WO2015142178A1 - Bile acid composition with enhanced solubility - Google Patents

Bile acid composition with enhanced solubility Download PDF

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Publication number
WO2015142178A1
WO2015142178A1 PCT/NL2015/050180 NL2015050180W WO2015142178A1 WO 2015142178 A1 WO2015142178 A1 WO 2015142178A1 NL 2015050180 W NL2015050180 W NL 2015050180W WO 2015142178 A1 WO2015142178 A1 WO 2015142178A1
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WIPO (PCT)
Prior art keywords
formulation
multiparticulate
weight
formulation according
ursodeoxycholic acid
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PCT/NL2015/050180
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French (fr)
Inventor
José Luis VELADA
Rasielle Joy GONZALES
Hiteshkumar Anilkant Doshi
Vilas JADHAV
Avni Shah
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Disphar International B.V.
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Application filed by Disphar International B.V. filed Critical Disphar International B.V.
Publication of WO2015142178A1 publication Critical patent/WO2015142178A1/en

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the invention relates to a pharmaceutical bile acid composition with enhanced solubility at lower pH for improved absorption after oral intake, a process for preparing said composition and the use thereof for treating cholestatic liver diseases.
  • Ursodeoxycholic acid is a naturally occurring secondary bile acid.
  • UDCA is prescribed for chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and cystic fibrosis-related liver diseases.
  • PBC primary biliary cirrhosis
  • PSC primary sclerosing cholangitis
  • cystic fibrosis-related liver diseases Dosing for these indications ranges from 13 to 20 mg/kg/day (i.e. approximately 4 to 8 tablets or capsules of 250 mg a day) distributed over one to four doses a day. Normally, during the first three months of treatment the daily dose is divided over the day. With improvement of the liver values the dose may be taken once daily in the evening.
  • EP 2623100 provides a solubility-improving preparation for improving the oral absorbability of a poorly soluble drug (such as UDCA), which comprises granules which contains said poorly soluble drug, and an alkaline agent and a surfactant and which contains substantially no disintegrating agent; and which is characterized in that the disintegrating agent is present only in the outside of the granules.
  • a poorly soluble drug such as UDCA
  • Suitable alkaline agents are magnesium oxide, magnesium hydroxide, hydroxylation alumina magnesium, synthetic hydrotalcite, calcium carbonate, magnesium carbonate, and calcium silicate.
  • the presence of extragranular disintegrant resulted in an increased dissolution, but is unfortunately not applicable to all types of dosage forms, such as for example multiparticulate formulations. Especially for higher dosage regimen, such multiparticulate dosage forms can be preferred.
  • the solubility may be improved by adding an alkalizing agent in order to create a suitable micro-environment in the vicinity of the drug adequate for dissolution.
  • EP 0574894 teaches to use buffered-UDCA instead of the acidic form of UDCA.
  • the disadvantage of this approach is that the presence of a polymer coating is necessary to protect the buffered-UDCA from gastric acidity and neutralization of the buffer by the gastric acid.
  • EP 0509335 describes an oral formulation coated by an enterosoluble gastroresistant film containing bile acids such as UDCA mixed with physiologically compatible basic substances such as sodium bicarbonate, disodium phosphate or sodium maleate or L- arginine in order to favour bile acid salification and therefore bile acids absorption in the intestinal tract.
  • bile acids such as UDCA mixed with physiologically compatible basic substances such as sodium bicarbonate, disodium phosphate or sodium maleate or L- arginine in order to favour bile acid salification and therefore bile acids absorption in the intestinal tract.
  • physiologically compatible basic substances such as sodium bicarbonate, disodium phosphate or sodium maleate or L- arginine
  • a first aspect of the invention is directed to a solid oral pharmaceutical formulation comprising ursodeoxycholic acid or its pharmaceutically acceptable salt as active ingredient and ammonium chloride.
  • ursodeoxycholic acid or "UDCA” encompasses pharmaceutically acceptable salts thereof.
  • the inventors have unexpectedly found that the presence of ammonium chloride as solubilizing agent in the UDCA formulation exhibited much improved solubility at a pH ⁇ 7 when compared to the absence of said ammonium chloride.
  • the presence of ammonium chloride exhibited an improved solubility at such low pH than currently accessible with the existing products in the market. Therefore, UDCA can now be absorbed over a larger area, starting already in the duodenum, which enhances the bioavailability of the product.
  • the UDCA in combination with ammonium chloride was still soluble at said low pH after it had been exposed for 2 hours at pH 1.2, in order to mimic the passage through the stomach.
  • the formulation of the present invention has the advantage that it does not necessarily need to be enteric coated in order to maintain its improved solubility.
  • the inventors believe that a non-enteric coated formulation has an additional beneficial effect on the bioavailability of UDCA since although the UDCA is not soluble at low pH in the stomach, it needs to be available in non-enteric form.
  • the molar ratio of UDCA and ammonium chloride is from 1 : 15 to 15: 1, preferably from 1 : 10 to 10: 1, more preferably from 1 :5 to 5: 1, more preferably from 1 :3 to 3 : 1.
  • the amount of ursodeoxycholic acid in the formulation is between 250 mg to 3000 mg per unit dose, and the formulation comprises at least 20 weight %, preferably at least 40 weight % ursodeoxycholic acid, based on total weight of the formulation.
  • a "unit dose" is to be understood as a dose which is to be ingested at a single time.
  • the amount of ursodeoxycholic acid in the formulation is between 250 mg to 3000 mg per unit dose.
  • the pharmaceutical formulation further comprises a disintegrant, a binder, a lubricant and/or spheronization aid.
  • the formulation further comprises one or more of a viscosity increasing agent, a sweetener and a flavouring agent.
  • a flavouring agent includes a flavour enhancer.
  • the formulation further comprises a sweetener and a flavouring agent and optionally a viscosity increasing agent.
  • the formulation further comprises a viscosity increasing agent a sweetener and a flavouring agent.
  • the pharmaceutical formulation is a multiparticulate, a tablet and/or a capsule.
  • said formulation is coated.
  • examples of such a formulation may be a multiparticulate in a monodose container, a multiparticulate in a capsule or a multiparticulate pressed into a tablet.
  • the formulation according to the invention does not comprise an enteric coating.
  • the present invention provides a solid oral pharmaceutical formulation comprising a multiparticulate comprising
  • the solid oral pharmaceutical formulation comprising a multiparticulate according to the invention is suitable for reconstitution in a liquid.
  • the present solid oral pharmaceutical formulation comprising a multiparticulate suitable for reconstitution in a liquid forms a suspension for oral administration.
  • the present solid oral pharmaceutical formulation comprising a multiparticulate suitable for reconstitution in a liquid is suitable for reconstitution in water.
