EP1901719A2 - Formulation de benzimidazole - Google Patents

Formulation de benzimidazole

Info

Publication number
EP1901719A2
EP1901719A2 EP06753346A EP06753346A EP1901719A2 EP 1901719 A2 EP1901719 A2 EP 1901719A2 EP 06753346 A EP06753346 A EP 06753346A EP 06753346 A EP06753346 A EP 06753346A EP 1901719 A2 EP1901719 A2 EP 1901719A2
Authority
EP
European Patent Office
Prior art keywords
alkaline substance
dry
benzimidazole
formulation
alkaline
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP06753346A
Other languages
German (de)
English (en)
Inventor
Poul Bertelsen
Peder Mohr Olsen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharma AS
Original Assignee
Nycomed Danmark AS
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 Nycomed Danmark AS filed Critical Nycomed Danmark AS
Publication of EP1901719A2 publication Critical patent/EP1901719A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer

Definitions

  • the present invention relates to the field of pharmaceutical formulation science.
  • the present invention relates to pharmaceutical formulations comprising acid labile benzimidazoles.
  • the invention provides cost-effective production methods providing stable formulations.
  • EP 0244380 e.g. discloses use of conventional granulation process, wherein a wet binder is used as well as an aqueous granulation liquid.
  • EP 0589981 e.g. discloses use of polyvinylpyrrolidone as a wet binder.
  • WO 05009410 discloses an enteric coated benzimidazole formulation, wherein the tablets are arrived at via different combinations of wet mixing and dry mixing.
  • Example 7 e.g. discloses dry mixing and compression of esomeprazole and magnesium oxide.
  • WO 9850019 discloses an enteric coated formulation comprising omeprazole or lanzoprazole.
  • Example 2C ten grams of omeprazole were mixed with pharmaceutical excipient lactose anhydrous USP/IMF and then passed through a screen to obtain a homogenous granule size.
  • Example 4 it is stated that "The individual core granulation was mixed with lactose and talc or magnesium stearate and compressed into tablets by known pharmaceutical techniques.” No stability assays are disclosed with tablets according to Example 2C+4.
  • WO 04075881 discloses an enteric coated formulation comprising rabeprazole and a low viscosity hydroxypropyfceflulose optionally in combination with antioxidants produced by a method comprising dry granulation.
  • the object of the present invention thus to provide a stable and cost-efficient pharmaceutical formulation intended for oral administration and subsequent efficient delivery of the active benzidimazote in the intestinal tract, wherein said formulation has a good shelf life stability and release profile.
  • the present invention relates to a method for producing a pharmaceutical tablet formulation comprising a benzimidazole as the biologically active component, wherein:
  • said formulation comprises an enteric coating for protection of the active component from acid attack in the stomach
  • said benzimidazole is further stabilized by an alkaline substance in the tablet, - said method comprising dry granulating steps and dry compressing of tablets, wherein said formulation is further characterized by one or more of the following features:
  • the alkaline substance is an alkali metal carbonate with high water solubility and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, (it) the alkaline substance is an alkaline earth metal carbonate with low water solubility and a BETT area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, (iii) the benzimidazole and the alkaline substance have been mixed and dry granulated together prior to dry compression, (iv) the weight ratio of benzimidazole and alkaline substance is from about 1:0.2 -
  • the alkaline substance has a pKa of at least about 10 and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, (vi) if the alkaline substance is polyvalent, said alkaline substance has a pKal-value of 6 or more and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, (vii) the alkaline substance has a BET-area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps,
  • the tablet formulation further comprises a disintegrant in an amount of about 1-30% by weight.
  • the invention furthermore relates to a pharmaceutical tablet formulation comprising a benzimidazole as the biologically active component, wherein:
  • said formulation comprises an enteric coating for protection of the active component from acid attack in the stomach, - said benzimidazole is further stabilized by an alkaline substance in the tablet, wherein said formulation is further characterized by one or more of the following features:
  • the alkaline substance raw material is an alkali metal carbonate with high water solubility and a BET area of at least about 1 m 2 /g
  • the alkaline substance raw material is an alkaline earth metal carbonate with low water solubility and a BET area of at least about 1 mVg
  • the benzimidazole and the alkaline substance raw material have been mixed and dry granulated together prior to dry compression
  • the weight ratio of benzimidazole and alkaline substance is from about 1:0.2 - 1:5,
  • the afkaline substance raw material has a pKa of at least about 10 and a BETT area of at least about 1 m 2 /g, (vi) if the alkaline substance is polyvalent, said alkaline substance has a pKal- value of 6 or more and a BET area of at least about 1 m 2 /g, (vii) the alkaline substance raw material has a BET-area of at least about 1 m 2 /g,
  • the tablet formulation further comprises a disintegrant in an amount of about 1-30% by weight.
  • a liquid can, however, be applicable in the subsequent coating steps providing an enteric coat and optionally a subcoat.
