DESCRIPTION PHARMACEUTICAL ORAL SUSPENSION COMPOSITIONS COMPRISING CHENODEOXYCHOLIC ACID (CDCA) AS ACTIVE INGREDIENT AND OTHER RELEVANT EXCIPIENTS Field of invention The present invention relates to the preparation of liquid pharmaceutical compositions comprising chenodeoxycholic acid (CDCA) is used in the treatment of cerebrotendineous xanthomatosis (CTX). 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 1 CDCA can be used also in the treatment of cerebrotendineous xanthomatosis (CTX). 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 oral suspension dosage form. Liquid oral preparations are preferred over oral solid formulations for various reasons. It is preferable for patients with physical disabilities and who are incapacitated. Patient compliance is often a problem with oral solid dosage forms, especially with young children and senior patients.
Liquid compositions could help a pharmacist to dispense the correct amount of drug without resorting to sub-division of a larger dosed tablet into pieces. A drug administered in liquid formulations is immediately available for absorption from the gastrointestinal tract and is more rapidly and efficiently absorbed than the same amount of drug administered in a tablet or capsule. However, the oral liquid dosage form is usually less stable in liquid media than as solid dosage forms. Oral liquid formulations and oral drug solutions are often preferred for children, and also for adults who have come across swallowing pills. A pharmaceutical composition may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients examples can be suspending agent, buffering agent, 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. 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 stable oral pharmaceutical suspension comprising Chenodeoxycholic acid (CDCA); one or more suspending agents; and pharmaceutically acceptable excipients. In this invention, a pharmaceutical composition comprising CDCA, wherein the suspension agents having a certain concentration range. Advantages There is no suspension product containing CDCA in the market. It is an invention that minimizes the risks in terms of patient compliance by using suspension dosage form especially for pediatric and geriatric application. Pharmaceutical suspensions can use as an alternative to administer drugs to children including paediatric and geriatric patients and older patients who have difficulty swallowing solid dosage forms. It is very important to have a product comprising CDCA on the pharmaceutical market for patient compliance.
The present invention provides pharmaceutical composition comprising CDCA and relevant excipients, characterized by i) A simple and exclusive manufacturing process ii) Stable formulation The oral suspension dosage form has advantages over other solid forms such as capsules. The manufacturing process is simpler compared to solid forms. The present invention provides a formulation with masking the unpleasant/ bitter taste of drug. Taste improvement is a necessity, especially for pediatric patients. Oral suspension dosage form is simple, cost-effective, easy and convenient to use, so it has high patient compliance. Dose titration (adjustment) can be done by adjusting volume to be administered which is not possible in capsule. It can be achieved by simply markings on dosing cup. The pharmaceutical compositions of the invention are particularly suited for the oral administration. 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. A liquid dosage form is preferred by pediatric and geriatric patients because of the ease with which it may be swallowed. In addition, patients may be more inclined to comply with their medication instructions if the dosages are easier to ingest. Commonly, pediatric and geriatric subjects encounter difficulty being administered solid oral dosage forms, such as tablets or capsules. Generally, these kind of formulations are unacceptable especially for pediatric subjects. There is a need for a liquid oral CDCA formulation designed especially for pediatric subjects. The present invention provides oral pharmaceutical suspension for providing a pharmaceutically effective amount of a CDCA, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, and especially for a pediatric subject. In pediatric patients, the posology can be adjusted depending on the weight. Accordingly, the dosage amount can be adjusted. The present invention provides a pharmaceutical composition comprising CDCA for the treatment of (CTX), wherein process including mixing 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 mixing method. The present invention relates to the preparation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the excipients are selected from the group including, but are not limited to solvents, suspending agents, buffer agents, osmotic agents, preservatives, diluents, glidants, lubricants, disintegrants, wetting agents, adhesives. The present invention relates to the preparation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the excipients are preferably at least one or a mixture of a solvent, a preservative, a buffer agent, a suspending agent, an osmotic agent, a sweetener and a flavour agent. In this invention, suspending agent is very critical. This suspending agent should be selected with a specific concentration range. The present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, including suspending agent with a specific concentration range. In this invention, the main point is that the (w/v) ratio of the suspending agent 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 present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the suspending agent is selected from a group including, but are not limited to, sodium carboxymethylcellulose (CMC), microcrystalline cellulose, mixture of microcrystalline cellulose and carboxymethylcellulose (marketed as brand name of Avicel RC 591), and other materials known to one of ordinary skill in the art and mixtures thereof. In the pharmaceutical excipient market, there are many co-process products of MCC. One of the mentioned product is MCC RC591, is also called Avicel RC591. MCC RC591 is co- processed product of Microcrystalline Cellulose (MCC) and Sodium Carboxymethylcellulose (CMC). This product has advantages for liquid, suspension and solution products. Some advantages are improved suspension power, higher thixotropy and gel strength and improved stabilization. In one embodiment, MCC RC-591 is used as suspending agent in this invention. In one embodiment, MCC RC-591 contains sodium carboxymethyl cellulose between the weight ratio of 8.3-22.0%. In one embodiment, MCC RC-591 contains 11.0% of sodium carboxymethyl cellulose.
