DESCRIPTION PHARMACEUTICAL COMPOSITIONS COMPRISING CDCA AS ACTIVE INGREDIENT AND 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), having a particle size distribution with d90 value of less than 20 µm, wherein the pharmaceutical tablet is prepared by wet granulation. 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-di methylhexadecahydro-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. 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. The measurement of particle size is crucial to ensuring product bioavailability, efficacy, and also shelf life, because of that particle size influences surface area and porosity. one of the most important parameters is particle size analysis for developing new pharmaceutical drugs. Particle size distribution (PSD) is among the most important parameters to check when evaluating new pharmaceutical projects. It also has big affect on tableting and granulation processes. 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. 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). The present invention relates to the preparation of pharmaceutical compositions comprising chenodeoxycholic acid (CDCA) is used in the treatment of cerebrotendineous xanthomatosis (CTX), having a particle size distribution with D90 value of less than 20 µm, wherein the pharmaceutical tablet is prepared by wet granulation. Detailed description of the invention The present invention relates to preperation of pharmaceutical compositions comprising CDCA for the treatment of cerebrotendineous xanthomatosis (CTX) and also in use of bile stone therapy. 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. Property of particle size directly effecs active ingredient’s absorption behavior, bioavailability, content uniformity, dissolution, and flowability. All these factors directly impact the product’s effectiveness. Particle size should not only monitored in quality control study, and also in the development of new active pharmaceutical ingredients. The particle size can affect the rate of dissolving. Smaller particles of active ingredients have a smaller surface area, therefore dissolution process occurs more quickly. This information is critical for the pharmaceutical industry, when designing drugs. It was found by the present inventors that this object can be achieved by using CDCA in the form of particles having a d90 value of less than 20 µm. The term "particle size" as used herein refers to the volume diameter of valsartan particles, as determined by laser light scattering using a Malvern-Mastersizer Apparatus MS 2000. Methods of determining the size of particles are well known in the art. For example, Laser Diffraction, Dynamic Light Scattering, Image Particle Analysis, Acoustic Spectroscopy etc. The dx value indicates that a certain percentage X of the particles has a size below a certain limit. d90 means that 90% of particles (V/V) have a higher volume diameter than the indicated value. A d90 value of less than 20 µm means that 90 % by volume of the particles have a diameter below 20 µm. The term " CDCA particle" means a particle that contains CDCA, preferably, a particle that essentially or completely consists of CDCA. In the present invention the pharmaceutical compositions of CDCA have a CDCA particle size such that d90 is 20 µm. In the present invention the pharmaceutical compositions of CDCA have a CDCA particle size such that d90 is 15 µm. In the present invention the pharmaceutical compositions of CDCA have a CDCA particle size such that d90 is 10 µm. In the present invention the pharmaceutical compositions of CDCA have a CDCA particle size such that d90 is 5 µm. 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 CDCA has lower than 20 µm of D90 value, wherein the composition has total two phases with internal and external phase. Excipients for this invention should be selected carefully. 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 using CDCA in the form of particles having a d90 value of less than 20 µm and using manufacturing method of wet granulation. 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 capsule for the stabilization of the composition. The main component of 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. Diluents can be selected from the group, but are not limited to, microcrystalline cellulose, powdered cellulose, sucrose, lactose, mannitol, dextrose, sorbitol, lactitol, saccharose, trehalose, fructose, dextranes, dried maize starch and its derivatives such as pregelatinized starch, calcium salts of phosphoric acid or a combination thereof. Diluents are preferably used in the range 20 to 90% (w/w). Dried maize starch and microcrystalline cellulose are being preferred. Lubricants can be selected from the group, but are not limited to, magnesium stearate, calcium stearate, aluminium stearate, sodium starch fumarate, sodium lauryl sulphate, sodium stearyl fumarate, hydrogenated vegetable oils, stearic acid, macrogols. A preferred lubricant is magnesium stearate. Solvents can be selected from the group, but 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 preferred solvent is isopropyl alcohol and also purified water. Glidants can be selected from the group, but are not limited to, colloidal silicon dioxide, colloidal silica, cornstarch, talc, calcium silicate, silica colloidal anhydrus, magnesium silicate, magnesium trisilicate, amorphous silica, colloidal silicon, silicon hydrogel, powdered cellulose, silicon dioxide, talc, tribasic calcium phosphate and other materials known to one of ordinary skill in the art. The preferred glidant is Silica Colloidal Anhydrus. 