  • the present invention provides a solid oral pharmaceutical formulation comprising ursodeoxycholic acid or its pharmaceutically acceptable salt and a solubilizing agent, characterized in that the dissolution of said ursodeoxycholic acid, when measured using a three stage dissolution test in a USP apparatus I (basket) at 37°C, said dissolution test consisting of a first stage wherein said formulation is exposed for 2 hours at 100 rpm to an hydrochloric acid solution with pH 1.2, a second stage wherein said formulation is exposed for 1 hour at 100 rpm to a phosphate buffer solution of pH 6.8 and a third stage wherein said formulation is exposed for 1 hour at 100 rpm to a phosphate buffer solution of pH 7.4, is
  • said dissolution at pH 6.8 is at least 75%.
  • the present invention provides a process for the preparation of the formulation according to the invention, comprising
  • granulating a composition comprising ursodeoxycholic acid, ammonium chloride, a binder and a disintegrant, to form a multiparticulate;
  • said process employs a wet granulation in (i).
  • the present invention provides a solid oral pharmaceutical formulation obtainable by said process.
  • the invention provides the pharmaceutical formulation according to the invention for use in treating cholestatic liver diseases such as biliary cirrhosis.
  • This aspect of the invention may also be worded as the use of UDCA and ammonium chloride for the manufacture of a pharmaceutical formulation according to the invention for treating cholestatic liver diseases such as biliary cirrhosis.
  • this aspect of the invention relates to a method of treating cholestatic liver diseases such as biliary cirrhosis, comprising administering to a subject in need thereof the pharmaceutical formulation according to the invention.
  • the invention provides a pharmaceutical formulation comprising UDCA as active ingredient in combination with ammonium chloride.
  • This formulation exhibits improved solubility of UDCA at lower pH (pH ⁇ 7).
  • EP 1156812 discloses a selection of the sodium salt of UDCA as penetration enhancer and the optional use of a mucolytic agent in order to improve delivery of oligonucleotides as therapeutic active ingredient across the mucosal membranes in the intestine.
  • a further selection of ammonium chloride as the mucolytic agent is not disclosed and hence the formulation according to the present invention is not anticipated by EP 1156812.
  • the formulation comprises as active pharmaceutical ingredient ursodeoxycholic acid (UDCA) or a pharmaceutically acceptable salt thereof such as the sodium or potassium salt.
  • Said UDCA may be crystalline or amorphous, optionally it may be micronized.
  • UDCA is the sole active ingredient, preferably the sole pharmaceutically active ingredient.
  • UDCA is present for treatment of chronic cholestatic liver diseases, or in other words, the formulation is a chronic cholestatic liver disease medicament.
  • the formulation of the present invention comprises the inorganic compound ammonium chloride.
  • Alkylated forms of ammonium chloride such as for example (tri)ethyl- or methyl-ammonium chloride are also to be comprised within the term ammonium chloride.
  • the tetra-hydrogen, or in other words non- alkylated, variant of ammonium chloride ( H 4 CI) is used.
  • the UDCA and ammonium chloride are used in a molar ratio of 1 : 15 to 15: 1, preferably of 1 : 10 to 10: 1, more preferably of 1 :5 to 5 : 1, more preferably of 1 :3 to 3: 1, even more preferably, the molar ratio is 1 :2 to 2: 1. Most preferably the molar ratio is about 1 : 1.25.
  • the molar ratio of the UDCA and ammonium chloride may even be increased to 1 :8 or 1 : 10.
  • the amount of UDCA in the pharmaceutical formulation is 250 mg to 3000 mg per unit dose, preferably 500 mg to 2000 mg, most preferably 750 mg to 1000 mg.
  • the formulation of the present invention may further comprise a disintegrant, a binder, a lubricant, a spheronization aid and/or a coating.
  • disintegrants include hydroxypropyl cellulose, carmellose, crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), sodium starch glycolate.
  • the amount of the disintegrant is preferably 4 to 30 weight %, and more preferably 6 to 25 weight %, based on total weight of the formulation.
  • binders include lactose, microcrystalline cellulose, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose and/or mixtures thereof.
  • the amount of the binder is preferably 5 to 20 weight %, and more preferably 7 to 15 weight %, based on total weight of the formulation.
  • lubricants examples include silica, colloidal silica, stearic acid, magnesium stearate, talc.
  • the amount of the lubricant is preferably 0.03 to 2 weight %, and more preferably 0.5 to 1.5 weight %, based on total weight of the formulation.
  • spheronization aids include propylene glycol, polyethylene glycol, triacetin, glycerin.
  • the amount of the spheronisation aid is preferably 1 to 10 weight %, and more preferably 2 to 7 weight %, based on total weight of the formulation.
  • examples of viscosity increasing agents are hydroxyethylcellulose, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, polyvinylpyrrolidone, carboxylmethyl cellulose, preferably carboxylmethyl cellulose sodium salt and the like .
  • the amount of viscosity increasing agent is preferably 3 to 20 weight %, and more preferably 5 to 15 weight %, based on the total weight of the formulation.
  • the viscosity increasing agent functions as suspension stabilizer of the formulation comprising a multiparticulate according to the present invention. There can be overlap for certain ingredients to act as a binder and as a viscosity increasing agent.
  • Example of sweeteners are xylitol, sucralose, sorbitol, mannitol and the like.
  • the amount of sweetener is preferably 30 to 60 weight %, more preferably 40 to 50 weight %,based on the total weight of the formulation.
  • flavouring agents and/or flavour enhancers are lemon flavour and citric acid.
  • the amount of flavouring agent is preferably 2 to 10 weight %, more preferably 3 to 5 weight %, based on the total weight of the formulation.
  • the oral dosage form of the present invention may be coated. Coating layers can be applied using commonly known techniques such as spray coating. Examples of coatings include a filmcoating, a taste-masking coating, and/or enteric coating. Also multiple coating layers may be applied.
  • the coating agent examples include but are not limited to ethyl cellulose, carboxymethylethyl cellulose, carmellose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose; hydroxypropylmethyl cellulose; polyvinyl alcohol (PVA), ethyl acrylate methyl methacrylate copolymer, amino alkyl methacrylate copolymer, carnauba wax, carboxy vinyl polymer, methacrylic acid copolymer, dimethylaminoethyl methacrylate methyl methacrylate copolymer, stearyl alcohol, shellac, hydroxypropylmethyl cellulose phthalate and mixtures hereof.
  • PVA polyvinyl alcohol
  • ethyl acrylate methyl methacrylate copolymer amino alkyl methacrylate copolymer
  • carnauba wax carboxy vinyl polymer
  • methacrylic acid copolymer dimethylaminoethy
  • the coating may be applied in amounts ranging from 2 to 20 weight %, preferably between 4 to 10 weight %, based on dry weight of the formulation.
  • the pharmaceutical formulation of the present invention is a solid oral dosage form such as a multiparticulate, tablet, caplet or capsule.
  • the multiparticulate comprises granules (a granulate) that are typically prepared by granulation (wet- or dry-granulation) or it comprises pellets or spheres that are typically prepared by extrusion and spheronization.
  • the multiparticulate, or pharmaceutical formulation may be packaged as such in a monodose container such as a sachet or stick pack. Alternatively, it may be encapsulated in a capsule or compressed into tablets.
