WO2024043842A1 - Pharmaceutical compositions comprising chenodeoxycholic acid (cdca) as active ingredient and other relevant excipients - Google Patents

Pharmaceutical compositions comprising chenodeoxycholic acid (cdca) as active ingredient and other relevant excipients Download PDF

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Publication number
WO2024043842A1
WO2024043842A1 PCT/TR2022/050888 TR2022050888W WO2024043842A1 WO 2024043842 A1 WO2024043842 A1 WO 2024043842A1 TR 2022050888 W TR2022050888 W TR 2022050888W WO 2024043842 A1 WO2024043842 A1 WO 2024043842A1
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Prior art keywords
cdca
pharmaceutical composition
composition according
pharmaceutically acceptable
isopropyl alcohol
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PCT/TR2022/050888
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French (fr)
Inventor
Abdulhaluk SANCAK
Yunus SANCAK
Ayse Figen ONUK GOREN
Hakan GURPINAR
Asiye Sezgin
Berkant KOSEBAS
Azmatullah ANSARI
Gizem ALKAN
Koray YILMAZ
Kadir CAKMAK
Furkan Enes DEMIRCAN
Elif Zehra ATUKEREN
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Pharmactive Ilac Sanayi Ve Ticaret A.S.
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Priority to PCT/TR2022/050888 priority Critical patent/WO2024043842A1/en
Publication of WO2024043842A1 publication Critical patent/WO2024043842A1/en

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    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the present invention relates to the preparation of pharmaceutical compositions comprising chenodeoxycholic acid (CDCA) is used in the treatment of cerebrotendineous xanthomatosis (CTX), a rare autosomal recessive disorder, having a specific ratio of solvents in internal phase and a diluent in external phase.
  • CX cerebrotendineous xanthomatosis
  • Chenodeoxycholic acid has a chemical name as (4R)-4- [(1R,3aS,3bR,4R,5aS,7R,9aS,9bS,11aR)-4,7-dihydroxy-9a,11a-dimethylhexadecahydro-1H- cyclopenta[ ⁇ ]phenanthren-1-yl]pentanoic acid and its chemical structure is shown in the Figure I.
  • CDCA has molecular weight of 392.6 g/mol. It is a white crystalline substance insoluble in water but soluble in alcohol and acetic acid, with melting point at 165–167 °C.
  • Figure 1 Chenodeoxycholic acid is a bile acid naturally found in the body.
  • CTX cerebrotendineous xanthomatosis
  • CTX is associated with abnormally high levels of cholestanol in the blood and accumulation of cholestanol and cholesterol in the brain, tendon xanthomas, and bile.
  • Treatment with chenodeoxycholic acid (CDCA; chenodiol) is the current standard of care.
  • CDCA can help restore normal sterol, bile acid, bile alcohol, and cholestanol levels.
  • CDCA also appears to be generally effective in preventing adverse clinical manifestations of the disease from occurring or progressing if administered early enough.
  • CDCA has been used as an orphan drug in the EU with the name Leadiant and is indicated for cerebrotendineous xanthomatosis (CTX).
  • One of the oral administration ways used commonly is hard gelatine capsule form.
  • Hard gelatine capsules often have been assumed to have better bioavailability than tablets. This assumption is derived from the fact that the gelatin shell rapidly dissolves and ruptures, which affords at least the potential for rapid release of the drug. Hards gelatin capsules allow a degree of flexibility of formulation not obtainable with tablets. Often, they are easier to formulate because there is no requirement that the powders be formed into a coherent compact that will stand up to handling.
  • a pharmaceutical composition may comprise one or more pharmaceutically acceptable excipient(s).
  • compositions examples can be solvent, diluent, lubricant, glidant, filler, disintegrant, binder, surfactant, antiadherent, flavor, preservative, sweetener, viscosity agent, colorant and other materials known to one of ordinary skill in the art and the mixtures thereof.
  • Ideal pharmaceutical excipient profile should have suitable physical and chemical properties with active ingredient and also other raw materials. These properties can be stable and reproducible, no unwanted interaction with active ingredient, inert property, desired functionality and cost effective. Relating to present invention, the use of some excipients and their ratio in composition are more critical than the other excipients.
  • One of the critical excipient for oral formulation such as capsule is solvent in a pharmaceutical composition.
  • Solvent refers to a liquid substance capable of dispersing or dissolving one or more substances.
  • Pharmaceutical solvents act as a reaction medium and provide molecules for drug manufacturing.
  • Pharmaceutical solvents can be purified water, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, and other materials known to one of ordinary skill in the art and mixtures thereof.
  • Another critical excipient for oral formulation such as capsule is diluent in a pharmaceutical composition.
  • a diluent also referred to as dilutant or thinner
  • Certain fluids are too viscous to be pumped easily or too dense to flow from one particular point to the other.
  • diluents decreases the viscosity of the fluids, thereby also decreasing the pumping/transportation costs.