  • the present invention relates to a pharmaceutical tablet formulation comprising a benzimidazole as the biologically active component, wherein:
  • said formulation comprises an enteric coating for protection of the active component from acid attack in the stomach
  • said benzimidazole is further stabilized by an alkaline substance in the tablet, wherein said formulation is further characterized by one or more of the following features: (i) the alkaline substance raw material is an alkali metal carbonate with high water solubility and a BET area of at least about 1 mVg, (ii) the alkaline substance raw material is an alkaline earth metal carbonate with low water solubility and a BET area of at least about 1 m 2 /g, (iii) the benzimidazole and the alkaline substance raw material have been mixed and dry granulated together prior to dry compression, (iv) the weight ratio of benzimidazole and alkaline substance is from about 1:0.2
  • the alkaline substance raw material has a pKa of at least about 10 and a BET area of at least about 1 m 2 /g,
  • alkaline substance if the alkaline substance is polyvalent, said alkaline substance has a pKal- value of 6 or more and a BET area of at least about 1 mVg,
  • the alkaline substance raw material has a BET-area of at least about 1 m 2 /g /
  • the tablet formulation further comprises a disintegrant in an amount of about 1-30% by weight.
  • the present Invention relates to a method for producing a pharmaceutical tablet formulation comprising a benzimidazole as the biologically active component, wherein: - said formulation comprises an enteric coating for protection of the active component from acid attack in the stomach,
  • said method comprising dry granulating steps and dry compressing of tablets
  • said formulation is further characterized by one or more of the following features: (i) the alkaline substance is an alkali metal carbonate with high water solubility and a BETT area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, (ii) the alkaline substance is an alkaline earth metal carbonate with low water solubility and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps,
  • the weight ratio of benzimidazole and alkaline substance is from about 1:0.2 -
  • the alkaline substance has a pKa of at least about 10 and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, (vi) if the alkaline substance is polyvalent, said alkaline substance has a pKal-value of 6 or more and a BEET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, (vii) the alkaline substance has a BET-area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps,
  • the tablet formulation further comprises a disintegrant in an amount of about 1-30% by weight.
  • the benzimidazole is pantoprazole such as pantoprazole sodium hydrate or pantoprazole sodium sesquihydrate.
  • the benzimidazole may be omeprazole or a salt and/or a hydrate thereof, lansoprazole or a salt and/or a hydrate thereof, esomeprazol or a salt and/or a hydrate thereof, aripiprazole or a salt and/or a hydrate thereof, rabeprazol or a salt and/or a hydrate thereof, or timoprazole or a salt and/or a hydrate thereof.
  • said formulation further comprises other pharmaceutically acceptable excipients such as fillers, dry binders, glidants and lubricants.
  • said formulation comprises crospovidone as a disintegrant in an amount of from about 5-20%, preferably 7,5-15%, most preferably 10- 13% by weight.
  • said formulation comprises a subcoat. in a particularly preferred embodiment however, said formulation does not comprise a subcoat.
  • the alkaline substance is a salt of an organic or an inorganic acid where the anion of the salt is carbonate (CO 3 2" ), hydrogenphosphate (HPO 4 2" ) or phosphate (PO 4 3" ).
  • the alkaline substance may also be a salt of an organic or an inorganic acid where the kation is sodium (Na + ), calcium (Ca 2+ ) or magnesium (Mg 2+ ).
  • the salt of the organic and/or inorganic acid according is sqdiumcarbonate (Na 2 CO 3 ), or Calciumcarbonate (CaCO 3 ) trisodiumphosphate (Na 3 PO 4 ), disodiumhydrogenphosphate (Na 2 HPO 4 ), hydrazine or derivatives thereof, lysine or a derivative thereof, arginine or a derivative thereof, or histidine or a derivative thereof.
  • dry granulation is provided by means of a roller compactor.
  • the mixture has been subject to sieving prior to tablet compression with a sieve size (Roller compactor) of 1,25 mm or less. It is shown in the examples that relatively small and, relatively homogenous particles result in a more accurate dosing of the active compound. Doze accuracy is of particular importance in production of relatively small tablets.
  • the present invention relates to products obtainable or obtained by the methods disclosed herein.
  • a pharmaceutical tablet formulation according to the present invention is equivalent to a solid dosis form.
  • the drug substance belongs to the group of benzimidazoles or salts and/or hydrates thereof.
  • the be ⁇ zimidazole is preferably pantoprazole, omeprazole, lansoprazole, timoprazol, aripiprazole, rabeprazol or esomeprazole, as well as pharmaceutically acceptable salts, hydrates and mixtures thereof.
  • the benzimidazole is pantoprazole sodium sesquihydrate. Any pharmaceutically acceptable salt can be used. Examples of conventionally used salts are sodium or potassium salts of the drug substance.
  • a pharmaceutical formulation according to the present invention comprises about 1 to 500 mg drug pr. dose; such as 1 to 200 mg; or 1 to 100 mg.
