IL169343A - Compositions for oral administration of active ingredients with unacceptable taste and a method for masking the taste of such compositions - Google Patents

Description

169343/2 169343 p'li I 453512 TAIN COMPOSITIONS FOR ORAL ADMINISTRATION OF ACTIVE INGREDIENTS WITH UNACCEPTABLE TASTE AND A METHOD FOR MASKING THE TASTE OF SUCH COMPOSITIONS Pearl Cohen Zedek Latzer P-7970-IL The present invention relates to compositions intended for the oral administration of active ingredients with unacceptable taste, and their preparation, In particular, the present invention relates to pharmaceutical compositions.

Some active ingredients have unacceptable organoleptic properties and are therefore . unsuitable for the preparation of paediatric formulations or oral formulations intended for subjects who find it difficult to swallow and for whom swallowing may pose problems,, For these reasons, some major products do not have paediatric formulations and furthermore some subjects are deprived of treatment by means of these active ingredients, which may have extremely damaging or even life threatening consequences ..

The problem of masking taste has always been a major problem for the pharmaceutical industry. Numerous systems have been tested, but iri the case of extremely bitter active ingredients, coating systems have in most cases proved inadequate and particular systems, when they are more effective, have disadvantages of an extremely large particle size which leads to a sandy mouthfeel and to the medicament being refused by the patient ..

A method for preparing particles coated by spray-coating by means of a molten wax sprayed by a dual fluid nozzle has been described in European patent EP 639365.. However, this method is based on spraying the molten wax on the particles in order to form the coating,, There is no prior mixing of the active ingredient with the wax; furthermore, the particles and the nozzle have large diameters. Finally, the trials according to the method of the present invention, based 169343/1 - la - solely on the use of a molten wax, did not give acceptable results in terms of kinetics of release at pH = 1 ,.

US 5,188,838 discloses a spray cooling process for the preparation of pearls based on a pharmaceutic l active substance exhibiting an indefinite crystallization point .

JP 59122425 (XP 002312796 Abstract) discloses sustained release preparation prepared by a spray codling process ..

US 5,498,447 (equivalent to EP 639365, cited in the application as filed) discloses a method for preparing simply and easily sustained release preparations, or preparations for masking materials of unpleasant and bitter tastes, without using any organic solvent for dissolving a wax, or without necessity of complicated operations for pulverizing a wax., US 5,294,298 discloses a spray-drying granulation apparatus which accommodates both a spray dryer and a grariulator in one chamber and wherein a two- fluid pressure nozzle of particular structure is present in the spray-drying section of spray-drying granulation apparatus ..

WO 00/40339 discloses a process for coating tablets by subjecting the tablets to an upward spray of coating liquid produced by a two-fluid nozzle.

It has now been found that compositions intended for oral administration could be developed and provide adequate masking of taste to be acceptable and to allow in particular administration of pharmaceutical compositions in young children or in subjects unable to swallow.

The composition according to the invention intended for oral administration of active ingredients with unacceptable taste, characterized in that it comprises from 15 to 30% of active ingredient mixed with 55 to 85% of an ester of glycerol or a fatty acid optionally supple-nmented with wax, and supplemented with a surfactant, and in that they are prepared by a spray-cooling process which can lead to a particle size of less than 350 urn.

Advantageously, the selection of glycerol esters having an appropriate pH-sensitivity profile allows the release of the active ingredient under acidic pH conditions as encountered in the stomach.

According to the invention, the glycerol or fatty acid esters used in the compositions according to the invention have the following characteristics: melting point of between- 256C and 100°C, preferably between 25 and 70°C, stability in the molten state. The glycerol ester may be chosen from glyceryl stearate or glyceryl palmitostearate, in particular Precirol®., The glycerol ester is advantageously between 50 and.85% by weight of the total mixture of the composition; preferably it is between 60 and 80% by weight and more particularly between 70 and 80% by weight., The wax which may be optionally added may be advantageously carnauba wax, it may also be chosen from paraffin or beeswax or candelilla wax., When a wax is added to the composition, it may be added in an amount - 3 -of 4 to 10% by weight of the total mixture of the composition and in a ratio of 5 to 20% relative to the glycerol ester introduced.

