WO2007107787A2 - Formulations galeniques liquides et solides contenant des dattes (phoenix dactylifera) - Google Patents

Formulations galeniques liquides et solides contenant des dattes (phoenix dactylifera) Download PDF

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Publication number
WO2007107787A2
WO2007107787A2 PCT/GB2007/050124 GB2007050124W WO2007107787A2 WO 2007107787 A2 WO2007107787 A2 WO 2007107787A2 GB 2007050124 W GB2007050124 W GB 2007050124W WO 2007107787 A2 WO2007107787 A2 WO 2007107787A2
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WIPO (PCT)
Prior art keywords
formulation
dates
date
dispersion
oil
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PCT/GB2007/050124
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English (en)
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WO2007107787A3 (fr
Inventor
Karrar Ahmad Khan
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Karrar Ahmad Khan
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Priority claimed from GB0605534A external-priority patent/GB0605534D0/en
Priority claimed from GB0605535A external-priority patent/GB0605535D0/en
Application filed by Karrar Ahmad Khan filed Critical Karrar Ahmad Khan
Publication of WO2007107787A2 publication Critical patent/WO2007107787A2/fr
Publication of WO2007107787A3 publication Critical patent/WO2007107787A3/fr

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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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L19/00—Products from fruits or vegetables; Preparation or treatment thereof
    • A23L19/09—Mashed or comminuted products, e.g. pulp, purée, sauce, or products made therefrom, e.g. snacks
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • 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
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals

Definitions

  • the present invention relates to liquid and solid dosage oral formulations containing processed dates (Phoenix dactylifera).
  • the formulations for oral use containing processed dates are useful as nutriceutical and/or pharmaceutical compositions.
  • the invention also relates to a process for the preparation of such formulations.
  • Dates are of course also widely used as foodstuffs, and it is known to produce date pastes and date preserves, e.g. for use in bakery products and confectionery.
  • fibrous nature of the date material, and the presence of insoluble material within the dates means that such preparations are generally rather inhomogeneous, have a poor mouth feel, and are difficult to formulate into a pharmaceutically acceptable liquid or compress into a tablet, for example.
  • Dates have been used to produce various date juice products. These are often clear or clarified liquids, containing only soluble components of the date. However, such products have found little use, due to their rather poor and bland taste. Attempts have also been made to prepare date-based beverages.
  • Dates syrups have also been produced, but again they comprise substantially only the soluble components of the dates, and are produced by extraction of the date juice, clarification and concentration. Date spread is also known, and fits between date paste, made of the whole date flesh, and date syrup, from which all non-solubles have been removed.
  • liquid or solid formulation suitable for nutriceutical or pharmaceutical use by oral administration, which formulation comprises processed dates.
  • Liquid preparations according to the invention are in the form of homogeneous aqueous suspensions using the whole date (without the stone). Such formulations have acceptable taste and mouthfeel, as well as offering certain other advantages over the prior art.
  • the solid formulations according to the invention may have various forms, eg compressed tablet forms and lozenges. Fundamental to both solid and liquid formulations according to the invention is the preparation of a fine and homogenous dispersion of processed dates
  • the dates dispersion of this invention exhibits "roundness" of taste particularly for a liquid product. This unique property will also apply to the dried dispersion presented in the form of solid dosage form such as chewable or dispersible tablets.
  • Dates are grouped generally into three varieties: soft, semi-soft and dry or bread dates. Some commonly available dates are as follows:
  • Deglet noor A semi-dry date, originally imported from France, possesses a delicate flavour, and is firm-textured in appearance, with a colour range from light red to amber or straw.
  • Halawy A soft date, thick flesh, caramelly and sweet, somewhat wrinkled in appearance, with a yellow colour ripening to a light amber and then to a golden brown. Originally this date was imported from Iraq.
  • Zahidi A semi-dry date from Iraq, distinguished by its large seed in proportion to the fruit itself. This date lends itself well to processing and softening by steam hydration.
  • Driest date variety with firm skin, less sticky; flesh chewiest and is the staple diet of the Nomadic tribes of the desert countries of the world.
  • Medjool 'Medjool' dates most likely exist as a landrace variety at its location of origin, the Tafilalt region of Morocco. Another possibility is that 'Medjool' date may have a very high mutation rate.