  • the unit dose comprises 10-120 mg; 15-100 mg; 15-80 mg, 15-70 mg; 15-60 mg; 15-50 mg; 15-45 mg; such as 20, 30, or 40 mg of benzimidazole, preferably pantoprazole.
  • dose is a pharmaceutically formulated unit comprising the dosage of drug substance intended for administration.
  • the dosage unit can be a tablet.
  • Alkaline substance Due to the acid labile nature of the drug substance, the unit dose comprises an alkaline substance, or a mixture of two or more different alkaline substances, in the core to confer shelf life stability of the pharmaceutical formulation.
  • the alkaline substance according to the present invention may be soluble in water or even practically insoluble in water.
  • 1 part of water soluble alkaline substance might be dissolved in about e.g. 100, 50, 30, or 10 parts of water or less.
  • 1 part of alkaline substance with low water solubility may be dissolved in at least about 100, 300, 500, 1000, 10,000 or even more than 10,000 parts of water. This is in contrast to conventional production methods employing wet granulation wherein water soluble alkaline substances are preferred.
  • the rationale behind using water soluble alkaline substances in conventional methods is that water soluble alkaline substances are thought to generate a humid environment with an alkaline pH protecting the active drug substance during disintegration of the tablet in the gastric system.
  • alkaline substances such as calcium carbonate which are practically insoluble in water (1 part in more than 10,000 parts of water according to handbook of Pharmaceutical Excipients, 5 th ed.) may result in stable formulations with good dissolution profiles. It however appears that alkaline substances with low water solubility should preferably have a relatively large BET area (about 1 m 2 /g or more).
  • alkaline earth metal salts such as e.g. calcium carbonate, magnesium oxide, magnesium carbonate
  • alkali metal salts such as e.g. sodium carbonate and potassium carbonate
  • ratios between benzimidazole and alkaline substance of about 1:0.17 are disclosed (Examples 1 and 2).
  • the weight ratio between the drug substance and the alkaline substance ranges between 1:0.2 to 1: 10, preferably between 1:0.5 and 1: 5, and most preferably between 1: 1 to 1:5 while surprisingly still providing formulations with a combination of good shelf life stabilities and good dissolution profiles (examples 6, 8, and 15).
  • the weight ratio between the drug and the alkaline substance may thus be about 1:0.2, or 1:0.3, or 1:0.4, or 1:0.5, or 1:0.6, or 1: 0.7, or 1: 0.8, or 1:0.9 or 1:1, or 1:1.5, or 1:2, or 1:2.5, or 1:3, or 1:3.5, or 1:4, or 1 :4.5, or 1:5, or 1:6, or 1:7, or 1:8, or 1:9, or 1: 10.
  • the pKa of the chosen alkaline material is at least 10. However, this alone is not sufficient. If the alkaline material is polyvalent the pKal, (where pKal is the most acidic pKa value) should be above 6. As shown in ex. 6 the use of tricalcium phosphate which has a pKal of 2.2 results in a poorer stability than if disodium carbonate (which has a pKal of 6.4) is used.
  • Alkaline substance preferably having a pKa value of 6 or above.
  • the alkaline substance will typically provide an alkaline pH in the range of 7-12, when being dissolved and/or dispersed in water at room temperature in an amount of about 10-100 mg/ml.
  • alkaline substance includes the corresponding base of an organic or an inorganic acid, such as provided In the form of a pharmaceutically acceptable salt of an organic or inorganic acid and/or a mixture thereof, and some amino acids. According to the present invention, it is understood that a pharmaceutical formulation may very well comprise more than one alkaline substance, if appropriate.
  • the alkaline substance raw material is understood to be the alkaline substance prior to any formulation processing steps.
  • alkaline substances examples are listed in the following table.
  • the pKa-values in this table are approximate values and refer to the pKa of the acid. Only relevant pKa values are included.
  • a suitable disintegration time means that the pharmaceutical formulation must comply with the standards set up in the European Pharmacopoeia. Those skilled in the art will appreciate that it is desirable for compressed tablets to disintegrate within 30 minutes, most desirable within 15 minutes upon contact with an aqueous solution, provided that the enteric coating is absent or bursted. Disintegration is preferably performed in a dissolution apparatus such as the Ph. Eur. Basket method as disclosed in e.g. example 11.
  • the alkaline substance should be provided in solid form, such as in the form of a powder, granulate or the like.
  • alkaline substances may have different surface areas (BET_areas) and that the same compound purchased under different trade names (e.g. calcium carbonate - "Sturcal L” and "Scoralite”) may have different BET areas (see the SEM pictures in the figures). It is furthermore demonstrated that alkaline substances with relatively large BET areas (at least about 0.5, 0.6, 0.7, 0.8, 0.9, preferably at least about 1.0, 1.1, 1.2, 1.3, 1.4, and most preferably 1.5 m 2 /g or more) tend to result in tablets with improved stability properties while at the same time retaining good dissolution properties (example 15).
