Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals

Definitions

• Composition having improved palatability having improved palatability, sieved freeze-dried particles, free-flowing compressible powder-like freeze-dried particles, process for making the same, pharmaceutical compositions with improved palatability, method for making the same and method for making tablets.
• This invention relates to freeze dried oral compositions, having improved palatability, comprising a pharmaceutically active substance with an unpleasant taste. It also concerns solid, oral pharmaceutical compositions and dosage units. It also relates to processes for preparing such compositions. Background Dosage forms which are deemed to rapidly disintegrate on being placed in the mouth of the patient, or by sucking or crunching, thereby delivering the desired dose of the pharmaceutically active substance are particularly useful when no additional water or beverage can be used for practical or medical reasons, for example when traveling or if any beverage in-take should be avoided. Dosage units occupy an important position amongst various dosage forms, not only for human adults, but also for children, old people, and even for animals. Examples include people or animals having difficulties related to or being uncooperative in swallowing and/or taking tablets or capsules. These dosage forms can be prepared by usual multistep processes.
• some processes comprise a lyophilization step during which the solvent is removed from a mixture comprising said solvent, the pharmaceutically active substance and a carrier material.
• the solid dosage forms as described above overcome the problem of swallowing tablets or capsules, the patient will taste the pharmaceutically active substrate as the dosage form disintegrates.
• the taste if slightly unpleasant, can be rendered acceptable by the use of sweetening agents or flavoring agents which modulate the taste.
• an unpalatable product will still be produced, despite the use of sweetening agents and flavoring agents. Unpalatable products decrease a patient's compliance.
• Piroxicam is a compound belonging to the class of the Non Steroidal Anti-Inflammatory drugs (NSAI) which, due to its remarkable analgesic and antiphlogistic activity, is employed in the treatment of arthro-rheumatic diseases.
• NSAI Non Steroidal Anti-Inflammatory drugs
• Piroxicam is responsible for lesion effects on the gastrointestinal mucosa. Piroxicam is however practically insoluble in water, and this may represent a limiting factor for an optimal employment of the substance. Piroxicam is therefore advantageously complexed by inclusion into ⁇ -, ⁇ - or ⁇ -type cyclodextrins. The obtained complex possesses a high solubility, is rapidly absorbed and is better tolerated. This complex is described in detail in EP 84113923.1 , which is hereby expressly incorporated by reference in its entirety. However, the complex has the drawback in that it retains the unpleasant bitter taste of piroxicam, which prevents it from being easily incorporated into oral compositions or dosage units which are deemed to disintegrate in the mouth.
• compositions having improved palatability prepared by freeze drying a mixture comprising a) at least one pharmaceutically active substance having an unpleasant taste; and b) at least one non-lipidic taste masking association comprising: b1 ) at least one acid and b2) at least one non-lipidic binder in sufficient amount to improve the palatability of the active substance having an unpleasant taste, and c) at least one filler.
• these compositions are prepared into oral pharmaceuticals.
• the applicant has observed that when the acid is used alone, bitterness may be modified but the lyophilized mixture might present problems related to its homogeneity. When the binder is used alone, an homogeneous lyophilized mixture might be obtained, but the bitter taste still remains.
• the lyophilized material can be screened or calibrated to obtain a granulate suitable for direct compression into tablets eventually after mixing with the eventual convenient excipient(s) and and/or before a further galenic step.
• Suitable acids can include citric acid or fumaric acid.
• the non- lipidic binder can be selected from the group consisting of pectin, gelatin, xanthan gum, guar gum, cellulose derivatives, soy derivatives, polysaccha des, pullolan, povidone and derivatives, polyethylene glycol, chitosan and its derivatives, fermentation obtained sugars like xanthan, alginates, and their mixtures, for example.
• Advantageous binders can be selected from the group of pectin, gelatin, xanthan gum, and apple pectin, and their mixtures.
• Suitable filler can be selected from the group consisting of dextrose, lactose, sucrose, fructose, galactose, starch, cellulose and its derivatives, polyols like mannitol, xylitol, sorbitol, maltodextrin, amino acids, and their mixtures.
• the filler is dextrose.
• Suitable pharmaceutically active substances can include piroxicam, piroxicam- ⁇ -(cyclodextrine) (BCDP), ambroxol hydrochloride, paracetamol, domperidone, nimesulide, ibuprofen, momiflumate, apomorphine and dihydroergocryptine.