  • Dates ripen in stages are when it reaches maximum size and identifying colour.
  • the rutab stage is when the fruit begins to soften at the tip.
  • the tamar stage is when the date is fully cured or dried.
  • One group of formulations according to the invention are in liquid form.
  • a liquid dosage formulation in the form of a homogeneous dispersion in water of date material in finely divided form.
  • the nutritional principles are better assimilated, which is of particular importance for formulations intended for dietetic and/or nutritional products, especially for children.
  • the fineness and uniformity of the dispersion may also lead to significantly improved physical stability.
  • the dispersion is physically stable over a long period and is not prone to separation. If some separation does occur, the homogenised product redisperses easily by simple shaking and reverts to its original homogeneous appearance. There is also a significant reduction or attenuation of the typical "collar" effect (separation and also floating of some suspended particles above the separated fluid, and also be some sediment at the bottom part of the bottle) that is commonly observed with suspension formulations, such as extemporaneously prepared dispersions of fruit juices.
  • homogeneous may mean that all or substantially all of the date material is present in the form of particles having a particle size of less than 500 ⁇ m, and more preferably less than 100 ⁇ m.
  • more than 90% w/w of the date material is preferably present in the form of particles with a size less than 10O ⁇ m, or a size less than 80 ⁇ m, or a size less than 50 ⁇ m.
  • the majority of the date material e.g. more than 90% w/w or more than 95% w/w, is present in the suspension in the form of particles with a size in the range 1 - 50 ⁇ m.
  • the dates must be stoned, but otherwise it is preferred that the date material used in the present invention is whole date material, i.e. substantially the whole of the material that constitutes the flesh of the date, and not just certain components of the date. Soluble components of the date material may dissolve in the aqueous carrier medium, while insoluble components are held in suspension.
  • the amount of dates, on dry basis will generally be at least 5% w/w, and up to 50% w/w, of the weight of the formulation, preferably between 5% w/w and 35 % w/w, e.g. about 30% w/w of the final weight of the formulation.
  • the liquid dosage formulation of the invention may be prepared by dispersing date material in water, and subjecting the dispersion to homogenisation. Such a process represents a further aspect of the invention.
  • Homogenisation of the date dispersion can be achieved by means of a high shear mixer such as a Silverson, which is well known to those skilled in the art.
  • a high shear mixer such as a Silverson
  • Other forms of colloid mill, fluid energy mill or high pressure homogenisation may also be suitable.
  • Conventional techniques such as wet milling, spray-drying and freeze- drying may also be used as part of the process. Additional ingredients of the formulation may be added either before or after homogenisation.
  • High pressure homogenisation is an entirely mechanical process, in which the product is forced by a high pressure piston pump through a homogenising valve.
  • the commercially available Niro Soavi homogeniser is an example of a suitable high pressure homogeniser.
  • the dimensions of the suspended particles of date material are reduced.
  • the suspension commonly presents a uniform distribution, according to a "Gaussian" curve, although such a particle size distribution may not be essential.
  • the particle size distribution will vary with the operating conditions.
  • the temperature at which dates are dispersed in water prior to or after homogenisation and the homogenisation pressure may require careful adjustment to achieve a commercially viable, stable, safe and elegant dispersion.
  • the yield and quality of the dispersion prepared from the dates by homogenisation will depend on the variety, ripeness and dimensions of the dates, as well as on the degree of integrity of dates, the manner in which they have been stored, and the preparation technique.
  • the liquid dosage formulation according to the invention represents a balanced nutritional source and may be used for that purpose.
  • Formulations for such use may additionally contain one or more additional nutritional components such as fats, carbohydrates, proteins, vitamins, drugs and minerals.
  • Fats or lipids that may be incorporated into the liquid formulation include, but are not limited to, coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, MCT oil (medium chain triglycerides), sunflower oil, high oleic sunflower oil, structured triglycerides, palm and palm kernel oils, palm olein, canola oil, marine oils, cottonseed oil and combinations thereof.
  • Carbohydrates that may be incorporated into the formulation may be simple or complex, lactose- containing or lactose-free, or combinations thereof.
  • suitable carbohydrates include hydrolysed corn starch, maltodexthn, glucose polymers, sucrose, corn syrup, corn syrup solids, rice-derived carbohydrate, glucose, fructose, lactose, high fructose corn syrup and indigestible oligosaccharides such as fructooligosaccharides, and combinations thereof.