  • multiparticulate encompasses multiple particles which, depending on their shape, may suitably be referred to by a person skilled in the art as a crystal, a granulate, a sphere, a bead, a pellet, a mini-pellet and a mini- or micro-tablet.
  • the multiparticulate comprises multiple particles, said particles comprise the active ingredient.
  • the pharmaceutical formulation or the multiparticulate of the present invention does not comprise carrier particles, i.e. granules comprising carrier material.
  • the pharmaceutical formulation of the present invention does not comprise an enteric coating, i.e. said pharmaceutical formulation is not gastro resistant.
  • the multiparticulate of the present invention comprises:
  • the present invention concerns a solid oral pharmaceutical formulation comprising the present multiparticulate and further comprising one or more of a viscosity increasing agent, a sweetener and a flavouring agent. In one embodiment the present invention concerns a solid oral pharmaceutical formulation comprising the present multiparticulate and further comprising a sweetener and a flavouring agent and optionally a viscosity increasing agent. In one embodiment the present invention concerns a solid oral pharmaceutical formulation comprising the present multiparticulate and further comprising a viscosity increasing agent, a sweetener and a flavouring agent.
  • the present invention concerns a solid oral pharmaceutical formulation comprising 30-50 weight % based on total weight of the pharmaceutical formulation of a multiparticulate comprising
  • flavouring agent 2 to 10 weight %
  • the above solid oral pharmaceutical formulation comprises viscosity increasing agent.
  • the above solid oral pharmaceutical formulation comprising a multiparticualte and further comprising a visoscity increasing agent, a sweetener and a flavouring agent is particularly suitable for reconstitution in a liquid, preferably for reconstitution in water.
  • the pharmaceutical formulation provides a stable suspension of the multiparticulate which is preferably for oral administration.
  • the formulation of the invention in particular the multiparticulate of the invention, is obtainable by the process as described here below, in particular by employing wet granulation.
  • the invention provides a process for preparing a solid oral formulation comprising UDCA and ammonium chloride, preferably a process for preparing the formulation according to the invention, more preferably for preparing the multiparticulate according to the invention, comprising:
  • a composition comprising UDCA, ammonium chloride, a binder and a disintegrant, to form a multiparticulate;
  • iii either packaging the optionally coated multiparticulate, preferably in monodose container (e.g. a sachet or stick pack), or tabletting or encapsulating the optionally coated multiparticulate.
  • monodose container e.g. a sachet or stick pack
  • said process comprises mixing the UDCA, ammonium chloride, binder, disintegrant and, where appropriate, further ingredients such as the spheronization aid and granulating the resulting mixture by methods known in the art such as wet granulation method or extrusion and spheronization.
  • the granulation method is wet granulation.
  • the resulting multiparticulate is dried and sized and can be coated or used as such. Coating layers can be applied using commonly known techniques such as spray coating. Suitable coatings are as described above for the formulation according to the invention.
  • said multiparticulate is encapsulated into capsules (e.g. hard gelatine capsules) or packaged in a monodose container such as a sachet or stick pack.
  • said multiparticulate is admixed with lubricant and compressed in a tablet press.
  • the process of the invention preferably employs the preferred binders, disintegrants, lubricants and spheronization aids as described above for the formulation of the invention.
  • the amount of each of the ingredients is preferably as described above for the formulation of the invention.
  • Dissolution testing is carried out according to a method known in the art as a three stage dissolution test.
  • Said 3 stage test is carried out in a dissolution apparatus USP Type I (basket).
  • the formulation is submerged in a stirred (100 rpm) solution at 37°C for a certain amount of time after which the pH of the dissolution medium is changed.
  • the first stage comprises exposure of the formulation for 2 hours to a hydrochloric acid solution with pH 1.2.
  • the second stage is exposure of the formulation to a phosphate buffer solution with pH 6.8 for 1 hour and the third stage is a 1 hour exposure to a phosphate buffer solution with pH 7.4.
  • the pH variation in the 3 stages is achieved without changing the dissolution media.
  • the dissolution medium in the first stage is 750 ml of an 0.1 N hydrochloric acid solution with pH 1.2 (pH adjusted when necessary with 5N HCl).
  • the pH is changed by adding 250 ml of a Na 3 P0 4 12H 2 0 buffer (prepared by dissolving 76 g of Na 3 P0 4 12H 2 0 in 1000 ml) equilibrated at 37°C to the dissolution medium of the first stage (0.1N HCl) in the same dissolution jar and stirring with a glass rod. If necessary, the pH is adjusted to 6.8 with 5N NaOH or 5N HCl.
  • the pH is changed by adding several ml of 5 N NaOH to the dissolution medium of the second stage to reach pH 7.4 in the same dissolution jar and stirring with a glass rod.
  • Samples of 10 ml are withdrawn from the solutions at designated time points, filtered through a micron filter and then analysed for drug release by UV adsorption.
  • the concentration of UDCA in the sample solution is determined by comparison of the absorbance at 210 nm with that of a standard solution. Since UDCA is not soluble at pH 1.2, dissolution results show less than 5% at this low pH. Significant UDCA solution is only observed in the second and third stages.
  • the present invention provides a solid oral pharmaceutical formulation comprising ursodeoxycholic acid or a pharmaceutically acceptable salt thereof and a solubilizing agent, characterized in that the dissolution of said ursodeoxycholic is
  • the solubilizing agent is ammonium chloride.
  • the dissolution after 1 hour in buffer at pH 6.8 is from 65% to 99%), preferably the dissolution after 1 hour in buffer at pH 6.8 is from 70%> to 97%>, preferably it is between 75%> to 95%> when measured according the three stage dissolution test as defined above.
  • the dissolution after 1 hour in buffer at pH 7.4 is between 80% to 100%, preferably between 95% to 100% when measured according the three stage dissolution test as defined above.
  • the pharmaceutical formulation of the present invention is especially suitable to be used for treating cholestatic liver diseases such as biliary cirrhosis.
  • Example 1 Preparation of multiparticulate, capsules and tablets according to the invention
  • Manufacturing process for UDCA multiparticulate involved the steps of first granulation of all ingredients using water as binder solution in a rapid mixer granulator. The obtained wet mass was divided into two parts. One part was extruded through 1 mm screen at 40 rpm feeder and impeller and spheronised for 30 seconds. Subsequently, the resulting pellets were dried in a fluid bed processor. Part of the pellets were encapsulated in hard gelatine capsules of size 00.
  • the other part of the wet mass was used for lubrication and then compressed into tablets.
  • the wet mass was dried and milled through 1.5 mm screen of Co-mill, to form a granulate.
  • the granulate was lubricated with Aerosil 200 and Magnesium and compressed into tablets.
  • the resulting formulation thus obtained was as follows:
  • Example 2 Dissolution testing.
  • the formulation was exposed for 2 hours at 100 rpm in an 0.1N hydrochloric acid solution with pH 1.2 (Dissolution medium I, pH 1.2).