• the pharmaceutically active substance can be non-complexed piroxicam or paracetamol.
• the pharmaceutically active substance is complexed with a cyclodextrin.
• the compositions herein can comprise at least 5% acid by weight, at least 6% binder by weight, and at least 20% filler by weight.
• the active substance is complexed piroxicam, and the weight ratio between the acid and binder is equal to or less than 1.
• the active substance is BCDP
• the percentage of acid, based on total weight is between 5 and 10%
• the percentage of the binder, based on total weight is between 6 and 10%
• the percentage of the filler, based on total weight is between 20 and 30%.
• the compositions are freeze-dried aqueous or hydroalcoholic gels. Freeze-dried aqueous or hydroalcoholic gels can include free-flowing compressible powders, for example.
• Further embodiments include sieved freeze dried particles comprising a) at least a pharmaceutically active substance which has an unacceptable taste; b) at least a non-lipidic taste masking association comprising: b1 ) at least an acid and b2) at least a non-lipidic binder; and c) at least a filler.
• Further embodiments include free-flowing compressible powder-like freeze-dried particles comprising a) at least a pharmaceutically active substance which has an unacceptable taste; b) at least a non-lipidic taste masking association comprising: b1 ) at least an acid and b2) at least a non- lipidic binder; and c) at least a filler.
• Further embodiments include methods for the preparation of freeze dried particles including a pharmaceutically active substance having an unpleasant taste, and a non-lipidic taste masking association comprising an acid and a binder, and a filler.
• the methods herein can include the following steps: preparing an aqueous or hydroalcoholic solution or suspension of the active substance having an unpleasant taste, preparing an aqueous or hydroalcoholic gel comprising said aqueous or hydroalcoholic solution or suspension and a.non-lipidic binder, an acid, and a filler, homogenizing the aqueous or hydroalcoholic gel, freeze drying said homogenized gel and, recovering the freeze dried material.
• the recovered freeze dried material can then be made into an oral pharmaceutical composition.
• Suitable oral pharmaceutical dose units can be sachet form or tablets.
• the freeze-dried compositions can be advantageous to sieve the freeze-dried compositions then recover the resulting sieved product.
• the freeze-dried material is sieved through a mesh of between about 200 ⁇ m to 5 mm. It can also be advantageous to provide the acid, the binder, and filler successively to the solution or suspension, either simultaneously or extemporaneously.
• the advantage of the invention process is the fact that the filler is added to the above mixture prior to the lyophilization step, leading to a simple production process for the freeze dried particles.
• Preferred pharmaceutically active substances include BCDP, for example.
• Further embodiments, include processes for administering an oral pharmaceutical composition having improved palatability.
• Such processes can include the following steps: providing an oral composition having a pharmaceutically active substance with an unpleasant taste, an acid and a non-lipidic binder in sufficient amount to improve the palatability of the active substance having an unpleasant taste, and administering said oral pharmaceutical composition to a patient in need, wherein said composition has improved palatability.
• Preferred pharmaceutically active substances can include piroxicam or piroxicam/cyclodextrin complex.
• Preferred binder include sugars, and preferred acids include citric and fumaric acid.
• Advantageous compositions for administration, including oral pharmaceuticals such as tablets can also include a filler in which case the filler is mixed with the active substance, the acid and the non lipidic binder prior to the freeze-drying step.
• the invention can include pharmaceutical compositions having improved palatability, comprising piroxicam or piroxicam/cyclodextrin complex, a non-lipidic binder, and an organic acid, and a filler wherein said composition results from lyophilization of a homogeneous liquid or gel.
• the compositions can further include a further filler for processing.
• the compositions described herein can be in the form of a particulate material.
• the compositions can also be pharmaceutical tablets.
• the organic acid can have from 2 to 8 carbon atoms and one or more carboxylic groups.
• the non-lipidic binder can be a thickening or gelling agent.
• the non-lipidic binder can be a polypeptide, a polyhydroxy compound, or a carbohydrate.
• Additional embodiments include methods for making a pharmaceutical material having improved palatability, comprising preparing a homogeneous liquid or gel comprising piroxicam or piroxicam/cyclodextrin complex, a non-lipidic binder, an organic acid and a filler; and lyophilizing the liquid or gel.