MCC RC591 has high wettability characteristic and it is well known in the pharmaceutical art for its usage in the preparation of pharmaceutical suspensions and emulsions to give thickness to obtain the suspension. MCC RC591 is a dispersible, colloidal MCC comprising medium viscosity. It is used in food and pharmaceutical suspensions to regulate and modify viscosity and for its thixotropic characteristics, manufactured by FMC Corporation. It has long shelf-life stability, is stable at pH range 4-11, and is odorless/tasteless. In one embodiment, the ratio of MCC RC591 used to the total weight is between 0.01%- 2.00% (w/v). The composition comprises MCC at the concentration of 0.01, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75 or 2.00 (w/v). The most preferred amount in this range is 1.00 %. The present invention relates to the preperation of pharmaceutical compositions comprising CDCA, and one or more pharmaceutically acceptable excipients, wherein the solvents are preferably Glycerol and Propylene glycol. Suitable solvents according to the present invention are selected from a group including, but are not limited to, benzoic acid, benzalkonium chloride, benzyl alcohol, butylene glycol 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 preservative is preferably benzoic acid. Suitable solvents according to the present invention are selected from a group including, but are not limited to, glycerol, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, distilled water 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 solvents are preferably glycerol and/or propylene glycol and mixtures thereof. Suitable osmotic agents according to the present invention are selected from a group including, but are not limited to sucrose, xylitol, glucose, lactose; sodium chloride, potassium chloride 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 osmotic agent is preferably Sodium Chloride.
Suitable buffer agents according to the present invention are selected from a group including, but are not limited to citric acid, citric acid anhydrous, sodium hydroxide, potassium citrate, acetic acid, sodium acetate 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 buffer agent is preferably citric acid anhydrous. Suitable sweeteners according to the present invention are selected from a group including, but are not limited to sodium citrate sodium cyclamate, xylitol, sugar such as brown sugar, white sugar, sucrose, lactose 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 sweeteners is preferably sodium citrate sodium cyclamate and/or xylitol and mixtures thereof. Suitable flavour agents according to the present invention are selected from a group including, but are not limited to lemon, raspberry, apple and rosemary 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 flavour agents is preferably lemon flavour. 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 liquid dosage form, wherein it can be suspension. This dosage form is also chemically stable under physiological conditions and is especially well suited for pediatric and geriatric applications. According to a preferred embodiment of this invention, the preferred dosage form is oral suspension. Suspensions are a useful drug delivery system for therapeutic agents that have a low solubility. In general, drug in suspension exhibits higher rate of bioavailability than other dosage forms. Also, oral suspension dosage form comprising CDCA can offer resistance to degradation of drugs due to hydrolysis, oxidation or microbial activity.
