WO2023128903A1 - Improved manufacturing method for formulations comprising amorphous tolvaptan - Google Patents
Improved manufacturing method for formulations comprising amorphous tolvaptan Download PDFInfo
- Publication number
- WO2023128903A1 WO2023128903A1 PCT/TR2021/051626 TR2021051626W WO2023128903A1 WO 2023128903 A1 WO2023128903 A1 WO 2023128903A1 TR 2021051626 W TR2021051626 W TR 2021051626W WO 2023128903 A1 WO2023128903 A1 WO 2023128903A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- immediate release
- release pharmaceutical
- composition according
- tolvaptan
- Prior art date
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- GYHCTFXIZSNGJT-UHFFFAOYSA-N tolvaptan Chemical compound CC1=CC=CC=C1C(=O)NC(C=C1C)=CC=C1C(=O)N1C2=CC=C(Cl)C=C2C(O)CCC1 GYHCTFXIZSNGJT-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 229960001256 tolvaptan Drugs 0.000 title claims abstract description 60
- 239000000203 mixture Substances 0.000 title claims description 33
- 238000004519 manufacturing process Methods 0.000 title claims description 15
- 238000009472 formulation Methods 0.000 title description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 39
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000007907 direct compression Methods 0.000 claims abstract description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 14
- 239000004094 surface-active agent Substances 0.000 claims description 10
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 9
- 229920000881 Modified starch Chemical class 0.000 claims description 9
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 9
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 9
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- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 8
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 8
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 7
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- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical class O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 2
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
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- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical group CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 claims description 2
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical group CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Definitions
- Tolvaptan appears as a white crystalline powder and non-hygroscopic and is soluble in benzyl alcohol and methanol but practically insoluble in hexane and water (0.00005 W7V% at 25°C) across a wide range of pH.
- Tolvaptan and its pharmaceutically acceptable salts thereof first have been described in EP1028111 numbered patent document by Otsuka Pharmaceutical Co. for treatment of hypertension, edema, ascites, heart failure, renal function disorder, vasopressin parasecretion syndrome (SIADH), hepatocirrhosis, hyponatremia, hypokaliemia, diabetic, and circulation disorder.
- SIADH vasopressin parasecretion syndrome
- Tolvaptan has an asymmetric centre and can exist as two enantiomers. However, the active substance has been developed as a racemate with R and S enantiomers. Since drug substance is a racemate it exhibits no optical rotation.
- the granulation solvent may include, but are not limited to methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dichloromethane, dichloroethane, chloroform, or carbon tetrachloride; and mixed solvents of those.
- the granulation solvents are ethanol and dichloromethane.
- Example-2 was designed based on the modifications to be implemented on Example- 1 below:
- Example 2 The formulation of proposed embodiment identified as Example 2 is given in the Table 5.
Abstract
The present invention relates to stable immediate release pharmaceutical composition comprising tolvaptan or one of its pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient manufactured by using direct compression process.
Description
IMPROVED MANUFACTURING METHOD FOR FORMUEATIONS COMPRISING AMORPHOUS TOEVAPTAN
Field Of Invention
The present invention relates to stable immediate release pharmaceutical composition comprising tolvaptan or one of its pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient manufactured by using direct compression process.
State Of Art
Arginine vasopressin (A VP) is a neuropeptide hormone that is synthesized in the brain by the hypothalamus. It actively plays role to the regulation of water and solute excretion by the kidney, as well as blood pressure control and associated disorders such as congestive heart failure (CHF), liver cirrhosis, and syndrome of inappropriate antidiuretic hormone (SIADH) secretion.
Conventional therapy to treat patients, who suffer from increased AVP levels, often exacerbates hyponatraemia and other electrolyte imbalances by promoting a loss of water together with electrolytes.
A selective vasopressin V2 receptor antagonist can be used for minimizing the effects of the increased AVP levels and reduce water retention without disturbing electrolytic balance.
Tolvaptan (OPC-41061) is a selective vasopressin V2-receptor antagonist that selectively inhibits AVP induced water reabsorption at the renal collecting ducts by blocking V2 receptors located therein, which increased water excretion without any change in electrolyte excretion is occurred.