  • Pharmaceutical diluents can be starches, hydrolyzed starches, partially pregelatinized starches, anhydrous lactose, lactose monohydrate, sugar alcohols such as sorbitol, xylitol and mannitol microcrystalline cellulose, lactose and other materials known to one of ordinary skill in the art and mixtures thereof. Summary of the invention The present invention relates to the preparation of pharmaceutical compositions comprising chenodeoxycholic acid (CDCA) and one or more pharmaceutically acceptable excipients, being used in the treatment of cerebrotendineous xanthomatosis (CTX).
  • CDCA chenodeoxycholic acid
  • CTX cerebrotendineous xanthomatosis
  • a pharmaceutical composition comprising CDCA or pharmaceutically acceptable salts thereof, wherein solvents in internal phase and a diluent in external phase with a specific ratio.
  • the present invention relates to preperation of pharmaceutical compositions comprising chenodeoxycholic acid (CDCA) for the treatment of cerebrotendineous xanthomatosis (CTX) and also in use of bile stone therapy.
  • the present invention provides a pharmaceutical composition comprising CDCA for the treatment of (CTX), wherein process including wet granulation method.
  • the present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein process including wet granulation method.
  • the present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the excipients are selected from the group including, but are not limited to solvents, diluents, glidants, lubricants, disintegrants, wetting agents, adhesives.
  • the present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the excipients are preferably at least one or a mixture of a solvent, a diluent, a glidant, a lubricant.
  • the present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the composition has an internal and an external phase.
  • the present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the active ingredient, solvents and a diluent are in internal phase.
  • the present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein a diluent, a glidant and a lubricant are in external phase.
  • solvents in internal phase are very critical.
  • the present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, including solvents with a specific ratio in internal phase.
  • the present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the solvents in internal phase are selected from a group including, but are not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, purified water and other materials known to one of ordinary skill in the art and mixtures thereof.
  • the present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the solvents in internal phase are preferably purified water and isopropyl alcohol.
  • the present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the weight ratio of isopropyl alcohol to purified water in internal phase is from 1/9 to 3/7, preferably 1/9.
  • compositions comprising CDCA and one or more pharmaceutically acceptable excipients, wherein the weight ratio of isopropyl alcohol to the total composition is from 0.01 to 0.10 (w/w), preferably 0,0025 to 0,0045 (w/w), more preferably from 0,0030 to 0,0040 (w/w).
  • diluent in external phase is very critical. This diluent should be selected with given ratio and properties.
  • the present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, including a diluent in external phase with a specific weight ratio to the total composition.
  • the present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the diluent in external phase is selected from a group including, but are not limited to mannitol, microcrystalline cellulose, lactose, pregelatinized starch 1500, dried maize starch and and other materials known to one of ordinary skill in the art and mixtures thereof.
  • the present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the diluent in external phase is preferably pregelatinized starch 1500.
  • the present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the weight ratio of pregelatinized starch 1500 in external phase to total composition is from % 5 to 10, preferably from 6 to 8.
  • the present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein a diluent is also in internal phase.
  • the present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the diluent in internal phase is preferably dried maize starch.
  • the present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein dried maize starch in internal phase is from 25 to 45 (w/w), preferably from 30 to 40 (w/w).
  • Suitable glidants according to the present invention are selected from a group including, but are not limited to starch, talc, silica derivatives, syloid, hydrated sodium sulfoaluminate, ascorbyl palmitate, calcium palmitate, magnesium stearate, silica colloidal anhydrus and other materials known to one of ordinary skill in the art and mixtures thereof.
  • the present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the glidant is preferably silica colloidal anhydrus.
  • Suitable lubricants according to the present invention are selected from a group including, but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearylfumarate, zinc stearate and polyethylene glycol and other materials known to one of ordinary skill in the art and mixtures thereof.
  • the present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the lubricant is preferably magnesium stearate.
  • the main point is that the weight ratio of the solvents in internal phase and the weight ratio of diluent in external phase to the total composition comprising CDCA.
  • the stability of the pharmaceutical composition can be tested in conventional manner, e.g. by measurement of CDCA and its degradation products, dissolution profile and appearance, e.g. after storage at 25 ⁇ C and 60% relative humidity, and/or storage at 40 ⁇ C and 75% relative humidity for defined periods of time.
  • compositions comprising CDCA and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is in a solid dosage form, wherein it can be tablet, capsule, granule, powder etc.
  • the preferred dosage form is capsule.
  • the capsule can be divided into solid drugs and liquid drugs based on the physical state (phase) of the medication to be filled. According to the raw material, the capsule can also be divided mainly into gelatin capsule and vegetarian capsule. Gelatin capsules are classified as hard gelatin capsule and soft gelatin capsule. Vegetarian capsules are classified as Hydroxypropylmethyl cellulose (HPMC) capsule and pullulan capsule.
  • HPMC Hydroxypropylmethyl cellulose
  • the most preferred capsule dosage form is hard gelatin capsule for the stabilization of the composition.
  • the main component of gelatin hard capsules which is gelatin, is a protein product which is harmless, inexpensive, edible, and degradable, and it is easy to store and use.