  • BET_areas surface areas
  • the same compound purchased under different trade names e.g. calcium carbonate - "Sturcal L” and "Scoralite”
  • alkaline substances with relatively large BET areas at least about 0.5, 0.6, 0.7, 0.8, 0.9, preferably at least about 1.0, 1.1, 1.2, 1.3, 1.4, and most
  • porous alkaline substances with relatively large BET areas used as a raw material tend to be crushed into fine particles upon mechanical S pressure such as e.g. dry granulation and/or dry compression.
  • substances with relatively small BET areas such as e.g. calcium carbonate purchased under the trade name "Scoralite"
  • porous and/or polycrystallic 0 alkaline substances with relative large BET area having a tendency to be crushed into very fine particles upon mechanical pressure.
  • the only pharmaceutical excipient apart from the alkaline substance, is minute amounts of MgStearate (example 5).
  • the only pharmaceutical excipient is minute amounts of MgStearate (example 5).
  • the only pharmaceutical excipient is a glidant or a lubricant, preferably along with at least one disintegrant, thus providing a simple and cost efficient production method.
  • glidant and lubricants are stearic acid, metallic stearates, talc, colloidal silica, 30 sodium stearyl fumarate and alkyl sulphates.
  • a dry binder such as e.g. sorbitol, isomalt, or mixtures thereof may be used.
  • the dry binder provides the effect of binding a material and thereby providing a powder that can be compressed into a tablet.
  • a filler substance is any pharmaceutically acceptable substance that does not interact with the drug substance or with other excipients.
  • Commonly used filler substances are: mannitol, Dextrins, maltodextrins (e.g. Lodex® 5 and Lodex® 10), inositol, erythritol, isomalt, lactitol, maltitol, mannitol, xylitol, low-substituted hydroxypropylcellulose (e.g LH
  • starches or modified starches e.g potato starch, maize starch, rice starch, pre-gelatinised starch
  • polyvinylpyrrolidone polyvinylpyrrolidone/vinyl acetate copo
  • a wet binder is an excipient that in combination with water facilitates a powder to be • compressed into coherent bodies such as tablets or facilitates a powder to be granulated into a particulate matter.
  • a wet binder must, at least to some extent, be soluble in water.
  • wet binders are PVP (polyvinylpyrrolidone), HPMC (hydroxymethylpropylcellulose) or gelatine. If a wet binder is used according to the present invention, the wet binder will merely act as a filler and will not exhibit the binding properties normally associated with such wet binders. It will therefore be understood that excipients conventionally regarded as wet binders might be used as mere fillers in the context of the present invention.
  • a disinte ⁇ rant is a pharmaceutically acceptable substance that improves the disintegration of tablets without interacting with the drug substance or with any other excipients.
  • the disintegrant has the capability of swelling upon contact with water, causing the tablet to swell/disintegrate and thus releasing the active compound. This effect is shown in the Examples (example 18), where dissolution profiles are improved upon addition of disintegrant in the tablet.
  • Traditional wet granulated benzimidazole formulations normally comprise large amounts of disintegrant ⁇ (at least about 30%) since "wet" production steps cause a significant proportion of the disintegrant to swell and thus irreversibly reducing its swelling capacity.
  • disintegrants examples include: Algtnic acid - alginates, carboxymethylcellulose calcium, carboxymethylce ⁇ ulose sodium, crospovidone, hydroxypropylcellulose, hydroxypropylmethylcellutose (HPMC), cellulose derivatives such as low-substituted hydroxypropylcellulose (e.g LH 11, LH 20, LH 21, LH 22, LH 30, LH 31, LH 32 available from Shin-Etsu Chemical Co.) and microcrystalline cellulose, polacrilin potassium or sodium, polyacrylic acid, polycarbofil, polyethylene glycol, polyvinylacetate, crosstinked polyvinylpyrrolidone (e.g.
  • Polyvidon® CL Polyvidon® CL-M, Kollidon® CL, Polyplasdone® XL, Polyplasdone® XL-IO); sodium carboxymethyl starch (e.g. Primogel® and Explotab®), sodium croscarmellose (i.e. cross-linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol®), sodium starch glycolate, starches (e.g potato starch, maize starch, rice starch), and pre-gelatinised starch.
  • the disintegrant may be present in the tablet in an amount of about 1-30%, preferably 3- 25%, more preferably 5-20% and most preferably 10-15%, and even most preferably about 8-14%.
  • Powders comprising either the drug in question, the alkaline substance, the pharmaceutical excipient(-s), or any combination thereof are subjected to a dry granulation process.
  • the dry granulation process causes the powder to agglomerate into larger particles having a size suitable for further processing. Dry granulation can thus be said to improve the flowability of a mixture in order to be able to produce tablets that comply with the demand of mass variation or content uniformity set out in the European Pharmacopoeia.
  • Formulations according to the invention may be produced using one or more mixing and dry granulations steps.
