived. Additionally, accelerated for 2 months at 40°C±2°C / 75%±5% relative humidity. On Sample 2 specimens kept under stable conditions, a validated test was performed. Stability study to determine impurity profile using analytical method. It has been done. Table 8: Sample 2 produced using the direct printing method. Results of the impurity analysis performed Maximum Impurity, % 2 months Beginning 40°C / 75%RH Example 2 0.12 0.13 According to the table above, the maximum impurity results for Sample 2 are after 2 months. It is almost identical to an accelerated stability study. The present invention involves amorphous tolvaptan with improved fluidity properties. improved pharmaceutical composition using direct printing method It has been produced; here, the final product has been made more difficult compared to the initial conditions. It is highly stable under degradation and accelerated stabilization conditions. Although the present invention is described in the specific examples above, The subject matter of the invention is defined by the claims presented, by a person skilled in the field. various modifications and changes can be made within the scope It should be known. 14

Claims

1. Amorphous tolvaptan and at least one pharmaceutically acceptable excipient. an immediate-release stable pharmaceutical produced using a direct printing method containing It is a composition, and its characteristic feature is that the composition is as follows: Contents a / a, % Amorphous Tolvaptan 15.0 – 18.0 Microcrystalline cellulose 17.0 – 20.0 Lactose 48.0 – 51.0 Croscarmellose sodium 7.0 – 8.0 Pregelatinized starch 7.0 – 8.0 Magnesium stearate 0.0 – 1.0 Core tablet 100.0 2. According to Claim 1, it is an immediate-release stable pharmaceutical composition with the following characteristics: The composition does not contain surfactants.

3. According to Claim 1, it is an immediate-release stable pharmaceutical composition with the following characteristics: fillers, binders containing at least one pharmaceutically acceptable excipient The process involves selecting a substance, a dispersing agent, and a lubricant.

4. According to claim 3, it is an immediate-release stable pharmaceutical composition with the following characteristics: Filling material: dibasic calcium phosphate dihydrate, polysaccharides, mainly. microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic Salts can include mainly calcium salts and mixtures of the same substances.

5. According to claim 3, it is an immediate-release stable pharmaceutical composition with the following characteristics: Binding agent: lactose monohydrate, starch, pregelatinized starch, cellulose or cellulose derivatives, povidone, sucrose, polyethylene glycol or mixtures thereof It is the ability to include.

6. According to claim 3, it is an immediate-release stable pharmaceutical composition with the following characteristics: Dispersing agents: croscarmellose sodium, sodium starch glycolate, crospovidon, corn starch, pregelatinized starch, low-substitution hydroxypropyl cellulose, and It can contain microcrystalline cellulose.

7. According to claim 3, it is an immediate-release stable pharmaceutical composition with the following characteristics: lubricant sodium stearyl fumarate, magnesium stearate, calcium stearate, talc, It may contain stearic acid and mixtures thereof.

8. An immediate-release stable pharmaceutical according to any of the previous requirements. It is a composition, and its distinguishing feature is that the composition is printed in tablet dosage form.

9. Production of immediate-release pharmaceutical compositions containing amorphous tolvaptan. The direct printing method involves the following steps: i. Amorphous tolvaptan, croscarmellose sodium, microcrystalline cellulose, lactose and Pregelatinized starch was sieved through a suitable sieve and cubic It was transferred to the mixer and mixed. ii. Lactose was sieved through a suitable sieve and prepared in Step (i). added to granules, iii. Magnesium stearate was sieved through a suitable sieve and in Step (ii) by adding to the prepared granules to obtain a homogeneous final mixture. It is mixed. Tablet printing was carried out with the final mixture in step (iii).

10. Hyponatremia, polycystic kidney disease, and body fluid loss in heart failure. Prevention of fluid retention in liver cirrhosis or liver disease, any of the previous requests for use in reducing or treating According to one source, it is an immediate-release, stable pharmaceutical composition. 16