  • pharmaceutical compositions comprising CDCA and one or more pharmaceutically acceptable excipients, wherein the hard gelatin capsule dosage form have standard sizes and they are numbered as 5, 4, 3, 2, 1, 0, 0E, 00, 000, 13, 12, 12el, 11, 10, 7, Su07.
  • pharmaceutical compositions comprising CDCA and one or more pharmaceutically acceptable excipients, wherein most preferred size is “0” for hard gelatin capsule.
  • target properties of capsule dosage form are below: ⁇ Capsule should be elegant product without any embossing, crack, discoloration or contamination. ⁇ Mechanical strength should be sufficient for product packaging, shipping and distributing. ⁇ Physical properties should maintain the chemical and physical stability. ⁇ Capsule form should have reproducible manner for releasing the active ingredients. In preformulation studies for the formulation development, physicomechanical properties are determined such as tapped density, color, appearance. Tapped density has an important role in filling the capsule effectively and in providing target weight for unit formula.
  • manufacturing process generally consisting of nine stages: 1) Sieving and mixing, 2) Wet Granulation, 3) Drying 4) Sieving and mixing granule with external excipients, 5) Sieving and mixing with lubricant 6) Slugging 7) Breaking and sieving 8) Final mixing 9) Capsule filling.
  • w/w% refers to a percentage by weight compared to the total weight of the composition considered.
  • a pharmaceutical composition according to the invention is considered “stable”, if during a certain period of time 70%, preferably 80% and most preferably 95% of the initial content of CDCA, is maintained over said period of time.
  • treatment means any treatment of a disease or condition in a subject, such as a mammal, including: 1) preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop; 2) inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or 3) relieving the disease or condition that is, causing the regression of clinical symptoms.
  • CX cerebrotendineous xanthomatosis
  • CTX Cerebrotendineous xanthomatosis
  • Wet granulation is the most widely used process of granulation in the pharmaceutical industry. Wet granulation process can be very simple or very complex depending on the characteristics of the powders and the available equipments.
  • wet granulation method involves addition of a liquid solution (with or without binder) to powders, to form a wet mass or it forms granules by adding the powder together with an adhesive, instead of by compaction. Then, drying process starts and then sized to obtained granules with desired mesh. The granulate may then be tabletted /compressed, or other excipients may be added prior to tableting with suitable excipients.
  • oral solid dosage form denotes solid preparations (e.g. tablets, capsules) for oral administration each containing a single dose of one or more active substances.
  • “pharmaceutically acceptable salt” refers to a salt of a compound that does not abrogate the biological activity and properties ofthe compound.
  • Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base.
  • the present invention is described in the following example in more details. This example is not limiting the scope of the present invention and is to be considered under the light of the foregoing detailed description.
  • Example 1 CDCA 250 mg hard gelatin capsule unit formula
  • the process for the preparation of CDCA 250 mg hard gelatin capsule according to the present invention can be carried out according to the following process: 1. Stage 1 Sieving and Mixing Sieving and mixing: Chenodeoxycholic acid and Dried Maize Starch. 2.
  • Stage 2 Wet Granulation Wet granulation is done with Purified Water which contains Isopropyl Alcohol into it (90/10). 3.
  • Stage 3 Drying Granules are dried.
  • Stage 4 Sieving and Mixing Dried granules are sieved and mixed with Starch 1500 and Silica Colloidal Anhydrus 5.
  • Stage 5 Sieving and Mixing Magnesium Stearate is sieved and added to the mix. 6.
  • Stage 6 Slugging Slug compressing is carried out using the appropriate round punch. 7.
  • Stage 7 Breaking and Sieving After slugging breaking is done and it is passed through appropriate sieve 8.
  • Stage 8 Mixing Final mixing is done.
  • Stage 9 Capsule Filling Capsule filling is performed.
  • Stage 10 Packaging Packaging is performed.
  • the pharmaceutical compositions of the invention are particularly suited for the oral administration.
  • the pharmaceutical compositions of the invention are particularly shows similar property to the reference product in the dissolution, it is extremely useful as a pharmaceutical product preparation technique.
  • the present invention provides pharmaceutical composition comprising CDCA and relevant excipients, characterized by i) A simple and exclusive manufacturing process ii) Stable formulation
  • Capsule dosage form is simple, cost-effective, easy and convenient to use, so it has high patient compliance.
  • the advantages of wet granulation method • Improving flow property and compression characteristics and increases density of granules • Reducing dust hazards • Preventing segregation of powders.
  • hard gelatin capsule containing solvents in internal phase and diluent in external phase in a spesific ratio shows similar dissolution property.
  • Dissolution test values for pharmaceutical compositions are one of the essential parameters for process development and solid dosage manufacturing. General properties of relevant batches are shown in Table 2. Table 2: Summary of Batches used in In Vitro Dissolution Tests In this invention, dissolution testing has been performed in pH 1.2 medium (0,1 N HCL + % 0,05 sodium lauryl sulfate (SLS)) and acetat buffer-pH 4.5 medium (% 0,05 sodium lauryl sulfate (SLS)). Dissolution testing has been performed in two mediums both with pregelatinized starch in external phase and without it. The results of the Leadiant 250 mg hard gelatin capsule (Reference product) and CDCA 250 mg hard gelatin capsule (Test product) have been compared.