When a fatty acid is introduced into the composition, it is advantageously chosen from palmitic, myristic or stearic acid. The fatty acid is introduced in an amount of 60 to 80% by weight of the total mixture of the composition .

The surfactant introduced into the composition is advantageously chosen from lecithins, in particular soybean lecithin, or surfactants of the sorbitan ester family having an HLB of less than 7. The surfactant is added in an amount of 1 to 3% by weight of the total mixture of the composition.

Preferably, the diameters are advantageously less than 350 μτη for more than 90% of the particles. More particularly, they may be between 100 μτη and 350 μπι for 25 to 65% of the particles and less than 100 Γη for 35 to 75% of the particles.

According to the invention, the spray cooling is performed by spraying by means of a dual-fluid nozzle which makes it possible to ensure that the desired particle size, that is to say a particle size of low diameter as described above, is obtained.

According to the invention, the preparation of the composition is carried out by mixing the active ingredient with the molten glycerol ester, supplemented with other excipients. The mixture is sprayed by the dual-fluid nozzle at the top of a tower into which a cold gaseous stream intended to aid the solidification of the sprayed droplets is optionally introduced countercurrentwise . The device is preferably provided with a fluidized bed which makes it possible to recover the particles and to improve the speed of - 4 -solidification .

The molten mixture introduced into the dual -fluid nozzle is generally heated to between 60 and 100°C.

Preferably, the dual-fluid nozzle advantageously has a diameter of 2.5 mm for the liquid section and a toroidal section of 0.3 mm for the air (or nitrogen) section. The flow rate of liquid and the flow rate of air (or nitrogen) sprayed into the nozzle are set beforehand according to the diameters of the sections of the dual-fluid nozzle used. Preferably, the flow rate of liquid is set at between 1 and 15 kg/h and the flow rate of air is set at between 2 and 5 m3/h.

The particle size of the active ingredient initially mixed with the glycerol ester ranges from 2 to 350 μπι. In some cases, it may be necessary to proceed to grinding before or after the mixing with the glycerol ester and prior to the spraying. Preferably, the dry grinding is performed prior to the mixing.

The tower used is a tower of the prilling tower type, but to which a dual-fluid nozzle has been fitted (contrary to the customary use of prilling) . The height of the tower is preferably between 2 and 8 m. The gaseous countercurrent intended for cooling is advantageously a nitrogen stream or a dry gas stream. The flow rate depends on many factors such as the tempe-rature, the chamber height, the quantities of product and the like. As a guide, it may be set in particular at values between slightly greater than 0 and 350 Nm3/h.

The composition may additionally contain other additives such as sweetening or taste-modifying agents ( saccharinate , aspartame, glycerin, vanillin, menthol and the like, or any other substance customarily used in the pharmaceutical industry), flavorings, glidants, - 5 -lubricants, ballasts or mineral agents [silicas, aluminum oxide, magnesium oxide, talc and the like, carbonates (calcium carbonate) , phosphates (tricalcium phosphate), lactose, sorbitol, glycine, mannitol, glucose, maltodextrins and the like] , preservatives (for example sodium metabisulfite , propylene glycol, ethanol or glycerin), and color-modifying agents. Preferably, it is a pharmaceutical composition.

The present invention relates to all the active ingredients, alone or as mixtures, administrable orally and exhibiting organoleptic problems, being consequently unacceptable to people who have to ingest them. The active ingredients are bitter and irritating substances and the like, or substances with unacceptable taste. Said active ingredients are compatible with the glycerol ester and its melting point.

Without limitation, in the case of pharmaceutical active ingredients, they may belong to all the therapeutic classes, such as for example antibacterial agents [macrolides (spiramycin, ketolides, such as for example telithromycin and the like) , streptogramins (pristinamycins such as pyostacin for example, virginiamycin for example) , quinolones and the like] , antifungal agents (metronidazole and the like) , antiparasitic agents (nivaquine and the like) , antiviral agents, anticancer agents, analgesics, nonsteroidal anti- inflammatory agents, antitussives, psychotropic agents, steroids, medicaments intended for the treatment of allergies, antiasthmatic agents, antispasmodic agents, cardiovascular agents (roxitromycin for example and the like) , therapeutic agents for the gastrointestinal tract and the like.

