WO1993015723A1 - Excipient pour fabrication de comprimes par compression directe - Google Patents

Excipient pour fabrication de comprimes par compression directe Download PDF

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Publication number
WO1993015723A1
WO1993015723A1 PCT/GB1993/000221 GB9300221W WO9315723A1 WO 1993015723 A1 WO1993015723 A1 WO 1993015723A1 GB 9300221 W GB9300221 W GB 9300221W WO 9315723 A1 WO9315723 A1 WO 9315723A1
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WO
WIPO (PCT)
Prior art keywords
excipient
ester
fatty acid
water
forming binder
Prior art date
Application number
PCT/GB1993/000221
Other languages
English (en)
Inventor
John Nicholas Staniforth
Original Assignee
Co-Ordinated Drug Development Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Co-Ordinated Drug Development Limited filed Critical Co-Ordinated Drug Development Limited
Publication of WO1993015723A1 publication Critical patent/WO1993015723A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/04—Oxygen-containing compounds
    • C08K5/09—Carboxylic acids; Metal salts thereof; Anhydrides thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/04—Oxygen-containing compounds
    • C08K5/10—Esters; Ether-esters
    • C08K5/101—Esters; Ether-esters of monocarboxylic acids
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
    • F04C—ROTARY-PISTON, OR OSCILLATING-PISTON, POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; ROTARY-PISTON, OR OSCILLATING-PISTON, POSITIVE-DISPLACEMENT PUMPS
    • F04C2210/00—Fluid
    • F04C2210/26—Refrigerants with particular properties, e.g. HFC-134a