  • the liquid formulation may further comprise any of a variety of vitamins, non- limiting examples of which include vitamin A, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, pyridoxine, vitamin B12, niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, inositol, salts and derivatives thereof, and combinations thereof.
  • vitamins non- limiting examples of which include vitamin A, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, pyridoxine, vitamin B12, niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, inositol, salts and derivatives thereof, and combinations thereof.
  • the liquid formulation may further comprise any of a variety of electrolytes, non- limiting examples of which include calcium, phosphorus, magnesium, iron, selenium, manganese, copper, iodine, sodium, potassium, chloride, and combinations thereof.
  • Another significant aspect of this invention relates to use the processed dates dispersion to manufacture solid dosage forms. This is particularly surprisingly because fibrous and adhesive materials such as dates are very difficult to compress into tablets and the fibrous materials are also not suitable for formulating into lozenges.
  • a solid formulation suitable for nutriceutical or pharmaceutical use by oral administration which formulation comprises processed dates.
  • the processed dates may themselves be of nutritional and/or therapeutic value.
  • the processed dates may have a demulcent effect.
  • the processed dates may function purely as an excipient, in particular as granulating agents, or as an agent capable of improving the palatability of a pharmaceutically active substance with an unpleasant taste.
  • the formulations offer a commercially acceptable, stable, economic, simple, consistent and convenient dosage form for the oral administration of processed dates, either alone or in conjunction with pharmaceutically active agents. Tablets that are dispersed in water prior to administration (e.g.
  • dispersible and effervescent tablets and also chewable tablets, as are widely used by patients and in particular children, who have difficulty in swallowing conventional tablets or capsules, often contain active ingredients with an unpleasant taste, such as some vitamins and analgesics (e.g. paracetamol).
  • active ingredients with an unpleasant taste, such as some vitamins and analgesics (e.g. paracetamol).
  • the processed dates used in the present invention have a long- lasting flavour and are capable of masking the after taste of such drugs, either alone or in conjunction with other suitable flavours and sweeteners.
  • the formulation according to the invention may take any one of numerous forms. Most preferably, however, the formulation takes the form of a tablet or lozenge.
  • the formulation may be swallowable, disintegratable, effervescent, chewable or suckable, and may be intended for buccal or sub-lingual administration.
  • a particularly preferred method involves the formation of a homogeneous dispersion of the date material in water, mixing of the date dispersion with some or all of the further ingredients of the formulation, and drying to remove excess water.
  • Homogenisation of the date dispersion can be achieved by means of a high shear mixer such as a Silverson, or high pressure homogenisation which is well known to those skilled in the art.
  • a high shear mixer such as a Silverson
  • high pressure homogenisation which is well known to those skilled in the art.
  • Other forms of colloid mill and fluid energy mill may also be suitable.
  • the process of wet massing is carried out in a suitable mixer such as a planetary, high shear mixer or in a fluid bed granulator
  • the tablet diluents are granulated with a fine dispersion of dates in water prepared by homogenisation and/or milling.
  • diluent bases such as glucose, sucrose, maltose, lactose, arabinose, xylose, ribose, fructose, mannose, galactose, sorbose, trehalose, sorbitol, xylitol, mannitol, maltitol, lactitol, isomaltol, maltodextrin, hydrogenated starch hydrolysis products and mixtures thereof, and sorbitol are employed for oral, suckable, dispersible, swallowable or chewable tablets.
  • diluent bases such as glucose, sucrose, maltose, lactose, arabinose, xylose, ribose, fructose, mannose, galactose, sorbose, trehalose, sorbitol, xylitol, mannitol, maltitol, lactitol, isomaltol, maltodextrin
  • insoluble diluents may be granulated with the date dispersion in the manufacturing processes as necessary to achieve the desired properties.
  • suitable insoluble materials include starches, water-insoluble cellulose derivatives, microcrystalline cellulose or an alkaline earth metal carbonate, sulphate or phosphate.
  • Lozenges may be prepared by combining sucrose and corn syrup in a ratio of 50:50 to 70:30, and incorporating a suitable amount of a dispersion of dates in water.
  • the liquid sucrose syrup and corn syrup and dates are cooked, eg at 125°C.