The chemical name of tolvaptan is (±)-4’-[(7- chloro-2,3,4,5-tetrahydro-5-hydroxy-lH-l- benzazepin-l-yl) carbonyl] -o-tolu-m-toluidide. The molecular formula is C26H25C1N2O3 and the compound has a molecular weight of 448.94 g/mol.
The structural formula of tolvaptan is shown in the Formula I.
Formula I
Tolvaptan appears as a white crystalline powder and non-hygroscopic and is soluble in benzyl alcohol and methanol but practically insoluble in hexane and water (0.00005 W7V% at 25°C) across a wide range of pH.
Tolvaptan and its pharmaceutically acceptable salts thereof first have been described in EP1028111 numbered patent document by Otsuka Pharmaceutical Co. for treatment of hypertension, edema, ascites, heart failure, renal function disorder, vasopressin parasecretion syndrome (SIADH), hepatocirrhosis, hyponatremia, hypokaliemia, diabetic, and circulation disorder.
Tolvaptan has an asymmetric centre and can exist as two enantiomers. However, the active substance has been developed as a racemate with R and S enantiomers. Since drug substance is a racemate it exhibits no optical rotation.
Tolvaptan was firstly commercially authorized by U.S. Food&Drug Administration in August 2009. The medicinal product of it been launched in the immediate release tablet dosage form under the name of the SAMSCA® in the strength of 15 mg and 30 mg which is used for the treatment of clinically significant a (serum sodium < 125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), in patients with heart failure, cirrhosis, and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).
Then, in 2013 Otsuka Pharmaceutical Co. proposed a higher dosing regimen to slow the rate of kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD).
The new proposed indication for tolvaptan has been launched in the film coated tablet form under the name of the JINARQUE® or JINARC® in the strength of 15 mg, 30 mg, 45 mg and 60 mg, wherein the 15 mg and 30 mg strengths are dose proportional with regard to the active substance and excipients. The 45 mg and 90 mg strengths of tablets were designed to be quantitatively proportional with the 60 mg tablets.
In the state of art there are many patents/patent applications which are summarized below.
EP2167046 relates to solid pharmaceutical composition comprising tolvaptan or a pharmaceutically acceptable salt thereof, hydroxypropylcellulose containing a hydroxypropyl group in an amount of 50 wt% or greater; and at least one member selected from the group consisting of carmellose, sodium carboxy methyl starch, crospovidone, and low substituted hydroxypropylcellulose with an average particle diameter of 30 to 70 pm, and a 90% cumulative particle diameter of 100 to 200 pm manufactured by wet granulation method.
EP2961383 relates to a suspension for oral pharmaceutical composition comprising amorphous tolvaptan, hydroxypropyl methylcellulose (HPMC) and a water.
JPH1121241 relates to a pharmaceutical composition comprising amorphous tolvaptan prepared by dissolving with hydroxypropyl cellulose in an organic solvent and spray-drying the mixture to obtain a powder.
WO2014068586 relates to solid pharmaceutical composition comprising tolvaptan or a pharmaceutically acceptable salt thereof, a polymer selected from povidone; graft co-polymer of polyethylene glycol, polyvinylcaprolactam and polyvinylacetate; and combinations thereof manufactured by fluid bed top spray granulation.
EP2586464 relates to solid pharmaceutical composition comprising amorphous tolvaptan and crosslinked polyvinylpyrrolidone, wherein the ratio of the active ingredient tolvaptan and the cross-linked polyvinylpyrrolidone by weight is 1:0.1-10. The manufacturing step of the composition is stalled with dissolving tolvaptan in the organic solvent.
W02020122670 relates to pharmaceutical composition comprising tolvaptan or a pharmaceutically acceptable salt thereof, polyvinylpyrrolidone used as a water penetration enhancer and at least one from the group consisting of methylene chloride and ethanol used as an organic solvent for dissolving tolvaptan and polyvinylpyrrolidone.
CN109646391 relates to a sustained release pharmaceutical composition comprising tolvaptan, hypromellose and at least one excipient, wherein the amount of hypromellose is between 30% and 45% of the total amount of the preparation with having viscosity ranges from 50 mPas to 10,000 mPas.
Tolvaptan active substance is poorly soluble in water and the solubility is poor across all pH ranges. Thus, it is expected to have low absorption due to poor solubility. However, following single dose of 30 to 480 mg, it is rapidly absorbed in healthy volunteers with a median time to peak plasma concentrations of about 2 hours. The absolute bioavailability is about 56% with close relative bioavailability between different dose strengths. The mean elimination half-life is 7.8 hour.