  • the dissolution test has been performed for Leadiant 250 mg hard gelatin capsule and CDCA 250 mg Tablet (Test Product) in pH 1.2 medium (0,1 N HCL + % 0,05 sodium lauryl sulfate (SLS)) without pregelatinized starch in external phase. It is shown in Figure 1. Drug release for both the test product and the reference product were not found to be satisfactory.
  • Figure 1 Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product) in pH 1.2 Medium (0,1 N HCl + % 0,05 SLS) (without pregelatinized starch in external phase).
  • the dissolution test has been performed for Leadiant 250 mg hard gelatin capsule and CDCA 250 mg Tablet (Test Product) in acetat buffer-pH 4.5 medium (% 0,05 sodium lauryl sulfate (SLS)) without pregelatinized starch in external phase. It is shown in Figure 2. Drug release for both the test product and the reference product were not found to be satisfactory.
  • Figure 2 Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product) in Acetat Buffer- pH 4.5 Medium (% 0,05 SLS) (without pregelatinized starch in external phase)
  • the dissolution test has been performed for Leadiant 250 mg hard gelatin capsule and CDCA 250 mg Tablet (Test Product) in pH 1.2 medium (0,1 N HCL + % 0,05 sodium lauryl sulfate (SLS)) with pregelatinized starch in external phase. It is shown in Figure 3. Drug release for both the test product and the reference product were found to be satisfactory.
  • Figure 3 Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product) in pH 1.2 Medium (0,1 N HCl + % 0,05 SLS) (final formula with pregelatinized starch in external phase)
  • the dissolution test has been performed for Leadiant 250 mg hard gelatin capsule and CDCA 250 mg Tablet (Test Product) in acetat buffer-pH 4.5 medium (% 0,05 sodium lauryl sulfate (SLS)) with pregelatinized starch in external phase. It is shown in Figure 4. Drug release for both the test product and the reference product were found to be satisfactory.
  • Figure 4 Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product) in Acetat Buffer- pH 4.5 Medium (% 0,05 SLS) (final formula with pregelatinized starch in external phase)
  • Figure 1 Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product) in pH 1.2 Medium (0,1 N HCl + % 0,05 SLS) (without pregelatinized starch in external phase)
  • Figure 2 Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product) in Acetat Buffer- pH 4.5 Medium (% 0,05 SLS) (without pregelatinized starch in external phase)
  • Figure 3 Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product

Abstract

The present invention relates to the preparation of pharmaceutical compositions comprising chenodeoxycholic acid (CDCA) is used in the treatment of cerebrotendineous xanthomatosis (CTX), a rare autosomal recessive disorder, having a specific ratio of solvents in internal phase and a diluent in external phase.

Description

DESCRIPTION PHARMACEUTICAL COMPOSITIONS COMPRISING CHENODEOXYCHOLIC ACID (CDCA) AS ACTIVE INGREDIENT AND OTHER RELEVANT EXCIPIENTS Field of invention The present invention relates to the preparation of pharmaceutical compositions comprising chenodeoxycholic acid (CDCA) is used in the treatment of cerebrotendineous xanthomatosis (CTX), a rare autosomal recessive disorder, having a specific ratio of solvents in internal phase and a diluent in external phase. Background of the invention Chenodeoxycholic acid (CDCA) has a chemical name as (4R)-4- [(1R,3aS,3bR,4R,5aS,7R,9aS,9bS,11aR)-4,7-dihydroxy-9a,11a-dimethylhexadecahydro-1H- cyclopenta[ɑ]phenanthren-1-yl]pentanoic acid and its chemical structure is shown in the Figure I. CDCA has molecular weight of 392.6 g/mol. It is a white crystalline substance insoluble in water but soluble in alcohol and acetic acid, with melting point at 165–167 °C.