  • the formulation was exposed for 1 hour at 100 rpm in a phosphate buffer with pH 6.8 (Dissolution medium II, pH 6.8).
  • the formulation was exposed for 1 hour at 100 rpm in a phosphate buffer with pH of 7.4 (Dissolution medium II, pH 7.4).
  • the pH variation in the 3 stages was achieved without changing the dissolution media.
  • the dissolution medium I is 750 ml of an 0.1 N hydrochloric acid solution with pH 1.2 (pH adjusted when necessary with 5N HC1).
  • the pH was changed by adding 250 ml of a Na 3 P0 4 12H 2 0 buffer (prepared by dissolving 76 g of Na 3 P0 4 12H 2 0 in 1000 ml) equilibrated at 37°C to dissolution media I (0.1N HC1) in same dissolution jar and stirred with a glass rod. If necessary, the pH was adjusted to 6.8 with 5N NaOH or 5N HC1.
  • the pH was changed by adding several ml of 5 N NaOH to dissolution media II to reach pH 7.4 in same dissolution jar and stirred with a glass rod.
  • Samples of 10 ml were withdrawn at designated time points, filtered through a micron filter and then analysed for drug release by UV adsorption.
  • the concentration of UDCA in the sample solution was determined by comparison of the absorbance at 210 nm with that of a standard solution. The average drug release at the function of pH and time are shown in the Table below. There was essentially no dissolution of UDCA after the 2 hours period at pH 1.2.
  • Multiparticulates were made substantially in the same manner as described in Example 1 and different amounts of ammonium chloride were used to test the effect on the solubility of the drug.
  • the solubility was measured according to the method described in Example 2 and the results are shown in the Table below.
  • Example 4 Comparative example. Preparation of multiparticulate with different solubilization agents
  • Multiparticulates were made essentially according to Example 1.
  • the following solubilizing agents were tested: ammonium carbonate, sodium carbonate, sodium bicarbonate, ammonium chloride, dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate copolymer (Eudragit EPO, Evonik).
  • no solubilizing agent specific for UDCA was present. All solubilizing agents were used in an amount corresponding to a molar ratio of 1 : 1 based on the amount of UDCA.
  • Example 2 the solubility of these samples were tested according to the method described in Example 2. Additionally, 2 different commercial available samples were also tested for their solubility. One sample is a 250 mg UDCA film coated tablet, the other sample is a 250 mg UDCA hard gelatine capsule.
  • the multiparticulate was packaged in stick packs in amounts corresponding to respectively 1000 and 2000 mg UDCA.
  • the formulation was packaged in a sachet with instruction to reconstitute in water.

Abstract

The present invention relates to solubility-improved solid bile acid formulations optionally for reconstitution for oral intake comprising ursodeoxycholic acid and ammonium chloride, a process for the preparation of said formulation and a method of treating cholestatic liver diseases such as biliary cirrhosis by administering said formulation.

Description

Bile acid composition with enhanced solubility
Field of the invention
The invention relates to a pharmaceutical bile acid composition with enhanced solubility at lower pH for improved absorption after oral intake, a process for preparing said composition and the use thereof for treating cholestatic liver diseases.
Background of the invention
Ursodeoxycholic acid (UDCA) is a naturally occurring secondary bile acid. Generally, UDCA is prescribed for chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and cystic fibrosis-related liver diseases. Dosing for these indications ranges from 13 to 20 mg/kg/day (i.e. approximately 4 to 8 tablets or capsules of 250 mg a day) distributed over one to four doses a day. Normally, during the first three months of treatment the daily dose is divided over the day. With improvement of the liver values the dose may be taken once daily in the evening. Recent studies report that higher doses, up to 30 mg/kg/day could have beneficial effects in some cholestatic liver diseases (EASL, 2009, 2011). UDCA is also commonly used for the dissolution of gallstones, with a once-daily dosing of 5 to 10 mg/kg/day.
Currently no high-dose UDCA formulation is available on the global market. Delursan® is available as a tablet of 250 mg UDCA dose strength. Ursofalk® is presented as a capsule of 250 mg UDCA dose strength and as a 500 mg tablet. In many cases, patients currently need to swallow (multiple) doses of multiple tablets or capsules. Hence, there is a clear, yet hitherto unmet, medical need for providing a high- dose UDCA product for cholestatic liver diseases to the community. The present invention provides for a once daily high-dosing strength and the much easier to swallow pellet character of the formulation would clearly improve patient quality of life and compliance.
It is generally accepted that after oral administration, the bioavailability of UDCA is very poor due to the low solubility at physiological intestinal pH. UDCA is sparingly soluble below pH 5, and maximum soluble at pH 8. Hence, the intestinal pH plays an important role in UDCA absorption as solubility of UDCA increases with pH and solubility of UDCA in principle increases upon transit through the gastro-intestinal tract. Several attempts have been made in the past to improve the solubility of UDCA, involving the use of various methods.
These methods included the formation of salt-forms of UDCA. However, according to EP 0509355 the disadvantage of preparing such salt-form of UDCA is that the pharmaceutical formulations must be gastro resistant, because otherwise the strong acid gastric juices would convert the soluble bile acids salt form back into their insoluble acid form.
Alternatively, EP 2623100 provides a solubility-improving preparation for improving the oral absorbability of a poorly soluble drug (such as UDCA), which comprises granules which contains said poorly soluble drug, and an alkaline agent and a surfactant and which contains substantially no disintegrating agent; and which is characterized in that the disintegrating agent is present only in the outside of the granules. Suitable alkaline agents are magnesium oxide, magnesium hydroxide, hydroxylation alumina magnesium, synthetic hydrotalcite, calcium carbonate, magnesium carbonate, and calcium silicate. The presence of extragranular disintegrant resulted in an increased dissolution, but is unfortunately not applicable to all types of dosage forms, such as for example multiparticulate formulations. Especially for higher dosage regimen, such multiparticulate dosage forms can be preferred.
Alternatively, the solubility may be improved by adding an alkalizing agent in order to create a suitable micro-environment in the vicinity of the drug adequate for dissolution. EP 0574894 teaches to use buffered-UDCA instead of the acidic form of UDCA. The disadvantage of this approach is that the presence of a polymer coating is necessary to protect the buffered-UDCA from gastric acidity and neutralization of the buffer by the gastric acid. Once the microspheres pass through the stomach in the duodenum, the microspheres disintegrate and release the buffered-UDCA into the intestine within ten to thirty minutes after which UDCA is rapidly neutralized to its soluble salt form. EP 0509335 describes an oral formulation coated by an enterosoluble gastroresistant film containing bile acids such as UDCA mixed with physiologically compatible basic substances such as sodium bicarbonate, disodium phosphate or sodium maleate or L- arginine in order to favour bile acid salification and therefore bile acids absorption in the intestinal tract. The distinctive feature is that the formulation is coated by an enterosoluble gastroresistant film which allows the mixture of bile acids and basic substance to cross the gastric juices unaltered and to be dissolved in the intestine where the absorption takes place.