• the methods herein can include sieving said lyophilized liquid or gel.
• the methods can also include a step for formulating an oral pharmaceutical composition from the lyophilized gel or liquid.
• the acid and the binder can be premixed with water prior to being combined with said piroxicam or piroxicam/cyclodextrin. Additional aspects can include adding a filler to the acid binder, and water premix.
• the compositions and methods herein can include both effervescent and non-effervescent tablets.
• a pharmaceutical material having improved palatability comprising at least: preparing a homogeneous liquid or gel comprising at least one active substance having an unpleasant taste; at least an acid selected from the group consisting of organic acids containing 2 to 8 carbon atoms; and at least one a non-lipidic binder selected from the group consisting of pectin, gelatin, xanthan gum, guar gum, cellulose derivatives, soy derivatives, polysaccharides, pullolan, povidone and derivatives, polyethylene glycol, chitosan and its derivatives, fermentation obtained sugars like xanthan, alginates, and their mixtures; and at least a filler selected from the group consisting of dextrose, lactose, sucrose, fructose, galactose, starch, cellulose and its derivatives, polyols like mannitol, xylitol, sorbitol, maltodextrin
• the invention concerns the use of the above non- lipidic taste masking association (acid + non-lipidic binder) in the presence of the above filler within a freeze dried mixture to improve the palatability of at least one pharmaceutically active substance having an unpleasant taste.
• the percentages are weight percentages based on the freeze-dried composition, particles or mixture of the invention comprising a), b1 ), b2) and c).
• the present invention relates to oral compositions having improved palatability comprising unpleasant tasting pharmaceutically active substance(s), including, but not limited to, piroxicam or to beta cyclodextrin piroxicam (BCDP).
• sievable freeze -dried particles comprising a) at least a pharmaceutically active substance which has an unpleasant taste; b) at least a non lipidic taste masking association comprising: b1 ) at least an acid and b2) at least a non lipidic binder; and c) at least a filler.
• a non lipidic masking association preferably the association of citric acid and/or fumaric acid, with a binder, preferably chosen from pectin and/or gelatin and/or xanthan gum allows to mask unpalatable taste.
• a filler allows to easily process the obtained freeze dried material.
• the Applicant has shown that the acid alone can modify the bitterness because of its acidity, but the taste can remain unpalatable. Furthermore, the use of a binder and/or a filler, without the acid does not generally mask the bitterness. It has also been shown that the use of a binder alone, without filler, does not generally lead to processed particles. This has been shown in the comparative examples. According to the invention, the taste masking effect does not depend on the use of any further sweetening or flavoring agent. The use of one or more flavoring agent is however not excluded. Compared to the use of lipids, the compositions of the present invention, with a non lipidic taste masking association present a better stability.
• the processes of the invention do not require a coating step and are easy to carry out.
• the freeze-drying process can be carried out with a gel, which does not need to be extruded, because such a gel is a non- pasty material.
• the freeze dried material obtained can then be easily sieved.
• the process can further comprise a step of sieving the freeze dried material to obtain sieved freeze dried particles.
• the particles are free-flowing compressible powder-like freeze-dried particles.
• the minimal size of the sieved particles can advantageously be about 200-5000 ⁇ m, preferably 250-400 ⁇ m, and more preferably about 315 ⁇ m, particularly in case of a further step of preparing tablets.
• the obtained particles might be directly further processed.
• a practitioner can easily process the sieved freeze dried particles, which can be directly and easily compressed to obtain oral tablets without bitter or unpalatable taste.
• pharmaceutical oral compositions comprising freeze dried particles as defined above or obtained by the above process are provided. These particles can be used in sachet form for example, or directly compressed to obtain tablets. Such tablets can be crunched and/or sucked by a patient or animal. These tablets disintegrate and the result of their disintegration can be swallowed without further liquid.
• the oral pharmaceutical formulations may also be in the form of a sachet, and/or a pulverulent material to be swallowed with a liquid like water to be extemporaneously mixed with the particles, just before in-take.
• active substance relates to a pharmaceutically substance, which in form has an unpleasant taste.