Figure imgf000002_0001
Figure 1 Chenodeoxycholic acid is a bile acid naturally found in the body. It works by dissolving the cholesterol that makes gallstones and inhibiting production of cholesterol in the liver and absorption in the intestines, which helps to decrease the formation of gallstones. It can also reduce the amount of other bile acids that can be harmful to liver cells when levels are elevated. Medical therapy with oral bile acids has been used in patients who have small cholesterol stones, and for patients with larger cholesterol gallstones who are unable or reluctant to have surgery. CDCA can be used also in the treatment of cerebrotendineous xanthomatosis (CTX). (CTX) is a rare autosomal recessive disorder of bile acid synthesis caused by mutations in the cytochrome P450 CYP27A1 gene that result in production of a defective sterol 27-hydroxylase enzyme. CTX is associated with abnormally high levels of cholestanol in the blood and accumulation of cholestanol and cholesterol in the brain, tendon xanthomas, and bile. Treatment with chenodeoxycholic acid (CDCA; chenodiol) is the current standard of care. CDCA can help restore normal sterol, bile acid, bile alcohol, and cholestanol levels. CDCA also appears to be generally effective in preventing adverse clinical manifestations of the disease from occurring or progressing if administered early enough. CDCA has been used as an orphan drug in the EU with the name Leadiant and is indicated for cerebrotendineous xanthomatosis (CTX). One of the oral administration ways used commonly is hard gelatine capsule form. Hard gelatine capsules often have been assumed to have better bioavailability than tablets. This assumption is derived from the fact that the gelatin shell rapidly dissolves and ruptures, which affords at least the potential for rapid release of the drug. Hards gelatin capsules allow a degree of flexibility of formulation not obtainable with tablets. Often, they are easier to formulate because there is no requirement that the powders be formed into a coherent compact that will stand up to handling. A pharmaceutical composition may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients examples can be solvent, diluent, lubricant, glidant, filler, disintegrant, binder, surfactant, antiadherent, flavor, preservative, sweetener, viscosity agent, colorant and other materials known to one of ordinary skill in the art and the mixtures thereof. Ideal pharmaceutical excipient profile should have suitable physical and chemical properties with active ingredient and also other raw materials. These properties can be stable and reproducible, no unwanted interaction with active ingredient, inert property, desired functionality and cost effective. Relating to present invention, the use of some excipients and their ratio in composition are more critical than the other excipients. One of the critical excipient for oral formulation such as capsule is solvent in a pharmaceutical composition. Solvent refers to a liquid substance capable of dispersing or dissolving one or more substances. Pharmaceutical solvents act as a reaction medium and provide molecules for drug manufacturing. Pharmaceutical solvents can be purified water, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, and other materials known to one of ordinary skill in the art and mixtures thereof. Another critical excipient for oral formulation such as capsule is diluent in a pharmaceutical composition. A diluent (also referred to as dilutant or thinner) is a diluting agent. Certain fluids are too viscous to be pumped easily or too dense to flow from one particular point to the other. Adding diluent decreases the viscosity of the fluids, thereby also decreasing the pumping/transportation costs. Pharmaceutical diluents can be starches, hydrolyzed starches, partially pregelatinized starches, anhydrous lactose, lactose monohydrate, sugar alcohols such as sorbitol, xylitol and mannitol microcrystalline cellulose, lactose and other materials known to one of ordinary skill in the art and mixtures thereof. Summary of the invention The present invention relates to the preparation of pharmaceutical compositions comprising chenodeoxycholic acid (CDCA) and one or more pharmaceutically acceptable excipients, being used in the treatment of cerebrotendineous xanthomatosis (CTX). In this invention, a pharmaceutical composition comprising CDCA or pharmaceutically acceptable salts thereof, wherein solvents in internal phase and a diluent in external phase with a specific ratio. Detailed description of the invention The present invention relates to preperation of pharmaceutical compositions comprising chenodeoxycholic acid (CDCA) for the treatment of cerebrotendineous xanthomatosis (CTX) and also in use of bile stone therapy. The present invention provides a pharmaceutical composition comprising CDCA for the treatment of (CTX), wherein process including wet granulation method. The present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein process including wet granulation method. The present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the excipients are selected from the group including, but are not limited to solvents, diluents, glidants, lubricants, disintegrants, wetting agents, adhesives. The present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the excipients are preferably at least one or a mixture of a solvent, a diluent, a glidant, a lubricant. The present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the composition has an internal and an external phase. The present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the active ingredient, solvents and a diluent are in internal phase. The present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein a diluent, a glidant and a lubricant are in external phase. In this invention, solvents in internal phase are very critical. These solvents should be selected with given ratio and properties. The present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, including solvents with a specific ratio in internal phase. The present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the solvents in internal phase are selected from a group including, but are not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, purified water and other materials known to one of ordinary skill in the art and mixtures thereof. The present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the solvents in internal phase are preferably purified water and isopropyl alcohol. The present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the weight ratio of isopropyl alcohol to purified water in internal phase is from 1/9 to 3/7, preferably 1/9. In this invention, it is obtained pharmaceutical compositions comprising CDCA and one or more pharmaceutically acceptable excipients, wherein