Definitions

  • the present invention relates to excipients for use in tablet manufacture, especially, but not necessarily, by direct compression.
  • the invention provides a novel excipient, a method of preparing the novel excipient, a method of forming tablets by directly compressing a particulate mixture comprising a preferred embodiment of the novel excipient, and the directly compressed tablets obtained thereby.
  • HVO hydrogenated vegetable oils
  • hydrophobic substances which are usually present in an amount of 30% to 60% by weight of the directly compressible tablet mixture, melt or soften and subsequently resolidify during the direct compression procedure to provide a sustained release matrix.
  • HVO concentrations require the tablet mixture to stick to the punch face and, to a lesser extent, to the die producing rough and uneven tablets. Further, the mixture was found to have poor compressibility. Attempts to overcome these problems by the conventional practice of use of an external lubricant or binder polymer have not been successful.
  • the most commonly used external tablet lubricant is magnesium stearate. At conventional concentrations (0.5 to 1% by weight) , it has little or no effect upon the sticking problem caused by the presence of HVO. If the magnesium stearate concentration is increased to a level (about 5%) which will prevent sticking, the tablets are weakened and suffer from capping (i.e. laminar disruption of the tablet as a result of bond weakening believed to be due inter alia to elastic recovery.
  • Polyvinylpyrrolidone is frequently used as a binder polymer in directly compressible tabletable compositions. Although incorporation of about 3% PVP improved the low compressibility problem when using HVO, it did not, even in the presence of magnesium stearate, prevent sticking.
  • Cig - C- fatty acids usually in amounts of 1 to 2% by weight, as tablet excipients.
  • the procedure involves dissolving the fatty acid in alcohol and then granulating the solution with the active ingredient(s) and any other excipients.
  • this procedure is not compatible with modern tableting techniques, especially direct compression.
  • the use of alcohol is undesirable for both environmental and health & safety reasons.
  • the Inventor has surprisingly found that the sticking and poor compressibility problems encountered when directly compressing a tabletable mixture containing HVO can be avoided, or at least significantly reduced, by pre-treating the HVO with a colloidal suspension of stearic acid in aqueous PVP and drying the resultant mixture.
  • the colloidal suspension is formed by mixing an aqueous solution of PVP with molten stearic acid.
  • the technique is applicable to hydrophobic tablet excipients other than HVO and to other CJQ - C2g fatty acids or esters thereof and water-soluble or water-dispersible film-forming binders than stearic acid and PVP respectively.
  • an excipient formed by mixing an aqueous solution of a water-soluble or water-dispersible film- forming binder with a molten CIQ - C2g fatty acid or ester thereof to form a colloidal solution and drying said solution or a mixture thereof with one or more additional excipient components.
  • the invention provides an excipient formed by mixing an aqueous solution of a water-soluble or water- dispersible film-forming binder with a molten CIQ - C2g fatty acid or ester thereof to form a colloidal solution; mixing said colloidal solution with a particulate hydrophobic tablet excipient; and drying the resultant mixture.
  • the invention provides a method of preparing an excipient which comprises mixing an aqueous solution of a water-soluble or water-dispersible film- forming binder with a molten C ⁇ - O. ⁇ fatty acid or ester thereof to form a colloidal solution and drying the solution or a mixture thereof with one or more additional excipient components.
  • the method comprises mixing an aqueous solution of a film-forming binder with a molten CJQ - C- ⁇ fatty acid or ester thereof to form a colloidal solution; mixing said colloidal solution with a particulate hydrophobic tablet. excipient; and drying the resultant mixture.
  • the present invention provides a directly compressed tablet comprising a tablet excipient formed by mixing a water-soluble or water-dispersible film- forming binder with a molten C ⁇ - C26 fatty acid or ester thereof to form a colloidal solution; mixing said colloidal solution with a particulate hydrophobic tablet excipient; and drying the resultant mixture.
  • the present invention provides A method of forming a tablet which comprises directly cc pressing a particulate mixture comprising a tablet excipient formed by mixing a water-soluble or water- dispersible film-forming binder with a molten CJQ - Cog fatty acid or ester thereof to form a colloidal solution; mixing said colloidal solution with particulate hydrophobic tablet excipient; and drying the resultant mixture.
  • the film-forming binder used in the present invention can be any pharmacologically acceptable water- soluble or water-dispersible film-forming binder which is compatible with the fatty acid or ester thereof and any other excipient component(s) .
  • suitable binders are polysaccharides, for example gum acacia, agar, agarose, cellulose ethers and esters, starches and gum tragacanth; proteins, for example gelatin and zein; and synthetic polymers, for example methacrylic acid/methacrylic acid methyl ester copolymers available under the Trade Mark EUDRAGIT, polyvinylalcohol, polyvinylacetatephthalate, and polyvinylpyrrolidone (PVP) .