  • the order and the number of the mixing and granulation steps do not seem to be critical. However, it seems to be of importance that at least one of the alkaline substance and the drug has been subject to dry granulation before compression into tablets. Dry granulation of drug and alkaline substance together prior to tablet compression seem, surprisingly, to be a simple, inexpensive and efficient way of providing close physical contact between the alkaline substance and the drug and thus a tablet formulation with good stability properties. Relatively large BEET areas of the alkaline raw material do also have a beneficial effect on the stability properties.
  • Dry granulation is carried out by a mechanical process, which transfers energy to the mixture without any use of any liquid substances (neither in the form of aqueous solutions, solutions based on organic solutes, or mixtures thereof) in contrast to conventional wet granulation processes.
  • the mechanical process requires compaction such as the one provided by roller compaction.
  • An example of an alternative method for dry granulation is slugging.
  • Roller compaction is a process comprising highly intensive mechanical compacting of one or more substances.
  • the powder is pressed, that is roller compacted, between 2 counter rotating rollers to make a solid sheet which is subsequently crushed in a sieve to form a particulate matter.
  • a close mechanical contact between the substance(-s) has been obtained.
  • An example of equipment is Minipactor ® or a Gerteis 3W-Polygran from Gerteis Maschinen + Processengineering AG.
  • Tablet compression according to the present invention takes place without any use of any liquid substances (neither in the form of aqueous solutions, solutions based on organic solutes, or mixtures thereof).
  • the resulting core or tablet must have a crushing strength in the range of 10 to 150 N; such as 15 to 125 N, preferably in the range of 20 to 100 N.
  • a core is thus provided by compression of a powder or a particulate matter.
  • the core has a weight in the range of 75 mg to 2.5 g; such as 80 mg to 1 g; such as 80 mg to 500 mg; such as 100 mg to 300 mg.
  • the core is a tablet with a weight in the range of 75 mg to 2.5 g; such as 80 mg to 1 g; such as 80 mg to 500 mg; such as 100 mg to 300 mg.
  • the core is further coated with an enteric coat and optionally a subcoat to obtain the desired tablet formulation.
  • Tablets according to the present invention may be smaller than conventional tablets, i.e. having a diameter of about 7, preferably about 6 and most preferably about 5 mm or below. In contrast to tablets with a diameter of e.g. 7.5 mm or above, tablets having a smaller diameter will be able to move freely through the pylorus sphincter into the small intestine and thus be less dependent on the gastric emptying.
  • Any conventionally used water soluble film forming excip ⁇ ent can be used for subcoating such as a sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylenaminoacetate, "Kollicoat IR" (polyvinyl alcohol - polyethylene grycol graft copolymer), etc. Water or any conventionally used organic solvent or a mixture thereof is suitable as a subcoating solvent.
  • enteric coating polymer such as cellulose acetate phthalate such as Aquacoat® CPD (FMC) or C-A-P NF (Eastman Chemical), polyvinyl acetate phthalate such as Sureteric® (Colorcon), carboxymethylethylcellulose, co- polymerized methacrylic acid/methacrylic acid methyl esters such as Eudragit® L 30 D, or Eudragit® L 12.5 or Eudragit®L 100 (Degu ⁇ sa - Rohm Pharma Polymers) or Kollicoat MAE 30 DP or Kollicoat IOOP (BASF) or Acryl-Eze (Colorcon) or Eastacryl 30 D (Eastman Chemical) etc.
  • cellulose acetate phthalate such as Aquacoat® CPD (FMC) or C-A-P NF (Eastman Chemical)
  • polyvinyl acetate phthalate such as Sureteric® (Colorcon)
  • carboxymethylethylcellulose co- polymerized methacrylic acid/methacrylic acid
  • Preferred plasticizers include cetanol, triacetin, citric acid esters such as Citroflex® (Pfizer), phthalic acid esters, dibutyl succinate, acetylated monogiycertde, acetyltributyl, acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, calcium stearate, castor oil, cetanot, chlorebutanol, colloidal silica dioxide, dibutyl phthalate, dibutyl sebacate, diethyl oxalate, diethyl malate, diethyl maleate, diethyl malonate, diethyl fumarate, diethyl phthalate, diethyl sebacate, diethyl succinate, dimethylphthalate, dioctyl phthalate, glycerin, glyceroltributyrate, glyceroltriacetate, gly
  • At least 95% (w/w) of the declared content of drug substance remains in the tablet formulation according to the present invention after storage at 25C°/60 %RH (relative humidity) of a period of 2, 3, 4, or 5 years.
  • the stability can be determined after storage at other conditions according to appropriate ICH guidelines. Methods of assessing stability are described in the Examples.
  • Figure 1 Stability test of coated tablets containing Sodium Carbonate, Calcium Carbonate (Sturcal L), or Tri calcium phosphate. Test performed in open petri dishes at 70° and not more than (nmt) 10 % relative humidity. Example 6.
  • Figure 2 Stability test of coated tablets containing Sodium Carbonate or Calcium Carbonate (Sturcal L) in the mixing ratio's of 1:0.2 or 1:0.8. Test performed in open petri dishes at 70° and not more than (nmt) 10 % relative humidity.