  • Final heating is performed, e.g. at 148 °C, under vacuum.
  • Any drugs or herbal ingredients such as liquorice are mixed with other ingredients such as flavours and benzyl alcohol.
  • Any acids, such as citric or tartaric acid are then mixed.
  • There are many ways of adding the drug and flavours However the most common method is to add the drug / flavour mixture and other constituents and additives (such as menthol etc) on the mixing table.
  • the candy base containing dates is then formed, rope-sized, moulded, cooled and sized.
  • Chewable tablets may be prepared as follows.
  • the formulation containing the drug and other excipients is granulated using the dates dispersion as granulating agent to granulate all or some of the ingredients of the formulation.
  • Another option is to produce base granules containing one or more diluents produced by granulating with the dates dispersion.
  • the base granules are then used for blending and compression with the drug, flavours, sweeteners and other excipients similar to the process used for direct compression.
  • the drug and other components of the formulation may also be granulated with water containing a binder and/or dates dispersion. These may then sieved, dried and tabletted.
  • the amount of dates, on dry basis will generally be at least 5% w/w, and up to 50% w/w, of the weight of the solid formulation, preferably between 5% w/w and 35 % w/w, eg about 30% w/w of the final weight of the solid formulation.
  • the aqueous dispersion of dates may be used to granulate (where present) diluents, excipients such as disintegrants, flavours, and wetting agents, and the pharmaceutically active agents.
  • the dates act as an efficient binder, aiding compaction of granules and obviating the need to include a conventional binding agent such as Povidone (PVP), as is typically used in tablets prepared by moist granulation.
  • a conventional binding agent such as Povidone (PVP), as is typically used in tablets prepared by moist granulation.
  • the formulations according to the invention are also of utility for the delivery of pharmaceutically active agents, and in particular are of benefit in the delivery of pharmaceutically active agents that have an unpleasant taste.
  • the longer-lasting taste profile of the homogenised date dispersion is capable of masking the unpleasant taste of a wide range of active agents.
  • liquid or solid dosage formulation comprising one or more pharmaceutically active agents, wherein the formulation further comprises processed dates.
  • flavours and/or sweeteners include, but are not limited to, natural flavours, natural fruit flavours, artificial flavours, artificial fruit flavours, flavour enhancers or mixtures thereof.
  • the natural flavour may be selected from apple essence, pear essence, peach essence, berry essence, wildberry essence, date essence, blueberry essence, kiwi essence, strawberry essence, raspberry essence, cherry essence, plum essence, pineapple essence, and apricot essence, natural mixed berry flavour, citric acid, malic acid, vanilla, vanillin, cocoa, chocolate, and menthol.
  • flavours may be selected from one or more of the group consisting of anise oil, cinnamon oil, peppermint oil, oil of wintergreen, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds, cassia oil, lemon oil, orange oil, lime oil, grapefruit oil, grape oil and combinations thereof.
  • Natural flavours, artificial flavours or mixtures thereof include mint (such as peppermint or spearmint), menthol, cinnamon, vanilla, artificial vanilla, chocolate, artificial chocolate or bubblegum.
  • Natural fruit flavours, artificial fruit flavours or mixtures thereof include, but are not limited to, cherry, grape, orange, strawberry or lemon.
  • Flavour enhancers include, but are not limited to, citric acid.
  • flavouring agents are generally provided as a minor component of the formulation, the addition of at least one flavouring agent is preferred. However, up to two flavouring agents may generally be employed.
  • the taste masking composition may further comprise an effective amount of a sweetener, at least one flavouring agent, and an artificial sweetening agent.
  • Optional sweetening agents include, but are not limited to, sugar sweeteners such as monosaccharides, disaccharides and polysaccharides.
  • suitable sugar sweeteners include, but are not limited to, xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially hydrolysed starch (such as maltitol syrup) or corn syrup, and sugar alcohols such as sorbitol, xylitol, mannitol, glycerin and combinations thereof.
  • Artificial sweeteners include, but are not limited to, aspartame, acesulfame potassium, cyclamate, saccharin, saccharin sodium, sucralose and mixtures thereof.
  • the amount of additional sugars, optional and artificial sweetener used in the formulation will vary depending on the degree of sweetness and palatability desired.
  • liquid formulations according to the invention are preferably formulated with a certain degree of viscosity, which may be imparted by the date material.