the weight ratio of purified water to the total composition is from 0,030 to 0,045, preferably from 0,035 (w/w) to 0,040 (w/w). In this invention, it is obtained pharmaceutical compositions comprising CDCA and one or more pharmaceutically acceptable excipients, wherein the weight ratio of isopropyl alcohol to the total composition is from 0.01 to 0.10 (w/w), preferably 0,0025 to 0,0045 (w/w), more preferably from 0,0030 to 0,0040 (w/w). In this invention, diluent in external phase is very critical. This diluent should be selected with given ratio and properties. The present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, including a diluent in external phase with a specific weight ratio to the total composition. The present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the diluent in external phase is selected from a group including, but are not limited to mannitol, microcrystalline cellulose, lactose, pregelatinized starch 1500, dried maize starch and and other materials known to one of ordinary skill in the art and mixtures thereof. The present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the diluent in external phase is preferably pregelatinized starch 1500. The present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the weight ratio of pregelatinized starch 1500 in external phase to total composition is from % 5 to 10, preferably from 6 to 8. The present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein a diluent is also in internal phase. The present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the diluent in internal phase is preferably dried maize starch. The present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein dried maize starch in internal phase is from 25 to 45 (w/w), preferably from 30 to 40 (w/w). Suitable glidants according to the present invention are selected from a group including, but are not limited to starch, talc, silica derivatives, syloid, hydrated sodium sulfoaluminate, ascorbyl palmitate, calcium palmitate, magnesium stearate, silica colloidal anhydrus and other materials known to one of ordinary skill in the art and mixtures thereof. The present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the glidant is preferably silica colloidal anhydrus. Suitable lubricants according to the present invention are selected from a group including, but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearylfumarate, zinc stearate and polyethylene glycol and other materials known to one of ordinary skill in the art and mixtures thereof. The present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the lubricant is preferably magnesium stearate. In this invention, the main point is that the weight ratio of the solvents in internal phase and the weight ratio of diluent in external phase to the total composition comprising CDCA. When other relevant publications and patent applications are evaluated, the originality and novelty of the subject can be seen. The stability of the pharmaceutical composition can be tested in conventional manner, e.g. by measurement of CDCA and its degradation products, dissolution profile and appearance, e.g. after storage at 25˚C and 60% relative humidity, and/or storage at 40˚C and 75% relative humidity for defined periods of time. In this invention, it is obtained pharmaceutical compositions comprising CDCA and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is in a solid dosage form, wherein it can be tablet, capsule, granule, powder etc. According to a preferred embodiment of this invention, the preferred dosage form is capsule. The capsule can be divided into solid drugs and liquid drugs based on the physical state (phase) of the medication to be filled. According to the raw material, the capsule can also be divided mainly into gelatin capsule and vegetarian capsule. Gelatin capsules are classified as hard gelatin capsule and soft gelatin capsule. Vegetarian capsules are classified as Hydroxypropylmethyl cellulose (HPMC) capsule and pullulan capsule. According to a preferred embodiment of this invention, the most preferred capsule dosage form is hard gelatin capsule for the stabilization of the composition. The main component of gelatin hard capsules, which is gelatin, is a protein product which is harmless, inexpensive, edible, and degradable, and it is easy to store and use. In this invention, it is obtained pharmaceutical compositions comprising CDCA and one or more pharmaceutically acceptable excipients, wherein the hard gelatin capsule dosage form have standard sizes and they are numbered as 5, 4, 3, 2, 1, 0, 0E, 00, 000, 13, 12, 12el, 11, 10, 7, Su07. In this invention, it is obtained pharmaceutical compositions comprising CDCA and one or more pharmaceutically acceptable excipients, wherein most preferred size is “0” for hard gelatin capsule. In this invention, target properties of capsule dosage form are below: ▪ Capsule should be elegant product without any embossing, crack, discoloration or contamination. ▪ Mechanical strength should be sufficient for product packaging, shipping and distributing. ▪ Physical properties should maintain the chemical and physical stability. ▪ Capsule form should have reproducible manner for releasing the active ingredients. In preformulation studies for the formulation development, physicomechanical properties are determined such as tapped density, color, appearance. Tapped density has an important role in filling the capsule effectively and in providing target weight for unit formula. In this invention, manufacturing process generally consisting of nine stages: 1) Sieving and mixing, 2) Wet Granulation, 3) Drying 4) Sieving and mixing granule with external excipients, 5) Sieving and mixing with lubricant 6) Slugging 7) Breaking and sieving 8) Final mixing 9) Capsule filling. The term “w/w%” as used herein, refers to a percentage by weight compared to the total weight of the composition considered. A pharmaceutical composition according to the invention is considered "stable", if during a certain period of time 70%, preferably 80% and most preferably 95% of the initial content of CDCA, is maintained over said period of time. The term "treatment" or "treating" means any treatment of a disease or condition in a subject, such as a mammal, including: 1) preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop; 2) inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or 3) relieving the disease or condition that is, causing the regression of clinical symptoms. In this invention, the term “cerebrotendineous xanthomatosis (CTX)” is a rare autosomal recessive disorder of bile acid synthesis and is associated with abnormally high levels of cholestanol in the blood and accumulation of cholestanol and cholesterol in the brain, tendon xanthomas, and bile. “Wet granulation” is the most widely used process