Co-administration with food had no significant or clinically relevant on plasma concentrations. In the plasma, it is highly bound mainly to plasma proteins of serum albumin and al-acid glycoprotein.
Based on the prior art given in the above, many formulation strategies have been carried out to overcome the poor solubility and low absorbability in the gastrointestinal tract of tolvaptan by processing with a solvent or performing pre-treatment with one or more excipient before further manufacturing steps.
However, the inventors of the present invention have succeeded to develop a pharmaceutical composition comprising tolvaptan or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient in the immediate release dosage form manufactured by using direct compression that presents improved stability and solubility without comprising any surfactant.
Summary Of The Invention
The object of this invention is to develop stable immediate release pharmaceutical composition comprising a therapeutically effective amount of tolvaptan or a pharmaceutically acceptable salt thereof, which is a selective vasopressin V2-receptor antagonist.
Another object of the present invention is to develop stable immediate release pharmaceutical composition comprising tolvaptan in amorphous form.
According to state of the art, tolvaptan active substance is known to be poorly soluble in physiological pH ranges with having very, very poor flowability. Thus, the objective of the present invention is to provide a pharmaceutical composition comprising amorphous tolvaptan that exhibits proper flowability. Thus, the processability could be improved in parallel with improving the dissolution profile.
Another object of the present invention is to obtain a stable immediate release pharmaceutical composition comprising amorphous tolvaptan which is the most unstable nature form.
Another object of the present invention is related to a pharmaceutical composition containing the active ingredient, diluent, binder, disintegrant and lubricant with respect to the intended form of administration. The formulation does not comprise any surfactant.
Further object of the present invention is to provide a stable immediate release pharmaceutical composition comprising amorphous tolvaptan, proper excipients selected to use direct compression manufacturing method.
Detailed Description Of The Invention
The present invention provides an immediate release pharmaceutical composition comprising tolvaptan or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipients manufactured with a proper manufacturing method to develop a stable drug product with enhanced dissolution profile.
Tolvaptan is a selective vasopressin V2 receptor antagonist that blocks renal collecting ductular arginine-vasopressin (A VP) V2-receptors to inhibit reabsorption of free water from glomerular filtrate in the kidneys.
The inventors conducted a characterization study on amorphous tolvaptan to obtain a pharmaceutical composition comprising amorphous tolvaptan or a pharmaceutically acceptable salt thereof with improved the dissolution rate, absorbability from the gastrointestinal tract and thereby enhance the bioavailability.
The amorphous dosage form is one of the promising strategy to overcome the poor oral bioavailability of poorly water soluble drugs in which it may increase the dissolution rate and apparent solubility of tolvaptan compared to that of its crystalline counterpart due to having higher free energy. However, it also causes to obtain thermodynamically unstable form.
According to the prior art, tolvaptan is classified as BCS Class IV, having low solubility and low permeability compound as per the Biopharmaceutical Classification System (BCS).
Table 1: Solubility results of Tolvaptan amorphous active substance
The given solubility results mean that tolvaptan is insoluble in water and its solubility is not pH dependent.
Moreover, a forced degradation study on amorphous tolvaptan was performed under oxidation and day-light stress conditions to evaluate the degradation degree. The study was performed with 30.0 mg of tolvaptan amorphous sample at 80°C (±2°C) for 4 days in 30% hydrogen peroxide solution. In addition, a separate 3 to 5 days under day-light stress condition study was performed. Then, the samples were subjected to HPLC analysis.
Table 2: The results of forced degradation study conducted on tolvaptan amorphous
According to the forced degradation study, amorphous tolvaptan decomposes under oxidation stress condition and no change in day-light stress condition.
Further, the flowability characteristics of tolvaptan amorphous was investigated.
The flowability of the amorphous tolvaptan was determined by applying analytical method in accordance with USP < 1174> wherein the compressibility index and Hausner ratio correspond to the ratio of tapped density to bulk density. The study presented compressibility index and Hausner ratio as 44.00 and 1.738, respectively wherein bulk density was 0.19 g/ml and tapped density was 0.34 g/ml.
Based on the results of scale of flowability considering international guidelines, flowability is classified as “very, very poor”.