  • additional viscosity enhancing agents may be included to achieve the optimum viscosity, taste masking and desired physical and/or chemical characteristics throughout product shelf life.
  • suspending agents examples include poly(vinylpyrrolidone); polyvinyl alcohol); methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and mixtures thereof; sodium alginate; polyacrylamides; polyacrylic acids; collagen; polyethylene glycol; polysaccharides and carbohydrates such as starch, cellulose, dextrans and derivatives; thixotropic media; and the like.
  • Other suspending agents include natural gums such tragacanth, acacia or xanthan gum, guar gum, and gelatin, as well as clays such as veegum, bentonite, and hectorite.
  • a preservative system is also generally required for an oral liquid such as the liquid formulations of the invention, and this may be selected from those conventionally employed in oral medicines. These usually consist of benzoic acid, sodium benzoate, potassium sorbate, ascorbic acid, sorbic acid, domiphen or other suitable preservatives and their mixtures.
  • liquid formulations of the invention may be thermodynamically unstable dispersed systems, in which the solid particles of the internal phase tend to aggregate and form sediment, the use of a coadjuvant may be required to improve dispersion, viscosity and other aspects so that a stable product is obtained.
  • a wetting agent may be required if relatively insoluble drugs or ingredients are present in the composition.
  • Such wetting agents may be selected from the group consisting of surface active agents, (eg anionic, non-ionic and cationic surfactants), glycerol, propylene glycol, liquid polyethylene glycols, sorbitol and mixtures thereof.
  • Pharmaceutically active compounds that may be incorporated into the solid dosage forms of the present invention include antihistamines, decongestants, antitussives, expectorants, non-steroidal anti-inflammatory drugs (NSAIDs) and other analgesic drugs, such as paracetamol (acetaminophen) and phenacetin.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • other analgesic drugs such as paracetamol (acetaminophen) and phenacetin.
  • Antihistamines that may be mentioned (along with their preferred salt form) are chlorpheniramine (maleate), brompheniramine (maleate), dexchlorpheniramine (maleate), dexbrompheniramine (maleate), triprolidine(HCI), diphenhydramine (HCI), doxylamine (succinate), tripelennamine (HCI), cyproheptatine (HCI), bromodiphenhydramine (HCI), phenindamine (tartrate), pyhlamine (maleate, tannante) and azatadine (maleate).
  • Antitussives that may be mentioned (along with their preferred salt form) are caramiphen (edisylate), dextromethorphan (HBr), codeine (phosphate, sulfate), and pholcodeine.
  • Decongestants that may be mentioned (along with their preferred salt form) are pseudoephedrine (HCI), phenylpropanolamine (HCI) and phenylephrine (bitartrate, tannate, HBr, HCI).
  • HCI pseudoephedrine
  • phenylpropanolamine HCI
  • phenylephrine bitartrate, tannate, HBr, HCI
  • Expectorants that may be mentioned are terpin hydrate, guaifenesin (glyceryl guaiacolate), potassium (iodide, citrate) and potassium guaicolsulfonate, and salbutamol and others
  • Non-steroidal anti-inflammatory drugs for use in the formulations of the invention may be selected from any of the following categories: (1 ) propionic acid derivatives;(2) acetic acid derivatives;(3) fenamic acid derivatives; (4) biphenylcarboxylic acid derivatives; and (5) oxicams.
  • propionic acid derivatives ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen, suprofen, fenbufen, and fluprofen may be mentioned as preferred compounds.
  • acetic acid derivatives tolmetin sodium, zomepirac, sulindac and indomethacin may be mentioned.
  • fenamic acid derivatives mefenamic acid and meclofenamate sodium are examples.
  • Diflunisal and flufenisal are biphenylcarboxylic acid derivatives.
  • the oxicams include piroxicam, sudoxicam and isoxicam.
  • Other analgesic compounds useful in the practice of the present invention include acetominophen (parecetamol) and phenacetin.
  • Active pharmaceutical ingredients are incorporated into the solid dosage forms in amounts governed by their physicochemical characteristics, and shall be in compliance with applicable regulatory guidelines.
  • compositions according to the invention that contain conventional pharmaceutical actives may be of utility in the treatment of any conditions that are conventionally treated with the actives concerned.