• Classes of pharmaceutically active substances which may be formulated in the process of the present invention include non steroidal anti-inflammatory drugs, antacids, analgesics, antalgics, sedatives, antipyretics, antispasmodics, coronary vasodilatators, peripheral vasodilatators, cerebral vasodilatators, anti-injectives, antibiotics, antiparasitics, antineoplasics, anxiolytics, tranquilizers, CNS stimulating agents, antihistaminics, laxatives, drugs for digestive motricity, anticoagulant, drug for use in thyroid dysfunction, nutriments, nutritional adjuvants, immuno-depressives, cholesterol-lowering agents, hormones, sex hormones, enzymes, antianginal drugs, anti-migraine drugs, myorelaxants, hypoglycemics, anorexiants, expector
• Non-Steroidal Anti- Inflammatory (NSAI) drugs may be processed according to the process of the invention or comprised in the freeze dried particles or pharmaceutical compositions of the invention.
• active substances that can be used with the teachings herein include, paracetamol and dihydroergocryptine.
• the active substance is piroxicam.
• This substance may be used in its complexed form, namely the forms where piroxicam is complexed by inclusion into ⁇ -, ⁇ - or ⁇ -type cyclodextrins.
• the cyclodextrins are natural cyclic compounds consisting of 6( ⁇ ), 7( ⁇ ) or 8( ⁇ ) (1 ⁇ 4) D-glucopyranosidic units.
• Non lipidic taste masking association comprises an acid and a non lipidic binder. Particularly, citric acid, but also fumaric acid is convenient as the acidic constituent of the non-lipidic association.
• the acid can be an organic acid. In more specific embodiments, the acid can contain 2 to 8 carbon atoms and one or more carboxylic groups.
• the organic acid is selected from the group consisting of citric, lactic, fumaric, sorbic, malic, propionic acid and the mixtures thereof.
• the acid is preferably chosen in such a way that, in combination with the binder, it does not prevent the formation of a gel.
• the acid can be used in an amount of about 5% to about 50% by weight of dried material.
• the acid can also be used in between about 5% to 10%, or 5% to 16% by weight of dried material.
• binder relates to the following groups of compounds, and the like: pectin, gelatin, xanthan gum, guar gum, cellulose derivatives, soya derivatives, polysaccharides, pullolan, povidone and derivatives, polyethylene glycol, chitosan and its derivatives, fermentation obtained sugars like xanthan, alginates, and their mixtures.
• Cellulose derivatives can include ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium hydroxypropylmethylcellulose, and their mixtures, for example.
• binder substances which may be used as the binder are, for example, hydrolyzed dextrose, dextran, dextrin, maltodextrin, corn-syrup solids, carrageenan, agar, locust bean gum, tragacanth, conjac flower, rice flower, wheat gluten, sodium starch glycolate, soy fiber protein, potato protein, papain, glycine, mannitol, carbomer, acacia, casein, povidone and derivatives and their mixtures.
• the preferred binders are of vegetal origin like pectin and xanthan gum, and the particularly preferred is pectin. Gelatin is also a preferred binder.
• the preferred binders are pectin, xanthan gum and gelatin.
• the pectin is apple pectin, but citrus pectin might be used as well as other fruit pectin.
• the binder can be used in an amount of about 6% to 30% by weight of the obtained dried material. The upper limit however depends on the binder. Other ranges include about 6% to 10%, and about 6% to 16%, for example.
• the upper limit of pectin can be of about 7% in the case of piroxicam complexed with betacyclodextrin, hereinafter BCDP (betacyclodextrin piroxicam) and about 15% in case of non complexed piroxicam.
• Pectin can be used as a stabilizer of the formed gel.
• the gel allows for easily processed particles, after the freeze- drying step and the sieving step.
• Pectin, or alginates are polysaccharides with D-galacturonic acid as the major constituent. Association thereof with an acid such as citric or fumaric acid can induce a modification of ionization of galacturonate residues, influencing the structure of gel. Different types of interactions may occur depending on the structure of the active substance. Possible direct interactions include hydrogen bonding between carbohydrates, ionic interaction with galacturonate residues. Indirect interaction is related to the surface active properties of the hydrocolloid agent acting like micelles.
• the active substance is complexed piroxicam and the weight ratio of citric acid/binder is equal or less than 1 , and more preferably the acid is citric acid and the binder is apple pectin.
• the term "filler,” according to the invention relates to a diluent selected from dextrose, lactose, sucrose, fructose, galactose, starch, cellulose and its derivatives, polyols like mannitol, xylitol, sorbitol and their mixtures; maltodextrin; amino acids and their mixtures, and more particularly dextrose, lactose, mannitol, sorbitol or mixtures thereof, and the like, for example.
