Pharmaceutical composition of chenodeoxycholic acid for pediatric use

Abstract

The present invention relates to the preparation of pharmaceutical compositions comprising chenodeoxycholic acid (CDCA) is used in the treatment of cerebrotendineous xanthomatosis (CTX), especially in the form of sachet and for pediatric use.

Description

[0001] PHARMACEUTICAL COMPOSITION OF CHENODEOXYCHOLIC ACID FOR PEDIATRIC USE

[0002] Field of the Invention

[0003] The present invention relates to the preparation of pharmaceutical compositions comprising chenodeoxycholic acid (CDCA) is used in the treatment of cerebrotendineous xanthomatosis (CTX), especially in the form of sachet and for pediatric use.

[0004] Background of the Invention

[0005] Chenodeoxycholic acid (CDCA) has a chemical name as (4 / )-4-| ( 1 3a5, 3b / ?. 4R. 5aS,lR, 9aS'.9b.SJ la / ?)-4.7-dihydroxy-9a. I la-dimethylhexadecahydro -1H- cyclopenta[a]phenanthren -1-yl] pentanoic acid and its chemical structure is shown in the Figure 1. 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.

[0006] Figure 1 : Chenodeoxycholic acid

[0007] 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.

[0008] 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.

[0009] Chenodeoxycholic acid is indicated for the treatment of inborn errors of primary bile acid synthesis due to sterol 27-hydroxylase deficiency presenting as cerebrotendinous xanthomatosis in infants, children and adolescents aged 1 month to 18 years and adults.

[0010] CDCA has been used as an orphan drug in the EU with the name Leadiant and is indicated for cerebrotendineous xanthomatosis.

[0011] In application of CDCA for pediatry, the capsule should be opened, the contents added to sodium bicarbonate solution and mixed to produce a suspension containing chenodeoxycholic.

[0012] Besides providing important contributions of Leadiant as a medicament for the treatment of cerebrotendineous xanthomatosis, there is a requirement to develop a simple, reproducible and cost-effective manufacturing process and a stable pharmaceutical composition comprising CDCA, especially in pediatric use, with an improved flowability, content uniformity and processability, while at the same time ensuring that the desired properties such as impurity, dissolution, stability, bioavailability are maintained and are comparable with respect to the Reference Product Leadiant.

[0013] The pharmaceutical composition according to the present invention has suitable physical and chemical properties with the active ingredient and also with excipients present in the composition. According to these properties, the composition is stable and reproducible as a result, without any unwanted interaction with the active ingredient, and it provides the requirements for desired functionality and cost effective preparation, as well as improved dissolution profile.

[0014] Summary of the Invention

[0015] The present invention relates to the preparation of pharmaceutical compositions comprising chenodeoxycholic acid (CDCA) is used in the treatment of cerebrotendineous xanthomatosis (CTX), especially in the form of sachet and thus pediatric use becomes easier. Detailed Description of the Invention

[0016] 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, wherein the CDCA composition is in the form of sachet to facilitate the pediatric use.

[0017] 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.

[0018] “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.

[0019] 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 solutes, diluents, glidants, lubricants, disintegrants, wetting agents, adhesives.

[0020] 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 solute, a diluent, a glidant, a lubricant.

[0021] Preferably, the present invention relates to the pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and at least one pharmaceutically acceptable excipients, wherein at least one pharmaceutical excipient is sodium bicarbonate.

[0022] Preferably, the present invention relates to the pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, and at least one pharmaceutically acceptable excipients, wherein at least one pharmaceutical excipient is sodium bicarbonate for pediatric use.

[0023] The present invention relates to the preparation of pharmaceutical compositions comprising CDCA or pharmaceutically acceptable salts or esters thereof, wherein sodium bicarbonate as a solute, maize starch as a diluent, silica colloidal anhydrous as a glidant and magnesium stearate as a lubricant. Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. For this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected.

[0024] Preferably, the present invention relates to the pharmaceutical composition comprising CDCA or pharmaceutically acceptable salts thereof, and also relevant excipients, wherein the excipients are selected from the group including, but are not limited to solvents, diluents, glidants, solutes, lubricants and other materials known to one of ordinary skill in the art and the mixtures thereof.

[0025] Suitable diluents according to the present invention are selected from the group including, but are not limited to, spray-dried or anhydrous lactose, sucrose, dextrose, maize starch, pregelatinized starch, mannitol, maltitol, sorbitol, xylitol, dextrin, cellulose derivatives including powdered cellulose, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate and calcium sulphate, kaolin, precipitated calcium carbonate, maltodextrin and other materials known to one of ordinary skill in the art. A preferred diluent is maize starch.

[0026] Suitable glidants according to the present invention are selected from the group including, but are not limited to, colloidal silicon dioxide, colloidal silica, Silica colloidal anhydrous, cornstarch, talc, calcium silicate, 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. A preferred glidant is silica colloidal anhydrous.

[0027] Suitable solutes can be used in this invention. Solutes may be selected sodium bicarbonate and other materials known to one of ordinary skill in the art.

[0028] 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 preferred lubricant is magnesium stearate.

[0029] The present invention relates to the preperation of pharmaceutical composition comprising CDCA or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein preferably maize starch are used as diluent, silica colloidal anhydrous can be used as glidant, sodium bicarbonate can be used as solute and magnesium stearate are used as lubricant. The present invention relates to a pharmaceutical compositions comprising:

[0030] CDCA and other pharmaceutically acceptable excipients and

[0031] Sodium bicarbonate as solute.