  • the compositions, either with or without conventional pharmaceutical actives may be useful in the treatment of conditions that may be ameliorated by the demulcent properties of dates.
  • the formulations of the present invention may be used to treat individuals suffering from the mucosal irritation associated with mucositis.
  • the formulations may also be suitable for the treatment of microbial infections such as influenza, rhinoviruses, or other microbial infections that can irritate the throat and tonsils.
  • the formulation may also contain demulcents additional to the date material, such as liquorice (Glycyrrhiza), to further enhance the demulcent properties of the formulation.
  • demulcents additional to the date material, such as liquorice (Glycyrrhiza), to further enhance the demulcent properties of the formulation.
  • dates from which the stones had been removed were used. These dates were readily available in the local market as rectangular 25Og blocks and those used were either Arabician or Amsterdamn dried (tamar) dates. Typically these contain 99% dates in a hydrated form.
  • the formulations described below are specific to the dates from these origins. Some adjustment to the formulation and the process may be needed to achieve the desired properties for compression and palatability if dates of other origin are used.
  • the formulations given below are for pharmaceutical oral liquid products containing drugs. Formulations of dates for nutritional use may require different criteria for palatability (e.g. sweetness, flavour), viscosity, preservation, taste and mouthfeel.
  • Dates dispersions were also prepared with a high pressure homogeniser ( Niro Soavi 2K ) at a range of pressures and using one and two passes to produce optimum dispersion characteristics
  • ibuprofen was first sieved to remove agglomerates then added to the suspension.
  • the moisture content of the dates used was determined using a moisture balance (Mettler PE360/LP15, setting 7) and the dates were heated for 45 minutes at 1 10°C.
  • the dates used had 12% water content.
  • Citric acid 1.0%
  • Citric acid 1.0%
  • Examples 9 to 18 relate to solid dosage forms.
  • An aqueous date dispersion was prepared by using dates from which the stones had been removed. A 40% dispersion of these stoned dates in water was prepared (40g of dates containing 12% moisture in 100g of water). The 100g of dispersion contained 40g of hydrated dates, i.e. 35.2g on dried basis.
  • the moisture content of the dates used was determined using a Moisture balance (Mettler PE360/LP15, setting 7) and the dates were heated for 45 minutes at 1 10 9 C.
  • the tablets produced were robust and there was no indication of any compressional problems or any sign of capping during and following compression.
  • An aqueous date dispersion was prepared by using a block of dates from which the stones had been removed as described in Example 1.
  • a 40% dispersion of these stoned dates in water was prepared (40 g of dates containing 12% moisture).
  • the 100 g of dispersion will contain 40g of dates and 35.2g on dried basis.
  • the tablets produced were robust and there was no indication of any compressional problems or any sign of capping during and following compression.
  • Date-based ibuorofen tablets In Examples 11 to 16, ibuprofen has been used as a model drug to represent drugs with poor compressional properties. Formation of robust and hard tablets containing a poorly compressible drug such as ibuprofen used at a high dose would show that dates act as an effective binding agent. Those skilled in the art would be able adjust the tablet formulation by adding suitable tablet excipients such as disintegrants, wetting agents, dispersants and polymers to achieve desired physico-chemical properties (including chewability, rapid dispersability, mouthfeel, taste-masking, immediate or controlled release of the drug contained in the tablet). The robust tablets can also be coated satisfactorily using dry, film or sugar coating.
  • the block stoned dates contained typically 12% moisture. Therefore 31.6g on dried basis is equivalent to 35.9g of the hydrated dates.
  • the ibuprofen and microcrystalline cellulose were sieved and blended.
  • the date dispersion was prepared by adding stoned dates to hot water and homogenizing using a Silverson mixer.
  • the ibuprofen/microcrystalline cellulose blend was placed in a planetary mixer and the date dispersion was added as the granulating agent.
  • Example 12 lbuprofen tablets using dates as a diluent and binder Table 4 - lbuprofen tablets prepared using dates at 10% w/w (used as granulating agent)
  • the date dispersion was prepared by adding the dates to hot water and homogenised using a Silverson mixer.
  • the wet granules were sieved through a 10 mesh sieve size (2000 micrometer) and dried in a hot air oven at 50 °C overnight.