The term “% w/v” as used herein, refers to a percentage by weight compared to the total weight of the composition considered. In general, by “(w/v)” as used herein is meant weight of substance per volume of the final preparation/formulation. In one embodiment, The term “% w/v” as used herein, refers to a percentage by weight compared to the total weight of the composition that is g/5mL. 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. “Mixing” is the main widely used process for suspension dosage form in the pharmaceutical industry. It has very simple steps and procedures depending on the characteristics and the available equipments. The term "oral suspension dosage form" as used herein denotes liquid preparations for oral administration each containing a single dose of one or more active substances. Suspending agents, which may be used according to the present invention, include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, mixture of microcrystalline cellulose and carboxymethylcellulose (marketed as brand name of Avicel RC 591), polyvinylpyrrolidone, xanthan gum, guar gum, xanthan gum, polyethylene glycol, polyethylene oxide and a mixture thereof. Preferably, the suspending agent is mixture of microcrystalline cellulose and carboxymethylcellulose. Preservatives can be selected from the group, but not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, calcium acetate, cetylpyridinium chloride, chlorhexidine, glycerin, potassium metabisulfite, potassium sorbate, propylene glycol, sodium acetate, sodium benzoate, sodium metabisulfite, sodium propionate, sodium sulfite, sorbic acid, zinc oxide, and a mixture thereof. The preferred preservative is benzoic acid. Solvents can be selected from the group, but not limited to, glycerol, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, distilled water and other materials
known to one of ordinary skill in the art and mixtures thereof. The preferred solvent is glycerol and/or propylene glycol and mixtures thereof. Buffering agent can be selected from the group, but not limited to, citric acid, citric acid anhydrous, sodium hydroxide, potassium citrate, acetic acid, sodium acetate, malic acid, lycine, sodium carbonate, maleic acid, sodium lactate and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred buffering agent is citric acid anhydrous. Flavoring agent can be selected from the group, but not limited to, lemon, raspberry, apple and rosemary and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred flavoring agent is lemon. Sweetener can be selected from the group, but not limited to, sodium citrate sodium cyclamate, xylitol, sugar such as brown sugar, white sugar, sucrose, lactose, lactulose maltose trehalose, saccharine and dextrose, potassium acesulfame, and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred sweetener is sodium citrate sodium cyclamate and/or xylitol and mixtures thereof. Osmotic agents can be selected from the group, but not limited to, simple sugars such as sucrose, xylitol, glucose, lactose; salts such as sodium chloride, potassium chloride; low molecular weight hydrophilic polymers such as cellulose ethers, maltodextrins, and cyclodextrins. The preferred osmotic agent is Sodium Chloride. 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: Chenodeoxycholic Acid Oral Suspension Unit Formula Content Function Unit Formula (g/5mL) Chenodeoxycholic acid Active Ingredient
0.2500 Benzoic acid Preservative
0.0075 Citric acid anhydrous Buffer 0.0100 Propylene glycol Solvent 0.5000 MCC RC591 Suspending agent 0.0500 S
odium Chloride Osmotic agent 0.0035 Sodium citrate sodium cyclamate Sweetener
0.0250 Glycerol Solvent
1.0000 Xylitol Sweetener
0.0250 Lemon flavour Flavour
0.0025 Purified water Solvent
q.s. to 5 ml T
otal 5 mL
Procedure for composition comprising Chenodeoxycholic Acid (CDCA) Oral Suspension; Stage 1: In main tank, water is taken. To that, Avicel RC 591 is added, homogenized & mixed till uniform suspension is formed. Stage 2: In another tank, water is taken & to that Benzoic acid, citric acid anhydrous, Sodium Chloride, Sodium citrate sodium cyclamate, Propylene glycol & Xylitol are added one after another & mixed till clear solution is obtained. Stage 3 Step 2 solution is added to step 1 & mixed. Stage 4 In separate container, Glycerol is taken. To that, Chenodeoxycholic acid is added & mixed till homogenous mixture is formed. This mixture is transferred to stage 3, main tank and mixed. Stage 5 Lemon flavour is added & mixed. Finally remaining water is added to make up the final volume & mixed.