In the state of art, to overcome its low solubility in physiological pH range and tendency to crystallization over time, amorphous composite comprising crystalline or amorphous form of tolvaptan and at least one pharmaceutically acceptable excipient is produced in many ways like dissolving tolvaptan and at least one polymer in a solvent or mixture of solvents.
Based on the information about the solubility, flowability and degradation of amorphous tolvaptan and the knowledge from prior art, development studies started with proposing a formulation design that could be manufactured by using wet granulation method using organic solvents.
At first, a pharmaceutical composition comprising amorphous tolvaptan or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient is manufactured by using wet granulation method based on the prior art.
Wet granulation method is one of the type of unit operations in the production of pharmaceutical dosage forms that refers to a process involving granulating the powder with granulating solution to achieve the desired properties for subsequent processes in which granulating solution can be used alone or as a solvent containing binder or granulating agent.
In a preferred embodiment of the present invention is to provide a pharmaceutical compositions containing tolvaptan or a pharmaceutically acceptable salt thereof by using wet granulation process wherein provided for the manufacture of tablets containing the active ingredient, diluents, binder, disintegrant, surfactant, lubricants and granulation solvent selected as to be the most suitable ones with respect to the intended form of administration.
In the preferred embodiment of the present invention, the diluent may include, but are not limited to dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof. Preferably, diluents are lactose and microcrystalline cellulose.
In the preferred embodiment of the present invention, the binder may include, but are not limited to lactose monohydrate, starch, pregelatinized starch, cellulose or cellulose derivatives, povidone, sucrose, polyethylene glycol, or mixtures thereof. Preferably, the binder is pregelatinized starch.
In the preferred embodiment of the present invention, the disintegrant may include, but is not limited to croscarmellose sodium, sodium starch glycolate, crospovidone, com starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose. Preferably, the disintegrants are croscarmellose sodium.
In the preferred embodiment of the present invention, the surfactant may include, but is not limited to betain, quaternary ammonium salts, polysorbates, poloxamer. Preferably, the surfactant is a poloxamer.
In the preferred embodiment of the present invention, the lubricants may include, but are not limited to sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof. Preferably, the lubricants are talc and magnesium stearate.
In the preferred embodiment of the present invention, the granulation solvent may include, but are not limited to methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dichloromethane, dichloroethane, chloroform, or carbon tetrachloride; and mixed solvents of those. Preferably, the granulation solvents are ethanol and dichloromethane.
Further, the preferred embodiment, a mixed solvent comprising dichloromethane and ethanol is in the ratio of 4:1.
The proposed embodiment provided an immediate release pharmaceutical composition wherein the amounts are in w/w% by weight of the total composition as stated in the Table 3 below:
Table 3: Unit Formula of Example 1
The detailed manufacturing steps of Example 1 for immediate release pharmaceutical were presented below:
i. Amorphous tolvaptan, croscarmellose sodium, microcrystalline cellulose, lactose and pregelatinized starch were screened through a proper sieve and transferred into cubic mixer and stirred, ii. Poloxamer was dissolved in sufficient quantity of dichloromethane and ethanol mixture iii. The preparation in Step (i) was added to solution in Step (ii) to perform high-shear granulation process, iv. The granules prepared in Step (iii) were dried and shifted through a proper sieve, v. Magnesium stearate and talc were screened through a proper sieve and added to the granules prepared in Step (iv) and stirred to obtain a uniform final blend.
After getting the final blend of Example 1, the compression was performed difficultly. Then, compressed tablets were subjected to in vitro dissolution study and the dissolution conditions were designated considering the gastrointestinal pathway of orally applied solid dosage forms.
The dissolution test is carried out at 0.22% sodium lauryl sulphate (SLS) aqueous solution. Other conditions are defined as; volume of dissolution media is 900 ml, temperature is 37°C±0.5°C, rotation speed is 50 rpm, apparatus is paddle and the duration of dissolution study is 60-minute.
The amount of dissolved active ingredient over time was determined by HPLC.
Table 4: Comparison of dissolution profiles of Example 1 and reference drug product in 0.22% sodium lauryl sulphate (SLS) aqueous solution
Based on the results presented in Table 3 above, the release pattern of Example 1 was remarkably slower than the reference drug product.
The similarity factor f2 is a value for the comparison of two drug profiles based on the value of, if that value is higher than 50, the two drug products in comparison show similar dissolution profiles.