[0032] An aim of the present invention to solve the problems of the prior art and is to provide an improved pharmaceutical composition comprising CDCA in the form of sachet and for pediatric use, wherein the sachet composition has concurrently comparable and satisfactory impurity and stability values and dissolution rates.

[0033] In general application of therapy for pediatric, the capsule should be opened, the contents added to sodium bicarbonate solution and mixed to produce a suspension containing chenodeoxycholic .

[0034] The present invention relates to adding the sodium bicarbonate directly to the sachet formula, and sodium bicarbonate is in the powder. So, the patient can pour the powder product in the sachet into water and drink it directly. It has high patient compliance for pediatric use.

[0035] In present invention, it is found that improved impurity values and an appropriate dissolution profile can be obtained, when using a sachet formulation comprising chenodeoxycholic acid as active ingredient and sodium bicarbonate as a solute.

[0036] According to an embodiment, the process of the invention may comprise the steps below:

[0037] 1- Chenodeoxycholic acid, diluent and solute are sifted.

[0038] 2- Granulation is carried out with purified water.

[0039] 3- Drying carried out in oven.

[0040] 4- Dried granules are passed through suitable sieve to get uniform granules.

[0041] 5- Granules mixed with pre-sifted glidant.

[0042] 6- Stage 5 blend is mixed with pre-sifted lubricant.

[0043] 7- Stage 6 blends are filled in sachets.

[0044] The term “sachet” is used in packaging of preparations, which are industrially produced powder, granular or effervescent granule-shaped. Its filling is done with special machines. The bags are shaped and closed with the help of heat. Paper or aluminum is used as packaging material. It is coated with polyethylene or poly vinyl chloride as a second layer.

[0045] According to an embodiment, an example for inventive pharmaceutical sachet composition is given as detailed in Example 1. These examples are not limiting the scope of the present invention and is to be considered according to the foregoing detailed description. Any other modifications of the composition or production methods are possible if they are implemented in line with maintaining the stability of the composition and the dissolution profile of the active substance.

[0046] Example 1: CDCA 250 mg sachet dosage form unit formula

[0047] The process for the preparation of CDCA 250 mg sachet according to the present invention can be carried out according to the following process:

[0048] Stage 1 : Chenodeoxycholic acid, Maize starch and Sodium bicarbonate are sifted through a suitable sieve & mixed for some time in granulation bowl. Stage 2: Granulation is carried out with purified water.

[0049] Stage 3: Drying carried out in oven.

[0050] Stage 4: Dried granules are passed through suitable sieve to get uniform granules.

[0051] Stage 5: Granules mixed with pre-sifted Silica colloidal anhydrous for some time.

[0052] Stage 6: Stage 5 blend is mixed with pre-sifted Magnesium stearate for some time. Stage 7: Stage 6 blends are filled in sachets. Advantages

[0053] Sachet dosage form is simple, cost-effective, easy and convenient to use, so it has high patient compliance for pediatric use.

[0054] The present invention provides pharmaceutical composition comprising CDCA and relevant excipients, characterized by i) A simple and exclusive manufacturing process ii) Stable formulation

[0055] In this invention, a stable formulation with solution (Sodium bicarbonate) has been developed.

[0056] The present invention introduces a pharmaceutical composition comprising CDCA, wherein the composition is in the form of sachet, thus pediatric use of a CDCA composition becomes easier.

[0057] According to Summary Of Product Characteristics of Reference product, it is recommended that this suspension is prepared at the pharmacy. The suspension is stable for up to 7 days.

[0058] Compared to reference product, this invention can provide an application that can be prepared at home using only water.

[0059] In addition, a superior product will be obtained in terms of stability compared to the Reference product. Once the sachet is opened, stability for at least one month is ensured.

[0060] Stability data

[0061] Storage condition is 40°C ± 2°C / %75 RH ± %5 RH for test product, given in table 1.

[0062] In table 2, the initial and 1stmonth stability results are presented, for Storage condition is 40°C ± 2°C / %75 RH ± %5 RH.

[0063] Table 1: Table 2:

[0064] Storage condition is 40°C ± 2°C / %75 RH ± %5 RH for test product, given in table 3.

[0065] In table 4, the initial and 1stmonth stability results are presented, for storage condition is 25°C ± 2°C / %65 RH ± %5 RH. Table 3: Table 4:

Claims

CLAIMS1. A stable sachet formulation comprising chenodeoxycholic acid (CDCA) or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipients, wherein at least one pharmaceutical excipient is sodium bicarbonate as solute.

2. A pharmaceutical composition according to Claim 1 for pediatric use.

3. A pharmaceutical composition according to Claim 1, characterized in further comprising maize starch as diluent.

4. A pharmaceutical composition according to Claim 1, characterized in further comprising silica colloidal anhydrous as glidant.

5. A pharmaceutical composition according to Claim 1, characterized in further comprising magnesium stearate as lubricant.

6. The stable sachet formulation according to claim 1, wherein the formulation comprises Chenodeoxycholic acid, Sodium bicarbonate,- Maize Starch,Silica colloidal anhydrous,- Magnesium stearate.

7. A manufacturing method of the formulation according to 1, characterized in comprising steps of a) Sieving and mixing Chenodeoxycholic acid, Maize starch and Sodium bicarbonate b) Granulation in purified water c) Drying in oven d) Sieving Dried granules e) Mixing Granules with pre-sifted Silica colloidal anhydrous f) adding pre-sifted Magnesium stearate g) Filling blend in sachets8. A pharmaceutical composition according to Claim 1, for use in the treatment of cerebrotendineous xanthomatosis.

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