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 (Content & Function) 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. 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. The proses preferably uses chenodeoxycholic acid which has a particle size distribution with d90 value of less than 20 µm. Advantages When the physical and chemical test results of the pharmaceutical composition obtained by using less than 20 µm of D90 value for CDCA particle size, it has been observed that it has increased production yield in the manufacturing process. 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 less than 20 µm of D90 value for CDCA particle size, shows similar dissolution property with reference product. It has advantage according to product that has higher than 20 µm of D90 value for CDCA particle size. Dissolution Tests Dissolution test values for pharmaceutical compositions are one of the essential parameters for process development and solid dosage manufacturing. In this study, results are relevant to CDCA particle size that has less than 20 µm of D90 value. 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 + % 0,1 sodium lauryl sulfate (SLS)) and acetat buffer-pH 4.5 medium (% 0,1 sodium lauryl sulfate (SLS)). Dissolution testing has been performed for final product with D90 value is lower than 20µm and also D90 value is higher than 20µm. The results of the Leadiant 250 mg hard gelatin capsule (Reference product) and CDCA 250 mg hard gelatin capsule (Test product) have been compared for D90 value is lower than 20µm (also called micronized) and also D90 value is higher than 20µm (also called non-micronized).

In this invention, the dissolution test has been performed for Leadiant 250 mg hard gelatin capsule and CDCA 250 mg Tablet (Test Product / with D90 value is higher than 20µm: 150µm) in pH 1.2 medium (% 0,1 sodium lauryl sulfate (SLS)). 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 / with D90 value is higher than 20µm: 150µm) in pH 1.2 Medium (% 0,1 sodium lauryl sulfate (SLS)) In this invention, the dissolution test has been performed for Leadiant 250 mg hard gelatin capsule and CDCA 250 mg Tablet (Test Product / with D90 value is higher than 20µm: 150µm) in pH 4.5 medium (% 0,1 sodium lauryl sulfate (SLS)). It is shown in Figure 2. Drug release for both the test product and the reference product were not found to be satisfactory. Time (min) Figure 2: Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product / with D90 value is higher than 20µm: 150µm) in pH 1.2 Medium (% 0,1 sodium lauryl sulfate (SLS)) In this invention, the dissolution test has been performed for Leadiant 250 mg hard gelatin capsule and CDCA 250 mg Tablet (Test Product / with D90 value is lower than 20µm: 15µm) in pH 1.2 medium (% 0,05 sodium lauryl sulfate (SLS)). It is shown in Figure 3. Drug release for both the test product and the reference product were found to be satisfactory. Time (min) Figure 3: Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product / with D90 value is lower than 20µm: 15µm) in pH 1.2 Medium ((% 0,1 sodium lauryl sulfate (SLS)) (final formula) In this invention, the dissolution test has been performed for Leadiant 250 mg hard gelatin capsule and CDCA 250 mg Tablet (Test Product / with D90 value is lower than 20µm: 15µm) in pH 4.5 medium (% 0,1 sodium lauryl sulfate (SLS)). 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 / with D90 value is lower than 20µm: 15µm) in pH 4.5 Medium ((% 0,1 sodium lauryl sulfate (SLS)) (final formula) 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 / with D90 value is higher than 20µm: 150µm) in pH 1.2 Medium (% 0,1 sodium lauryl sulfate (SLS)) (final formula) Figure 2: Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product / with D90 value is higher than 20µm: 150µm) in pH 1.2 Medium (% 0,1 sodium lauryl sulfate (SLS)) (final formula) Figure 3: Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product / with D90 value is lower than 20µm: 15µm) in pH 1.2 Medium ((% 0,1 sodium lauryl sulfate (SLS)) (final formula) Figure 4: Comparative Dissolution Profiles of Leadiant 250 mg Hard Gelatin Capsule (Reference Product) and CDCA 250 mg Hard Gelatin Capsule (Test Product / with D90 value is lower than 20µm: 15µm) in pH 4.5 Medium ((% 0,1 sodium lauryl sulfate (SLS)) (final formula)