The similarity factor f2 of Example 1 and the reference drug product was calculated as 17 since this value was less than 50 the product compared was not similar.
The surfactant is one of the pharmaceutically acceptable excipient used in pharmaceutical formulations to increase the dissolution rate or active ingredient release by increasing hydrophilicity.
However, in the present embodiment, even if, the dissolution media and pharmaceutical composition included surfactant, the release rate of active substance in Example 1 was not suitable to get desired therapeutically effective solubility.
Thus, another example was proposed to overcome the low dissolution profile with having stable to oxidation. Therefore, the manufacturing process was solvent free. Besides, the proposed formulation was also surfactant free.
Direct compression is another manufacturing processes that is the tableting of a blend of ingredients without a preliminary granulation or agglomeration process. Thus, direct compression process has only few process steps where all ingredients are mixed and placed in a tablet press to make a tablet without any of the ingredients having to be altered. Thus, some kind of active substance having poor solubility and flowability can have challenges during proceeding steps in direct compression.
Use of direct compression manufacturing method in pharmaceutical compositions comprising tolvaptan amorphous has multiple challenges due to the nature of active substance itself. Therefore, formulation design was proposed to be able to perform direct compression method.
Nevertheless, the inventors of the present invention have surprisingly succeeded to formulate a pharmaceutical composition comprising amorphous tolvaptan and at least one pharmaceutically acceptable excipient manufactured by using direct compression method with having improved dissolution profile and stability.
Thus, another embodiment, Example-2, was designed based on the modifications to be implemented on Example- 1 below:
Poloxamer was removed from the composition.
Magnesium stearate was assigned as the only lubricant in the composition.
The amount of pregelatinized starch was adjusted to be used both as binder and disintegrant.
The amount of microcrystalline cellulose was adjusted to be used as diluent due to dry binding properties
The amount of croscarmellose sodium used as disintegrant was adjusted.
Amounts of other excipients were adjusted to keep the final weight constant.
The formulation of proposed embodiment identified as Example 2 is given in the Table 5.
Table 5: Unit Formula of Example 2
The detailed manufacturing steps for immediate release pharmaceutical composition are presented below: i. Amorphous tolvaptan, croscarmellose sodium, microcrystalline cellulose, lactose and pregelatinized starch were screened through a proper sieve and transferred into cubic mixer and stirred, ii. Lactose was screened through a proper sieve and added to the granules prepared in Step (i), iii. Magnesium stearate was screened through a proper sieve and added to the granules prepared in Step (ii) and stirred to obtain a uniform final blend, iv. Tablet compression was performed with the final blend in Step (iii).
After getting the final blend of Example 1, the flowability of final blend of Example 2 was investigated by performing analytical method in accordance with USP <1174> the compressibility index and Hausner ratio correspond to the ratio of tapped density to bulk density.
The compressibility index and Hausner ratio were calculated as 18.0 and 1.22, respectively and the results of bulk and tapped densities were 0.89 g/ml and 1,09 g/ml.
Based on the results of scale of flowability, the final blend had “fair” flow characteristic which means that the disadvantage of flow properties raised from amorphous tolvaptan active substance was improved in Example 2.
Then, the compression press was performed to conduct the in vitro dissolution study within the conditions stated above and the comparative results are presented in Table 6.
Table 6: Comparison of dissolution profiles of Example 2 and reference drug product in 0.22% sodium lauryl sulphate (SLS) aqueous solution
Based on the results presented in Table 6 above, the release pattern of Example 2 was similar to the reference drug product, in which the similarity factor f2 were calculated as 56 even though the Example 2 does not comprise any surfactant.
Then, to evaluate the effects of manufacturing process on degradation of Example 2, the oxidation study was carried out as identified above. Table 7: The results of forced degradation study conducted on Example 2
According to the results above, the developed pharmaceutical composition comprising amorphous tolvaptan manufactured by direct compression process became stable under forced degradation stress condition.
Although direct compression has some challenges for amorphous tolvaptan due to having poor solubility and flowability properties, in the preferred embodiment, the developed pharmaceutical composition was overcome all challenges.
Further, stability study was conducted to detect the impurity profile with a validated analytical method on Example-2 samples expose to accelerated stability conditions of 40°C±2°C/75%±5% relative humidity for 2-month period.