This may also involve active ingredients, alone or as mixtures, intended for cosmetic use, such as vitamins or plant or animal extracts. - 6 - The present invention has the advantage of effective masking of taste combined with an absence of, or with a very low sandy feel of the composition the mouth.

Dissolution tests were performed and show a low dissolution at neutral pH and therefore appropriate masking of taste and a dissolution at levels of 80 to 100% at pH = 1 after 60 minutes, showing the release of the active ingredient into the gastric medium.

The maximum bitterness, according to the nature of the active ingredient, is measured. Dissolution trials are performed in particular in a dissolution test at neutral pH : glass of water test at concentrations of 250 or 500 mg/1. The results are assessed in the light of the maximum bitterness value evaluated. A dissolution is observed which is approximately 4 times slower at neutral pH than at pH = 1.

The dissolution kinetics at pH = 1 is measured for solutions with a concentration of 500 mg/1, in 0. IN HC1 medium, in a dissolution medium containing 0.2% of sodium lauryl sulfate.

The following examples, given without limitation, illustrate the present invention.

Example 1 2400 g of precirol, melted beforehand in an oven at 60°C, are introduced into a jacketed reactor in which the jacket reference temperature is set at 75°C. 78 g of soybean lecithin are added. When the soybean lecithin is dissolved, the reference temperature is reduced to 65°C and 540 g of pristinamycin are added. The mixture is stirred for 20 minutes at 300 rpm and then the suspension is put through a ball mill. 1248 g of the ground suspension are then sprayed by means of a dual-fluid nozzle into a prilling tower - 7 -cooled beforehand by a cold nitrogen stream. At the start of spraying, the temperature is 0°C at the top of the tower and -20°C at the bottom of the tower. The air pressure on the dual-fluid nozzle is 1.5 bar, leading to a spraying air flow rate of 2.3 m3/h. The flow rate of liquid is 4.7 kg/h.

After spraying, the product is then filtered for 20 minutes at -20 °C, and then for 2 hour's at 32 °C.

The particle size of the product obtained, measured by sieving, is: - 26% of particles between 0 and 100 μπι - 62% of particles between 100 and 315 μπι - 12% of particles between 315 and 500 μτη - 1% of particles greater than 500 μπι The dissolution kinetics at pH 1 is 92% in 60 minutes for the crude product and 99% in 60 minutes for the particle size cut 100-315 μΓη .

The concentration of active material in a glass of water (neutral pH) is 182 mg/1 after 5 minutes and 473 mg/1 after 15 minutes for the crude granules. It is 89 mg/1 after 5 minutes and 280 mg/1 after 15 minutes for the granules of the 100-315 μιη cut.

Example 2 704 g of precirol are introduced into a jacketed reactor in which the jacket reference temperature is set at 75°C. When the precirol has melted, 18 g of soybean lecithin are added. When the soybean lecithin has dissolved, 182 g of pristinamycin, micronized beforehand in an air jet micronizer and having, after grinding, a median diameter of 2 μιτι , are added. The mixture is stirred for 45 minutes at 800 rpm in order to obtain a homogeneous suspension.

The suspension is then sprayed by means of a dual -fluid - 8 -nozzle into a prilling tower cooled beforehand by a cold nitrogen stream. At the start of spraying, the temperature is -14°C at the top of the tower and -42°C at the bottom of the tower. The air pressure on the dual -fluid nozzle is 1.5 bar, leading to a spraying air flow rate of 2.3 m3/h. The flow rate of liquid is 10.8 kg/h.

The particle size of the product obtained, measured by sieving, is: - 30% of particles between 0 and 100 μτη - 54% of particles between 100 and 315 μιτι - 11% of particles between 315 and 500 μτη - 5% of particles greater than 500 μπι The dissolution kinetics at pH 1 for the crude product is 86% in 60 minutes and 97% in 120 minutes.

The concentration of active material in a glass of water (neutral pH) is 22 mg/1 after 5 minutes and 140 mg/1 after 15 minutes for the crude granules.