  • Example 8 Stability test of coated tablets containing Sodium Carbonate or Calcium Carbonate (Sturcal L) in the mixing ratio's of 1:0.2 or 1:0.8. Test performed in open petri dishes at 70° and not more than (nmt) 10 % relative humidity.
  • Example 8 Stability test of coated tablets containing Sodium Carbonate or Calcium Carbonate
  • Figure 3 Stability test of coated tablets containing Sodium Carbonate (Sturcal L) 1:0.8 based on different sequential order of mixing and roller compaction. Test performed in open petri dishes at 70° and not more than (nmt) 10 %-relative humidity. Example 10.
  • Figure 4 Particle size distribution using two different sieve sizes (1.25 mm and 1.0 mm) during roller compaction.
  • Example 11 Particle size distribution using two different sieve sizes (1.25 mm and 1.0 mm) during roller compaction.
  • Figure 7 Impact on dissolution of type of subcoat, HPMC E 5 and HPMC E 15. Evaluated on subcoated tablets. Example 12.
  • Figure 8 Impact on dissolution of type of subcoat, HPMC E 5 and HPMC E 15. Evaluated for enteric coated tablets.
  • Figure 9 Stability of batches 13030634 and 31030634 ⁇ without the application of a sub coat) at 70 0 C in open petri dishes.
  • FIG. 10 Pantoprazole Sodium Sesquihydrate (SEM picture).
  • FIG. 11 Calcium Carbonate (Sturcal L) (SEM picture).
  • FIG. 12 Calcum Carbonate (Scoralite) (SEM picture).
  • FIG. 15 Pantoprazole Sodium Sesquihydrate and Calcium Carbonate (Sturcal L); Mixing followed by slugging (SEM picture).
  • FIG 16 Pantoprazole Sodium Sesquihydrate and Calcium Carbonate (Scoralite) Mixing followed by slugging (SEM picture).
  • Figure 17 Pantoprazole Sodium Sesquihydrate and Sodium Carbonate; Mixing followed by slugging (SEM picture).
  • FIG. 18 Pantoprazole Sodium Sesquihydrate and Sodium Carbonate Pre rollercompaction of Pantoprazole, mixing with sodium carbonate, and slugging (SEM picture).
  • the drug substance 1) (having a mean particle size of about 7 ⁇ m) was mixed by hand with the alkaline substance 2) and with 3).
  • the resulting particulate matter of the dry granulated ingredients 1) to 3) was admixed with 4) and 5). Thereafter, tablets were compressed of the mixture of ingredients 1) to 5) using a Diaf TM 20 press and 7.5 mm standard concave punch design. Unless otherwise stated, a relatively low compression force was used.
  • batches lla+b and 12 a+b illustrate that the crushing strength can be increased without any significant influence on the disintegration time.
  • the tablets are of a quality that allows the application of a standard enteric coating using standard coating equipment and parameters.
  • a sub coat comprising a standard water-soluble film like HPMC (Hydroxypropy! methylcellulose) can be used to protect the enteric coat from the alkaline reacting core.
  • HPMC Hydropropy! methylcellulose
  • the tablets are thus of a quality that allows the application of a standard enteric coating using standard coating equipment and parameters.
  • a sub coat comprising a standard water-soluble film like HPMC can be used to protect the enteric coat from the alkaline reacting core.
  • the drug substance 1) and the ingredient 2) were mixed by hand followed by admixing of 3).
  • the mixture of ingredients 1) to 3) was compressed into tablets using a Diaf TM 20 press and 7.5 mm standard concave punch design.
  • the resulting tablets are of a quality that allows the application of a standard enteric coating using standard coating equipment and parameters.
  • a sub coat comprising a standard water soluble film like HPMC can be used to protect the enteric coat from the alkaline reacting core.
  • the drug substance 1) was mixed by hand with 2) and 3).
  • the resulting particulate matter of the dry granulated ingredients 1) to 3) was admixed with 4).
  • the resulting mixture of the ingredients 1) to 4) was compressed into tablets using a 5.0 mm standard concave punch design.
  • the resulting tablets are of a quality that allows applying a standard enteric coat using standard coating equipment and parameters.
  • a sub coat consisting of a standard water soluble film like HPMC can be used to protect the enteric coat from the alkaline reacting core.
  • Table 12 Composition of sub coat [% w/w]:
  • Pantoprazole was mixed with the alkaline excipient in a tumble mixer together with Crosspovidone and mannitol followed by roller compaction as described in example 1.
  • the remaining tablet core excipients were admixed and tablets were compressed by use of a Korsch PH106 tablet press and 6 mm concave punches aiming at a mean weight of 160 mg and a crushing strength of 50 N.
  • the tablet cores were coated with the sub coat followed by the enteric coat by use of a lab-scale Combi Coata.
  • the obtained coated tablets were used for stability testing as described in example 6.
  • a stability testing program with batches obtained in example 5 was performed.