of granulation in the pharmaceutical industry. Wet granulation process can be very simple or very complex depending on the characteristics of the powders and the available equipments. Basicly, wet granulation method involves addition of a liquid solution (with or without binder) to powders, to form a wet mass or it forms granules by adding the powder together with an adhesive, instead of by compaction. Then, drying process starts and then sized to obtained granules with desired mesh. The granulate may then be tabletted /compressed, or other excipients may be added prior to tableting with suitable excipients. The term "oral solid dosage form" as used herein denotes solid preparations (e.g. tablets, capsules) for oral administration each containing a single dose of one or more active substances. As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound that does not abrogate the biological activity and properties ofthe compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. The present invention is described in the following example in more details. This example is not limiting the scope of the present invention and is to be considered under the light of the foregoing detailed description. Example 1: CDCA 250 mg hard gelatin capsule unit formula
Figure imgf000009_0001
The process for the preparation of CDCA 250 mg hard gelatin capsule according to the present invention can be carried out according to the following process: 1. Stage 1 Sieving and Mixing Sieving and mixing: Chenodeoxycholic acid and Dried Maize Starch. 2. Stage 2 Wet Granulation Wet granulation is done with Purified Water which contains Isopropyl Alcohol into it (90/10). 3. Stage 3 Drying Granules are dried. 4. Stage 4 Sieving and Mixing Dried granules are sieved and mixed with Starch 1500 and Silica Colloidal Anhydrus 5. Stage 5 Sieving and Mixing Magnesium Stearate is sieved and added to the mix. 6. Stage 6 Slugging Slug compressing is carried out using the appropriate round punch. 7. Stage 7 Breaking and Sieving After slugging breaking is done and it is passed through appropriate sieve 8. Stage 8 Mixing Final mixing is done. 9. Stage 9 Capsule Filling Capsule filling is performed. 10. Stage 10 Packaging Packaging is performed. Advantages It is obtained optimum value for pharmaceutical composition comprising CDCA that has well ratio for hard gelatin capsule form by using solvents and a diluent in internal phase, a glidant, a lubricant and a diluent also in external phase as excipients. When the physical and chemical test results of the pharmaceutical composition obtained by using a specific ratio of solvents in internal phase are evaluated, it has been observed that it has increased production yield in the manufacturing process. Purified water and isopropyl alcohol are used as solvent in the invention product, whereas only water is used in the reference product. Isopropyl alcohol has solved the active ingredient better, thus it has prevented the composition from adhering to the mixing tank and increased product yield. The pharmaceutical compositions of the invention are particularly suited for the oral administration. The pharmaceutical compositions of the invention are particularly shows similar property to the reference product in the dissolution, it is extremely useful as a pharmaceutical product preparation technique. The present invention provides pharmaceutical composition comprising CDCA and relevant excipients, characterized by i) A simple and exclusive manufacturing process ii) Stable formulation Capsule dosage form is simple, cost-effective, easy and convenient to use, so it has high patient compliance. The advantages of wet granulation method: • Improving flow property and compression characteristics and increases density of granules • Reducing dust hazards • Preventing segregation of powders. In present invention, hard gelatin capsule containing solvents in internal phase and diluent in external phase in a spesific ratio shows similar dissolution property. Dissolution Tests Dissolution test values for pharmaceutical compositions are one of the essential parameters for process development and solid dosage manufacturing. General properties of relevant batches are shown in Table 2. Table 2: Summary of Batches used in In Vitro Dissolution Tests
Figure imgf000011_0001
In this invention, dissolution testing has been performed in pH 1.2 medium (0,1 N HCL + % 0,05 sodium lauryl sulfate (SLS)) and acetat buffer-pH 4.5 medium (% 0,05 sodium lauryl sulfate (SLS)). Dissolution testing has been performed in two mediums both with pregelatinized starch in external phase and without it. The results of the Leadiant 250 mg hard gelatin capsule (Reference product) and CDCA 250 mg hard gelatin capsule (Test product) have been compared. In this invention, the dissolution test has been performed for Leadiant 250 mg hard gelatin capsule and CDCA 250 mg Tablet (Test Product) in pH 1.2 medium (0,1 N HCL + % 0,05 sodium lauryl sulfate (SLS)) without pregelatinized starch in external phase. It is shown in Figure 1. Drug release for both the test product and the reference product were not found to be satisfactory.
Figure imgf000011_0002
Figure 1: Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product) in pH 1.2 Medium (0,1 N HCl + % 0,05 SLS) (without pregelatinized starch in external phase). In this invention, the dissolution test has been performed for Leadiant 250 mg hard gelatin capsule and CDCA 250 mg Tablet (Test Product) in acetat buffer-pH 4.5 medium (% 0,05 sodium lauryl sulfate (SLS)) without pregelatinized starch in external phase. It is shown in Figure 2. Drug release for both the test product and the reference product were not found to be satisfactory.
Figure imgf000012_0001
Figure 2: Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product) in Acetat Buffer- pH 4.5 Medium (% 0,05 SLS) (without pregelatinized starch in external phase) In this invention, the dissolution test has been performed for Leadiant 250 mg hard gelatin capsule and CDCA 250 mg Tablet (Test Product) in pH 1.2 medium (0,1 N HCL + % 0,05 sodium lauryl sulfate (SLS)) with pregelatinized starch in external phase. It is shown in Figure 3. Drug release for both the test product and the reference product were found to be satisfactory.
Figure imgf000013_0001
Figure 3: Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product) in pH 1.2 Medium (0,1 N HCl + % 0,05 SLS) (final formula with pregelatinized starch in external phase) In this invention, the dissolution test has been performed for Leadiant 250 mg hard gelatin capsule and CDCA 250 mg Tablet (Test Product) in acetat buffer-pH 4.5 medium (% 0,05 sodium lauryl sulfate (SLS)) with pregelatinized starch in external phase. It is shown in Figure 4. Drug release for both the test product and the reference product were found to be satisfactory.