  • Suitable cellulose ethers and esters include hydroxypropylcellulose, hydroxypropy1-meth lcellulose, methylcellulose, ethylcellulose, cellulose acetate and cellulose acetate phthalate. It is presently preferred that the binder is water-soluble. The presently most preferred binder is PVP.
  • the film-forming binder usually will be present in an amount of 25% or less, preferably 10% or less, especially 0.25 to 5%, by weight on a dry weight basis.
  • the fatty acid or ester thereof used in the present invention has 10 to 26, preferably 14 to 20, carbon atoms in the acid moiety.
  • the acid or ester thereof will be saturated but unsaturated fatty acids and esters can be used.
  • Suitable acids include lauric, linoleic, oleic, palmitic, and stearic acids.
  • Suitable esters include glyceryl behenate, sodium stearoyl lactylates, sodium stearyl fumarate, and stearyl monoglyceridyl citrate.
  • the fatty acid or ester is stearic acid.
  • the amount of fatty acid or ester thereof usually will be 10% or less, preferably 0.25 to 5%, on a dry weight basis.
  • ratio by weight of film-forming binder to fatty acid or ester thereof will be in the range 2:1 to 1:2 with a ratio of about 1:1 being preferred.
  • the invention includes, in its broadest aspect, the fatty acid or ester/binder product obtained on drying a colloidal solution containing only the fatty acid or ester and binder.
  • a product can be reconstituted into a colloidal solution for mixing with a particulate hydrophobic tablet excipient and/or other tablet excipients and the resultant mixture dried.
  • the product can be used as such as an excipient in direct compression or other tableting procedures.
  • a hydrophobic tablet excipient When, in accordance with the preferred embodiments of the present invention, a hydrophobic tablet excipient is present, it will be a solid oil derivative, a fat or a fat derivative having a liquid/solid phase transition temperature of 40°C to 120°C, preferably 60 to 80. Below 40°C, particles of the substances are likely to agglomerate and hence be insuf iciently particulate to prepare a satisfactory excipient. Above 120°C, the substances are unlikely to soften or melt sufficiently to form the required matrix during direct tablet compression.
  • the hydrophobic tablet excipient is a hydrogenated vegetable oil (“HVO") .
  • HVOs includes hydrogenated natural oils and waxes such as canola oil, castor oil, coconut oil, cottonseed oil, illipe oil, palm oil, palm kernel oil, saf lower oil, and sunflower oil.
  • canola oil castor oil
  • coconut oil cottonseed oil
  • illipe oil palm oil
  • palm kernel oil palm kernel oil
  • saf lower oil saf lower oil
  • sunflower oil presently, hydrogenated cottonseed oil and, especially, hydrogenated castor oil are preferred.
  • the HVO can be replaced completely or in part by one or more other particulate hydrophobic tablet excipients, for example acetylated monoglycerides; beeswax; carnauba wax; non- hydrogenated vegetable oils or waxes, lactylated fatty acid esters of glycerol and propylene glycol; lactylated itiono- and di-glycerides; stearyl monoglyceridyl citrate; succinylated monoglycerides; and triacetin.
  • acetylated monoglycerides for example acetylated monoglycerides; beeswax; carnauba wax; non- hydrogenated vegetable oils or waxes, lactylated fatty acid esters of glycerol and propylene glycol; lactylated itiono- and di-glycerides; stearyl monoglyceridyl citrate; succinylated monoglycerides; and tri
  • the excipient of the invention may include one or more components conventionally used in tabletable formulations.
  • it can include one or more of an ionic surfactant, for example sodium lauryl sulphate; a non-ionic surfactant, for example a poloxamer; or other surface active materials such as polyethylene glycols, sucrose esters and distilled monoglycerides.
  • an ionic surfactant for example sodium lauryl sulphate
  • a non-ionic surfactant for example a poloxamer
  • surface active materials such as polyethylene glycols, sucrose esters and distilled monoglycerides.
  • the excipient of the invention is formed by drying a colloidal suspension formed by mixing an aqueous solution of the film-forming binder with the fatty acid or ester thereof in its molten state.
  • the fatty acid or ester is melted prior to addition to the aqueous binder but the colloidal solution can be formed by heating an agitated suspension of the fatty acid or ester thereof in the aqueous binder.
  • the excipient If other components are to be present in the excipient, they can be present in the aqueous solution or added to the colloidal solution before drying. If any additional water-soluble or water-dispersible component is to be incorporated in the excipient, it will usually be present in the aqueous solution unless its presence interferes with formation of the colloidal solution. In this connection, it will be appreciated that the components of the excipient will be selected to be compatible both in terms of preparation of the excipient and the tableting performance thereof. It is well within the ability of those of average skill in the art to determine by simple experimentation whether or not a particular combination of components is compatible and, if necessary, to modify that combination to avoid any incompatibility between the components thereof.
  • any water-insoluble additional component especially the preferred hydrophobic tablet excipient, usually will be added to the colloidal solution because its presence in the aqueous solution would interfere with formation of the colloidal solution.
  • the colloidal solution will be cooled before addition of water-insoluble components.
  • mixing of water-insoluble components, especially the preferred hydrophobic tablet excipient, with the colloidal suspension is conducted by granulation, especially in a high speed mixer granulator.