• the amino acids are, for example, involved in usual edulcorants.
• the filler can be used to obtain effective cohesion of the freeze dried particles.
• Preferred fillers are sugar-type fillers, and a particularly preferred filler is dextrose.
• the filler can be added to the solution or suspension of the gel in an amount of about 20% to 80% by weight of the obtained dried material.
• the percentage may be from 15 to 80%, preferably from 17 to 55%, more preferably from 17 to 30%.
• the filler is used in percentages of about 20% to 30%, 17% to 55%, or 17% to 30% by weight of the obtained dry material.
• the percentages in acid, binder and filler depend on the active substance to be processed, and the man skilled in the art is able to adapt the percentages to each case.
• the preferred range of acid is of between 5 and 10% wt of the freeze dried material
• binder can be in proportions of between 6 and 10% wt of the freeze-dried material
• the filler can be in proportions of between 20 and 30% wt of the freeze-dried material.
• Advantageous upper ranges of preferred ingredients are described in the table below.
• the preferred percentage of the acid or mixture of acids is of about 6 to 8%.
• the preferred percentage of binder is of about 6 to 8%.
• the preferred percentage of the filler is of about 22 to
• EP 84113923.1 discloses the use of BCDP, the formulations disclosed in said reference do not contain sufficient amounts of acid, binder, or filler to mask the unpleasant taste of this complex. More specifically, EP 84113923.1 fails to discuss taste masking at all, much less improving the palatability of an unpleasant tasting active substance through a non-lipidic combination of acid, binder and filler. With respect to processes for making the compositions described herein, it should be noted that the disclosed methods are more efficient than those described in the prior art. The methods provided herein allow for all ingredients, in amounts sufficient to improve the palatability of an unpleasant tasting active substance, to be added prior to lyophilization.
• the resulting palatable freeze-dried compositions contain the desired active substance and a sufficient amount of acid, binder and filler, to mask the unpleasant taste of the active substance. Furthermore, the processes for making the compositions described herein do not require a coating step or the addition of a flavor enhancer in order to improve the palatability of an unpleasant tasting active substance.
• step a) of a process to make the oral compositions described herein can be carried out as disclosed in 84113923.1 , and as it appears in the following examples.
• step b) can be carried out by incorporating the acid, the binder and the filler into the aqueous or hydroalcoholic solution or suspension of the first step a). (Embodiment 1 ). This leads to an aqueous or hydroalcoholic gel.
• step b) can be carried out by incorporating the aqueous or hydroalcoholic solution or suspension obtained in step a) into an aqueous gel by successively adding the acid, the binder, and then the filler to water.
• step b) can be carried out by incorporating the aqueous or hydroalcoholic solution or suspension obtained in step a) into an aqueous gel by successively adding the acid, the binder, and then the filler to water.
• This embodiment is preferred.
• Preparation can also be carried out by incorporating a premix comprising the acid and the binder into the aqueous, hydroalcoholic solution, or suspension obtained in step a) and subsequently incorporating the filler. (Embodiment 3), or extemporaneously incorporating the filler (Embodiment 4).
• Preparation can also be carried out by incorporating a premix comprising the acid, the binder and the filler into the aqueous, hydroalcoholic solution, or suspension of the active substance obtained in step a).
• step b) is made by incorporating the aqueous, hydroalcoholic solution, or suspension obtained in step a) into an aqueous gel by successively adding the acid, the binder and then the filler into water.
• the gel can be prepared by successively incorporating the acid, the binder and the filler to water simultaneously or extemporaneously.
• a premix of the acid and the binder is prepared and added to water, then the filler can be added.
• a premix of the acid, the binder and the filler is incorporated into water.
• Any of the above embodiments lead to a gel which can then be directly freeze dried. Directly means here that the gel is not extruded.
• the freeze dried material can be sieved, and then directly compressed to obtain tablets which are palatable.
• the obtained sieved particles can also be homogenized before any further processing step, such as a compression step, for example.
• the mean diameter of the sieved particles depends on the mesh used.
• the mesh is preferably between about 200 ⁇ m to 5 mm.
• the mesh as exemplified is of 1 mm. This is however not restrictive, and a mesh of about 0.5 to about 2 mm can be used.