  • Disintegration time over 30 minutes (mean hardness 1 1.6 kp) Disintegration time : 7 minutes 50 seconds (mean hardness 7.8kp)
  • Example 13 lbuprofen tablets using dates as a diluent and binder
  • Dates contain 12% w/w moisture: 106.Og anhydrous 120.5g hydrated. To add 120.5g of dates in dispersion (30% w/w), need 401.7g of 30% w/w dispersion Process :
  • the date dispersion was prepared by adding the dates to hot water and homogenised using a Silverson mixer.
  • the ibuprofen and microcrystalline cellulose blend was placed in a planetary mixer and the date dispersion added as the granulating agent.
  • Example 14 lbuprofen tablets using dates as a diluent and binder
  • Dates contain 12% w/w moisture: 150.Og anhydrous 170.5g hydrated.
  • the ibuprofen and microcrystalline cellulose were sieved and blended.
  • the date slurry was prepared by adding the dates to very hot water and homogenising using a Silverson mixer.
  • the ibuprofen / microcrystalline cellulose blend was placed in a planetary mixer and the date dispersion added as the granulating solution.
  • the wet granules were sieved through a 10 mesh sieve (2000 micrometer) and dried in a hot air oven at 50 °C overnight. 6 The dried granules were sieved through a 16 mesh sieve (1 190 micrometer).
  • the granules were divided into two parts. The first part only contained magnesium stearate (1 % w/w of the dried granules); the second part contained magnesium stearate (1 % w/w of the dried granules) and crosscarmellose sodium.
  • Disintegration time greater than 30 minutes
  • Disintegration time greater than 30 minutes
  • Example 15 lbuprofen tablets using dates as a diluent and binder Table 7 lbuprofen tablets prepared using dates at 26% w/w (used as granulating agent)
  • Disintegration time greater than 30 minutes
  • Example 16 lbuprofen tablets using PVP as a diluent and binder
  • the magnesium stearate was added and the granules blended.
  • Disintegration time greater than 30 minutes
  • the above blend is heated to around 140/145° C until the moisture is reduced to less than 4%.
  • the mass is poured on to a hot plate. Any additional ingredients such as menthol, antiseptics, cough suppressants, antifungal agents, anaesthetics such as benzocaine, benzyl alcohol, dextromethorphane, zinc, flavours, buffers, preservatives, colours, acidulents or salts to adjust the pH may be added.
  • the mass is then rolled and moulded and may be passed through a calendar to form lozenges which are then cooled and dried.
  • Granules of microcrystalline cellulose are produced by granulating microcrystalline cellulose alone or with other diluents such as sweeteners lactose, sucrose or mannitol using the dates dispersion as the granulating agent. The granules are then sieved and dried. These dried granules are then blended with antacids such as calcium carbonate, aluminium hydroxide and magnesium carbonate or with vitamins, food and minerals, herbs, antihistamines, laxatives, cough suppressants and any other drug or combination for which the chewable form may be considered appropriate and/or convenient.
  • antacids such as calcium carbonate, aluminium hydroxide and magnesium carbonate or with vitamins, food and minerals, herbs, antihistamines, laxatives, cough suppressants and any other drug or combination for which the chewable form may be considered appropriate and/or convenient.
  • microcrystalline cellulose such as sugar or lactose, sucrose or mannitol, sorbitol and others listed as soluble or insoluble diluents in the detailed description of the invention given above.

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Abstract

La présente invention concerne des formulations galéniques orales liquides et solides qui comprennent une dispersion homogène de matériau à base de dattes sous forme finement divisée. La formulation peut présenter une valeur nutritionnelle et/ou thérapeutique. En variante, les dattes traitées se présentant sous forme liquide et solide peuvent uniquement servir d'excipient, notamment d'agent permettant d'accroître la sapidité d'une substance pharmaceutiquement active dotée d'un goût désagréable. La formulation liquide peut être préparée en dispersant le matériau de dattes dénoyautées mais entières dans de l'eau, et en soumettant la dispersion à l'homogénéisation. La formulation galénique solide se présente de préférence sous la forme de granules, d'un comprimé ou d'une pastille et est de préférence préparée selon un procédé qui consiste à former une dispersion homogène de matériau de dattes dans de l'eau, à mélanger la dispersion de dattes avec certains ou tous les autres ingrédients de la formulation et à procéder au séchage afin d'éliminer l'excès d'eau.