  • the batches were stored at accelerated stability testing conditions (open petri dishes at 7O 0 C and not more than 10% relative humidity for three months). Such conditions probably correspond to shelf life stability testing of at least two years.
  • the analytical method is as follows: 10 tablets are transferred to a 200 ml volumetric flask. 150 ml mobile phase (the initial composition) is added and sample is shaken for 90 minutes. After the solutions pH-values have been adjusted to 8.0, mobile phase is added to the mark. The sample solution is filtered through 0.45 ⁇ m filter and analysed by reverse phase HPLC in order to quantify the amount of Pantoprazole as well as degradation products thereof. The amount is given in % of total area, see table 19. Furthermore, in figure 1 is shown the amount of pantoprazole as a function of time.
  • Example 7 Dry manufacture of tablets containing pantoprazole and Sodium carbonate or calcium carbonate and a disintegrant followed by application of a sub coat and an enteric coating.
  • Table 20 Composition of tablet core % w/w:
  • pantoprazoie was pre-rollercompacted prior to mixing with the alkaline excipient by use of the following parameters
  • the pre-roller compaction leads to formation of pantoprazole granules.
  • the obtained coated tablets were used for stability testing with the purpose of investigating the impact of lower amounts of alkaline material than used in example 5 and the use of pre-rollercompaction of the pantoprazole. The stability testing is disclosed in example 8.
  • a stability program including batches obtained in example 7 was performed. The batches were stored in open petri dishes at 70 0 C and not more than 10 % RH for up to six weeks.
  • Table 23 Sequential order of mixing and rotler compaction:
  • tablet core excipients (Dicafos A, Crosspovidone and Mg-stearate) were admixed and tablets were compressed and coated in accordance with example 5.
  • batches 01050633 and 05050638 were used for stability testing in example 10 and 05050635 was used for comparison with batches of example 16 with the purpose of evaluating excipient homogeneity of granules.
  • a stability program including batches mentioned in example 9 was performed.
  • the batches were stored in open petri dishes at 70 0 C for 2 weeks.
  • panoprazole degradation is relatively small when pantoprazole is pre-ro!ler compacted, mixed with the alkaline exciptent and then roller compacted again.
  • the pantoprazole degradation is relatively high when pantoprazole is pre-roller compacted and mixed with the alkaline excipient without including a step of roller compacting pantoprazole and alkaline substance together. The impact on stability is seen already after two weeks.
  • Table 25 Composition of tablet core % w/w:
  • pantoprazole was pre-rollercompacted prior to mixing with the alkaline excipient by use of the following parameters
  • Gap size 1.0 mm
  • Table 27 Composition of tablet core % w/w:
  • Tablet cores according to the above mentioned composition were manufactured as described in example 5.
  • Sub coat was applied as laid out in example 5 with the exception of variation in applied amount and type of polymer as shown in table 28: Table 28: Amount (approximately) and type of sub coat applied
  • Enteric coat was applied as described in example 5.
  • Figures 6, 7 and 8 disclose the impact of type of sub coat on the dissolution rate form both sub coated tablets and sub + enteric coated tablets.
  • a HPMC E5 based sub coat results in a relatively quick dissolution rate.
  • Example 13 Dry manufacture of tablets containing pantoprazole and alkaline excipients followed by application of an enteric coating.
  • Tablet cores of batch 13030634 and 31030634 were manufactured as described in example 12.
  • the tablet cores of batch 13030634 were enteric coated as described in example 5.
  • Batch 31030634 was produced with an enteric coating but without the application of a sub coat.
  • the enteric coated tablets were used for stability testing in example 14.
  • a stability program including batches mentioned in example 13 was performed.
  • the batches were stored in open petri dishes at 70 0 C for respectively 2 and 3 months.
  • Example 15 Impact of type and amount of alkaline ex ⁇ pient on degradation of pantoprazole in a stress test by the addition of a weakly acidic component (ibuprofen)
  • Mixtures were made by grinding the raw materials in a steel bowl and subsequently placing the mixture in petri dishes in sealed alu-bags for two weeks at ambient conditions.
  • Table 32 Discoloration scale of powder mixtures of table 30 and 31:
  • Alkaline substance raw material particle sizes have, been measured by laser light scattering (Malvern) and BET area has been measured by use of a Micromeritics Gemini 2375 at relative target pressures (P/P o ) of 0.1 and 0.2 and 0.3. Samples have been dried for minimum 12 hours at 4O 0 C prior to the measurements.
  • the SEM pictures illustrate considerable differences in size and morphology on the alkaline raw materials. It should be noted that even though Sodium carbonate anhydrate has a larger particle size than the Calcium carbonate (Scoralite), sodium carbonate anhydrate has the largest BET area. This difference is further illustrated in example 17 by use of Scanning Electron Microscope pictures. The impact of the BET area and particle size on stability was illustrated in example 15. The discoloration shown in table 32 demonstrates the impact of BEET area (see example 16, table 33) and mixing ratio on pantoprazole stability. A high BETT area favours good stability results. It appears from example 16 that a relatively small particle size may not suffice to ensure a satisfactory stability. Relatively big particles can be useful, provided that their porosity leads to a sufficiently high BET area.