Hence, although the prior art teaches the use of many different alkalizing agent in order to improve the solubility of UDCA, all of them still require the use of enteric coatings in order to protect the formulation from breakdown in the stomach. The disadvantage of using an enteric coating is that once the oral formulation leaves the stomach and enters the duodenum, it requires in general 10 to 30 min. before the enteric polymer coating is dissolved and the release of the UDCA can start. Ideally, UDCA should be maximally dissolved when passing the upper intestine in order to avoid that significant part of dose is directly excreted. Hence, dissolution of UDCA in the duodenum would be desirable. Although there is no clear correlation between in vitro dissolution behavior and in vivo- plasma levels, a clear trend was observed in previous studies that a faster dissolution corresponds to higher plasma levels. Therefore an early and fast dissolution is a key parameter for a high bioavailability. Hence it is an object of the present invention to provide for an oral UDCA formulation already quickly dissolving at pH values <7.
Summary of the invention
A first aspect of the invention is directed to a solid oral pharmaceutical formulation comprising ursodeoxycholic acid or its pharmaceutically acceptable salt as active ingredient and ammonium chloride. In the context of the present invention, the term "ursodeoxycholic acid" or "UDCA" encompasses pharmaceutically acceptable salts thereof. In the instant invention, the inventors have unexpectedly found that the presence of ammonium chloride as solubilizing agent in the UDCA formulation exhibited much improved solubility at a pH <7 when compared to the absence of said ammonium chloride. In particular the presence of ammonium chloride exhibited an improved solubility at such low pH than currently accessible with the existing products in the market. Therefore, UDCA can now be absorbed over a larger area, starting already in the duodenum, which enhances the bioavailability of the product.
Further, it was unexpectedly found that the UDCA in combination with ammonium chloride was still soluble at said low pH after it had been exposed for 2 hours at pH 1.2, in order to mimic the passage through the stomach. Hence the formulation of the present invention has the advantage that it does not necessarily need to be enteric coated in order to maintain its improved solubility. Additionally, without being bound to theory, the inventors believe that a non-enteric coated formulation has an additional beneficial effect on the bioavailability of UDCA since although the UDCA is not soluble at low pH in the stomach, it needs to be available in non-enteric form.
Additionally, it was surprisingly found that the improved solubility as found for ammonium chloride, could not be found for other agents such as e.g. sodium carbonate, which is generally used in the prior art to improve solubility.
In another embodiment of the invention, the molar ratio of UDCA and ammonium chloride is from 1 : 15 to 15: 1, preferably from 1 : 10 to 10: 1, more preferably from 1 :5 to 5: 1, more preferably from 1 :3 to 3 : 1.
In yet another embodiment, the amount of ursodeoxycholic acid in the formulation is between 250 mg to 3000 mg per unit dose, and the formulation comprises at least 20 weight %, preferably at least 40 weight % ursodeoxycholic acid, based on total weight of the formulation. Herein, a "unit dose" is to be understood as a dose which is to be ingested at a single time. In one embodiment, the amount of ursodeoxycholic acid in the formulation is between 250 mg to 3000 mg per unit dose. In yet another embodiment, the pharmaceutical formulation further comprises a disintegrant, a binder, a lubricant and/or spheronization aid.
In yet another embodiment, the formulation further comprises one or more of a viscosity increasing agent, a sweetener and a flavouring agent. A flavouring agent includes a flavour enhancer. Preferably the formulation further comprises a sweetener and a flavouring agent and optionally a viscosity increasing agent. In one embodiment the formulation further comprises a viscosity increasing agent a sweetener and a flavouring agent.
In yet another embodiment, the pharmaceutical formulation is a multiparticulate, a tablet and/or a capsule. Optionally, said formulation is coated. Examples of such a formulation may be a multiparticulate in a monodose container, a multiparticulate in a capsule or a multiparticulate pressed into a tablet.
In yet another embodiment, the formulation according to the invention does not comprise an enteric coating.
In yet another aspect the present invention provides a solid oral pharmaceutical formulation comprising a multiparticulate comprising
) 40 to 80 weight % of ursodeoxycholic acid and
i) 10 to 20 weight % of ammonium chloride
ii) 5 to 20 weight % of binder
v) 4 to 30% weight % of disintegrant, and
v) optionally 1 to 10 weight % of spheronization aid,
based on the total weight of the multiparticulate.
In yet another embodiment, the solid oral pharmaceutical formulation comprising a multiparticulate according to the invention is suitable for reconstitution in a liquid. Preferably the present solid oral pharmaceutical formulation comprising a multiparticulate suitable for reconstitution in a liquid forms a suspension for oral administration. Preferably the present solid oral pharmaceutical formulation comprising a multiparticulate suitable for reconstitution in a liquid is suitable for reconstitution in water.
In yet another aspect, the present invention provides a solid oral pharmaceutical formulation comprising ursodeoxycholic acid or its pharmaceutically acceptable salt and a solubilizing agent, characterized in that the dissolution of said ursodeoxycholic acid, when measured using a three stage dissolution test in a USP apparatus I (basket) at 37°C, said dissolution test consisting of a first stage wherein said formulation is exposed for 2 hours at 100 rpm to an hydrochloric acid solution with pH 1.2, a second stage wherein said formulation is exposed for 1 hour at 100 rpm to a phosphate buffer solution of pH 6.8 and a third stage wherein said formulation is exposed for 1 hour at 100 rpm to a phosphate buffer solution of pH 7.4, is
i. at least 65% after 1 hour in phosphate buffer at pH 6.8; and
ii. at least 80% after 1 hour in phosphate buffer at pH 7.4
In yet another embodiment said dissolution at pH 6.8 is at least 75%.
In yet another aspect the present invention provides a process for the preparation of the formulation according to the invention, comprising
i. granulating a composition comprising ursodeoxycholic acid, ammonium chloride, a binder and a disintegrant, to form a multiparticulate;
ii. optionally coating the resulting multiparticulate; and
iii. either packaging the optionally coated multiparticulate in a monodose container, or tabletting or encapsulating the optionally coated multiparticulate.
In yet another embodiment said process employs a wet granulation in (i).
In yet another aspect the present invention provides a solid oral pharmaceutical formulation obtainable by said process.
In yet another embodiment the invention provides the pharmaceutical formulation according to the invention for use in treating cholestatic liver diseases such as biliary cirrhosis. This aspect of the invention may also be worded as the use of UDCA and ammonium chloride for the manufacture of a pharmaceutical formulation according to the invention for treating cholestatic liver diseases such as biliary cirrhosis. In other words, this aspect of the invention relates to a method of treating cholestatic liver diseases such as biliary cirrhosis, comprising administering to a subject in need thereof the pharmaceutical formulation according to the invention.
Detailed description of the invention
Accordingly, the invention provides a pharmaceutical formulation comprising UDCA as active ingredient in combination with ammonium chloride. This formulation exhibits improved solubility of UDCA at lower pH (pH <7).