Figure imgf000013_0002
Figure 4: Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product) in Acetat Buffer- pH 4.5 Medium (% 0,05 SLS) (final formula with pregelatinized starch in external phase) Brief description of the figures Figure 1: Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product) in pH 1.2 Medium (0,1 N HCl + % 0,05 SLS) (without pregelatinized starch in external phase) Figure 2: Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product) in Acetat Buffer- pH 4.5 Medium (% 0,05 SLS) (without pregelatinized starch in external phase) Figure 3: Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product) in pH 1.2 Medium (0,1 N HCl + % 0,05 SLS) (final formula with pregelatinized starch in external phase) Figure 4: Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product) in Acetat Buffer- pH 4.5 Medium (% 0,05 SLS) (final formula with pregelatinized starch in external phase)

Claims

CLAIMS 1. A pharmaceutical composition comprising Chenodeoxycholic acid or pharmaceutically acceptable salts thereof, wherein the composition comprises isopropyl alcohol as a solvent and pregelatinized starch as a diluent.
2. A pharmaceutical composition according to claim 1, wherein the amount of isopropyl alcohol is from 0.01 to 0.10 % by weight to the total weight of the composition.
3. A pharmaceutical composition according to claim 2, wherein the amount of isopropyl alcohol is 0.003% by weight to the total weight of the composition.
4. A pharmaceutical composition according to any one of the previous claims, wherein the amount of pregelatinized starch is from 5 – 10 % by weight to the total weight of the composition.
5. A pharmaceutical composition according to claim 4, wherein the amount of pregelatinized starch is 6% by weight to the total weight of the composition.
6. A pharmaceutical composition according to any one of the previous claims, wherein the composition further comprises purified water as a solvent.
7. A pharmaceutical composition according to claim 6, wherein the weight ratio of isopropyl alcohol to purified water is from 1/9 to 3/7.
8. A pharmaceutical composition according to claim 7, wherein the weight ratio of isopropyl alcohol to purified water is 1/9.
9. A pharmaceutical composition according to any one of the previous claims, wherein pregelatinized starch is Pregelatinized Starch 1500 (Starch 1500).
10. A pharmaceutical composition according to any one of the previous claims, wherein the composition further comprises glidant and/or lubricant.
11. A pharmaceutical composition according to claim 10, wherein the glidant is Silica Colloidal Anhydrus.
12. A pharmaceutical composition according to claim 10 or 11, wherein the lubricant is Magnesium Stearate.
13. A pharmaceutical composition according to any one of the previous claims, wherein the composition comprises; • Chenodeoxycholic Acid, Dried Maize Starch, Isopropyl Alcohol and Purified Water in the internal phase, and • Pregelatinised Starch, Silica Colloidal Anhydrus and Magnesium Stearate in the external phase.
14. A wet-granulation process for preparing a pharmaceutical composition comprising Chenodeoxycholic acid or pharmaceutically acceptable salts thereof, wherein Isopropyl Alcohol is used as a solvent in the internal phase and Pregelatinized starch is used as a diluent in the external phase.
15. A wet-granulation process according to claim 14, wherein Purified Water is used as a further solvent in the internal phase.
16. A wet-granulation process according to claim 14 or 15, wherein Dried Maize Starch is used as a Diluent in the internal phase.
17. A wet-granulation process according to any one of the claims 14-16, wherein Silica Colloidal Anhydrus is used as a glidant in the extragranular phase.
18. A wet-granulation process according to any one of the claims 14-17, wherein Magnesium Stearate is used as a Lubricant in the extragranular phase.
19. A wet-granulation process according to any one of the claims 14-18, wherein the weight ratio of isopropyl alcohol to purified water is from 1/9 to 3/7.
20. A pharmaceutical composition according to claim 19, wherein the weight ratio of isopropyl alcohol to purified water is 1/9.
PCT/TR2022/050888 2022-08-22 2022-08-22 Pharmaceutical compositions comprising chenodeoxycholic acid (cdca) as active ingredient and other relevant excipients WO2024043842A1 (en)

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Citations (3)

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WO2016176208A1 (en) * 2015-04-27 2016-11-03 Intercept Pharmaceuticals, Inc. Compositions of obeticholic acid and methods of use
EP3260463A1 (en) * 2015-02-16 2017-12-27 Suzhou Zelgen Biopharmaceutical Co., Ltd. Deuterated chenodeoxycholic acid derivative and pharmaceutical composition comprising compound thereof
WO2022051321A1 (en) * 2020-09-03 2022-03-10 Coherus Biosciences, Inc. Fixed dose combinations of chs-131 and a fxr agonist

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EP3260463A1 (en) * 2015-02-16 2017-12-27 Suzhou Zelgen Biopharmaceutical Co., Ltd. Deuterated chenodeoxycholic acid derivative and pharmaceutical composition comprising compound thereof
WO2016176208A1 (en) * 2015-04-27 2016-11-03 Intercept Pharmaceuticals, Inc. Compositions of obeticholic acid and methods of use
WO2022051321A1 (en) * 2020-09-03 2022-03-10 Coherus Biosciences, Inc. Fixed dose combinations of chs-131 and a fxr agonist

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Title
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