  • Example 17 Impact of type and amount of alkaline excipient on homogeneity of a mixture with pantoprazole with alkaline materials.
  • Pantoprazole, Vh H2O Calcium carbonate (Sturcal L) and Pantoprazole, IV2 H2O :
  • Calcium carbonate (Scoralite) batches have been mixed in a lab. scale high shear mixer for 1 minute.
  • the Pantoprazole, IVz H2O (pre-roller compacted) batch was manufactured as described in example 7 prior to mixing with sodium carbonate. The mixing was done as described above.
  • Figure 13 is a magnification of the particles shown in figure 14.
  • the magnification showing the porosity of the particles clearly supports the finding of a high BET area of Sodium Carbonate is illustrated.
  • FIGs 15 and 16 show that the use of Calcium carbonate (Sturcal L) leads to a much more homogeneous mixture than Calcium carbonate (Scoralite). The impact on stability of this difference was illustrated in example 15.
  • Figure 17 shows that the sodium carbonate particles are crushed during manufacturing. The physical structure of Sturcal L results in an improved distribution of the particles during mechanical pressure. An acceptable stability is obtained as illustrated in examples 15 and 6, 8 and 10.
  • Figure 18 illustrates the effect of pre-roller compacting pantoprazole prior to mixing with alkaline substance. Slugging (or roller compaction) of the mixture results in “coating” of the surface of the relative large pantoprazole granules with calcium carbonate particles (Sturcal L). This "coating” also leads to an acceptable stability as shown in example 6 and 8. The need for using roller compaction to apply this coat is indicated in example 9, which was based on the use of sodium carbonate.

Abstract

L'invention concerne un procédé de fabrication à sec destiné à la production d'une formulation pharmaceutique d'un benzimidazole et d'une substance alcaline. Un comprimé est comprimé directement à partir d'une poudre sèche ou d'une substance particulaire sèche, contournant ainsi l'utilisation d'un liquide ou excipient quelconque généralement utilisé comme liant humide. Le procédé de fabrication présente un caractère avantageux en ce qu'il est simple et rentable, une étape de séchage onéreuse étant superflue. La formulation pharmaceutique obtenue présente une bonne stabilité et un bon profil de dissolution.
EP06753346A 2005-07-11 2006-07-11 Formulation de benzimidazole Withdrawn EP1901719A2 (fr)

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PCT/DK2006/000409 WO2006105798A2 (fr) 2005-07-11 2006-07-11 Formulation de benzimidazole

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JP5228359B2 (ja) * 2007-04-12 2013-07-03 ニプロ株式会社 主薬粒子及びその製造方法ならびに口腔内崩壊錠
KR20100129761A (ko) 2008-03-11 2010-12-09 다케다 야쿠힌 고교 가부시키가이샤 경구 붕해 고형 제제
TR201000948A1 (tr) * 2010-02-09 2011-08-22 Sanovel İlaç San.Ve Ti̇c.A.Ş. Aripiprazol formülasyonları.
US9945862B2 (en) 2011-06-03 2018-04-17 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
CN103479593B (zh) * 2013-05-10 2014-10-08 青岛双鲸药业有限公司 一种奥美拉唑肠溶片的制备方法
CN103386133A (zh) * 2013-07-09 2013-11-13 重庆莱美药业股份有限公司 一种质子泵抑制剂的口腔速溶制剂及其制备方法
EP4089076A1 (fr) 2014-08-28 2022-11-16 Eisai R&D Management Co., Ltd. Dérivé de quinoline à pureté élevée et son procédé de fabrication
CA2976325C (fr) 2015-02-25 2023-07-04 Eisai R&D Management Co., Ltd. Procede de suppression de l'amertume d'un derive de quinoleine
WO2016140717A1 (fr) 2015-03-04 2016-09-09 Merck Sharp & Dohme Corp. Association d'un antagoniste de pd-1 et d'un inhibiteur des tyrosines kinases vegfr/fgfr/ret pour traiter le cancer
CN104825414B (zh) * 2015-05-07 2018-11-16 山东新时代药业有限公司 一种稳定的s-泮托拉唑钠肠溶片
KR20180018695A (ko) 2015-06-16 2018-02-21 가부시키가이샤 프리즘 파마 항암제
CN113318079B (zh) * 2021-05-13 2024-01-09 江西博莱大药厂有限公司 一种提高三氯苯达唑颗粒溶出度的方法及其溶出度检测方法
CN115645373B (zh) * 2022-12-24 2024-01-30 山东理工职业学院 一种奥美拉唑钠片的制备方法

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AU2006230974B2 (en) 2011-09-29
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CA2614526A1 (fr) 2006-10-12
WO2006105798A3 (fr) 2006-12-07

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