EP 1156812 discloses a selection of the sodium salt of UDCA as penetration enhancer and the optional use of a mucolytic agent in order to improve delivery of oligonucleotides as therapeutic active ingredient across the mucosal membranes in the intestine. A further selection of ammonium chloride as the mucolytic agent is not disclosed and hence the formulation according to the present invention is not anticipated by EP 1156812.
In one embodiment, the formulation comprises as active pharmaceutical ingredient ursodeoxycholic acid (UDCA) or a pharmaceutically acceptable salt thereof such as the sodium or potassium salt. Said UDCA may be crystalline or amorphous, optionally it may be micronized. In a particular embodiment, UDCA is the sole active ingredient, preferably the sole pharmaceutically active ingredient. Preferably, UDCA is present for treatment of chronic cholestatic liver diseases, or in other words, the formulation is a chronic cholestatic liver disease medicament.
Additionally the formulation of the present invention comprises the inorganic compound ammonium chloride. Alkylated forms of ammonium chloride such as for example (tri)ethyl- or methyl-ammonium chloride are also to be comprised within the term ammonium chloride. Preferably, the tetra-hydrogen, or in other words non- alkylated, variant of ammonium chloride ( H4CI) is used. In the present invention the UDCA and ammonium chloride are used in a molar ratio of 1 : 15 to 15: 1, preferably of 1 : 10 to 10: 1, more preferably of 1 :5 to 5 : 1, more preferably of 1 :3 to 3: 1, even more preferably, the molar ratio is 1 :2 to 2: 1. Most preferably the molar ratio is about 1 : 1.25. For higher amounts of UDCA, e.g. > 1000 mg per unit dose, the molar ratio of the UDCA and ammonium chloride may even be increased to 1 :8 or 1 : 10.
In another embodiment, the amount of UDCA in the pharmaceutical formulation is 250 mg to 3000 mg per unit dose, preferably 500 mg to 2000 mg, most preferably 750 mg to 1000 mg.
In another embodiment, the formulation of the present invention may further comprise a disintegrant, a binder, a lubricant, a spheronization aid and/or a coating. Examples of disintegrants include hydroxypropyl cellulose, carmellose, crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), sodium starch glycolate. The amount of the disintegrant is preferably 4 to 30 weight %, and more preferably 6 to 25 weight %, based on total weight of the formulation.
Examples of binders include lactose, microcrystalline cellulose, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose and/or mixtures thereof. The amount of the binder is preferably 5 to 20 weight %, and more preferably 7 to 15 weight %, based on total weight of the formulation.
Examples of lubricants include silica, colloidal silica, stearic acid, magnesium stearate, talc. The amount of the lubricant is preferably 0.03 to 2 weight %, and more preferably 0.5 to 1.5 weight %, based on total weight of the formulation.
Examples of spheronization aids include propylene glycol, polyethylene glycol, triacetin, glycerin. The amount of the spheronisation aid is preferably 1 to 10 weight %, and more preferably 2 to 7 weight %, based on total weight of the formulation. Examples of viscosity increasing agents are hydroxyethylcellulose, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, polyvinylpyrrolidone, carboxylmethyl cellulose, preferably carboxylmethyl cellulose sodium salt and the like . The amount of viscosity increasing agent is preferably 3 to 20 weight %, and more preferably 5 to 15 weight %, based on the total weight of the formulation. Preferably the viscosity increasing agent functions as suspension stabilizer of the formulation comprising a multiparticulate according to the present invention. There can be overlap for certain ingredients to act as a binder and as a viscosity increasing agent.
Example of sweeteners are xylitol, sucralose, sorbitol, mannitol and the like. The amount of sweetener is preferably 30 to 60 weight %, more preferably 40 to 50 weight %,based on the total weight of the formulation.
Examples of flavouring agents and/or flavour enhancers are lemon flavour and citric acid. The amount of flavouring agent is preferably 2 to 10 weight %, more preferably 3 to 5 weight %, based on the total weight of the formulation. The oral dosage form of the present invention may be coated. Coating layers can be applied using commonly known techniques such as spray coating. Examples of coatings include a filmcoating, a taste-masking coating, and/or enteric coating. Also multiple coating layers may be applied. Examples of the coating agent include but are not limited to ethyl cellulose, carboxymethylethyl cellulose, carmellose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose; hydroxypropylmethyl cellulose; polyvinyl alcohol (PVA), ethyl acrylate methyl methacrylate copolymer, amino alkyl methacrylate copolymer, carnauba wax, carboxy vinyl polymer, methacrylic acid copolymer, dimethylaminoethyl methacrylate methyl methacrylate copolymer, stearyl alcohol, shellac, hydroxypropylmethyl cellulose phthalate and mixtures hereof. Typically, the coating may be applied in amounts ranging from 2 to 20 weight %, preferably between 4 to 10 weight %, based on dry weight of the formulation. In yet another embodiment, the pharmaceutical formulation of the present invention is a solid oral dosage form such as a multiparticulate, tablet, caplet or capsule. The multiparticulate comprises granules (a granulate) that are typically prepared by granulation (wet- or dry-granulation) or it comprises pellets or spheres that are typically prepared by extrusion and spheronization. The multiparticulate, or pharmaceutical formulation, may be packaged as such in a monodose container such as a sachet or stick pack. Alternatively, it may be encapsulated in a capsule or compressed into tablets. Herein, the term "multiparticulate" encompasses multiple particles which, depending on their shape, may suitably be referred to by a person skilled in the art as a crystal, a granulate, a sphere, a bead, a pellet, a mini-pellet and a mini- or micro-tablet. In the present invention, the multiparticulate comprises multiple particles, said particles comprise the active ingredient.
In one embodiment, the pharmaceutical formulation or the multiparticulate of the present invention does not comprise carrier particles, i.e. granules comprising carrier material. In yet another embodiment, the pharmaceutical formulation of the present invention does not comprise an enteric coating, i.e. said pharmaceutical formulation is not gastro resistant.
In one embodiment, the multiparticulate of the present invention comprises:
i) 40 to 80 weight % of ursodeoxycholic acid,
ϋ) 10 to 20 weight % of ammonium chloride,
iii) 5 to 20 weight % of binder,
iv) 4 to 30% weight % of disintegrant, and
v) optionally 1 to 10 weight % of spheronization aid
based on the total weight of the multiparticulate.
In one embodiment the present invention concerns a solid oral pharmaceutical formulation comprising the present multiparticulate and further comprising one or more of a viscosity increasing agent, a sweetener and a flavouring agent. In one embodiment the present invention concerns a solid oral pharmaceutical formulation comprising the present multiparticulate and further comprising a sweetener and a flavouring agent and optionally a viscosity increasing agent. In one embodiment the present invention concerns a solid oral pharmaceutical formulation comprising the present multiparticulate and further comprising a viscosity increasing agent, a sweetener and a flavouring agent.