  • excipients in accordance with the preferred (i.e. hydrophobic tablet excipient - containing) embodiments of the present invention have unexpected properties.
  • excipients obtained using PVP as the binder, stearic acid or ester thereof as the fatty acid and HVO as the hydrophobic tablet excipient appear to have a sustained drug release profile which is more or less independent of excipient particle size, compaction force and the presence of surfactant in the excipient. It was expected that the rate of drug release would be increased by increasing particle size, decreasing compaction strength and adding surfactant.
  • the excipient of the invention can be mixed with one or more additional conventional excipients if required.
  • Sterotex K is hydrogenated castor oil and PVP K90 has a molecular weight of about 360,000.
  • the stearic acid was melted and added to a solution of the PVP in water which had been heated to 70°C whilst agitating the solution using a Silverson homogeniser for about 5 minutes.
  • the resultant colloidal solution was cooled and then granulated with the Sterotex in a L ⁇ dige high speed mixer granulator for successive periods of 2 minutes, l minute and l minute using a main impeller setting of 20 and a chopper speed setting I (equivalent to about 1,000 rev ir n " -*)
  • the granulate was then dried for 12 hours at 30°C and dry screened through a 1.25mm diameter screen using Frewitt.
  • the screened excipient was dry mixed with propranolol hydrochloride to provide a directly compressible tablet formulation comprising 70% excipient and 30% drug.
  • 150 milligram tablets were successfully directly compressed over compaction forces ranging between 6 and 18kN. The tablets were smooth and even and of good strength.
  • Sterotex K is hydrogenated castor oil and PVP K30 has a molecular weight of about 30,000.
  • Example 1 The procedure of Example 1 was repeated using the above components but adding the colloidal suspension to the Sterotex K powder in a food processor and blending for about 3 minutes. The blended mixture was passed through a 710 - lOOO ⁇ screen and dried over night at 40°C. The dried product was then dry screened through a 500 ⁇ m sieve.
  • Fast Flo is spray dried lactose present as a bulking agent, compression aid and release modifier; sodium stearyl fu arate is a lubricant; and Aerosil 200 is colloidal silicon dioxide and is a flow aid.
  • Sterotex is hydrogenated castor oil and PVP K90 has a molecular weight of about 30,000.
  • Example 2 The procedure of Example 2 was repeated to provide lOOmg tablets by direct compression of the formulation of Example 2 but using the excipient of the present Example.
  • the tablets were smooth and even and of good strength.
  • Figure 1 shows the release profile of the tablets under standard conditions (plotted as °) .
  • Example 2 The excipient of Example 2 was mixed with the following additional ingredients to form directly compressible tablet formulations:-
  • Emcompress is dicalcium phosphate dihydrate and Aerosil 200 is colloidal silicon dioxide .
  • Emcocel is macrocrystalline cellulose.
  • Example 2 The excipient of Example 2 was mixed with the following additional ingredients to form a directly compressible tablet formulation:-
  • Fast Flo is spray dried lactose and Aerosil 200 is colloidal silicon dioxide.
  • Example 2 The procedure of Example 2 was repeated except that the amount of HVO (Sterotex K) was decreased to 3750g and the amount of Stearic acid was increased to 450g to provide more efficient anti-adherent protection.
  • HVO Sterotex K
  • Sterotex K is hydrogenated castor oil and PVP K30 has a molecular weight of about 30,000.
  • the PVP was dissolved in the water at 70°C, the stearic acid added in the molten state and the mixture homogenized in a Silverson homogenizer for 2 minutes.
  • the HVO was then added in a mixer/granulator and blended at high speed for 4 minutes.
  • the resultant mixture was dried and screened through a 7l0 ⁇ m to provide an excipient, which was mixed with propranolol in the weight ratio 70:30 (excipient: active) to form a directly compressible tablet formulation. This formulation was directly compressed into 150mg tablets.
  • Figure 4 shows the release profile of the tablets under standard conditions.
  • Figure 5 shows the effect on the release profile of particle size of the excipient component of the tabletable formulation.
  • Particle size less than 90 ⁇ m is plotted as o; particle size 90 to 250 ⁇ m is plotted as x; particle size 250 to 500 ⁇ m is plotted as °; and particle size 500 to 710 ⁇ m is plotted as ⁇
  • Figure 6 shows the effect of tablet compaction force on the release profile of the tablets. Compaction at 15000N is -plotted as o and compaction at 18000N is plotted as x.
  • Figure 7 shows the effect on ⁇ Q (ie time required to release 50% of the propranolol content) of tablet compaction force.
  • Figure 8 shows the effect on tablet lubricity of particle size of the excipient component of the tabletable formulation.
  • the value "LP/UP" is the ratio of lower punch force to upper punch force. High values (close to unity) indicate good transmission of forces and hence good lubricity.
  • A represents a particle size of 500 to 710 ⁇ m (mean upper punch force 17592.9N) ;
  • B represents a particle size 250 to 500 ⁇ m (mean upper punch force 18224.3N) ;
  • C represents a particle size 90 to 250 ⁇ m (mean upper punch force 18016.7N) and D represents a particle size below 90 ⁇ m (mean upper punch force 18020.ON) .
  • Figure 9 shows the effect on tablet lubricity of changes in tablet compaction force when the excipient particles are unfractionated (ie passes the 7l0 ⁇ m sieve) .