Table 8: The results of impurity analysis conducted on the Example-2 manufactured by direct compression process
According to the table above, maximum impurity results of Example 2 were approximately not changed under the accelerated stability study for 2-month period.
In the present invention, the developed pharmaceutical composition comprising amorphous tolvaptan having improved flowability properties was manufactured by using direct compression process where the final product is quite stable under forced degradation and accelerated stability conditions compared to initial conditions.
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.
Claims
1. A stable immediate release pharmaceutical composition comprising amorphous tolvaptan and at least one pharmaceutically acceptable excipient manufactured by using direct compression process.
2. A stable immediate release pharmaceutical composition according to Claim 1, wherein the composition does not comprise any surfactant.
3. A stable immediate release pharmaceutical composition according to Claim 1, wherein at least one pharmaceutically acceptable excipient is selected from diluents, binder, disintegrant, and lubricant.
4. A stable immediate release pharmaceutical composition according to claim 3, wherein the diluents are selected from dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof.
5. A stable immediate release pharmaceutical composition according to claim 3, wherein the binder is selected from lactose monohydrate, starch, pregelatinized starch, cellulose or cellulose derivatives, povidone, sucrose, polyethylene glycol, or mixtures thereof.
6. A stable immediate release pharmaceutical composition according to claim 3, wherein the disintegrant is selected from croscarmellose calcium, croscarmellose sodium, sodium starch glycolate, crospovidone, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose.
7. A stable immediate release pharmaceutical composition according to claim 3, wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof.
8. A stable immediate pharmaceutical composition according to any one of the preceding claims, wherein the composition is compressed into a tablet dosage form.
9. A stable immediate release pharmaceutical composition according to any one of the preceding claims; wherein the composition is:
10. A direct compression method for producing immediate release pharmaceutical composition comprising amorphous tolvaptan comprises the steps of; i. Amorphous tolvaptan, croscarmellose sodium, microcrystalline cellulose, lactose and pregelatinized starch are screened through a proper sieve and transferred into cubic mixer and stirred, ii. Lactose is screened through a proper sieve and added to the granules prepared in Step (i), iii. Magnesium stearate is screened through a proper sieve and added to the granules prepared in Step (ii) and stirred to obtain a uniform final blend, iv. Tablet compression is performed with the final blend in Step (iii).
11. A stable immediate release pharmaceutical composition according to any one of the preceding claims for use in the treatment of preventing, reducing, or treating hyponatremia, polycystic kidney disease, body fluid retention in heart failure, or body fluid retention in liver cirrhosis.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102406622A (en) * | 2011-11-16 | 2012-04-11 | 浙江华海药业股份有限公司 | Tolvaptan solid preparation |
| WO2014068586A2 (en) * | 2012-10-31 | 2014-05-08 | Hetero Research Foundation | Solid oral compositions of tolvaptan |
| CN107432867A (en) * | 2016-05-26 | 2017-12-05 | 天津市汉康医药生物技术有限公司 | A kind of tolvaptan piece |
| CN107898759A (en) * | 2017-12-06 | 2018-04-13 | 佛山市腾瑞医药科技有限公司 | A kind of Tolvaptan solid dispersion preparation and preparation method thereof |
| CN108014098A (en) * | 2017-12-06 | 2018-05-11 | 佛山市腾瑞医药科技有限公司 | A kind of tolvaptan fast release micropill preparation, preparation method |
-
2021
- 2021-12-30 WO PCT/TR2021/051626 patent/WO2023128903A1/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102406622A (en) * | 2011-11-16 | 2012-04-11 | 浙江华海药业股份有限公司 | Tolvaptan solid preparation |
| WO2014068586A2 (en) * | 2012-10-31 | 2014-05-08 | Hetero Research Foundation | Solid oral compositions of tolvaptan |
| CN107432867A (en) * | 2016-05-26 | 2017-12-05 | 天津市汉康医药生物技术有限公司 | A kind of tolvaptan piece |
| CN107898759A (en) * | 2017-12-06 | 2018-04-13 | 佛山市腾瑞医药科技有限公司 | A kind of Tolvaptan solid dispersion preparation and preparation method thereof |
| CN108014098A (en) * | 2017-12-06 | 2018-05-11 | 佛山市腾瑞医药科技有限公司 | A kind of tolvaptan fast release micropill preparation, preparation method |
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