In one embodiment the present invention concerns a solid oral pharmaceutical formulation comprising 30-50 weight % based on total weight of the pharmaceutical formulation of a multiparticulate comprising
i) 40 to 80 weight % of ursodeoxycholic acid and
ϋ) 10 to 20 weight % of ammonium chloride
iii) 5 to 20 weight % of binder
iv) 4 to 30 weight % of disintegrant, and
v) optionally 1 to 10 weight % of spheronization aid,
based on the total weight of the multiparticulate and further comprising
vi) optionally 3 to 20 weight % of viscosity increasing agent
vii) 30-60 weight % of sweetener and
viii) 2 to 10 weight % of flavouring agent
based on total weight of the pharmaceutical formulation.
In one embodiment, the above solid oral pharmaceutical formulation comprises viscosity increasing agent. The above solid oral pharmaceutical formulation comprising a multiparticualte and further comprising a visoscity increasing agent, a sweetener and a flavouring agent is particularly suitable for reconstitution in a liquid, preferably for reconstitution in water. Advantageously upon reconstitution the pharmaceutical formulation provides a stable suspension of the multiparticulate which is preferably for oral administration.
In one embodiment, the formulation of the invention, in particular the multiparticulate of the invention, is obtainable by the process as described here below, in particular by employing wet granulation. In another embodiment, the invention provides a process for preparing a solid oral formulation comprising UDCA and ammonium chloride, preferably a process for preparing the formulation according to the invention, more preferably for preparing the multiparticulate according to the invention, comprising:
i. granulating a composition comprising UDCA, ammonium chloride, a binder and a disintegrant, to form a multiparticulate;
ii. optionally coating the resulting multiparticulate; and
iii. either packaging the optionally coated multiparticulate, preferably in monodose container (e.g. a sachet or stick pack), or tabletting or encapsulating the optionally coated multiparticulate.
Particularly, said process comprises mixing the UDCA, ammonium chloride, binder, disintegrant and, where appropriate, further ingredients such as the spheronization aid and granulating the resulting mixture by methods known in the art such as wet granulation method or extrusion and spheronization. Preferably, the granulation method is wet granulation. The resulting multiparticulate is dried and sized and can be coated or used as such. Coating layers can be applied using commonly known techniques such as spray coating. Suitable coatings are as described above for the formulation according to the invention. Subsequently, said multiparticulate is encapsulated into capsules (e.g. hard gelatine capsules) or packaged in a monodose container such as a sachet or stick pack.
Alternatively, said multiparticulate is admixed with lubricant and compressed in a tablet press. The process of the invention preferably employs the preferred binders, disintegrants, lubricants and spheronization aids as described above for the formulation of the invention. The amount of each of the ingredients is preferably as described above for the formulation of the invention.
Dissolution testing is carried out according to a method known in the art as a three stage dissolution test. Said 3 stage test is carried out in a dissolution apparatus USP Type I (basket). In each stage, the formulation is submerged in a stirred (100 rpm) solution at 37°C for a certain amount of time after which the pH of the dissolution medium is changed. The first stage comprises exposure of the formulation for 2 hours to a hydrochloric acid solution with pH 1.2. The second stage is exposure of the formulation to a phosphate buffer solution with pH 6.8 for 1 hour and the third stage is a 1 hour exposure to a phosphate buffer solution with pH 7.4. The pH variation in the 3 stages is achieved without changing the dissolution media. The dissolution medium in the first stage is 750 ml of an 0.1 N hydrochloric acid solution with pH 1.2 (pH adjusted when necessary with 5N HCl). After completion of the first dissolution stage, the pH is changed by adding 250 ml of a Na3P04 12H20 buffer (prepared by dissolving 76 g of Na3P04 12H20 in 1000 ml) equilibrated at 37°C to the dissolution medium of the first stage (0.1N HCl) in the same dissolution jar and stirring with a glass rod. If necessary, the pH is adjusted to 6.8 with 5N NaOH or 5N HCl. After completion of the second dissolution stage, the pH is changed by adding several ml of 5 N NaOH to the dissolution medium of the second stage to reach pH 7.4 in the same dissolution jar and stirring with a glass rod. Samples of 10 ml are withdrawn from the solutions at designated time points, filtered through a micron filter and then analysed for drug release by UV adsorption. The concentration of UDCA in the sample solution is determined by comparison of the absorbance at 210 nm with that of a standard solution. Since UDCA is not soluble at pH 1.2, dissolution results show less than 5% at this low pH. Significant UDCA solution is only observed in the second and third stages. In one embodiment, the present invention provides a solid oral pharmaceutical formulation comprising ursodeoxycholic acid or a pharmaceutically acceptable salt thereof and a solubilizing agent, characterized in that the dissolution of said ursodeoxycholic is
i. at least 65% after 1 hour in phosphate buffer at pH 6.8; and
ii. at least 80% after 1 hour in phosphate buffer at pH 7.4
when measured according the three stage dissolution test as defined above.
Preferably the solubilizing agent is ammonium chloride.
In another embodiment, the dissolution after 1 hour in buffer at pH 6.8 is from 65% to 99%), preferably the dissolution after 1 hour in buffer at pH 6.8 is from 70%> to 97%>, preferably it is between 75%> to 95%> when measured according the three stage dissolution test as defined above. The dissolution after 1 hour in buffer at pH 7.4 is between 80% to 100%, preferably between 95% to 100% when measured according the three stage dissolution test as defined above.
The pharmaceutical formulation of the present invention is especially suitable to be used for treating cholestatic liver diseases such as biliary cirrhosis.
EXAMPLES
Example 1: Preparation of multiparticulate, capsules and tablets according to the invention
Manufacturing process for UDCA multiparticulate involved the steps of first granulation of all ingredients using water as binder solution in a rapid mixer granulator. The obtained wet mass was divided into two parts. One part was extruded through 1 mm screen at 40 rpm feeder and impeller and spheronised for 30 seconds. Subsequently, the resulting pellets were dried in a fluid bed processor. Part of the pellets were encapsulated in hard gelatine capsules of size 00.
The other part of the wet mass was used for lubrication and then compressed into tablets. Hereto, the wet mass was dried and milled through 1.5 mm screen of Co-mill, to form a granulate. Subsequently, the granulate was lubricated with Aerosil 200 and Magnesium and compressed into tablets. The resulting formulation thus obtained was as follows:
Figure imgf000015_0001
Example 2: Dissolution testing.