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Abstract

Un excipient utilisé dans la fabrication de comprimés par compression directe est obtenu en mélangeant une solution aqueuse d'un agent de liaison formant un film soluble ou dispersible dans l'eau avec un acide gras C10-C26 fondu ou un ester de celui-ci afin de former une solution colloïdale et en séchant cette solution ou un mélange de celle-ci avec au moins un composé d'excipient supplémentaire. L'agent de liaison formant un film est de préférence du polyvinylpyrrolidone et l'acide gras ou un ester de celui-ci est de l'acide stéarique. Un excipient particulaire de comprimé hydrophobe, notamment une huile végétale hydrogénée, est de préférence présent sous forme d'un composé d'excipient supplémentaire. Les problèmes de consistance collante et de mollesse des comprimés lorsqu'on utilise de l'huile végétale hydrogénée sous forme d'excipient en compression directe sont surmontés à l'aide de l'huile végétale hydrogénée sous la forme d'un excipient décrit dans la présente invention.
PCT/GB1993/000221 1992-02-05 1993-02-03 Excipient pour fabrication de comprimes par compression directe WO1993015723A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9202436A GB2263910A (en) 1992-02-05 1992-02-05 Direct compression tablet excipient
GB9202436.3 1992-02-05

Publications (1)

Publication Number Publication Date
WO1993015723A1 true WO1993015723A1 (fr) 1993-08-19

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AU (1) AU3457793A (fr)
GB (1) GB2263910A (fr)
WO (1) WO1993015723A1 (fr)
ZA (1) ZA93812B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5458888A (en) * 1994-03-02 1995-10-17 Andrx Pharmaceuticals, Inc. Controlled release tablet formulation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2680823B1 (fr) * 2011-02-28 2024-05-15 Nano4M Ltd Poudres liantes

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4710519A (en) * 1985-09-30 1987-12-01 Basf Corporation Process for preparing spray dried acetaminophen powder and the powder prepared thereby
EP0254978A1 (fr) * 1986-07-18 1988-02-03 Eisai Co., Ltd. Préparation pharmaceutique à libération prolongée

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4710519A (en) * 1985-09-30 1987-12-01 Basf Corporation Process for preparing spray dried acetaminophen powder and the powder prepared thereby
EP0254978A1 (fr) * 1986-07-18 1988-02-03 Eisai Co., Ltd. Préparation pharmaceutique à libération prolongée

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5458888A (en) * 1994-03-02 1995-10-17 Andrx Pharmaceuticals, Inc. Controlled release tablet formulation

Also Published As

Publication number Publication date
GB2263910A (en) 1993-08-11
AU3457793A (en) 1993-09-03
GB9202436D0 (en) 1992-03-18
ZA93812B (en) 1993-12-20

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