PCT/GB2007/050124 2006-03-20 2007-03-15 Formulations galeniques liquides et solides contenant des dattes (phoenix dactylifera) WO2007107787A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0605534A GB0605534D0 (en) 2006-03-20 2006-03-20 Liquid Dosage Formulations Containing Dates (Phoenix Dactylifera)
GB0605534.7 2006-03-20
GB0605535.4 2006-03-20
GB0605535A GB0605535D0 (en) 2006-03-20 2006-03-20 Solid Dosage Formulations Containing Dates (Phoenix Dactylifera)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009027159A1 (fr) * 2007-08-24 2009-03-05 Granmalt Brewing Solutions Gmbh Procédé de fabrication d'un granulat à base de dattes
WO2010108683A1 (fr) * 2009-03-25 2010-09-30 King Saud University Utilisation du sirop de dattes comme liant
US9132096B1 (en) 2014-09-12 2015-09-15 Alkermes Pharma Ireland Limited Abuse resistant pharmaceutical compositions
WO2016079553A1 (fr) * 2014-11-17 2016-05-26 Umm-Al-Qura University Procédé et composition ayant une activité prophylactique à l'encontre des venins et toxines
IT201700035418A1 (it) * 2017-03-31 2017-07-01 Brovind Tech S R L Succo di dattero e applicazioni di un succo di dattero
US9861675B1 (en) 2016-06-29 2018-01-09 King Abdulaziz University Method of treating ischemic heart disease
WO2021001820A1 (fr) * 2019-07-02 2021-01-07 D&D - Food Horizons Ltd. Compositions de substitut du sucre

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001097633A2 (fr) * 2000-06-19 2001-12-27 General Mills, Inc. Groupes d'elements nutritifs pour aliments et leurs procedes de preparation
WO2006014878A1 (fr) * 2004-07-28 2006-02-09 Abbott Laboratories Compositions nutritives et procedes pour traiter ou prevenir l'osteoporose

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001097633A2 (fr) * 2000-06-19 2001-12-27 General Mills, Inc. Groupes d'elements nutritifs pour aliments et leurs procedes de preparation
WO2006014878A1 (fr) * 2004-07-28 2006-02-09 Abbott Laboratories Compositions nutritives et procedes pour traiter ou prevenir l'osteoporose

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009027159A1 (fr) * 2007-08-24 2009-03-05 Granmalt Brewing Solutions Gmbh Procédé de fabrication d'un granulat à base de dattes
WO2010108683A1 (fr) * 2009-03-25 2010-09-30 King Saud University Utilisation du sirop de dattes comme liant
US8647674B2 (en) 2009-03-25 2014-02-11 King Saud University Use of date syrup as a binder
US9486451B2 (en) 2014-09-12 2016-11-08 Recro Gainesville Llc Abuse resistant pharmaceutical compositions
US9452163B2 (en) 2014-09-12 2016-09-27 Recro Gainesville Llc Abuse resistant pharmaceutical compositions
US9132096B1 (en) 2014-09-12 2015-09-15 Alkermes Pharma Ireland Limited Abuse resistant pharmaceutical compositions
US9713611B2 (en) 2014-09-12 2017-07-25 Recro Gainesville, LLC Abuse resistant pharmaceutical compositions
US10092559B2 (en) 2014-09-12 2018-10-09 Recro Gainesville Llc Abuse resistant pharmaceutical compositions
US10960000B2 (en) 2014-09-12 2021-03-30 Recro Gainesville Llc Abuse resistant pharmaceutical compositions
WO2016079553A1 (fr) * 2014-11-17 2016-05-26 Umm-Al-Qura University Procédé et composition ayant une activité prophylactique à l'encontre des venins et toxines
US9616095B2 (en) 2014-11-17 2017-04-11 Umm Al-Qura University Method and a composition having prophylactic activity against venoms and toxins
US9861675B1 (en) 2016-06-29 2018-01-09 King Abdulaziz University Method of treating ischemic heart disease
IT201700035418A1 (it) * 2017-03-31 2017-07-01 Brovind Tech S R L Succo di dattero e applicazioni di un succo di dattero
WO2021001820A1 (fr) * 2019-07-02 2021-01-07 D&D - Food Horizons Ltd. Compositions de substitut du sucre

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