The resulting multiparticulate, tablets and capsules as described in example 1, were tested in a three stage dissolution test in a dissolution apparatus USP Type I (basket). In the first dissolution stage, the formulation was exposed for 2 hours at 100 rpm in an 0.1N hydrochloric acid solution with pH 1.2 (Dissolution medium I, pH 1.2). In the second dissolution stage, the formulation was exposed for 1 hour at 100 rpm in a phosphate buffer with pH 6.8 (Dissolution medium II, pH 6.8). In the third dissolution stage, the formulation was exposed for 1 hour at 100 rpm in a phosphate buffer with pH of 7.4 (Dissolution medium II, pH 7.4). The pH variation in the 3 stages was achieved without changing the dissolution media. The dissolution medium I is 750 ml of an 0.1 N hydrochloric acid solution with pH 1.2 (pH adjusted when necessary with 5N HC1). After completion of the first dissolution stage, the pH was changed by adding 250 ml of a Na3P04 12H20 buffer (prepared by dissolving 76 g of Na3P04 12H20 in 1000 ml) equilibrated at 37°C to dissolution media I (0.1N HC1) in same dissolution jar and stirred with a glass rod. If necessary, the pH was adjusted to 6.8 with 5N NaOH or 5N HC1. After completion of the second dissolution stage, the pH was changed by adding several ml of 5 N NaOH to dissolution media II to reach pH 7.4 in same dissolution jar and stirred with a glass rod. Samples of 10 ml were withdrawn at designated time points, filtered through a micron filter and then analysed for drug release by UV adsorption. The concentration of UDCA in the sample solution was determined by comparison of the absorbance at 210 nm with that of a standard solution. The average drug release at the function of pH and time are shown in the Table below. There was essentially no dissolution of UDCA after the 2 hours period at pH 1.2.
Figure imgf000016_0001
It is shown that the dissolution of the pharmaceutical formulation of the invention at pH 6.8 is between 75% to 96% and full dissolution at pH 7.4 is obtained. Example 3: Ammonium chloride used in different ratios
Multiparticulates were made substantially in the same manner as described in Example 1 and different amounts of ammonium chloride were used to test the effect on the solubility of the drug. The solubility was measured according to the method described in Example 2 and the results are shown in the Table below.
Figure imgf000017_0001
Example 4: Comparative example. Preparation of multiparticulate with different solubilization agents
Multiparticulates were made essentially according to Example 1. The following solubilizing agents were tested: ammonium carbonate, sodium carbonate, sodium bicarbonate, ammonium chloride, dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate copolymer (Eudragit EPO, Evonik). In one comparative example, no solubilizing agent specific for UDCA was present. All solubilizing agents were used in an amount corresponding to a molar ratio of 1 : 1 based on the amount of UDCA.
Subsequently, the solubility of these samples were tested according to the method described in Example 2. Additionally, 2 different commercial available samples were also tested for their solubility. One sample is a 250 mg UDCA film coated tablet, the other sample is a 250 mg UDCA hard gelatine capsule.
% Dissolution
pH 6.8 pH 7.4 (after 1 hour) (after 1 hour)
No solubilizing agent 37.00 77.00
Sodium carbonate 54.50 61.50
Sodium bicarbonate 53.00 57.50
Ammonium carbonate 36.00 60.00
Eudragit EPO 51.00 96.00
Commercial capsule sample 48.33 85.00
Commercial tablet sample 63.33 94.83 The dissolution data clearly show that both the commercially available products and the different known solubilizing agents known in the prior art have a release at pH 6.8 of maximal 63%. Interestingly, some of the solubilizing agents, such as sodium carbonate and ammonium carbonate, seem to lose their solubilizing effect once they are exposed to acid of pH 1.2, since only maximal release up to respectively 62% and 60 % could be obtained.
Example 5: Preparation of high dose UDCA multiparticulate formulations
In the same manner as described in Example 1, high dose formulation of UDCA multiparticulates were prepared.
Figure imgf000018_0001
The multiparticulate was packaged in stick packs in amounts corresponding to respectively 1000 and 2000 mg UDCA.
Example 6: Preparation of high dose UDCA multiparticulate for reconstitution
Figure imgf000018_0002
The formulation was packaged in a sachet with instruction to reconstitute in water.

Claims

Claims:
1. A solid oral pharmaceutical formulation comprising ursodeoxycholic acid or a pharmaceutically acceptable salt thereof as active ingredient and ammonium chloride.
2. The formulation according to claim 1, comprising ursodeoxycholic acid or its salt and ammonium chloride in a molar ratio of 1 : 5 to 5 : 1.
3. The formulation according to claim 1 or 2, wherein the amount of ursodeoxycholic acid is 250 mg to 3000 mg per unit dose and wherein the formulation comprises at least 20 weight % preferably at least 40 weight % ursodeoxycholic acid or salt thereof.
4. The formulation according to any one of claims 1 to 3, further comprising a disintegrant, a binder, a lubricant and/or spheronization aid.
5. The formulation according to any one of claims 1 to 4, wherein said formulation is a multiparticulate, a tablet and/or a capsule, optionally said formulation is coated.
6. The formulation according to any one of claims 1 to 5, characterized in that no enteric coating is present.
7. The formulation according to any one of claims 1 to 6, compri
multiparticulate comprising
i) 40 to 80 weight % of ursodeoxycholic acid,
ii) 10 to 20 weight % of ammonium chloride,
iii) 5 to 20 weight % of binder,
iv) 4 to 30% weight % of disintegrant, and
v) optionally 1 to 10 weight % of spheronization aid,
based on the total weight of the multiparticulate.
The formulation according to any one of claims 1 to 7, further comprising more of a viscosity increasing agent, a sweetener and a flavouring agent.
9. A solid oral pharmaceutical formulation comprising ursodeoxycholic acid or a pharmaceutically acceptable salt thereof and a solubilizing agent, characterized in that the dissolution of said ursodeoxycholic acid, when measured using a three stage dissolution test in a USP apparatus I at 37°C, said dissolution test consisting of a first stage wherein said formulation is exposed for 2 hours at 100 rpm in a hydrochloric acid solution with pH 1.2, a second stage wherein said formulation is exposed for 1 hour at 100 rpm in phosphate buffer solution with pH of 6.8 and a third stage wherein said formulation is exposed for 1 hour at 100 rpm in phosphate buffer solution with a pH of 7.4, is
i. at least 65% after 1 hour at pH 6.8; and
ii. at least 80% after 1 hour at pH 7.4.
10. The formulation according to claim 9, wherein said dissolution at pH 6.8 is at least 70%.
11. A process for the preparation of the formulation according to any of claims 1 to 8, comprising
i. granulating a composition comprising ursodeoxycholic acid, ammonium chloride, a binder and a disintegrant, to form a multiparticulate;
ii. optionally coating the resulting multiparticulate; and
iii. either packaging the optionally coated multiparticulate in a monodose container or tabletting or encapsulating the optionally coated multiparticulate.
12. The process according to claim 11, which employs wet granulation in (i).
13. The formulation according to any one of claims 1 to 8, which is obtainable by the process according to claim 11 or 12.
14. The solid oral pharmaceutical formulation according to any one of claims 1 to 10 or 13, for use in treating cholestatic liver diseases.
15. A method of treating cholestatic liver diseases, comprising administering to a subject in need thereof the solid oral pharmaceutical formulation according to any one of claims 1 to 10 or 13.
16. Use of ursodeoxycholic acid and ammonium chloride for the manufacture of a solid oral pharmaceutical formulation according to any one of claims 1 to 10 or 13, for treating cholestatic liver diseases.
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