• the choice of the mesh depends on the active substance and of the selected acid, binder and filler, and the further process steps for producing the oral pharmaceutical compositions. Namely in the formulation of the pharmaceutical composition, it is also possible, and it may be suitable, to add further excipients such as disintegration agents, effervescent agents, further flavoring agents and sweeteners, ligands, lubricants, solubilizers, colorings, diluents, wetting agents and mixtures thereof to the particles before or even after compression.
• further excipients such as disintegration agents, effervescent agents, further flavoring agents and sweeteners, ligands, lubricants, solubilizers, colorings, diluents, wetting agents and mixtures thereof to the particles before or even after compression.
• tablets have been prepared either by direct compression of the freeze-dried particles or, after addition of usual excipients, such as an aroma, a sweetener and a lubricant to the particles, by subsequent compression of the obtained mixture.
• excipients can be further added.
• it can be useful to add preservatives and/or tensioactive substances to the gel before freeze-drying, and particularly in the solution or suspension of step a).
• Some of the active substances can be micronized and formulated with surfactants.
• paracetamol can be solubilized with lauryl sulfate.
• excipients selected from the following list of excipients, tensioactives, lipids and preservatives, during the process of preparing the oral pharmaceutical compositions, whatever its form.
• additional excipients selected from the following list of excipients, tensioactives, lipids and preservatives, during the process of preparing the oral pharmaceutical compositions, whatever its form.
• a person skilled in the art will be able to formulate the oral composition based on the particles of the invention, and to choose the useful or necessary additional excipients from the lists below.
• Excipients can include lactose, glycine, mannitol, xylitol, sorbitol, maltitol, glucose, sucrose, maltodextrin, dextrose, fructose, galactose, sodium phosphate, sodium chloride, aluminum silicates, glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine, L-phenylalanine, beta-cyclodextrin: dimethyl beta-cyclodextrin and hydroxy- propyl beta-cyclodextrin, polysaccharides, carboxymethylcelluloses, reticulated sodium carboxymethylcellulose, precipitated silica, colloidal silica, starch, modified starch, directly compressed sugar, stearic acid, magnesium stearate, sodium stearate, sodium stearylfumarate, "macrogol 6000", leu
• Tensioactives can include polysorbates such as Tween 60 and Tween 80, sorbitum esters, polyethers of fatty glycerids, lecithin, sodium lauryl sulfate, sodium dioctysulfosuccinate, alkaline sulfate of lauryl acid (sodium laurylsulfate between 0.5 to 0.7%) monoethyl ether of diethyleneglycol and the like, for example.
• polysorbates such as Tween 60 and Tween 80, sorbitum esters, polyethers of fatty glycerids, lecithin, sodium lauryl sulfate, sodium dioctysulfosuccinate, alkaline sulfate of lauryl acid (sodium laurylsulfate between 0.5 to 0.7%) monoethyl ether of diethyleneglycol and the like, for example.
• Lipids can include beeswax, wax of carnouba, lavolin, stearic acid, oleic acid, sodium steryl fumarate, glycerin monostearate, glycerine palmitostearate, soya lecithin, yellowegg lecithin, phosphotidylcholine, phosphotidylethanolamina, phosphotidylinosine, phosphotidylserina, phosphatidic acid, cerebrosides, cholesterol, mineral oil, ricin oil, cotton seed oil, soya oil, peanut oil, copra oil, hydrogenated vegetable oil, hydrocarbons, fatty alcohol, and the like, for example.
• Preservatives can include benzalkonium chloride, chlorhexidine, sodium or non sodium parabens, benzoic acid, sorbic acid, and the like, for example.
• benzalkonium chloride chlorhexidine
• sodium or non sodium parabens sodium or non sodium parabens
• benzoic acid sodium or non sodium parabens
• sorbic acid sorbic acid
• Steps for preparing palatable Formulations 1 to 14 The constituents as listed in the following table were mixed and treated in line with the steps depicted at the last line of the table. These steps 1 to 10 were carried out according to the following steps (1) to (10).
• Tablets are compressed with an average compression force set in the range [30 - 60]N
• the dimensions of produced tablets are about 16 mm diameter, 3.5 mm thickness and the weight is 850 mg. Tablets are yellowish, round, flat.

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• 2004
  • 2004-03-31 EP EP04290848A patent/EP1582221A1/de not_active Withdrawn
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