Example 3 907 g of precirol are introduced into a jacketed reactor in which the jacket reference temperature is set at 70°C. When the precirol has melted, 23 g of soybean lecithin are added. When the soybean lecithin has dissolved, 207 g of unground telithromycin having a median diameter of 114 μτ are introduced. The mixture is stirred for 50 minutes at 500 rpm in order to obtain a homogeneous liquid: the telithromycin is visibly soluble in the precirol.

The suspension is then sprayed by means of a dual-fluid nozzle into a prilling tower cooled beforehand by a cold nitrogen stream. At the start of spraying, the temperature is 0°C at the top of the tower and -20°C at the bottom of the tower. The air pressure on the dual-fluid nozzle is 1.3 bar, leading to a spraying air flow - 9 -rate of 4 m3/h. The flow rate of liquid is 8.5 kg/h.

The particle size of the product obtained, measured by sieving, is: - 59% of particles between 0 and 100 μπι - 38% of particles between 100 and 315 μτη - 3% of particles between 315 and 500 μηι The dissolution kinetics at pH 1 for the crude product is 98% in 60 minutes.

The concentration of active material in a glass of water (neutral pH) is 387 mg/1 after 5 minutes and 873 mg/1 after 15 minutes for the crude granules. It is 181 mg/1 after 5 minutes and 475 mg/1 after 15 minutes for the granules of the 100-315 μτη cut.

Example 4 782 g of precirol and 115 g of carnauba wax are introduced into a jacketed reactor in which the jacket reference temperature is set at 95°C. When the fatty substances have melted, 23 g of soybean lecithin are added. When the soybean lecithin has dissolved, 230 g of unground telithromycin having a median diameter of 114 μτη are introduced. The mixture is stirred for 60 minutes at 500 rpm in order to obtain a homogeneous liquid .

The suspension is then sprayed by means of a dual-fluid nozzle into a prilling tower cooled beforehand by a cold nitrogen stream. At the start of spraying, the temperature is -7°C at the top of the tower and -29°C at the bottom of the tower. The air pressure on the dual-fluid nozzle is 1.3 bar, leading to a spraying air flow rate of 4 m3/h. The flow rate of liquid is' 5 kg/h.

The particle size of the product obtained, measured by sieving, is: - 27% of particles between 0 and 100 μιη - 10 - - 50% of particles between 100 and 315 μιη - 16% of particles between 315 and 500 μπι - 7% of particles greater than 500 μτπ The dissolution kinetics at pH 1 for the crude product is 77,5% in 60 minutes..

The concentration of active material in a glass of tral pH) is 90 mg/1 after 5 minutes and ter 15 minutes for the crude granules.. It is :er 5 minutes and 658 mg/1 afte 15 minutes nules of the 100-315 pm cut, Material described in the specification, which is not within the ambit of the claims is not covered by the claimed invention. The scope of protection is as defined in the claims and as stipulated in the Patent Law (5727-1967) . 11 169343/3

Claims (7)

1. A composition intended for oral administration of active ingredients with unacceptable taste, characterized in that it comprises from 15 to 30% of active ingredient mixed with 55 to 85% of an ester of glycerol or a fatty acid optionally supplemented with wax, and supplemented with a surfactant, and in that they are prepared by a spray- cooling process which can lead to a particle size of less than 350 pm.

2. The composition as claimed in claim 1 , characterized in that the glycerol ester is chosen from glyceryl stearate or glyceryl palmitostearate.

3. The composition as claimed in claim 1 , characterized in that the glycerol ester is between 60 and 80% by weight of the total mixture of the composition.

4. The composition as claimed in one of claims 1 to 3, characterized in that the glycerol ester is between 70 and 80% by weight of the total mixture of the composition.

5. The composition as claimed in one of claims 1 to 4, characterized in that the active ingredient is a pharmaceutical active ingredient.

6. A method for masking the taste of compositions for oral administration containing active ingredients with unacceptable taste comprising the preparation of a composition as claimed in one of claims 1 to 5, characterized in that the active ingredient is mixed with the molten glycerol ester, supplemented with other excipients, and then a spray-cooling process is performed by spraying by means of a dual-fluid nozzle at the top of a tower into which a cold gaseous stream is optionally introduced countercurrentwise.

7. The process of preparation as claimed in claim 6, characterized in that the device is provided with a fluidized bed. For the Applicant, P-7970-IL